Tag Archives: hematology

Thrombocytosis in the ED

Authors: Jessica Fujimoto, MD (EM Resident Physician, Temple EM) and Zachary Repanshek, MD (Assistant Professor of Emergency Medicine, Lewis Katz School of Medicine; Assistant Program Director, Temple EM) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

A clinical case

A 44yo F presents with progressive DOE for 3 weeks. She has no PMH, and she first noted dyspnea while walking upstairs 3 weeks ago. Since onset, she has been dyspneic only with exertion, but is asymptomatic at rest. She reports recent heavy menstruation, but otherwise no bleeding. She denies hematemesis, hemoptysis, or rectal bleeding. On exam, her vital signs are within normal limits with the exception of mild tachypnea, and she has pale conjunctiva. Her CBC reveals a Hgb of 2.9, with a WBC of 18.2 and a platelet count of 1042 x10^9/L.

The big question

When does thrombocytosis require emergent workup and management?


Thrombocytosis is defined as platelet count exceeding 450,000/microL.1 Typically in the ED, new thrombocytosis will be an asymptomatic lab finding.2 The two most important things to try to distinguish up front are:

  1. Is this a myeloproliferative/clonal or secondary/reactive thrombocytosis?
  2. Is the patient at risk for acute complications from this thrombocytosis?

First, rule out spurious thrombocytosis.

Then, look for evidence of reactive thrombocytosis on history, exam, and lab work. Approximately 80% of cases of thrombocytosis are reactive, even in cases of extreme thrombocytosis (i.e. platelet count >1,000,000/microL). Therefore, platelet count is not helpful in distinguishing reactive vs. clonal thrombocytosis.1,3 Things to look for on history and exam:

  • Recent trauma/surgery
  • History of splenectomy
  • Evidence of infection or inflammation
  • History of bleeding, thrombosis, or iron deficiency
  • History of chronic hematologic disorder
  • Complaints suggesting malignancy
  • Medication use

If reactive thrombocytosis seems unlikely, then the etiology may be myeloproliferative/clonal. This DDx is suggested by:

  • Chronic/persistent thrombocytosis
  • Organomegaly
  • CBC findings: concomitant elevation of hemoglobin, neutrophils, basophils, myeloid immaturity3

What difference does it make, anyways?

Screen Shot 2017-02-05 at 12.41.10 PMBoth reactive thrombocytosis and clonal thrombocytosis may be associated with vasomotor symptoms. The key difference is that thrombotic and bleeding events are much more common in myeloproliferative thrombocytosis, whereas they are unusual in reactive thrombocytosis, regardless of platelet count.4 There is a reported 24% incidence of thrombosis in untreated high risk patients with clonal thrombocytosis.3 It is unclear what pathophysiologic mechanism is responsible for this difference in incidence of thrombotic and bleeding complications. Nonetheless, treatment of asymptomatic reactive thrombocytosis is generally not recommended.1,4

Management of myeloproliferative/clonal thrombocytosis in the ED

Asymptomatic patients may need treatment to prevent thrombotic complications. Treatment varies based on risk factors:

Screen Shot 2017-02-05 at 12.40.23 PM

Thrombosis is the most concerning complication of clonal thrombocytosis. Classically, patients with essential thrombocythemia develop Budd-Chiari syndrome, or thrombotic occlusion of the hepatic vein and/or IVC. However, they may develop many types of vascular occlusion, including venous occlusion (e.g. DVT/PE) and arterial occlusion (e.g. CVA, MI, erythromelalgia). Treatment includes:

  • Anticoagulation with low molecular weight heparin. NOAC’s should be avoided due to lack of data in myeloproliferative neoplasms and potential for drug interactions with JAK inhibitors7
  • Cytoreductive agent (see table below), with platelet goal <400,000/microL
  • ASA 81mg daily
  • Immediate platelet apheresis if platelets >800,000/microL1

Screen Shot 2017-02-05 at 12.40.42 PMBleeding is another potentially dangerous complication of essential thrombocythemia; however, serious bleeding is less common than thrombosis. Typically, it affects the nasal and buccal mucosa and the GI tract.3 Treatment includes:

  • Discontinue antiplatelet medications
  • Consider a cytoreductive agent (see table)

Serious bleeding in association with thrombocytosis should raise suspicion for DIC, coagulation factor deficiency, and acquired von Willebrand disease. Extreme thrombocytosis occurs in von Willebrand disease due to abnormal platelet adsorption of circulating vW factor. Treatment is immediate apheresis and cytoreductive agent.1

Vasomotor symptoms include headache, visual symptoms, lightheadedness, chest pain, acral dysesthesia, erythromelalgia (occlusion of small blood vessels, manifested by discomfort and burning sensations in the fingers or toes). These are the most common symptoms of clonal thrombocytosis. Treatment includes:

  • ASA 81mg daily1

Pearls and Pitfalls

  1. In the ED, we must try to differentiate myeloproliferative/clonal thrombocytosis from secondary/reactive thrombocytosis.
  2. Reactive thrombocytosis may be secondary to trauma/surgery, splenectomy, infection or inflammation, blood loss, malignancy, medication use, etc. Reactive thrombocytosis tends to be transient, whereas clonal thrombocytosis is sustained. Platelet count does NOT help distinguish the two!
  3. Even in cases of extreme thrombocytosis, treatment of reactive thrombocytosis with antiplatelets or cytoreductive agents is NOT recommended.
  4. Given the relatively high incidence of thrombotic complications in essential thrombocythemia, high-risk, asymptomatic patients should be treated prophylactically with antiplatelet agents + cytoreductive agents.
  5. Essential thrombocythemia patients with acute thrombotic complications require treatment with a cytoreductive agent, anticoagulation, aspirin, and possibly apheresis.


References / Further Reading

  1. Tefferi, A. Approach to the Patient with Thrombocytosis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on January 30, 2017.)
  2. Schafer AI. Thrombocytosis. The New England Journal of Medicine. 350(12):1211-9. 2004.
  3. Beer PA, Green AR. Essential Thrombocythemia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M. eds. Williams Hematology, 9e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com.lproxy.nymc.edu/Content.aspx?bookid=1581&sectionid=101239221. Accessed January 30, 2017.
  4. Kaushansky K. Reactive Thrombocytosis. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M. eds. Williams Hematology, 9e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com.lproxy.nymc.edu/Content.aspx?bookid=1581&sectionid=108081634. Accessed January 29, 2017.
  5. Tefferi, A. Prognosis and Treatment of Essential Thrombocythemia. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on January 31, 2017.)
  6. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia.Blood Cancer Journal. 2015;5(11). doi:10.1038/bcj.2015.94.
  7. Kreher S, Ochsenreither S, Trappe RU, et al. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.).Annals of Hematology. 2014;93(12):1953-1963. doi:10.1007/s00277-014-2224-8.

The Thromboelastogram (TEG®): A Five-Minute Primer for the Emergency Physician

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC)

It’s three o’clock in the morning on your fourth night shift in a row.  While mustering the courage to rescue your energy drink from the dank, dark depths of the staff mini-fridge, you hear a familiar page: “trauma team to the trauma room.”  As you walk towards the ambulance bay, the trauma surgeon approaches with information regarding the incoming transfer:

  • 17 year-old male – MVC versus pedestrian
  • Seen at OSH where CTs demonstrated: epidural hematoma, grade III liver laceration, grade II splenic laceration, open book pelvic fracture, and extraperitoneal bladder rupture
  • Patient underwent external pelvic fixation and transfusion of blood products (8U PRBCs, 8U FFP and 4U Plts)
  • Most recent VS: BP 136/89, HR 92, RR (intubated/ventilated):14, SpO2 99% (FiO2 70%)

Drawing your attention to a piece of paper in his hand, detailing what appear to be labs from the outside facility, the surgeon points to a colorful figure: “I’m very concerned about this”:


Scanning your mind for intelligent thought, you realize that it’s been some time since you’ve ordered a thromboelastogram (TEG), let alone interpreted one.

If you’re like this physician, take a few minutes to scan the following review – the quick and dirty on TEGs is coming your way.

Thromboelastography – What is it?

Developed in 1948 by Dr. Hellmut Harter, thromboelastography is a mechanism of assessing coagulation based upon the viscoelastic properties of whole blood.2-8  In contrast to traditional, static measurements of hemostasis (PT, aPTT, INR, fibrinogen level, and fibrin degradation products), thromboelastography allows for an assessment of near real-time, in-vivo clotting capacity, providing the interpreter information regarding the dynamics of clot development, stabilization, and dissolution.7  When utilized as a point-of-care assay, graphic interpretation of thromboelastography (the TEG), offers the opportunity for an expedited assessment of coagulopathies (thrombocytopenia, factor deficiency, heparin effect, hypofibrinogenemia, and hyperfibrinolysis).7,9,12,13

How is a TEG performed?

In order to perform a TEG, a citrated-sample of whole blood is placed into a heated sample cup with calcium chloride (to overcome the effects of the citrate), kaolin (a negatively charged molecule known to initiate the intrinsic pathway10), and phospholipids (required for optimal functioning of the extrinsic pathway11) (Figure 2).  As the sample cup oscillates in a limited arc, formation of clot results in the generation of rotational forces on a pin suspended from a torsion wire.  Forces translated to the torsion wire are then, in turn, transmitted to an electrical transducer, creating a characteristic waveform (Figure 3).



I’ve heard of the Rapid TEG (r-TEG), is there a Difference?

When performed by a trained laboratory specialist, an r-TEG may be completed within 15 minutes as compared to the average 30-45 minutes processing time for a standard TEG.4,5,14  In contrast to a TEG, whole blood samples for an r-TEG may be performed with citrated or non-citrated samples.4 Samples utilized for an r-TEG are combined with tissue factor (activating the extrinsic pathway), and kaolin (activating the intrinsic pathway as above) +/- calcium chloride as applicable.4

I’ve also heard of ROTEM, what is it?

Although utilizing the technique developed by Dr. Harter, rotational thromboelastometry (ROTEM) differs from traditional thromboelastography in its mechanical application.  Unlike traditional thromboelastography, which utilizes a sample cup rotating in a limited arc, ROTEM employs a static sample cup with an oscillating pin/wire transduction system.  By comparison, ROTEM is also a more complex diagnostic test as it requires a number of differing reagents.  A complete discussion of ROTEM is outside the scope of this review.  If interested in further reading, see:

Tanaka K, Bolliger D. Practical aspects of rotational thromboelastometry (ROTEM). Available from: https://www.scahq.org/sca3/events/2009/annual/syllabus/workshops/subs/wkshp6pdfs/ROTEM%20-%20Tanaka.doc.pdf

Haemoview Diagnostics. ROTEM analysis: thromboelastometry. Available from http://www.haemoview.com.au/rotem-analysis.html

Haemoview. The 5 ROTEM tests. Available from http://www.haemoview.com.au/uploads/2/5/4/9/25498232/the_5_rotem_tests.pdf

How Do I Interpret TEG and r-TEG Results?

Drs. Semon and Cheatham of the Orlando Regional Medical Center Department of Surgical Education generated an excellent quick reference chart:


*Note: TEG-ACT (rapid) – reported for r-TEG only.

A TEG-Guided Transfusion Strategy

In addressing TEG and r-TEG abnormalities, experts recommend the following3:


The Quick and Dirty: Pattern Recognition

Perhaps most useful for the ED physician is knowledge of qualitative TEG representations:


Some clarification on DIC Stage 1 and 2:

  • Stage 1: Fibrinolysis results in the degradation of fibrin, increasing fibrin degradation products (FDPs). Excess FDPs result in clot de-stabilization.1
  • Stage 2: The cycle of clot formation and breakdown results in platelet and clotting factor consumption.1

Why Might an Emergency Medicine Physician Want to Know about this Test?

Coagulation abnormalities in trauma patients have demonstrated a significant association with infection, multi-organ failure, and death.15-18 Given its ability to quickly detect hematologic pathology, the TEG is becoming a tool for the evaluation of transfusion requirements/coagulopathy post transfusion in this patient population.3,12,13

What does the literature say?

