EM@3AM: Idiopathic Thrombocytopenic Purpura

Author: Sean O’Hara, MD (EM Attending Physician, San Antonio, TX) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 72-year-old male presents with chief complaint of fatigue. He states that he has been having gradually worsening fatigue over the past several months, but noticed in the last couple of days that he has been too tired to complete his normal activities. He sometimes has prolonged bleeding when he brushes his teeth. He denies weight loss, night sweats, or any other symptoms apart from his fatigue. He has no significant past medical or surgical history, takes no medications, and was never a smoker or a drinker.

Initial VS include T 36.2, HR 67, BP 125/70, RR 18, SpO2 96% RA.

Exam reveals a well appearing elderly male without signs of distress. Exam is unremarkable except for one hemorrhagic bullae on his oral mucosa. He has no lymphadenopathy or hepatosplenomegaly.

What do you think is going on with this patient? What are the next steps in management?

Answer: Immune Thrombocytopenic Purpura (ITP)

• Background:
  • Acquired, isolated thrombocytopenia (platelet count <100 x 10³/µL).
  • Up to one-third of patients are asymptomatic, but ITP can be associated with serious bleeding events.
  • Important to exclude more dangerous causes of thrombocytopenia.
  • Mortality for patients with ITP is not significantly increased compared to baseline.
  • Thought to be caused by autoimmune production of antibodies, which leads to destruction of platelets by splenic macrophages.
  • Types of ITP:
    • Primary: Platelet destruction not associated with another condition.
    • Secondary: Platelet destruction associated with another condition. Referred to as “secondary ITP (associated condition),” with common conditions including HIV, HCV, SLE, etc. This is essentially due to cross reactivity from antibodies against the secondary condition.
  • Duration of symptoms:
    • Acute: 0-12 months from diagnosis.
    • Chronic: longer than 12 months from diagnosis.
  • Adult:
    • Often chronic.
    • Usually primary (80%).
    • Prevalence 9-12 per 100,000 population.
    • Predominantly female in younger patients; even distribution in elderly patients.
  • Pediatric:
    • Often acute with high likelihood of spontaneous remission (80% with remission within 6 months).
    • Usually secondary to viral infections; can also be caused by MMR vaccine.
    • Prevalence 5-8 per 100,000 population.
    • For infants, males more common; equal M:F after. Most less than 8 years old.

• Evaluation: Important to exclude other causes of thrombocytopenia.
  • History: Most often patients are asymptomatic. Most common complaints will be minor bleeding when brushing teeth, frequent nose bleeds, skin rashes (petechiae, purpura, ecchymosis), or generalized fatigue. Ask regarding recent infections. Elicit signs of intracranial bleeding – acute headache, vision changes, somnolence. Ask regarding other serious sources of bleeding – hemoptysis, hematuria, hematochezia. Determine if recent trauma. Obtain past medical hx, surgical hx, medication lists, family hx, social hx, recent vaccine administration (MMR).
  • Exam: Typically, patients appear healthy. Detailed skin, mucosa, and lymph node exam is important. Petechiae, ecchymoses, and purpura are commonly found in dependent areas. Purpura may be divided into dry (on skin) vs. wet (hemorrhagic bullae on mucosal surfaces). Wet purpura is regarded a predictor of more serious bleeding. Purpura typically not pruritic nor palpable in ITP. Epistaxis may occur, but it is typically not life threatening. Presence of lymphadenopathy or hepatosplenomegaly should NOT be found in ITP and requires consideration of more serious causes of thrombocytopenia. Neurologic exam is needed, looking for signs of ICH (asymmetric findings, unequal pupils, ataxia, headache, altered mental status) or signs of other serious bleeding (signs of gross hemoptysis, hematuria, hematochezia).
  • Obtain:
    • Labs – CBC, BMP, LFTs, Type/Rh, peripheral blood smear, coagulation studies, pregnancy test, direct antigen (Coombs) test, HIV, HCV. H. Pylori testing no longer recommended in U.S.
    • Imaging studies – Not typically needed for diagnosis of ITP, unless concerned with major internal bleeding.

