What are the causes of a decreasing platelet count (thrombocytopenia)?

Causes of Decreasing Platelet Count (Thrombocytopenia)

Thrombocytopenia results from four primary mechanisms: decreased bone marrow production, increased peripheral destruction (immune or non-immune), splenic sequestration, and dilution—with the most critical first step being exclusion of pseudothrombocytopenia via peripheral blood smear review before any further workup. 1

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I. Confirm True Thrombocytopenia First

• Pseudothrombocytopenia from EDTA-dependent platelet clumping is a laboratory artifact that mimics true thrombocytopenia and must be excluded immediately by repeating the count in heparin or citrate tubes and reviewing a manual peripheral smear. 1, 2
• Automated counters miss pseudothrombocytopenia in up to 0.1% of samples; never diagnose thrombocytopenia without hematopathologist smear review. 1
• In polycythemia or cyanotic congenital heart disease, increased hematocrit reduces plasma volume, requiring anticoagulant volume adjustment to avoid falsely low counts. 2

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II. Decreased Platelet Production (Bone Marrow Failure)

A. Bone Marrow Suppression

• Chronic alcohol use suppresses megakaryocyte function and platelet production. 1
• Viral infections (HIV, hepatitis C, EBV, CMV) directly suppress bone marrow platelet production. 1
• Medications including chemotherapy, valproic acid, and certain antibiotics cause dose-dependent marrow suppression. 1
• Nutritional deficiencies such as vitamin B12 or folate deficiency (megaloblastic anemia) produce large platelets with elevated mean platelet volume (MPV) and platelet distribution width (PDW). 3

B. Bone Marrow Infiltration or Failure

• Myelodysplastic syndromes (MDS) and leukemias impair megakaryocyte function; bone marrow examination is mandatory in patients ≥60 years to exclude these. 1
• Aplastic anemia produces pancytopenia without lymphadenopathy. 1
• Metastatic solid tumors or lymphoproliferative disorders infiltrate marrow and cause thrombocytopenia with systemic symptoms (fever, weight loss, bone pain). 1

C. Inherited Thrombocytopenias

• MYH9-related disease, Wiskott-Aldrich syndrome, and thrombocytopenia-absent radius (TAR) syndrome affect platelet production; giant platelets or leukocyte inclusion bodies on smear are diagnostic clues. 1
• 22q11.2 deletion syndrome causes characteristically lower platelet counts with large platelets and reduced platelet quality. 1

D. Cirrhosis and Liver Disease

• Reduced thrombopoietin production in cirrhosis decreases platelet production; 80% of cirrhotic patients have platelet counts below normal, though severe thrombocytopenia (<50 × 10⁹/L) is uncommon in compensated disease. 4
• Bone marrow suppression from underlying liver disease (alcohol, viral hepatitis) further reduces production. 4

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III. Increased Platelet Destruction

A. Immune-Mediated Destruction

1. Primary Immune Thrombocytopenia (ITP)

• Primary ITP is an autoimmune disorder with antibody-mediated destruction of otherwise normal platelets; diagnosis requires exclusion of all secondary causes. 1
• In children, ITP typically follows viral infection and two-thirds recover spontaneously within 6 months. 1
• In adults, ITP has insidious onset without preceding illness and follows a chronic course. 1
• Physical exam is normal except for bleeding manifestations; splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP. 1

2. Secondary Immune Thrombocytopenia

• HIV-associated thrombocytopenia can be clinically indistinguishable from primary ITP and may precede other HIV manifestations by years; HIV testing is mandatory in all adults with suspected ITP. 1
• Hepatitis C virus (HCV) causes thrombocytopenia that may appear years before other symptoms; successful antiviral therapy can lead to complete hematologic remission. 1
• H. pylori infection causes ITP in endemic regions; eradication therapy can normalize platelet counts. 1
• Autoimmune diseases (systemic lupus erythematosus, antiphospholipid syndrome) cause secondary ITP with other systemic features. 1
• Lymphoproliferative disorders (chronic lymphocytic leukemia, lymphoma) cause secondary ITP; flow cytometry on bone marrow is useful for detection. 1