Cotton, et al., 20114:

  • Pilot study to evaluate the timeliness of r-TEG results, their correlation to conventional coagulation testing (CCT – PT, aPTT, INR, platelet count, fibrinogen), and the ability of r-TEG to predict early blood transfusion.
    • 272 patients meeting requirements for major trauma activation
    • Outcomes:
      • All r-TEG values available within 15 minutes vs. 48 minutes for CCTs
      • ACT, r-value, k-time correlated with PT, INR, PTT (r >0.70; p<0.001)
      • MA and a-angle correlated with platelet count (p<0.001, p<0.001)
      • Controlling for demographics and ED vitals: ACT>128 predicted massive transfusion (>10 U) in the first 6 hours of presentation and treatment

Bottom line – r-TEG results were available within minutes, results correlated with conventional coagulation test results, and were predictive of the requirement for early massive transfusion.

Holocomb, et al., 201219:

  • Study to evaluate the reliability of r-TEGs versus CCTs in predicting blood product transfusion
    • 1974 major trauma patients, median ISS 17 (25% meeting criteria for shock; 28% transfused, 6% died within 24 hours)
    • Outcomes
      • When controlling for age, injury mechanism, weighted-Revised Trauma Score, base excess and hemoglobin, ACT predicted RBC transfusion and a-angle predicted massive transfusion better than PT/aPTT or INR (p<0.001).
      • a-angle was superior to fibrinogen for predicting plasma transfusion, and MA was superior to platelet count for predicting platelet transfusion (p<0.001)

Bottom line – r-TEG was more accurate in the prediction of requirements for RBC, plasma, and platelet transfusions as compared to traditional CCTs.

Wikkelso A, et al., 201612:

  • Cochrane Review including 17 current RCTs (n=1493 participants)
    • Per the authors:
      • Low quality studies: numerous biases
      • Limited generalizability: majority of studies center on cardiac patients undergoing surgical intervention

Bottom line – There is growing evidence to suggest that the utilization of TEG and ROTEM reduce transfusion requirements and improve morbidity in patients with bleeding, but additional studies are required.

Back to Our Case

Why was the trauma surgeon concerned? If we interpret our TEG values:

  • R time 20.0 => well above the upper limit of normal (10.0 minutes) = significantly prolonged time for clot formation
  • K time 13.2 => normal: up to 10.0 = prolonged fibrin cross-linking
  • a-angle 16.5 => normal >53.0 = limited clot formation
  • MA 38 => normal platelet function >50 = limited platelet function

More importantly, one quick glance at our TEG and through pattern recognition, we known that aside from his significant traumatic injuries, the patient is in trouble. This waveform is characteristic of DIC Stage 2.

Key Pearls

  • A TEG can be used as a rapid assessment of thrombosis and fibrinolysis.
  • Although additional RCTs are needed, TEGs utilized in trauma patients have been demonstrated to reduce transfusion requirements (important when we consider TACO/TRALI, risk of DIC, and blood-borne pathogens).
  • If nothing else, take a few minutes to review the characteristic TEG waveforms – depending on your laboratory processing time, knowledge of above tracings could allow early identification of coagulopathy and immediate treatment.


References / Further Reading

  1. Williams. Haemscope Basic Clinician Training: Fibrinolysis and Hyperfibrinolysis TEG Analysis. Available from: www.medicine.wisc.edu/~williams/TEG5_analysis.ppt
  2. Walsh M, Thomas S, Howard J, Evans E, Guyer K, et al. Blood component therapy in trauma guided with the utilization of the perfusionist and thromboelastography. J Extra Corpor Technol. 2001; 43(4):162-167.
  3. Semon G, Cheatham M. Thromboelastography in Trauma. Surgical Critical Care Evidence-Based Guidelines Committee. 2014. Available from: www.surgicalcriticalcare.net/Guidelines/TEG%202014.pdf
  4. Cotton B, Faz G, Hatch Q, Radwan Z, Podbielski J, et al. Rapid thromboelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma. 2011; 71:407-417.
  5. Teodoro da Luz L, Nascimento B, Rizoli S. Thromboelastography (TEG): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2013; 21:29.
  6. Bollinger D, Seeberg M, Tanaka K. Principles and practice of thromboelastography in clinical coagulation management and transfusion practice. Transfus Med Rev. 2012: 26(1): 1-13.
  7. Thakur M, Ahmed A. A review of thromboelastography. Int J periop Ultrasound Apply Technol. 2012; 1(1):25-29.
  8. Nickson C. Critical Care Compendium: Thromboelastogram (TEG). 2014. Available from http://lifeinthefastlane.com/ccc/thromboelastogram-teg/
  9. Kashuk J, Moore E, Sawyer M, Wolhauer M, Pezold M, et al. Primary fibrinolysis is integral in the pathogenesis of acute coagulopathy of trauma. Ann Surg. 2010; 252: 434-444.
  10. Zhu S, Diamond S. Contact activation of blood coagulation on a defined kaolin/collagen surface in microfluidic assay. Thromb Res. 2014; 134(6): 1335-1343.
  11. Heemskerk J, Bevers E, Lindhout T. Platelet activation and blood coagulation. Throm Haemost. 2002; 88(2):186-193.
  12. Wikkelso A, Wetterslev J, Moller A, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding (Review). Cochrane Database of Systematic Reviews. 2016; 8:1-149.
  13. Luddington R. Thromboelastography/thromboelastometry. Clin Lab Haematol. 2005; 27(2):81-90.
  14. Jeger V, Zimmerman H, Exadaktylos A. Can rapid TEG accelerate the search for coagulopathies in the patient with multiple injuries? J Trauma. 2009; 66:1253-1257.
  15. Niles S, McLaughlin D, Perkins J et al. Increased mortality associated with the early coagulopathy of trauma in combat casualties. J Trauma. 2008; 64:1459-1463.
  16. Brohi K, Sing J, Heron M. Coats T. Acute traumatic coagulopathy. J Trauma. 2003; 54:1127-1130.
  17. Cotton B, Gunter O, Isbell J, et al. Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma. 2008; 64;1177-1182.
  18. Cohen J, Call M, Nelson M, et al. Clinical and mechanistic drivers of cute traumatic coagulopathy. J Trauma Acute Care Surg. 2013; 75:S40-47.
  19. Holocomb J, Minei K, Scerbo M, Radwan Z, Wade C, et al. Admission rapid thromboelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012

Chronic Liver Disease and Hemostasis

Author: Jennifer Robertson, MD, MSEd // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital)


A 57-year-old male with a history of asthma, type 2 diabetes and end stage liver disease due to hepatitis C and alcohol abuse presents to the emergency department with a chief complaint of right lower extremity pain, edema and erythema. He denies trauma, fevers or any personal history of blood clots. His home medications include an albuterol inhaler and metformin 500mg twice daily.

Initial vital signs are unremarkable except for mildly low blood pressure of 90/60 mmHg which he states is his baseline blood pressure. His right lower extremity has the following appearance:


Initial laboratory tests that were ordered in triage show a hemoglobin of 10.2g/dL, a normal white blood cell count, a platelet count of 60 x 103/uL, a normal basic metabolic panel except for a creatinine of 1.5 mg/dL and an international normalized ratio (INR) of 1.7.

A Doppler ultrasound was also ordered in triage as the physician assistant in triage was worried about a blood clot. However, the ultrasound technician has not arrived to the emergency department yet. You consider discontinuing this ultrasound because this most certainly could not be a blood clot with such a low platelet count and elevated INR? Or could it be?

Hemostasis and the Liver

The balance between bleeding and clotting is complicated. It involves platelets, clotting factors, anti-coagulant factors and anti-fibrinolytic factors (1). The first step in coagulation is vasoconstriction after injury. However, the next two steps, (a) formation of platelet plug and (b) the coagulation cascade and the formation of thrombin, are important steps that the liver helps coordinate.

Formation of a platelet plug obviously requires platelets. However, most patients with cirrhosis have thrombocytopenia. It is thought that the majority of thrombocytopenia is due to splenic sequestration, however, it is also thought to be due to decreased production of thrombopoietin in the liver (2). Thrombopoietin (TPO) is a hormone that is mostly produced in the liver and it regulates the production of platelets. Patients with liver disease are known to have reduced levels of TPO and thus, thrombocytopenia is thought to be partially due to lower levels of this hormone (2)

Another important aspect of the concept of hemostasis is the clotting cascade. This is the last step of hemostasis where the platelet plug is reinforced with a fibrin mesh. While the key steps of coagulation cascade are complicated and difficult to remember, it is important to broadly understand and review. Below is a diagram demonstrating the coagulation cascade.


The liver not only produces the majority of the coagulation factors, anticoagulant proteins and elements of the fibrinolytic system, but it also helps clear these factors from the bloodstream (1). The clotting factors include all of the vitamin K dependent proteins (Factors II,VII, IX, X, protein C, protein S and protein Z) and factors V, XIII, fibrinogen, antithrombin and plasminogen. There are other factors such as von Willebrand factor and thrombomodulin that are synthesized elsewhere but it is important to know the importance the liver has in the process of hemostasis. In addition, it should be remembered that protein C, protein S and anti-thrombin are important anti-coagulants that inactivate the various clotting factors (1).

Finally, fibrinolysis is also an important part of hemostasis, except that it helps break up clots, rather than form them. Proteins in the fibrinolytic system are also produced by the liver.  In liver disease, tissue plasminogen activator is increased along with lower levels of alpha 2 antiplasmin and thrombin activator fibrinolysis inhibitor. However, there are also increased levels of plasminogen activator inhibitor, which balances out the increased fibrinolytic activity (3).

Given the large number of components of hemostasis that are produced by the liver, it is not surprising that patients with cirrhosis are considered to have abnormal hemostasis. However, the pathophysiology is complicated and patients with cirrhosis may actually be prone to clotting just as much as bleeding (3). In fact, patients with cirrhosis may even be slightly more at risk for clotting than those without liver disease (4).

Bleeding and Clotting in Cirrhosis

Patients with chronic liver disease often have low platelet counts, elevated international normalized ratios (INR) and abnormal activated partial thromboplastic times (aPTT). (5). While these tests may be abnormal in patients with cirrhosis, this does not mean that these patients are naturally anticoagulated and can never develop blood clots (6, 7). In addition, these tests do not necessarily predict bleeding events, especially during procedures (3, 5, 8).

As previously mentioned, hemostasis starts with vasoconstriction but platelet plugs are formed next.  This platelet plug step is primarily mediated by platelets and plasma von Willebrand factor (vWF) (5). As a review, vWF is a large protein involved in platelet adherence. After a vessel wall is damaged, vWF finds the damage and binds to exposed collagen fibers in the subendothelium. After this, the vWF -collagen complex binds to platelet glycoproteins and eventually a platelet plug is formed (9).  While patients with cirrhosis have thrombocytopenia, they also have been found to have higher levels of vWF and also decreased levels of the vWF cleaving protease, ADAMTS13, and adequate platelet adhesion (9, 10, 11).  Because of these factors, platelet adherence may be normal or near normal in patients with cirrhosis, despite lower absolute platelet levels (9, 23).

The coagulation cascade is the last step of hemostasis and this step essentially reinforces the platelet plug with a fibrin mesh. As seen in the above diagram, the cascade involves several coagulation factors and thrombin and fibrin. The coagulation tests of PT and aPTT measure the overall speeds of how blood clots via the intrinsic and extrinsic pathways. The aPTT measures the intrinsic and common coagulation pathways while the PT measure the speed of clotting via the extrinsic pathway. In patients with cirrhosis, these tests are usually abnormal because of the abnormal levels of clotting factors (produced by the liver) in the body (13). However, just as with platelet counts, the abnormal coagulation tests do not necessarily predict bleeding or clotting in patients with liver disease (5).  Standard coagulation tests including the PT and aPTT were developed to monitor therapy and also evaluate for single factor deficiencies such as hemophilia. They were not developed to evaluate in-vivo hemostasis and overall have not been found to correlate well with bleeding risk (8, 12).