• Differential Diagnosis: Infections (EBV, HIV, HCV, H. Pylori etc.), drug induced thrombocytopenia (HIT, quinine, Bactrim, etc.), hereditary thrombocytopenia, liver disease, microangiopathic disorders (TTP, HUS, DIC, etc.), nutrient deficiencies, pregnancy (HELLP, gestational thrombocytopenia), cancer (leukemia, lymphoma), myelodysplasia, aplastic anemia, systemic lupus erythematosus, rheumatoid arthritis.
• Grading Bleeding: Bleeding occurs in 2/3 of patients with ITP. Vast majority is skin or mucosal bleeding. Skin bleeding is characterized as mild bleeding, while mucosal bleeding or hemodynamically stable internal bleeding is characterized as moderate bleeding. Severe bleeding defined as intracranial bleeding or any unstable bleeding (from gastrointestinal, pulmonary, menstrual, or epistaxis sources). Severe bleeding occurs in approximately 10% of adult patients and 3% of pediatric patients (with intracranial bleeding occurring in 1% and 0.5% of adult and pediatric patients, respectively).
  • Multiple scoring systems exist that attempt to predict which mild or moderate bleeding will lead to severe bleeding.
  • WHO Scale: Classic scale used. Developed for chemotherapy induced bleeding, has limited utility for ITP, and only grossly grades bleeding.
    • Graded 0 through 4: 0 (no bleeding), 1 (petechiae), 2 (mild blood loss), 3 (gross blood loss), 4 (debilitating blood loss).
  • ITP-BAT (ITP-specific bleeding assessment tool):
    • Score assigned based on presence of bleeding in three domains: Skin, Mucosa, or Organs (internal bleeding – GI, pulmonary, hemarthroses, intracranial, etc.).
    • Ranked between 0 and 5 with varied definitions for rankings in each domain. For skin domain the maximum score is 3, corresponding to greater than 50 petechiae or more than 5 palm-sized ecchymoses. In the mucosa and organ domains the score ranges from 0 (no bleeding observed) to 4 (bleed with a 2g/dL Hgb drop) to 5 (fatal hemorrhage).
    • Report the highest grade in each domain as a SMOG index. If the grades were 1,1,2 for skin, mucosa, organs respectively, then the SMOG index would be S1M1O2.
    • Goal to characterize bleeding, eventual aim is to be able to predict which types of bleeding lead to severe bleeding in the future.

• Management: If asymptomatic or mild bleeding (only skin symptoms) and PLT > 30 x 10³/µL, most patients do not require acute treatment. Goal of treatment isn’t to normalize PLT, but instead ensure safe platelet count that prevents further serious bleeding.
  • Platelet Transfusion:
    • Typically will result in destruction of transfused PLT by same destructive mechanisms, i.e. transfusion will not significantly raise the PLT count.
    • Only recommended in severe bleeding.
    • Appears to be more effective when combined with immunosuppressive therapy.
  • First Line Treatments:
    • Corticosteroids: Preferred first line therapy. Prednisone 1mg/kg/day PO, or methylprednisolone 15mg/kg/day IV if not PO tolerant (switch to prednisone as soon as able, typically by day 4). Classically have used long course (21 days prednisone followed by taper). Some evidence that high dose dexamethasone (40mg/day for 4 days) confers similar benefit without long term steroid risks.
    • IVIG: Used if need increased PLT count for surgical procedure or if severe bleeding present. Most rapid rise in PLT count (within 48 hrs) but limited long term effect (lasts up to 6 weeks). Administered in dose of 1g/kg IV; can be repeated as needed daily.
    • Anti-RhD: Effective in patients who are Rh+ and still have their spleens. Dose of 50mcg/kg IV. Can cause hemolytic anemia; avoid in patients with positive direct antigen test. Close monitoring is needed. Thought to occupy spleen in clearing coated RBCs, instead of spleen destroying platelets.
  • Second Line Treatments:
    • Splenectomy: Removes site of platelet destruction/some antibody creation. Usually delayed 6-12 months to determine if spontaneous resolution will occur. Can be used in acute severe bleeding if other treatments not improving. Prefer to obtain pre-operative immunizations vs. encapsulated organisms, raise PLT over 50 x 10³/µL. Case reports of splenic embolectomy as bridge until able to raise PLT count for splenectomy. Overall increase in rates of venous thromboembolism and overwhelming infection, although these increases are low.
    • Rituximab: Monoclonal antibody against B cells. Used for patients with inadequate responses to steroids plus splenectomy, or if they are not candidates for splenectomy.
    • Thrombopoietin receptor agonists (TPO-RAs): Induce bone marrow to produce platelets. Causes delayed increase in PLT count (7-14 days). Used for severe bleeding, in patients not responding to splenectomy plus rituximab, or patients not suitable for other second line treatments. Most commonly used agent is romiplostim, injected once weekly.
    • TXA and factor VIIa: can be used in cases with severe bleeding not controlled by mechanisms above.
  • Treatment Considerations:
    • If severe bleeding present, typically all first line medications given to patient and platelets transfused, with addition of romiplostim.
    • If secondary ITP, typically most effective to treat primary disorder.