3. Drug-Induced Immune Thrombocytopenia

• Antibiotics (vancomycin, cefazolin, oxacillin, clindamycin, doxycycline, SMX-TMP), GPIIb-IIIa inhibitors, quinine, and sulfonamides cause drug-dependent antibody formation with onset typically 5–14 days after exposure. 1
• Heparin-induced thrombocytopenia (HIT) presents 5–10 days after heparin exposure with moderate thrombocytopenia (30–70 × 10⁹/L) and paradoxical thrombosis risk; calculate the 4T score immediately and discontinue all heparin if score ≥4. 1
• Drug-dependent platelet antibody testing requires specialized immunoassays and samples collected during the acute episode or within 3 weeks, as antibodies disappear rapidly. 1

B. Non-Immune Destruction

1. Thrombotic Microangiopathies (TMA)

• Thrombotic thrombocytopenic purpura (TTP) causes platelet consumption through microvascular thrombosis with schistocytes on smear; untreated mortality exceeds 90%, requiring urgent ADAMTS13 activity testing. 1
• Hemolytic uremic syndrome (HUS) and disseminated intravascular coagulation (DIC) consume platelets within widespread fibrin clot formation; coagulation studies (PT, aPTT, fibrinogen, D-dimers) are essential. 1
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnancy requires emergency hospitalization. 5

2. Consumption Thrombocytopenia

• Extracorporeal circuits, intra-aortic balloon pumps, and cardiac surgery with cardiopulmonary bypass cause mechanical platelet consumption. 1
• Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding. 1

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IV. Splenic Sequestration

• Portal hypertension in cirrhosis causes hypersplenism and platelet sequestration; thrombocytopenia severity correlates with splenomegaly and portal pressure. 4
• Functional hyposplenism or post-splenectomy states paradoxically cause thrombocytosis, not thrombocytopenia. 6

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V. Dilutional Thrombocytopenia

• Massive transfusion or fluid resuscitation dilutes circulating platelets without affecting production or destruction. 7

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VI. Essential Diagnostic Algorithm

Step 1: Exclude Pseudothrombocytopenia

• Repeat platelet count in heparin or citrate tube and obtain manual smear review by hematopathologist. 1, 2

Step 2: Obtain Complete Blood Count with Differential

• Isolated thrombocytopenia (normal hemoglobin and WBC) suggests ITP, drug-induced, or splenic sequestration. 1
• Pancytopenia (low hemoglobin, WBC, and platelets) suggests bone marrow failure, aplastic anemia, or marrow infiltration. 1

Step 3: Review Peripheral Blood Smear

• Schistocytes → TTP, HUS, or DIC; urgent ADAMTS13, LDH, haptoglobin, and coagulation studies required. 1
• Giant platelets (approaching RBC size) → inherited thrombocytopenias (MYH9-related, Bernard-Soulier). 1
• Leukocyte inclusion bodies → MYH9-related disease. 1
• Immature or abnormal WBCs → leukemia or MDS; bone marrow examination mandatory. 1

Step 4: Mandatory Infectious Disease Testing in All Adults

• HIV antibody testing – HIV-associated thrombocytopenia mimics primary ITP. 1
• Hepatitis C virus serology – HCV can cause thrombocytopenia years before other symptoms. 1
• H. pylori testing (urea-breath or stool antigen) – eradication can normalize platelet counts. 1

Step 5: Assess for Heparin-Induced Thrombocytopenia

• Calculate 4T score in any patient who received heparin within the past 3 months. 1
• If 4T score ≥4, discontinue all heparin immediately and obtain anti-PF4 antibody testing; initiate non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux) without awaiting results. 1

Step 6: Bone Marrow Examination Indications

• Mandatory in: age ≥60 years, systemic symptoms (fever, weight loss, bone pain), abnormal CBC beyond isolated thrombocytopenia, atypical smear findings (schistocytes, immature cells, giant platelets), splenomegaly/hepatomegaly/lymphadenopathy, or prior to splenectomy. 1
• Not required in patients with typical ITP features (isolated thrombocytopenia, normal physical exam, no systemic symptoms). 1
• When performed, obtain both aspirate and core biopsy; include flow cytometry and cytogenetic studies. 1

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VII. Critical Pitfalls to Avoid

• Never diagnose thrombocytopenia without personal smear review, as automated counters miss pseudothrombocytopenia, giant platelets, and schistocytes. 1
• Never omit HIV and HCV testing in adults, as these infections masquerade as primary ITP. 1
• Missing TTP, HIT, or DIC carries high mortality risk (untreated TTP >90% mortality; HIT thrombosis risk 30–50%); prompt exclusion is essential. 1
• Presence of splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP; pursue alternative diagnoses aggressively. 1
• Do not delay bone marrow examination in patients ≥60 years, as MDS and leukemia have catastrophic mortality if missed. 1