Studies have demonstrated that in patients with cirrhosis, the hemostatic system manages to balance itself out because decreased procoagulant proteins are accompanied by decreased levels of anti-coagulant proteins (1, 3, 14). In addition, the standard laboratory tests of the PT and aPTT are not very sensitive to detect levels of anticoagulation proteins, nor can they detect overall thrombin formation (3, 5, 12). The standard PT and aPTT were designed to measure only the early phases of thrombin and initial clot formation. However, in patients with liver disease, this first step is slower due to the lower levels of plasma coagulation factors. Thus, the standard PT and aPTT are erroneously prolonged in these patients (3, 12).  In fact, there is also evidence to show that patients with cirrhosis actually have intact thrombin generating capacity (10, 15, 16). This may, in part, be due to the fact that patients with liver disease are resistant to the action of thrombomodulin, which is the main activator of protein C (15, 16).

Given the limitations of the standard PT/aPTT, other testing modalities including whole blood global viscoelastic tests, have been examined to better evaluate clotting in patients with liver disease. One of these tests, rotational thromboelastometry (ROTEM), may help provide more accurate and useful information regarding the hemostatic state in patients with liver disease (12). Viscoelastic tests are helpful because, unlike the standard coagulation tests, they continuously evaluate rates of coagulation from initial clot formation to final clot strength (12).  They also provide a better idea of a patient’s blood status in vivo and provide information on the presence and severity of fibrinolysis and coagulability (12, 16). While viscoelastic tests are not widely used, they have recently been studied in patients with cirrhosis and found to paint a better overall picture of these patient’s clotting and bleeding tendencies (16, 17, 18, 19).

What about fibrinolysis? It has been demonstrated that patients with cirrhosis also have reduced levels of fibrinolysis inhibitors and thus, must have an overall increase in fibrinolysis. There have been varying reports on this, with some studies showing increased fibrinolysis in patients with cirrhosis (20, 21), while others showing a more “balanced” fibrinolytic state. In other words, some reports show overall increased fibrinolysis while others show decreased levels of fibrinolytic inhibitors and decreased levels of the fibrinolytic factors and thus, no significant difference in the rates of fibrinolysis in patients with cirrhosis (3, 22, 23).

Because of these variations in findings, further studies are needed. However, at least currently, the literature supports normal or even enhanced clotting tendencies in patients with cirrhosis, despite possibly increased fibrinolytic states (4, 6, 7, 9, 19, 20, 21).  The take home point is not the nuances of testing but rather, that patients with cirrhosis can clot and will clot, even with thrombocytopenia and elevated PT/INR levels.


While more studies need to be conducted on bleeding and clotting risk in patients with cirrhosis, especially with newer, more sensitive tests for the coagulation system, the point of this review is that patients with cirrhosis CAN form clots. Thus, if there are any signs and/or symptoms of a blood clot in your next patient with cirrhosis, then adequate workup should be obtained.

References/Further Reading

  1. DeSancho M, Pastores S. The liver and coagulation. Textbook of Hepatology: From Basic Science to Clinical Practice 2007; 3:255-3.
  2. Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Management of thrombocytopenia due to liver cirrhosis. World J Gastroenterol. 2014; 20(10):2595-605.
  3. Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. J Thromb Haemost 2006; 4: 721–3.
  4. Søgaard KK, Horváth-Puhó E, Grønbæk H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case–control study. Am J Gastroenterol. 2009; 104(1):96-101.
  5. Tripodi A, Mannucci PM. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research. J Hepatol. 2007; 46(4):727-33.
  6. Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. CHEST 2010; 137(5):1145-9.
  7. Schaden E, Saner FH, Goerlinger K. Coagulation pattern in critical liver dysfunction. Curr Opin CritCare 2013; 19(2):142-8.
  8. Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence‐based review. Transfusion 2005; 45(9):1413-25.
  9. Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, Leebeek FW. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44(1):53-61.
  10. Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41(3):553-8.
  11. Beer JH, Clerici N, Baillod P, Von Felten A, Schlappritzi E, Büchi L. Quantitative and qualitative analysis of platelet GPIb and von Willebrand factor in liver cirrhosis. Thrombosis and haemostasis. 1995; 73(4):601-9.
  12. Mallett SV, Chowdary P, Burroughs AK. Clinical utility of viscoelastic tests of coagulation in patients with liver disease. Liver Int 2013; 33(7):961-74.
  13. Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, Tripodi A, Trotter JF, Valla DC, Porte RJ, Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010; 53(2):362-71.
  14. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood. 2010; 116(6):878-85.
  15. Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52(3):355-61.
  16. Tripodi A, Primignani M, Chantarangkul V, Viscardi Y, Dell’Era A, Fabris FM, Mannucci PM. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Thromb res 2009; 124(1):132-6.
  17. Popescu M, Bădărău IA, Bacalbașa N, Tomescu D. To clot or not to clot? A comparison between standard coagulation tests and rotational thromboelastometry in patients with End-Stage Liver Disease.
  18. Ben-Ari Z, Panagou M, Patch D, Bates S, Osman E, Pasi J, Burroughs A. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26(3):554-9.
  19. Kleinegris MC, Bos MH, Roest M, Henskens Y, Cate‐Hoek A, Van Deursen C, Spronk HM, Reitsma PH, De Groot PG, Cate H, Koek G. Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. J Thromb Haemost. 2014; 12(10):1647-57.
  20. Rijken DC, Kock EL, Guimarães AH, Talens S, Murad SD, Janssen HL, LEEBEEK F. Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost 2012; 10(10):2116-22.
  21. Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, Gresele P. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38(1):230-7.
  22. Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG. Thrombin-fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology. 2001 Jul 31;121(1):131-9.
  23. Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology. 2001 Jul 31;121(1):131-9.

Blast Crisis: ED-focused management

Authors: Patrick C Ng, MD (EM Chief Resident, SAUSHEC Emergency Medicine Department) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC Emergency Medicine Department) // Editors: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Case 1

A 66-year-old male, recently diagnosed with chronic myelogenous leukemia (CML) presents with a sudden onset of pain and loss of vision in the left eye while eating lunch. He had been previously asymptomatic. He reports no relieving or exacerbating features. Labs were at baseline two weeks prior to this visit.

On exam, he has normal vital signs. His visual acuity reveals 20/200 OS and 20/40 OD with his corrective lenses. His exam is otherwise unremarkable.

Some standard labs are ordered, and his white blood cell count returns at 50 x 109/L. With progression of his symptoms despite supportive care, the patient is admitted for further management. MRI reveals enhancement of soft tissue are around the orbit and optic nerve of the left eye. He undergoes enucleation of the left eye. Histopathology reveals thickening of the choroid and infiltration of the choroid by blast cells. The working diagnosis of extramedullary blast crisis in CML is made and induction therapy is started1.

Case 2

A 58 year old female, with a history of hypertension and CML, on imatinib, presents to your ED with 2 weeks of generalized fatigue and a 10lb weight loss.  For the past 24 hours, she has started to experience left upper quadrant abdominal pain with decreased appetite. Her review of systems is positive for bilateral knee pain and fever with a Tmax of 101°F. She has never experienced this constellation of symptoms in the past and reports minimal relief with OTC antipyretics.

Vitals: T101°F, HR 100, BP 170/90, RR 18, Sat 100% on RA

Exam is positive for a palpable spleen approximately 3cm below the costal margin, tachycardia, and suprapubic pain.

Labs are significant for a white blood cell count of 40.4 x 109/L with 25% blasts, platelet count of 110 x 103/µL, Hb of 8g/dL, and a normal chemistry.  UA is positive for nitrite, leukocyte esterase and 2+bacteria.

The patient is started on IV fluids, antipyretics, and broad spectrum antibiotics. Hematology/Oncology service is consulted, and the patient is started on ponatinib for the suspected progression of her CML despite first generation tyrosine-kinase inhibitor therapy. She is admitted with continued treatment to the hematology/oncology service. While in the hospital, she underwent a bone marrow biopsy which revealed hypercellularity with a predominance of neutrophils, eosinophils, and basophils with many megakaryocytes. Peripheral smear revealed a myeloid cell predominance.

During her hospital stay, she showed improvement with continued antibiotic and tyrosine kinase inhibitor therapy. She underwent a hematopoietic cell transplant by hematology/oncology and was discharged from the hospital with continued outpatient therapy.


Chronic myeloid leukemia (CML) is a hematological malignancy that affects the leukocyte cell linage. In essence, malignancies occur when cells have a reproductive advantage over others, with disruption in the balance of cell proliferation and cell death2. In CML, this balance of cell proliferation and cell death is disrupted secondary to a reciprocal translocation between chromosome 9 and 22, t(9:22)(q34;q11), also known as the Philadelphia (Ph) chromosome. These chromosomes contain the BCR and ABL genes. The translocation forms a BCR-ABL gene which is a tyrosine kinase. This ultimately leads to an increase in myeloid cells in the blood3.

There are three phases of CML: Chronic, Accelerated and Blast, shown below in Figure 1. Approximately 90% of patients present in the chronic phase3. Blast phase is a poor prognostic marker. According to some reports, the median survival after diagnosis of blast crisis ranges from 7-11 months and that patients with 20%-29% blasts at diagnosis have a better prognosis than those with >30%4. Typically, patients present in the chronic phase and are diagnosed with routine blood testing. CML can progress to the accelerated phase, followed by the blast phase. The disease is on a continuum and nonspecific characteristics of each phase are summarized in Table 1. Many of the symptoms are nonspecific, especially in the chronic and accelerated phases. The blast phase may present with signs/symptoms similar to infection.



CML Phase Chronic Accelerated Blast
Onset Indolent <1 year <6months
Signs/Symptoms Often asymptomatic, Fatigue, Decreased Appetite, Abdominal Pain/Fullness Same as Chronic Phase +/-Bone pain Same as accelerated phase+/- symptoms consistent with infection
Characteristic Clinical Findings Hepato/Splenomegaly Hepato/Splenomegaly unresponsive to treatment


Fever not otherwise explained




Same as accelerated phase +/- Bleeding, Infection


Symptoms refractory to treatment

Laboratory Abnormalities Including Peripheral Smear Leukocytosis, Anemia, Thrombocytosis Leukocytosis(>50 x 109/L)

Anemia (Hct <25%)

Thrombocytopenia (<100 x 109/L) or

Thrombocytosis (>1,000 x 109/L)

Blasts (≥10%)

Basophils (≥20%)

Thrombocytopenia(<100 x 109/L)


≥20% Blasts


Bone Marrow Aspirate Characteristics Hypercellular Hypercellular

≥10% Blasts


Same as accelerated +/-Megakaryocytes

≥20% Blasts


Table 1: Characteristics of CML phases,4,5,6,7,8

What are the key ED studies?

When the progression of CML is suspected in the ED, key studies to obtain include the CBC with differential, peripheral smear, chemistry, magnesium, coags, LFTs, lactate, uric acid, LDH, and phosphorous. As seen in Table 1, the diagnosis can be difficult due to the often vague symptoms, and lab abnormalities that are required for diagnosis confirmation. Patients that carry a diagnosis of CML can progress to the accelerated/blast phase despite being on treatment. CBC and differential with smear are important to obtain to determine whether or not a leukocytosis with a left shift is present, which can help you and your consultants narrow in on the diagnosis. Additionally, patients can present with varying degrees of platelet abnormalities and anemia, both of which may require specific interventions. It is important to consider these possible abnormalities as procedures such as bone marrow aspiration/biopsy can pose a significant bleeding risk.

The response to treatment and progression of CML is monitored by three different responses: hematologic, cytogenic, and molecular. In the ED, we can assess the hematologic changes in these patients with the labs mentioned above. Cytogenic and molecular testing are out of the scope of the ED provider and will be assessed by our consultants.

Additionally, infection can accompany progression of this disease. Based on the patient’s presentation and lab results, further workup (CXR, Blood cultures, UA, etc) and treatment with appropriate fluid resuscitation and antibiotics should be considered and discussed with the oncology team. Patients with documented fever will likely warrant broad-spectrum antibiotics. The ED provider must have a high degree of suspicion for infection in febrile patients presenting in blast crisis, as patients can be functionally asplenic. The proliferation of malignant cells in CML, particularly in the accelerated/blast phases, can lead to damage of the spleen secondary to splenic congestion and even splenic rupture5.

With the rapid proliferation of cell lines, patients may present with signs of end organ damage, likely secondary to hyperviscosity6-7, which can lead to end organ dysfunction and electrolyte abnormalities. Symptoms include but are not limited to bleeding, ocular, neurological, and cardiovascular problems8.