• Disposition:
  • Depends on platelet count and presence of severe bleeding:
    • PLT < 30 x 10³/µL:
      • Consult Hematology.
      • If signs of life threatening bleeding (ICH, unstable GI, unstable pulmonary): Resuscitate, initiate treatment for ITP.
      • Admit to Hospital: Need for further workup, evaluate for mimics.
    • PLT > 30 x 10³/µL:
      • Consult Hematology: To determine if inpatient/outpatient workup.
      • Inpatient: Risk factors for severe bleeding (prior severe bleeding, recent trauma, etc.).
      • Outpatient: No risk factors for severe bleeding. Counsel to avoid extreme sports if PLT < 50 x 10³/µL and avoid antiplatelet agents unless medically necessary.

A 3-year-old girl is brought in after her mother noticed a rash and bruising over her trunk and extremities. She also has intermittent epistaxis over the past few days. She had an upper respiratory illness two weeks ago but otherwise is well. Examination reveals a well-appearing child with scattered petechiae. Hemoglobin is 12 g/dL, WBC 8,000, INR 1.0, and platelets 8,000. Which of the following is the most appropriate initial treatment?

A. Corticosteroids and intravenous immunoglobulin

B. Observation

C. Platelet transfusion

D. Splenectomy

Answer: A

The child has idiopathic thrombocytopenic purpura (ITP), an acquired autoimmune disorder that results in platelet destruction. It often follows a viral illness and is more common in children than adults. It is characterized by thrombocytopenia in the absence of other bone marrow pathology. Signs and symptoms include petechiae, purpura, and gingival bleeding. Management depends on degree of thrombocytopenia and presence of bleeding, and should be performed in consultation with a hematologist. In general, patients with platelet count of 10,000-20,000 µL and mucosal bleeding or those with platelet counts < 10,000 µL and no bleeding are treated with corticosteroids or intravenous immunoglobulin (IVIG) or both. Asymptomatic patients with platelets > 20,000µL can be observed, as the condition is often self-limited.

Observation (B) is indicated for asymptomatic patients with platelets > 20,000/µL. Platelet transfusion (C) is only indicated for life-threatening bleeding after administration of IVIG and steroids. Splenectomy (D) is rarely required for ITP and is only considered in refractory cases.

Rosh Review Website Link

FOAMed:

1. http://www.emdocs.net/immune-thrombocytopenic-purpura-pearls-pitfalls/
2. http://pedemmorsels.com/itp-immune-thrombocytopenia-purpura/

References:

1. Lambert MP, Gernsheimer TB (2017). “Clinical updates in adult immune thrombocytopenia.” Blood. 129:2829-2835.
2. Neunert C et al (April 2011). “The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.” 117(16):4190-4207.
3. Page LK et al (2007). “The immune thrombocypoenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP.” British Journal of Haematology. 138: 245-248.
4. Rodeghiero F et al (2013). “Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group.” Blood.121: 2596-2606.
5. Osman ME (2012). “Childhood immune thrombocytopenia: clinical presentation and management.” Sudan J Paediatr.12(1): 27-39.
6. Farhangi H (2016). “Clinical features and treatment outcomes of primary immune thrombocytopenic purpura in hospitalized children under 2-years old.” Iran J Ped Hematol Oncol. 6(1): 24-31.