Approach to Thrombocytopenia Usha Perepu, MD Assistant Professor, Internal Medicine 4/18/2017

Disclosure No conflicts of interest associated with this presentation

Learning Objectives Understand the platelet biology and its function Importance of history taking in a patient with thrombocytopenia Identify the common causes of thrombocytopenia and their management

Platelet Biology Platelets are normally produced in the bone marrow from progenitor cells known as megakaryocytes Production stimulated from thrombopoietin Platelet life span: 7-10 days Clearance via macrophages in the RE system 25-35% of platelets located in the spleen Young platelets more active than older platelets Normal platelet count is between 150,000 and 450,000/µL

Platelet Function PLATELET ACTIVATION

Concern for Bleeding In the absence of qualitative platelet dysfunction: >100,000/µL--no increased risk of bleeding 50,000 to 100,000/µL--possible increased risk of bleeding with major trauma or surgery 10,000 to 50,000/µL--increased risk of bleeding with minor trauma or surgery <10,000/µL--increased risk of spontaneous life-threatening bleeding

History and Physical Examination Prior platelet counts History of bleeding Infections, other medical conditions Diet Drug history Family history PE: organomegaly, site of bleeding, evidence of thrombosis New onset, chronic, or relapsing. Disease history with particular reference to autoimmune disorders, infections, malignancies, pregnancy, recent medications and vaccines. Travel ( malaria, rickettsia, dengue fever). Recent transfusions, organ transplantation Alcohol, quinine containing beverages Dietary habits Questions to think about Is the patient bleeding? Do the sites of bleeding suggest a platelet defect? Duration- is thrombocytopenia- acute or chronic? Is there a history of medications, alcohol use or recent transfusion? Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) Heparin exposure- recent of within the past 3 months? Are there risk factors for HIV infection? History of liver disease Is there a family history of thrombocytopenia?

Laboratory Testing CBC: Peripheral blood smear isolated thrombocytopenia Combined anemia and thrombocytopenia Leukocytosis Peripheral blood smear Clumps: Pseudothrombocytopenia Schistocytes: microangiopathic process Leukoerythroblastic picture: bone marrow infiltration Hypersegmented neutrophils: ? B12 deficiency Liver function tests, renal function, coagulation profile, nutrient workup (B12 , folate), viral infections (HIV hepatitis), autoimmune workup, bone marrow biopsy Peripheral blood smear still remains the most important investigation guiding our diagnostic approach to thrombocytopenia

Causes of Thrombocytopenia Decreased production Increased destruction /consumption Sequestration Intoxication ( alcohol) Immune thrombocytopenia Portal hypertension Viral infections (HIV, HCV, EBV, CMV) Thrombotic microangiopathy Infiltrative diseases of the spleen Bone marrow infiltration( leukemia, tumors etc) Post transfusion purpura Radiation/chemotherapy Drug induced ( heparin, quinine etc) Drug induced Nutrient deficiencies (B12, folate, copper) DIC/trauma Hereditary Cardiopulmonary bypass Several causes Can be broadly classified into five categories Pseudo or spurious thrombocytopenia Dilutional Decreased production Increased destruction Altered distribution (increased sequestration)

Hematology Am Soc Hematol Educ Program. 2012;2012:191-7.

Thrombocytopenia in Pregnancy Very common in pregnancy: ~5-10% The most common causes are: Gestational thrombocytopenia (70%) Preeclampsia (21%) ITP (3%)

Gestational Thrombocytopenia Etiology: – Dilutional – decreased platelet production – Increased platelet turnover Occurs later in pregnancy Usually mild thrombocytopenia, >70,000/µL Diagnosis of exclusion……but so is ITP Not associated with adverse events Resolves 1-2 months after delivery Treatment not usually required

Immune Thrombocytopenia (ITP) Children: acute, self-limited Adults: chronic Severe thrombocytopenia due to anti-platelet antibodies Normal or increased numbers of megakaryocytes in bone marrow May be associated with other autoimmune disorders Treated with corticosteroids, IVIG or anti-D immunoglobulin, splenectomy, or rituximab (anti-CD20 monoclonal antibody) Thrombopoietin (TPO) receptor agonists IVIG increases the platelet count by interfering with macrophage uptake of autoantibody-coated platelets (ie, "overwhelming" the reticuloendothelial system)

Thrombotic Thrombocytopenic Purpura (TTP) Syndrome of thrombocytopenia, fever, acute renal insufficiency, CNS dysfunction, and microangiopathic hemolytic anemia Many cases caused by deficiency of vWF-cleaving protease (ADAMTS13) Schistocytes and elevated LDH PT and APTT are usually normal TTP is a medical emergency that is often fatal if not treated urgently with plasma exchange

Hemolytic Uremic Syndrome (HUS) Variant of TTP Predominant renal involvement Often associated with pathogenic E. coli harboring a plasmid encoded Shiga toxin Leading cause of renal failure in children worldwide Not caused by deficiency of ADAMTS13 Treatment is supportive

Drug Induced Immune Thrombocytopenia Several drugs are known to cause thrombocytopenia Mechanism: development of drug dependent Abs against new epitopes of platelet glycoproteins created by their interaction with the drug Presents with moderate to severe thrombocytopenia 2-3 days after drug exposure Resolves spontaneously in 5-10 days after drug discontinuation Can be confused with ITP

Heparin Induced Thrombocytopenia Occurs in 0.5-5% of heparin treated subjects Develops 5-10 days after heparin exposure Antiplatelet Abs cause platelet activation, resulting in increased risk of thrombosis Thrombocytopenia is moderate around 50,000-80,000/µL, rarely < 20,000/µL > 50% drop in platelet count while on heparin Management: calculate 4T score, discontinue heparin and consider alternate anticoagulation, heparin PF4 Ab testing

Algorithm for Workup of Thrombocytopenia Hematology Am Soc Hematol Educ Program. 2012;2012:191-7.