On a case by case basis, targeted diagnostics including labs and imaging may be indicated. There are rare presentations of blast crisis, particularly when there is an infiltration of leukemic blasts in areas other than the bone marrow, called extramedullary blast crisis9-12. Various case reports that describe extramedullary blast crisis include: presenting in the scalp, in the paravertebral area causing spinal cord compression, as leukemic ascites with liver disease and coagulopathy, in the eye with pain and vision changes eventually leading to enucleation, as an initial presentation with lymphadenopathy, with palpitations and dyspnea, with an osteolytic lesion presenting with leg pain, and as an osteolytic bone lesion leading to a pathologic fracture12-17. Although rare, extramedullary blast crisis can occur. However, this form is difficult to diagnose and requires oncology consultation.


As seen, the clinical presentation of CML can vary widely; however, the treatment is relatively consistent. The ED management requires initial resuscitation and stabilization. Assessment for infection and hyperviscosity syndrome is required, as these account for significant mortality. Hyperviscosity syndrome can be treated with plasmapheresis, plateletpheresis, or phlebotomy. For a further read on this dangerous manifestation, please see http://www.emdocs.net/hyperviscosity-syndrome/.

The mainstay of oncologic therapy is with tyrosine-kinase inhibitors, with imatinib traditionally serving as the first line18. Patients not responding to initial dosing may be given a trial of an increased dose of imatinib. According to a recent survey, due to improved methods of disease monitoring and new generation tyrosine-kinase inhibitors, the use of imatinib as a first line agent has decreased. The use of newer generation tyrosine kinase inhibitors such as nilotinib/dasatinib has replaced imatinib as a first line agent according to several reports19-20. In patients that progress to blast crisis despite therapy, initial stabilization and resuscitation depending on the clinical presentation is indicated. Early consultation with a hematologist/oncologist is indicated as many of these patients with go on to combination chemotherapy with tyrosine-kinase therapy, and/or hematopoetic cell transplantation18-20.


-CML is a myeloproliferative disorder that can present at any age, but typically presents in the 6th decade of life

-CML has three phases: Chronic(most common), Accelerated, and Blast

-Blast phase is a poor prognostic factor

-Blast phase can present in a variety of ways including but not limited to eye pain, vision changes, neurologic complaints, joint pain, and bleeding. The emergency provider must maintain a high suspicion for this diagnosis, particularly in patients that carry a diagnosis of CML, although these can serve as initial presentations of the disease as well

-Blast phase can present in conjunction with other pathology including but not limited to fractures and infections. The emergency provider must be aware of this key point to properly address these pathologies in the initial resuscitation and management of the patient.

-Tyrosine kinase inhibitors serve as the first line of treatment for CML, those progressing to later phases may require other specialized therapy such as combination therapy or cell transplantation that will require expert consultation with a hematologist/oncologist.


References/Further Reading

  1. Gulati R, Alkhatib Y, Donthireddy V, Felicella MM, Menon MP, Inamdar KV. Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature. Case Rep Pathol 2015:380451.
  2. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancerbase no.5, version 2.0. Available at: http://citeseerx.ist.psu.edu Last accessed 14July2016.
  3. Thora NK, Gundeti S, Linga VG, Coca P, Tara RP, Raghunadharao. Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis. Indian Journal of Cancer 2014 51(1):5-9.
  4. Hehlmann R. How I treat CML blast crisis. Blood 2012 120:737-747.
  5. Jafferbhoy S, Chantry A, Atkey N, Turner D, Wyld L. Spontaneous splenic rupture: an unusual presentation of CML. BMJ Case Rep 2011 Mar 24;2011.
  6. Druker, BJ. Translation of the Philadelphia chromosome into therapy of CML. Blood 2008 112:4808-4817.
  7. Faderl S, Kantarjian HM, Talpaz M. Chronic Myelogenous Leukemia: Update of Biology and Treatment. Oncology 1999 Feb;13(2):169-80.
  8. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost 2003 Oct;29(5):467-71.
  9. Jabbour E, Kantarjian H, O’Brien S, Rios MB, Abruzzo L, Verstovsek S et al. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 2006 107:480-482.
  10. Besa E. Chronic Myelogenous Leukemia. Medscape. Available at: http://emedicine.medscape.com/article/199425 Last accessed: 14July2016
  11. Granatowicz A, Piatek C, Moschiano E, El-Hemaidi I, Armitage JD, Akhtari M. An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean J Fam Med 2015 Sep;36(5):197-202.
  12. Sahu KK, Malhotra P, Uthamalingam P, Prakash G, Bal A, Varma N, Varma SC. Chronic Myeloid Leukemia with Extramedullary Blast Crisis: Two Usual Sites with Review of Literature. Indian J Hematol Blood Transfus 2016 Jun;32:89-95.
  13. Said MR, Yap E, Jamaluddin WF, Wahid FS, Shuib S. A case of chronic myeloid leukaemia in blast transformation with leukemic ascities. Med J Malayasia 2016 Apr;71(2):85-7.
  14. Ai DI, Liu W, Lu G, Patel KP, Chen Zl. Extramedullary blast crisis as initial presentation in chronic myeloid leukemia with the e1a2 BCR-ABL1 transcript: A case report. Mol Clin Oncol 2015 Nov;3(6):1319-1322.
  15. Zeng DF, Chang C, Li JP, Kong PY, Zhang X, Gao L. Extramedullary T-lymphoblastic blast crisis in chronic myelogenous leukemia: A case report of successful diagnosis and treatment. Exp Ther Med 2015 Mar;9(3):850-852.
  16. Tsukamoto S, Ota S, Ohwada C, Takeda Y, Takeuchi M, Sakaida E, et al. Extramedullary blast crisis of chronic myelogenous leukemia as an initial presentation. Leuk Res Rep 2013 Aug 13;2(2):67-69.
  17. Yu HH, Lu MY, Lin DT, Lin KH, Tang JL, Jou ST. Pathological fracture as a manifestation of extramedullary blast crisis in chronic myelogenous leukemia: a report of one case. Acta Paediatr Taiwan 2006 May-Jun;47(3):150-4.
  18. Kantarjian HM, Larson RA, Cortes JE, Deering KL, Mauro MJ. Current Practices in the Management of Chronic Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 2013 Feb; 13(1):48-54.
  19. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Labo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010 Jun 17;362(24):2251.
  20. Axdorph U, Stenke L, Grimfors G, Carneskog J, Hansen J, Linder O et al. Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase-a report from the Swedish CML Group. Br J Haematol 2002 Sep;118(4):1048-54.



Immune Thrombocytopenic Purpura: Pearls and Pitfalls

Authors: Patrick C Ng, MD (EM Chief Resident, SAUSHEC Emergency Medicine Department) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC Emergency Medicine Department) // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)


A 7-year-old male, previously healthy and born at term, presents to the emergency department (ED) accompanied with his parents with a chief complaint of knee pain and subsequent difficultly walking. The child woke up with the knee pain, and it progressed throughout the day to the point where the child could not bear weight.  Oral acetaminophen and ibuprofen provided minimal pain relief at home. To add to the history, the patient was seen recently in the ED for a fever, nonproductive cough, and runny nose approximately 14 days prior. He was diagnosed with a viral syndrome, and his symptoms resolved with supportive care. A review of systems (ROS) is negative for numbness, weakness, fever, nausea, vomiting, or pedal edema. Surgical history is significant for a circumcision shortly after birth. There are no significant medical problems in the family.

On examination in the ED, vital signs are all within normal limits. The child holds his left knee in approximately 120 degrees of flexion. He displays significant pain with extension and flexion of the knee. There is no obvious deformity, nor is there any significant swelling or joint line tenderness. He has no tenderness on the tibial tuberosity or with manipulation of the patella. The rest of the child’s exam is unremarkable.

His workup consists of x-rays of the left lower extremity, revealing a knee effusion and mild soft tissue swelling, and a normal basic metabolic panel (BMP). His complete blood count (CBC) reveals a platelet count of 6,000/ uL. A diagnosis of hemarthrosis is made and it is likely secondary to immune thrombocytopenic purpura (ITP). Thus, the child is admitted for further management.

Immune Thrombocytopenic Purpura (ITP)

Immune thrombocytopenic purpura was once known as idiopathic thrombocytopenic purpura until it was discovered that the pathophysiology of the thrombocytopenia involved the host immune system [1]. In ITP, thrombocytopenia occurs secondary to antiplatelet antibodies that are produced in the spleen. These antibodies first bind to platelets, followed by phagocytosis of the platelet/antibody complex by the reticuloendothelial system [1,8,9]. ITP is the leading cause of thrombocytopenia in children [2]. It is defined as a platelet count of <100,000/uL. Other common characteristics of ITP include petechiae and/or purpura, normal hemoglobin and white blood cell (WBC) count, and the absence of other signs of identifiable causes of thrombocytopenia. Acute ITP typically resolves within 6-12 months and often occurs shortly after an infection or a vaccination [2,3]. The disease is considered chronic if the thrombocytopenia lasts longer than 6-12 months without another identified etiology. ITP can occur in both children and adults. Approximately 80% of ITP seen in children is acute. Adults are typically affected with the chronic form [3].  Regardless of the patient’s age and his or her form of ITP, the most feared complication of the disease is major bleeding. This includes, but is not limited to, life threatening gastrointestinal bleeding and intracranial hemorrhage. According to Farhangi et al, the overall risk of serious bleeding in children with ITP is 3%, while the risk of intracranial hemorrhage (ICH) is 0.5% [2]. Most cases present with less significant bleeding, however. In a retrospective analysis of infants with ITP from 1987 to 2002, the majority were found to present with purpura and active mucosal bleeding [4]. Other studies have found serious bleeding rates ranging from 2.9% to 17%. The definitions of serious bleeding were defined differently in each study, however ICH, bleeding with a drop in hemoglobin, bleeding that required hospitalization or blood transfusion, epistaxis requiring cautery or nasal packing, and/or gross hematuria were all included as definitions of severe bleeding [5, 6,7]. In a more in 2008, Neunert et al reported on 1106 ITP patients enrolled into the Intercontinental Childhood ITP Study group (ICIS). In this report, the authors conclude that severe bleeding is uncommon at diagnosis of ITP in children [7].  Finally, there a few reports, in form of case studies, that focus on other complications of ITP such as spontaneous hemarthrosis, as in the case above. The rates of such presentations are not well characterized in the literature but are important for the emergency physician to recognize as a potential presentation [8].

Some studies describe ITP as a more serious disease in adults due to higher ICH rates (5%) as compared to children [9]. Typically, adult cases have a more insidious onset, often without any preceding infection on history and physical [10].

The clinical presentation of ITP, particularly in children, is variable. There is no consensus on how to predict the chances of serious bleeding on initial presentation. Recognizing this is important as the emergency medicine provider must maintain a high degree of suspicion for a major bleed, particularly in patients with platelet counts <50,000/ uL and in those with wet purpura (mucosal sites with purpura).

What are the key ED laboratory studies?

The laboratory tests that are essential include CBC and peripheral smear, as the hemoglobin, WBC, and WBC morphology may suggest other diagnoses such as malignancy. Thrombocytopenia is essential to making the diagnosis of ITP.

So you have a patient with plt count 20,000/uL. Is this ITP?

History and physical, CBC, and peripheral smear can suggest a more sinister condition. Evaluate closely for a history of joint/bone pain or a family history of easy bruising. These are signs of malignancy or familial coagulopathy, respectively. Examination findings that are not consistent with ITP include soft tissue or bony abnormalities, a non-petechial rash, hepatosplenomegaly, and lymphadenopathy. Laboratory findings such as an abnormal hemoglobin, an abnormal WBC morphology, and abnormal WBC count suggest another etiology.

Is there a scoring system available?

The spectrum of ITP presentations can range from asymptomatic to life threatening bleeds. An objective measurement of bleeding in patients with ITP can be accomplished using the ITP Bleeding Scale (IBLS) and/or ITP-specific bleeding assessment tool (ITP-BAT) [11,12]. The ITP-BAT scoring system is more prevalent in the literature. In essence, the scoring system takes into account the bleeding manifestations by organ system: Skin(S), visible Mucosae (M) and Organs (O) with Gradation of severity (SMOG). The emergency provider (EP) may not be specifically calculating this score upon initial evaluation, as it is primarily used to evaluate the patient’s response to treatment. However, the EP should be aware of this score, paying particular attention to the specific organ systems to evaluate for major bleeding when considering the diagnosis of ITP.


