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).
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
||Naphthalene (mothballs, deodorizers)
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).
Important laboratory tests:
- 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.
- 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).
- 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.
- 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.
- 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).
- 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).
- 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).
- 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).
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.
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