The initial treatment is targeted at blunting the activity of the reticuloendothelial system and is primarily based on expert opinion. Treatment and admission is indicated in patients that have a major bleeding episode and/or platelet counts < 10,000/ uL [10]. Corticosteroids are the initial treatment for non-life threatening bleeds. Examples of corticosteroid regimens include prednisolone/prednisone at 1-2mg/kg per day or dexamethasone at 40mg/day for 4 days [10]. For ITP patients with major bleeds, treatment includes IVIG at 1g/kg, IV methylprednisolone 1g/d x 3 days, and platelet transfusions [9,10,13].

Patients may present with wet or dry purpura and management of both is similar. However, it is important to make this clinical distinction. Wet purpura indicates active bleeding which puts patients at increased risk for anemia. These patients may need to be monitored more closely, with serial laboratory studies and more frequent physical examinations to assess for the extent of bleeding. These patients may also require more aggressive transfusions cases of severe bleeding.

Newer therapeutic approaches with medications such as rituximab, cyclophosphamide, vinca alkaloids, and mycophenolate mofetil have been explored in cases of refractory ITP [10]. Splenectomy serves as an effective second line therapy in cases refractory to initial treatments [15]. These approaches are more often needed in adults.


  • ITP can present with severe, life threatening bleeding including, but not limited to, intracranial hemorrhage.
  • Physical examination should focus on signs of bleeding intracranially, intra-abdominally, in the skin, and from the mucosa.
  • Initial workup includes CBC, WBC morphology, and peripheral smear.
  • Initial management of steroids and admission should be considered depending on the clinical presentation.
  • There are atypical presentations of ITP such as hemarthrosis that the EP should consider.
  • Emergency physicians should maintain a broad differential, as subtle abnormalities in the workup other than low platelets can suggest alternative diagnoses such as malignancy.

References/Further Reading

  1. Lusher JM, Zuelzer WW. Idiopathic thrombocytopenic purpura in childhood. J Pediatr 1966;68:971-9.
  2. Fargangi H, Ghasemi A, Banihashem A, Badiei Z, Jarahi L, Esami G, Langaee T. Clinical Features and Treatment Outcomes of Primary Immune Thrombocytopenic Purpura in Hospitalized Children Under 2-Years Old. Iran J Ped Hematol Oncol. 2016; 6(1): 24-31.
  3. Kuhne T. Idiopathic thrombocytopenic purpura of childhood: a problem-oriented review of the management. Transfus Apher Sci 2003 Jun;28(2):243-8.
  4. Sandoval C, Visintainer P, Ozkaynak MF, Tugal O, Jayabose S. Clinical features and treatment outcomes of 79 infants with immune thrombocytopenic purpura. Pediatr Blood Cancer 2004 Jan;42(1):109-12.
  5. Watts RG. Idiopathic thrombocytopenia purpura: a 10-year natural history study at the Children’s hospital of Alabama. Clin Pediatr (Phila). 2004 Oct;43(8):691-702.
  6. Medeiros D, Buchanan GR. Major hemorrhage in children with idiopathic thrombocytopenic purpura: immediate response to therapy and long-term outcome. J Pediatr 1998 Sep;133(3):334-9.
  7. Neunert CE, Buchanan GR, Imbach P, Bolton-Maggs PH, Bennett CM, Neufeld EJ. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood 2008 Nov 15;112(10):4003-8.
  8. Moller DE, Goldstein K. Hemarthrosis and idiopathic thrombocytopenic purpura. J Rheumatol 1987 Apr;14(2):382-3.
  9. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic Thrombocytopenic Purpura: A Practice Guideline Developed by Explicit Methods for The American Society of Hematology. Blood 1996;88:3-40.
  10. Stasi R. Pathophysiology and therapeutic options in primary immune thrombocytopenia. Blood Transfus 2011 Jul; 9(3): 262-273.
  11. Page LK, Psaila B, Provan D, Hamilton JM, Jenkins JM, Elish AS, et al. The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP. British Journal of Haematology 138, 245-248.
  12. Rodeghiero F, Michel M, Gernsheimer T, Stasi R. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood 2013;121(14).
  13. Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004 Apr;79(4):504-22.
  14. Supe A, Parikh M, Prabhu R, Kantharia C, Farah J. Post-splenectomy response in adult patients with immune thrombocytopenic purpura. Asian J Transfus Sci 2009 Jan; 3(1):6-9.
  15. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response and surgical complications. Blood 2004;10:2623-34.

DIC in the ED: What can you do about it?

Author: Ashley Phipps, MD (EM Chief Resident, UTSW / Parkland Memorial Hospital // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

 Patient Case

A 67 year-old male presents to the emergency department (ED) for fevers, nausea, vomiting, and severe epigastric pain for the past 2 days. The patient has a history of alcoholism, hypertension, and diabetes. On exam, he is ill-appearing, tachycardic, and mildly tachypneic. Laboratory studies and a computed tomography (CT) abdomen/pelvis are obtained showing a lipase of 316 and pancreatic stranding making pancreatitis the most likely diagnosis. Other notable laboratories studies include leukocytosis to 22,000/microliter (uL), thrombocytopenia to 42,000/uL, hyperglycemia to 351, and a mild transaminitis. His nurse tells you that there is blood oozing around his intravenous (IV) sites. Being an astute clinician, you recognize that this patient is critically ill, and you begin to worry about disseminated intravascular coagulation (DIC).


DIC is an acquired coagulation syndrome that results in excessive clotting and clotting factor consumption, with subsequent severe bleeding in severely ill patients. Many different conditions can lead to DIC (table 1); however, the mechanism for DIC is the same in each case. In DIC, the coagulation cascade is activated and its control mechanism is lost. This leads to the formation of thrombin clots that are then deposited in capillaries and small vessels. The large amount of thrombin and fibrin clot deposition has three big consequences. First, the excessive clotting effectively consumes the body’s store of clotting factors and platelets. Next, the clot deposition in the microcirculation leads to hemolysis as red blood cells attempt to pass through. Lastly, the counter-regulatory system, the fibrinolytic system, also gets activated and starts dissolving the clots. At this point, clotting factors are depleted and significant bleeding can ensue. (1)

Table 1. Known causes of DIC

Infection (bacterial, viral, & fungal)
Pregnancy complications (placental abruption, intrauterine fetal demise, amniotic fluid embolus, HELLP syndrome)
Acute Respiratory Distress Syndrome (ARDs)
Acute liver failure
Malignancy (most common in leukemia), chemotherapy
Envenomation (rattlesnakes, vipers)
Transfusion reactions

Clinical Presentation

The clinical presentation will vary based on the precipitating cause. Patients can present with hypercoagulation, hyperfibrinolysis, or a mixed picture of both. If hypercoagulation predominates, clinical presentation can include signs of end-organ failure or gangrene in small vascular beds such as the fingers or toes. This is the most common initial presentation of DIC in septic patients. Contrastingly, if bleeding predominates, the patient may have petechiae or large ecchymosis, hematuria or hematochezia, or oozing from IV sites and any other sites of trauma. This is the most common presentation of DIC in patients with trauma, malignancy, pregnancy, or liver failure related illnesses. (2)

 Diagnostic Studies

In all severely ill patients, especially those with symptoms or signs of DIC, coagulation laboratories studies should be obtained. These include platelet count, prothrombin time (PT), and fibrinogen. Additional tests including d-dimer, fibrin degradation products, activated partial thromboplastin time (aPTT), clotting time, and specific factor assays can be helpful. (1) DIC is often associated with several characteristic laboratory findings, shown in Table 2. This disease differs from other coagulation disorders in the degree and number of laboratory abnormalities.

Table 2. Laboratory abnormalities in DIC

Platelet count
Fibrinogen ↓ (can be elevated in early DIC)
Fibrin degradation products
Clotting time
Specific factor assays ↓ (especially Factor II, V, VII, X)

Several scoring systems exist to determine the likelihood of DIC as well as prognosis (2). For example, the International Society on Thrombosis and Haemostasis has a scoring system that gives points for the degree of thrombocytopenia, degree of elevation in the d-dimer, degree of prolongation of the PT, and if the fibrinogen level is low or not. If that score is greater than or equal to 5, the presentation is consistent with DIC. (3) This score was then validated in a prospective study looking at 217 intensive care patients at an academic center resulting in a sensitivity of 91% and specificity of 97%. The study also showed a strong correlation between DIC and 28-day mortality (4), further illustrating how important it is to start treatment for DIC in the emergency department if it is suspected.

Treatment: What can we do about it?

  1. Treat the underlying disease. For most cases, DIC will resolve on its own if the underlying condition is appropriately treated (5).
  1. If bleeding is the main problem and there is continuing active bleeding or a high risk for more bleeding:
Lab Abnormality Treatment
Hgb <7 or active significant bleeding on exam PRBCs (packed red blood cells)
Platelets <50,000 Platelets
PT >1.5 or fibrinogen <100 FFP (fresh frozen plasma)

Vitamin K

Trauma-related bleeding TXA (tranexamic acid)

The dosing for transfusions will vary based on the exact lab values and presentation. For platelet transfusion, the platelet count should rise by 5,000/uL for each unit of platelets (6). For FFP, the initial recommended dose is 15 cc/kg (2).

If the patient cannot tolerate large volumes of fluid, small volume PCC (prothrombin complex concentrate) can be substituted for FFP. However, giving only PCC will not replenish all of the needed clotting factors, especially factor V and fibrinogen. Thus, cryoprecipitate should also be given to help replenish the patient’s depleted fibrinogen. (6)

Some patients in DIC will also continue to have low fibrinogen levels that are refractory to FFP administration. These patients require concomitant cryoprecipitate (7).

Disposition for all of these patients should be to an intensive care unit (ICU). However, depending on how long it takes to get the patient out of the ED and into the ICU, it is important to keep in mind that the DIC labs should be repeated every six hours in critically ill patients and after any interventions (7).

  1. If hypercoagulation is the main problem, consider therapeutic doses of low molecular weight heparin. A small randomized control study showed this was superior to using unfractionated heparin. The predominately hyperfibrinolytic patients are also at increased risk for venous thromboembolism and should be started on prophylactic anticoagulation with low molecular weight heparin as soon as the bleeding risk is mitigated. (5)

 Case Resolution

You reassess the patient and notice that he indeed is continuing to ooze from his two IV sites. You also notice petechiae on his lower extremities. Concerned for DIC, you immediately start treating the patient’s underlying condition of pancreatitis and a urinary tract infection. The patient is made nil per os (NPO) and given IV fluids, antiemetics, and analgesia. His hyperglycemia is controlled after fluids are started. He has known thrombocytopenia and the rest of his DIC labs show an INR of 1.8, a low fibrinogen level, and an elevated d-dimer. The patient is given two units of platelets, 15 cc/kg FFP, 10 mg IV Vitamin K and is admitted to the ICU laboratory tests are frequently checked and he is given blood products as needed. On day two, the patient begins to improve and by day eight, the patient is discharged home.


DIC is an important clinical entity seen in critically ill patients. Laboratories studies may demonstrate low platelets, an elevated INR, an elevated d-dimer, and low fibrinogen levels. Rapid identification and treatment of the underlying cause as well as supplementation with blood products is important to reduce mortality in these patients.

References/Further Reading

  1. Tintinalli JE et al. Acquired bleeding disorders: disseminated intravascular coagulation. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 2011; 7.
  2. Wada H, Matsumoto T, Yamashit Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014; 2(1):15.
  3. Taylor FB, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001; 86: 1327-30.
  4. Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med. 2004; 32(12): 2416-21.
  5. Wada H, et al. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines. J Thrombosis & Haemostasis. 2013; 11: 761-7.
  6. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006; 10(4): 222.
  7. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009; 145(1): 24-33.

Hemolytic Anemias: Rare but Important Diagnosis in the Emergency Department

Authors: Jennifer Robertson, MD, MSEd, Elizabeth Brem, MD (Heme-Onc Fellow, BIDMC), and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) // Editor: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC)


A 35-year-old G1P0 female at approximately 10-weeks gestational age presents to the emergency department (ED) with a two-day history of fatigue, generalized weakness, dark urine, and mild jaundice. She denies chest pain, difficulty breathing, vaginal bleeding, any new medications, or any recent illnesses. She has a family history of systemic lupus erythematous and rheumatoid arthritis. Her vital signs demonstrate a heart rate of 120 beats per minute, a blood pressure of 90/60 mm Hg and a temperature of 100.4° Fahrenheit (F). Laboratory testing shows a hemoglobin of 6.5 grams (gm)/deciliter (dL) and an elevated indirect bilirubin. What is the differential diagnosis? What other tests should be ordered, and what initial treatments are recommended?


Hemolytic anemia is defined as the premature destruction of red blood cells (RBCs) (1). Under normal conditions, the RBCs are in circulation approximately 120 days and then are destroyed via the mononuclear phagocyte system (2, 3). The most pressing concerns for the emergency medicine physician are the acute hemolytic anemias that may cause immediate, life-threatening complications (4). The primary goal for the EM physician is of course, resuscitation. However, an important secondary goal is for the provider is recognition of the hemolytic process and initiation of appropriate therapy. Some anemias are chronic, while others can cause acute and devastating complications. Hemolysis can occur extravascularly or intravascularly, and typically, intravascular hemolysis causes more rapid and devastating hemolysis (4, 5). 

Extravascular Hemolysis

Pathologic extravascular hemolysis occurs when RBCs are prematurely removed by macrophages in the liver, spleen, and/or bone marrow due to abnormal shape or binding of an antibody (3,6). The presence of spherocytes on a blood smear denotes the presence of extravascular hemolysis (1, 4).

Examples: hereditary spherocytosis, RBC enzyme abnormalities such as glucose-6-phosphate-dehydrogenase (G6PD) deficiency, hemoglobinopathies, and hypersplenism (2, 7). This is not an exclusive list and of note, some of these disorders may also undergo intravascular hemolysis (4).

Table 1: Medications/exposures that cause hemolysis in G6PD deficiency

Trimethoprim/sulfa (Bactrim) Aniline dyes
Nitrofurantoin Naphthalene (mothballs, deodorizers)
Phenazopyridine Henna
Dapsone Fava beans

 Intravascular Hemolysis

When intravascular hemolysis occurs, hemoglobin is released into the circulation, binds to haptoglobin and hemopexin, and is transported to the liver. Here, this complex is conjugated to bilirubin and excreted. With large amounts of intravascular hemolysis, the binding system may become saturated and free hemoglobin can appear in the bloodstream and urine, leading to hemoglobinemia and hemoglobinuria (4, 8). A marker of intravascular hemolysis on a peripheral blood smear is the schistocyte (1, 4). 

Examples: mechanical trauma from prosthetic heart valves, disseminated intravascular coagulation (DIC), toxins such as the brown recluse spider venom, infections such as malaria, ABO incompatibility reactions, paroxysmal nocturnal hemoglobinuria (PNH), and autoimmune hemolytic anemias (3, 4).

Presentation, History, and Physical Examination

Symptoms: Fatigue, tachycardia, pallor, shortness of breath, or chest pain (1, 3, 9). More specific symptoms concerning for an acute hemolytic process can include new onset jaundice, dark colored urine, fever, abdominal pain, back pain, and/or altered mental status (1, 3, 4, 5).

History: Ask about changes in the color of their urine or feces, recent bleeding or trauma, fever, malaise, night sweats, or other systemic symptoms. The past medical history should specifically address whether there is a history of connective tissue disease, renal failure, malignancy, or prosthetic heart valve placement. Patients should be asked about a family history of anemia or jaundice. Physicians should inquire if these symptoms have ever happened before and whether patients have recently started any new medications (4, 9).

Physical examination: Always evaluate vital signs first. After initial stabilization of any hemodynamic instability, the rest of the examination should include evaluating for hepato-or splenomegaly, signs of liver disease such as ascites, lymphadenopathy, heart murmurs consistent with prosthetic heart valves, and skin changes such as purpura or petechiae (4, 9). Lymphadenopathy may suggest a lymphoproliferative disease, while petechiae or bruising may suggest concomitant thrombocytopenia, which can help narrow the differential. (9). Skin ulcerations and/or necrosis may be consistent with brown recluse spider bites, snake bites, or chronic hemolytic diseases such as sickle cell anemia (3, 10, 11).

ED Testing

Important laboratory tests:

  1. Complete blood count: evaluate for a decrease in hemoglobin and hematocrit. Platelet count should be noted if a thrombotic microangiopathic hemolytic anemia (MAHA) is in the differential.
  1. Reticulocyte count: the reticulocyte count will usually be elevated as the bone marrow attempts to make up for the decreasing hemoglobin by increasing RBC production (9, 12). With anemia, the percentage of reticulocytes may be elevated but the absolute number can be different, so a more useful value is the reticulocyte index. This is defined as the reticulocyte percentage multiplied by the radio of the patient’s hemoglobin or hematocrit to the expected hemoglobin or hematocrit based on age and gender of the patient. For example, in an adult male patient whose expected hemoglobin is 15 gm/dL, his current measured reticulocyte count is 10% and current hemoglobin is 7.5 gm/dL, the absolute reticulocyte count should be 10 x (7.5/15), which is equal to 5% (9).
  1. Lactate dehydrogenase (LDH): LDH is an enzyme that catalyzes the conversion of lactate into pyruvic acid and is released into the serum when cells are rapidly LDH (3, 4, 8, 13). LDH is not specific for hemolysis as it can be elevated in other conditions such as heart failure, malignancy, and even severe vitamin B12 deficiency (13). However, in the proper clinical circumstances, an elevated LDH can point toward a hemolytic process.
  1. Indirect Bilirubin: When RBCs are rapidly destroyed, excess bilirubin is produced by the large amount of hemoglobin that is released from RBCs (14, 15). The hemoglobin is then converted into unconjugated bilirubin and transported to the liver for conjugation, but the process becomes overwhelmed (3, 8). This leads to indirect hyperbilirubinemia.
  1. Haptoglobin: When RBCs are prematurely destroyed by intravascular hemolysis, haptoglobin becomes saturated with free hemoglobin. The mononuclear phagocyte system then quickly clears these haptoglobin-hemoglobin complexes, and the levels of serum haptoglobin decline (3, 8, 13).
  1. Direct Anti-Globulin Test: The direct anti-globulin test (DAT) or Coombs test (13) is positive in approximately 90% of patients with warm autoimmune hemolytic anemias (WAIHA) (4).
  1. Peripheral Blood Smear: While the smear cannot determine the exact cause of the hemolytic anemia, the presence of schistocytes or spherocytes can indicate if a hemolytic process is present (16).
  1. Urinalysis, Urine Hemoglobin, Urine Hemosiderin: Hemoglobinuria and hemosiderinuria can also occur and therefore, a urinalysis and urine free hemoglobin should be obtained. (4, 8, 12, 13, 14).  Hemosiderin is an iron storage complex commonly found in macrophages and is a marker for intravascular hemolysis because it binds iron as excess hemoglobin is filtered by the kidney. While hemosiderinuria is a good marker for intravascular hemolysis, it usually does not occur until three to four days after the onset of hemolysis (3, 13). If hemolysis occurs rapidly enough, hemoglobinuria can also be seen (8, 17). In fact, hemoglobinuria is one of the most prominent clinical signs of severe intravascular hemolysis. Note that hemoglobinuria can occur in other conditions such as chronic renal failure and therefore, like all the tests described above, hemoglobinuria should be interpreted as a clue to the diagnosis only in the right clinical context (17).


“Cannot Miss” Acute Hemolytic Diseases in the ED

(1) The Microangiopathic Hemolytic Anemias (MAHA):

In general, MAHA refers to conditions where red blood cells become fragmented as they pass through platelet-fibrin rich microthrombi that accumulate in capillaries and arterioles (8, 18, 19). The pathophysiology of the development of these clots is complicated and there are many underlying contributors to the development of MAHA including bacterial toxins, radiation treatments, autoimmune diseases, and medications (8, 19, 20, 21). Due to intravascular platelet aggregation and deposition, varying degrees of thrombocytopenia will be present along with the hemolytic anemia (19, 20).


(1a) Disseminated Intravascular Coagulation (DIC): DIC is a syndrome caused by systemic inflammation due to another underlying disease (22, 23). The most common underlying causes of DIC are sepsis, trauma, malignancy, placental abruption, and severe liver disease (22). The pathophysiology is complicated, but, briefly, inflammatory cytokines that initiate the intrinsic (tissue factor) pathway of the coagulation (23). Simultaneously, endogenous fibrinolytic or anticoagulant systems cannot be maintained (23, 24). This leads to excessive coagulation and consumption of platelets and clotting factors, which can subsequently lead to excessive bleeding as well at thrombosis (23, 25). DIC should be suspected in very ill patients with purpura, bleeding and/or thrombosis, and/or organ injury such as kidney failure (25). The prothrombin (PT) and partial thromboplastin (PTT) times will be prolonged, d-dimer is elevated, and fibrinogen is low, indicating consumption of coagulation factors. Schistocytes and RBC fragments are often visualized on peripheral smear (25, 26).

The main goals in emergency care of DIC include recognition of the disorder, proper resuscitation, treatment of the underlying disorder and when indicted, treatment focused on reversing the coagulopathy (25). Platelets should be considered when the platelet count is < 50,000mm3 and/or significant bleeding is present (25, 26). RBCs should be provided if there is active bleeding present and or if the patient is hemodynamically unstable (25, 27). Coagulation factor replacement with fresh frozen plasma (FFP) should also be given when active bleeding exists (25, 26, 28). If massive bleeding is present or fibrinogen is < 150, fibrinogen should be replaced via cryoprecipitate (26, 28). Anti-fibrinolytic treatment, such as tranexamic acid is recommended only for the active or massive bleeding (26, 28)

In patients with evidence of excessive thrombosis and fibrin deposition such as in venous thromboembolism and purpura fulminans, heparin may decrease the incidence of further clotting (25, 26, 28), although it should be noted that data from large randomized controlled trials is lacking in terms of its overall mortality benefit (25, 26).


(1b) Thrombotic Thrombocytopenic Purpura (TTP): TTP is defined as a MAHA and thrombocytopenia without a clear alternative cause (20, 29). It can be fatal due to ischemia resulting from platelet agglutination in the arterial microvasculature.

Approximately 60% of cases of TTP arise from a congenital or acquired deficiency in the ADAMTS13 protease enzyme (13, 30, 31). ADAMTS13 cleaves von Willebrand factor (vWF) multimers. Without ADAMTS13, excessive platelet aggregation and thrombosis can occur (32). The other 40% of TTP cases are idiopathic or due to secondary causes such as cancer, human immunodeficiency virus (HIV)-1 infection, pregnancy, and certain medications including acyclovir, quinine, oxymorphine, clopidogrel, and tacrolimus (21, 30).

To diagnose TTP in adults, MAHA and thrombocytopenia with or without renal failure or neurologic abnormalities should be present. The symptoms and presentation of TTP can vary and, unfortunately, the pentad of fever, anemia, thrombocytopenia, renal dysfunction, and neurologic abnormalities occur in only a small number of patients (29, 31).  Other symptoms include generalized weakness, hematuria, purpura, and other signs of bleeding (29). Laboratory tests reveal anemia and thrombocytopenia with typically normal PT and PTT levels (33). Schistocytes will be visualized on the peripheral blood smear, and a schistocyte count of more than 1% is typical (13).

The treatment of TTP plasma exchange. While waiting for plasma exchange, FFP should also be administered as soon as possible (29, 31). It is classically taught that platelet transfusions are harmful in those with TTP, but may be indicated in some circumstances (29). The 2012 American Society for Apheresis (ASFA) recommends that platelet transfusions be conducted in cases where TTP is associated with overt hemorrhage and/or for the prevention of bleeding in a “surgical procedure that involves a risk for clinically important bleeding” (34).


(1c) Hemolytic Uremic Syndrome (HUS):  While the symptoms of HUS may be similar to TTP, the pathophysiology and treatments differ. The pathophysiology of TTP is mainly one that is idiopathic, secondary or due to ADAMTS13 deficiency, while HUS usually follows an acute, bloody diarrheal illness caused by a bacterial toxin, most commonly from certain strains of Escherichia coli (E. coli). This toxin, produced by certain enterohemorrhagic (E. coli) (EHEC) strains, causes microvasculature endothelial and epithelial cell damage that leads to the thrombosis and renal failure seen in HUS (35).

Atypical HUS is so named because it does not follow an acute diarrheal illness (35).  Causes of atypical HUS include many factors that cause dysregulation of the complement system, which is beyond the scope of this article (36). While children with typical HUS usually have only a one- time episode, atypical HUS patients may have recurrent episodes (37).

The clinical features of HUS are similar to TTP in that both involve MAHA and thrombocytopenia. However, renal failure typically is more pronounced in HUS, while neurologic abnormalities are more likely to occur in TTP (31). Typical HUS should be suspected in any child who presents with a history of bloody diarrhea and new onset anemia, thrombocytopenia and renal failure. Atypical HUS should be suspected in patients with similar symptoms but no history of acute diarrheal illness, particularly if there have been similar episodes previously.

The treatment of typical HUS is supportive as well as possible dialysis (38). The primary therapy for atypical HUS has traditionally been plasmapharesis, but new options are emerging, including eculizumab, a monoclonal antibody that inhibits complement (39, 40). It is important to remember that antibiotics should never be given in acute, bloody diarrheal illness in children, as this remains an important risk factor for the development of HUS (41).


(1d) Malignant Hypertension: Malignant hypertension is defined as severe hypertension with associated organ damage, including renal and heart failure (42). This disorder is similar to TTP and HUS in that endothelial cell damage plays a key role in the pathophysiology. However, unlike TTP and HUS, the key factor related to the signs and symptoms seen in malignant hypertension is via direct damage to arterioles from elevated blood pressure. It has been demonstrated that treating blood pressure will help improve the condition (43).

The renin-angiotensin-aldosterone system is abnormally activated in malignant hypertension (42). It is postulated that the activated renin-angiotensin system causes endothelial cell damage, fibrinoid necrosis, and platelet and fibrin clots in arterioles. Ultimately, excessive platelet aggregation and fragmentation of RBCs occur, which illustrates the thrombosis and MAHA seen in malignant hypertension (42, 43). Along with markedly elevated blood pressures, patients may present with thrombocytopenia, microangiopathic hemolytic anemia, papilledema, encephalopathy and/or renal failure (42).

Treatment is aimed at decreasing the blood pressure as clinically indicated, with or without renin-angiotensin-aldosterone antagonists (42).


(2) The Warm Autoimmune Hemolytic Anemias (AIHA): Unlike many autoimmune diseases, patients with warm AIHAs have the ability to present with severe, life-threatening symptoms (5). EM physicians should understand the risk factors for warm AIHA, recognize the symptoms, and consider warm AIHA as a possible cause for a patient’s hemolytic anemia. Additionally, EM physicians should understand the basic principles of treatment and know when to consult a hematology specialist (44).

In general, AIHA is the clinical condition where autoantibodies are produced and directed against self RBCs (5,45). There are multiple causes and types of immune related hemolytic anemias, including alloimmune related from blood transfusions and drug related, but this is beyond the scope of this article.

The AIHAs can be divided into two major categories – cold AIHA and warm AIHA. This categorization refers to the temperature that antibodies react optimally with human RBCs. Warm antibodies (IgG) react best at 37° Celsius (C), while cold antibodies (IgM) react best at colder temperatures, typically around 0-4°C (5). While EM physicians should be aware that cold AIHA exists, it typically has more of an indolent course and is less common than the warm AIHAs (5,45).

Warm AIHAs may be primary or secondary, either idiopathic or due to an underlying cause such as lymphoproliferative diseases and viral infections (5,46).  Patients with idiopathic warm AIHA may have a history of relapses and remissions and their disease can present more severely (45).

To diagnose warm AIHA, there must be a positive DAT and laboratory findings of hemolysis as detailed above (5,13). Platelet counts are usually normal (45). A peripheral blood smear should also be obtained. The severity of spherocytosis correlates with the extent of hemolysis well (45).

The initial treatment of AIHA depends on the severity of hemolysis (5). As with any unstable patient, abnormal vital signs should be addressed first. While RBC transfusion is not contraindicated in warm AIHA, it should be limited to cases of life-threatening anemia or in those patients with a high risk of ischemia (5,45). This is because transfusions may induce further autoantibody production, and it may be difficult to find an accurate crossmatch (45, 47). When transfusion is necessary, the most compatible units should be administered and the RBCs should be infused as slowly as possible (5,45). During transfusion, patients should be monitored closely for signs of a hemolytic transfusion reaction (45).

Corticosteroids slow the rate of hemolysis and are a first line therapy that should be started as soon as possible (5,45). Critically ill patients with rapid hemolysis should be given intravenous (IV) methylprednisolone 100 to 200 mg in divided doses over the first 24 hours, while more stable patients can be given oral prednisone at an initial dose of 60 to 100mg daily. Occasionally, splenectomy, IV immunoglobulin, or drugs such as rituximab or cyclophosphamide may provide therapeutic relief in those unresponsive to steroids (5,45).


Case Resolution

The EM physician immediately noticed the patient’s abnormal vital signs and placed her on the cardiac monitor, placed two large bore IV lines and initiated a one-liter crystalloid bolus. Based on the patient’s gestational age and blood pressure, pre-eclampsia and HELLP were not suspected, but a urinalysis showed hemoglobinuria. Labs revealed an elevated indirect bilirubin, a low hemoglobin without bleeding and an elevated reticulocyte count. A peripheral smear demonstrated spherocytes. The EM physician called the hematology specialist who recommended a type and screen and a DAT. The patient’s vital signs improved with fluids and the patient was admitted to the intensive care unit. The patient’s DAT was positive, consistent with AIHA. Corticosteroids were administered to the patient in the hospital and she improved without permanent sequelae.



Hemolytic anemias are rare and many present with gradual onset of symptoms. However, some can cause rapid hemolysis and contribute to high morbidity and mortality (2). The primary goal for the EM physician is, of course, resuscitation. However, recognizing that a hemolytic process is present is also very important, as this will guide workup and occasionally, specific treatments.


References / Further Reading

  1. Kelton JG, Chan H, Heddle N, et al. Blood and Bone Marrow Pathology. New York: Churchill Livingstone; c2002. Chapter 10, Acquired hemolytic anemia; p. 185-202.
  2. Ucar K. Clinical presentation and management of hemolytic anemias. Oncology 2002; 16 (9, Suppl 10): 163-70.
  3. Dhaliwal G, Cornett PA, Tierney LM. Hemolytic anemia. Am Fam Physician 2004; 69 (11): 2599-2606.
  4. Hamilton GC, Janz TG. Anemia, polycythemia, and white blood cell disorders. 5th ed. Saint Louis: Elsevier Mosby, c2002. P. 1665-87. (Marx JA, editor-in-chief. Rosen’s Emergency Medicine; vol. 2.)
  5. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002; 69: 258-71.
  6. Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev 2008; 1: 17-31.
  7. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21 (1): 37-47.
  8. Bunn HF, Rosse W. Harrison’s Internal Medicine. 16th Ed. New York: McGraw Hill; c2005. Hemolytic anemias and acute blood loss; p. 607-617.
  9. Adamson JW, Longo DL. Harrison’s Internal Medicine. 16th Ed. New York: McGraw Hill; c2005. Anemia and polycythemia; p. 329-336.
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  11. Mandal L. Venomous snake bites. Postgrad Med J of NAMS 2012; 12 (1): 57-65.
  12. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc 2003; 78 (1): 1274-80.
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  15. Schaer DJ, Buehler PW, Alayash AI, et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013; 121 (8): 1276-84.
  16. Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353: 498-507.
  17. Rother RP, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293 (13): 1653-62.
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  19. Martinez, J. Microangiopathic hemolytic anemia. Hematology 1995, ed4: 657.
  20. George JN, Charania RS. Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia. Semin Thromb Hemost 2013; 39: 153-60.
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  22. Levi M, de Jonge E, van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med 2004; 36 (1): 41-9.
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  25. Janz TG, Hamilton GC. Disorders of hemostasis. 5th ed. Saint Louis: Elsevier Mosby, c2002. P. 1688-1700 (Marx JA, editor-in-chief. Rosen’s Emergency Medicine; vol. 2.)
  26. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care 2014;2:15.
  27. Weiskopf RB. Emergency transfusion for acute severe anemia: a calculated risk. Anesth Analg 2010; 111 (5): 1088-92.
  28. Levi M, Toh CH, Thachil J, et al. Guidelines for diagnosis and management of disseminated intravascular coagulation. British journal of haematology 2009; 145 (1): 24-33.
  29. George JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood 2010; 116(20):4060-4069
  30. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347 (8): 589-600.
  31. Koyfman A, Brem E, Chiang VW. Thrombotic Thrombocytopenic Purpura. Pediatr Emer Care 2011; 27: 1085-91.
  32. Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87 (10): 4235-44.
  33. Rock G, Kelton JG, Shumak KH. Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Br J Haematol 1998;103 (4): 1031-36
  34. Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher 2014; 29 (3): 148-67.
  35. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet2005; 365 (9464): 1073-86.
  36. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis2011; 6 (1): 60.
  37. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 2008; 23 (10): 1749-60.
  38. Michael M, Elliott EJ, Ridley GF, et al. Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev1 2009.
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  41. Wong CS, Mooney JC, Brandt JR, et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157: H7: a multivariable analysis. Clin Infect Dis 2012; 55 (1): 33-41.
  42. Shibagaki Y, Fujita T. Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): Can We Differentiate One from the Other? Hypertens Res 2005; 28 (1): 89-95.
  1. Khanna A, McCullough PA. Malignant hypertension presenting as hemolysis, thrombocytopenia, and renal failure. Rev Cardiovasc Med 2002; 4 (4): 255-59.
  2. Petz, Lawrence D. Emergency transfusion guidelines for autoimmune hemolytic anemia.Lab Med 2005; 36 (1): 45-48.
  3. Packman C. Williams Hematology. 8th Ed. New York: McGraw Hill; c2010. Hemolytic anemia resulting from immune injury; p. 729-750.
  4. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed)1981: 282 (6281): 2023-27.
  5. Ness PM, Shirey RS, Thoman SK, et al. The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings, and clinical significance. Transfusion 1980; 30 (8): 688-93.

Heparin Induced Thrombocytopenia (HIT): An ED-Focused Review of the Literature

Authors: Sean Murnan, MD and Richard Slama, MD (EM Resident Physicians, NMCP Emergency Medicine Residency) // Edited by: Erica Simon, DO, MHA (@E_M_Simon), Brit Long, MD (@long_brit), & Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

A 56 year-old female with a PMHX of lung cancer presents to the ED for “abnormal labs.” Review of systems is significant for hospitalization five days prior secondary to multiple sub-segmental pulmonary emboli. The patient notes that during her hospital stay heparin therapy (unfractionated heparin (UFH)) was initiated, and that she was subsequently transitioned to lovenox (low molecular weight heparin (LMWH)). The patient states that she has been compliant with her lovenox injections, but that she was directed to the ED after her PCM follow-up due to her “abnormal blood counts.” Current labs demonstrate a platelet count of 16 x103/L. Review of the patient’s record reveals a platelet count of 140 x103/L just prior to her hospitalization.

What is the underlying cause of this patient’s thrombocytopenia? How will you manage her condition? What laboratory studies will you order? If it’s time for a HIT refresher, we have you covered:

First, let’s talk Heparin:

  • Heparin produces its anticoagulant effect through inhibition of thrombin and factor Xa through an antithrombin dependent binding process.1

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What is HIT?

  • When heparin is administered exogenously, platelet factor 4 (PF4) (a neutralizing chemokine of heparin and heparin-like compounds released from alpha granules upon platelet activation), binds to heparin, forming heparin-PF4 complexes.1,2
  • Formation of the heparin-PF4 complex results in an intrinsic conformational change of the PF4 protein, thereby generating a neoantigen.3
  • Although the autoimmune system mounts an allogenic response to the neoantigen through the generation of IgG, IgM, and IgA antibodies; the formation of IgG antibodies (the only subclass recognized by the platelet Fc receptor) is thought to result in HIT.4,5

HIT comes in two flavors:

  • HIT Type I is defined as a transient decrease in platelets (nadir commonly around 100 x103/L) that occurs during the first few days of heparin exposure. HIT Type 1 is not immune-mediated, and can be managed without discontinuation of heparin therapy.6,7
  • HIT Type II references the aforementioned immune-mediated process by which IgG antibodies bind the heparin-PF4 complex, leading to platelet activation, and subsequent venous or arterial thrombosis.6,8 The thrombocytopenia observed in HIT Type II is a result of platelet consumption and removal by macrophages in the reticuloendothelial system.2

The Clinical Presentation of HIT: A Spectrum of Disease

 Early Features

  • 85-90% of patients present with thrombocytopenia: platelet count < 150 x103/L OR a decrease in the patient’s baseline platelet count by ≥ 50%.6,9,10
    • Thrombocytopenia typically occurs within 5-10 days of the initiation of UFH or LMWH therapy.6
    • It is important to note that HIT may occur independent of the heparin dose, schedule, or administration route (even heparin flushes are not excluded).8,11

Delayed Features: “White Clot Syndrome” 6,12

  • Venous Thrombosis:
    • Lower limb DVT – present in roughly 20-50% of patients with HIT6,13
    • Upper extremity DVT – associated with IV catheter use14
  • Arterial Thrombosis:
    • Occurs in 3-10% of patients with HIT6,13
    • Typically involves the heart, central nervous system, and limbs.15

Rare Presentations of HIT

  • Anaphylaxis:
    • Case reports detail acute, fatal systemic anaphylactic reactions in patients experiencing HIT.6,16

 Alright, that sounds great, but why should I care about HIT in the emergency department?

The acute presentation of HIT is rare, occurring in 2.6% of patients receiving UFH and 0.2% receiving LMWH,6,17 however, as outpatient DVT/PE therapy becomes increasingly commonplace, we are likely to see an increase in the number of incident cases of HIT presenting to the ED.18

 I hear that HIT is often misdiagnosed, are there any tools to help me in determining how likely it is that my patient actually has HIT?

Thrombocytopenia is a common finding in ill patients. Some studies suggest that 46% of individuals admitted to the ICU will have a platelet count <150,000.19 What is even more challenging is that only 10% of patients initially investigated for HIT, will ultimately have laboratory studies confirming the diagnosis.10

This is where the 4T Score comes in handy: allowing for the determination of a patient’s pretest probability of HIT, and thus aiding in the clinical decision to initiate HIT evaluation and treatment.

The 4T Score ranges from 0-8, with 0-3 = low pre-test probability, 4-5 = intermediate pre-test probability, and 6-8 = high pre-test probability of HIT.6

  • Categories include:
    • Thrombocytopenia
      • 0 Pts = <30% platelet fall or nadir <10,000/microL
      • 1 Pts = 30-50% platelet count fall, or >50% directly resulting from surgery, or nadir 10,000-19,000/micoL
      • 2 Pts = > 50% platelet fall to nadir ≥ 20,000/microL
    • Timing
      • 0 Pts = Platelet count fall <4 days without recent exposure
      • 1 Pts = Consistent fall 5-10 post treatment, but not entirely clear (missing platelet counts) OR ≤ 1 day or less exposure to heparin within past 31 to 100 days
      • 2 Pts = Clear onset between 5 and 10 days or platelet count fall ≤ 1 day if prior heparin exposure within the last 30 days
    • Thrombosis
      • 0 Pts = None
      • 1 Pts = Progressive or recurrent thrombosis, or erythematous skin lesions (at an injection site), or suspected thrombosis that has not been proven
      • 2 Pts = Confirmed new thrombosis or skin necrosis (at injection site), or acute systemic reaction after IV UFH bolus
    • Other Causes of Thrombocytopenia
      • 0 Pts = Definite other cause is present
      • 1 Pts = Possible other cause is evident
      • 2 Pts = No explanation for the decrease in platelet count is evident

Key Points Regarding the 4T Score

The 4T Score is meant to capture the MAJOR clinical features of HIT (thrombocytopenia, thrombosis, etc.) and the likelihood that these findings are due to a temporal relationship with heparin administration.6  A 4T Score ≥ 4 should prompt hematology consultation for consideration of evaluation and therapy.

Treatment and Management of HIT in the Emergency Setting

  • Consult Hematology
  • Discontinue all forms of heparin (to include heparin flushes administered for IV catheters).
  • Initiate an alternative anticoagulant based upon discussions with a hematologist. Options include:6,20,21
  • Bivalirudin – direct thrombin inhibitor – 0.15mg/kg/hr IV
    • Renal dosing for GFR <30
    • Dose adjustment required for impaired hepatic function
    • Monitor activity with aPTT: Goal = 1.5-2x normal
  • Argatroban – direct thrombin inhibitor – 2mcg/kg/min IV
    • No dose adjustment in isolated renal impairment
    • Dose adjustment required for impaired hepatic function
    • Monitor activity with aPTT: Goal = 1.5-3x normal
  • Fondaparinux – synthetic pentasaccharide subunit of heparin that lacks endogenous interaction with PF4 – 5-10mg/day SQ
    • Not first line for HIT per the 2012 Chest Guidelines,20 but may be an option in patients with hepatic dysfunction (no dosing adjustment for hepatic impairment required)
    • Not for use in patients with renal dysfunction secondary to renal elimination
    • No activity monitoring, non-titrateable

 Laboratory Studies for The Confirmation of HIT 6,9,10,22-24

 If a presumed clinical diagnosis of HIT is made based upon history, physical exam, platelet count, and the 4T score, the following laboratory studies should be ordered as their processing time often requires >48 hours:

  • Immunoassay (ELISA) – HIT antibody testing
    • Sensitivity and specificity of 97.5 and 83.4%6
      • If low, optical density (OD) <0.40, then the diagnosis of HIT is excluded6
      • If high, OD >2.00, then diagnosis of HIT6
      • If intermediate, OD 0.40-2.0, then a functional assay should be ordered by the inpatient team6
  • Functional Assays
    • Serotonin Release Assay – Quantifies the platelet activation capacity of the patient’s serum HIT antibodies
      • Sensitivity and Specificity of > 95%23
    • Heparin Induced Platelet Aggregation (HIPA) – Quantifies platelet aggregation in the presence of heparin (when donor platelets are placed in the platelet poor serum of a patient with suspected HIT) and aggregation in the absence of heparin
      • >90% specific, but lacks sensitivity25

If the Shoe Doesn’t Fit

Remember, HIT evaluation in the emergency department should be based upon clinical suspicion (with the help of the 4T Score). If the patient is thrombocytopenic and bleeding or the platelet count is <10,000, this is not consistent with HIT6 => Broaden your differential diagnosis:

Differential Diagnosis6

  • DIC, Sepsis, Infection
    • Both accompanied by thrombosis
    • DIC also has bleeding AND abnormal coagulation studies – PT, aPTT, low Fibrinogen, Elevated D-Dimer
    • Sepsis – look for marrow suppression – anemia, leukopenia, decreased bone marrow megakaryocytes
  • Immune Thrombocytopenia – ITP
    • Both caused by antibodies – BUT only HIT antibodies activate platelets
    • HIT will resolve without heparin – ITP will persist
  • Post Transfusion Purpura – postpartum patient previously sensitized to platelet antigens during pregnancy
  • Thrombotic Microangiopathy – includes TTP and HUS
    • Fragmented RBC – Schistocytes à Hemolysis AND low platelets
  • Drug Induced Thrombocytopenia – antibiotics, glycoprotein IIb/IIIa inhibitors, quinine
  • Platelet reactive antibodies
  • VTE unrelated to heparin
    • D-Dimer can be a clue
  • Lupus and/or antiphospholipid antibody syndrome
    • Platelet counts <50,000 are rare


  1. HIT is relatively rare, but can occur even after receiving the smallest dose of heparin.
  2. Despite thrombocytopenia, HIT is a prothrombotic state that can cause disastrous vascular complications.
  3. In the ED, clinical history and a CBC can be suggestive of the diagnosis. Use the 4T Score and consult as appropriate.
  4. Suspect HIT? Treatment = stop heparin and discuss an alternative agent for anticoagulation with a hematologist.

References / Further Reading

  1. Hirsh J, Anand S, Halperin L, Fuster V. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001; 21:1094–1096.
  2. Janz T, Hamilton G. Disorders of Hemostasis. 2013. Rosen’s Emergency Medicine (8th ed., 1606–1616). Saunders.
  3. Newman P, Chong B. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood. 2000; 96(1);182.
  4. Napolitano L, Warkentin T, Almahameed A, Nasraway A. Heparin induced thrombocytopeniain the critical care setting: diagnosis and management. Critical Care Medicine. 2014; 34(12):2898–911.
  5. Seybert A, Coons J, Zerumsky K. Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2014; 26(2): 229-41.
  6. Coutre S. Clinical presentation and diagnosis of heparin-induced thrombocytopenia. Up to Date. 2016. Available from: https://www.uptodate.com/contents/clinical-presentation-anddiagnosis-of-heparin-inducedthrombocytopenia?source=search_result&search=heparin+induced+thrombocytopenia&selectedTitle=1%7E150#H369779234
  7. Thong C, Kam P. Heparin-induced thrombocytopenia. Current Anaesthesia & Critical Care.2005; 16(3):143–150.
  8. Brieger D, Mak K, Kottke-Marchant K, Topol E. Heparin-induced thrombocytopenia. Journal of the American College of Cardiology. 1998;31(7):1449–59.
  9. Warkenten T. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost. 1999; 82(2):439.
  10. Warkentin T. How I diagnose and manage HIT. American Society of Hematology Education Book. 2011; 2011(1): 143-149.
  11. Levine R, Hursting M, Drexler A, Lewis B, & Francis L. Heparin-induced thrombocytopenia in the emergency department. Annals of Emergency Medicine. 2014; 44(5):511–515.
  12. Stanton P, Evans J, Lefemine A, et al. White clot syndrome. South Med J 1988; 81:616.
  13. Linkins L, Dans A, Moores L, Bona R, Davidson B, Schulman S, Crowther M. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis; 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2Suppl):e495S.
  14. Hong A, Cook D, Sigouin C, Warkentin T. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Blood. 2003; 101(8):3049ad
  15. LaMonte M, Brown P, Hursting M. Sroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med. 2004; 32(4):976.
  16. Singla A, Amini M, Alpert M, Gornik H. Fatal anaphylactoid reaction associated with heparin-induced thrombocytopenia. Vasc Med. 2013; 18(3):136-138.
  17. Martel N, Lee J, Wells P. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005; 106(8):2710.
  18. Foreman J, Daniels M, Stettner, E. Heparin-induced anaphylactoid reaction associated with heparin-induced thrombocytopenia in the ED. American Journal of Emergency Medicine. 2014; 32(12):1559.e5–1559.e6.
  19. Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, et al. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. Journal of Critical Care. 2014; 29(3): 470.e7–470.e15.
  20. Linkins L, Dans A, Moore L, Bona R, Davidson B, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e495S–530S.
  21. Seybert A, Coons J, Zerumsky K. Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2006: 26(2):229-241.
  22. Levine R, Hursting M, Drexler A, Lewis B, Francis J. Heparin-induced thrombocytopenia in the emergency department. Annals of Emergency Medicine. 2004; 44(5):511–515.
  23. Napolitano L, Warkentin T, Almahameed A, Nasraway S. Heparin induced thrombocytopenia in the critical care setting: diagnosis and management. Crit Care Med. 2006;34(12):2898–2911.
  24. Warkentin T, Sheppard J, Moore J, Sigouin C, Kelton G. Quantitative interpretation of optical density measurements using PF4-dependent enzyme immunoassays. J Thromb Haem2004:6(8);1304-1312.
  25. Thong C, Kam P. Heparin-induced thrombocytopenia. Current Anaesthesia & Critical Care. 2005;16(3):143–150.