What is Thrombocytopenia?
Thrombocytopenia is a platelet count below the lower limit of the normal laboratory range—typically defined as <150 × 10⁹/L—resulting from decreased platelet production, increased destruction, splenic sequestration, or dilution. 1, 2, 3
Definition and Laboratory Thresholds
- The standard definition uses a cutoff of <150 × 10⁹/L, though the exact lower limit varies slightly by laboratory reference ranges. 1, 2
- A platelet count below this threshold does not automatically indicate disease; the clinical significance depends on the degree of reduction, underlying cause, and presence of bleeding. 3, 4
Mechanisms of Thrombocytopenia
Thrombocytopenia arises through four principal pathophysiologic mechanisms:
Decreased Platelet Production
- Bone marrow disorders—including myelodysplastic syndromes, leukemias, aplastic anemia, and metastatic malignancies—impair megakaryocyte function and reduce platelet output. 5
- Chronic alcohol use, certain medications, viral infections (HIV, hepatitis C, parvovirus B19), and iron overload suppress bone marrow platelet production. 5, 6
- Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth. 5
Increased Platelet Destruction
- Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated destruction of otherwise normal platelets, diagnosed only after excluding secondary causes. 5, 3
- Secondary immune thrombocytopenia occurs with autoimmune diseases (systemic lupus erythematosus), viral infections (HIV, hepatitis C), lymphoproliferative disorders, and drug-induced mechanisms. 5
- Drug-induced thrombocytopenia can result from heparin (causing heparin-induced thrombocytopenia), GP IIb/IIIa inhibitors, quinine, sulfonamides, and many other medications. 1, 5
- Thrombotic microangiopathies—including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC)—consume platelets through widespread microvascular thrombosis. 5, 2
Splenic Sequestration
- Portal hypertension from cirrhosis induces hypersplenism, leading to platelet sequestration; approximately 80% of cirrhotic patients have platelet counts below normal, though severe thrombocytopenia (<50 × 10⁹/L) is uncommon in compensated disease. 5
- Reduced thrombopoietin production in cirrhosis further compounds the thrombocytopenia. 5
Dilution
- Massive transfusion or fluid resuscitation dilutes circulating platelets, causing transient thrombocytopenia. 3, 7
Clinical Severity and Bleeding Risk
The risk of bleeding correlates imperfectly with platelet count; additional factors—including age, comorbidities, platelet function, and concurrent antiplatelet medications—modify hemorrhagic risk. 8, 3
Mild Thrombocytopenia (50–150 × 10⁹/L)
- Patients are typically asymptomatic and discovered incidentally during routine blood counts. 8, 2, 3
- No activity restrictions are required at this level. 5
Moderate Thrombocytopenia (20–50 × 10⁹/L)
- Cutaneous bleeding manifestations appear: petechiae, purpura, ecchymoses, and easy bruising. 8, 2, 3
- Patients should avoid contact sports and activities that increase trauma risk. 5, 8, 2
- Medications that impair platelet function—aspirin and NSAIDs—must be avoided because they increase bleeding risk even at moderate platelet counts. 5, 8
Severe Thrombocytopenia (<20 × 10⁹/L)
- High risk of serious bleeding, including gastrointestinal hemorrhage and intracranial hemorrhage. 8, 2, 3
- Platelet counts <10 × 10⁹/L carry the highest bleeding risk and typically require hospitalization and urgent treatment. 5, 3
- In immune thrombocytopenia, the risk of intracranial hemorrhage is approximately 0.1–0.5% in children and 1.5% in adults, with most events occurring within the first 5 weeks of diagnosis. 5, 8
Critical Paradox: Thrombosis Despite Low Platelets
Certain thrombocytopenic conditions paradoxically increase thrombotic risk rather than bleeding risk:
- Heparin-induced thrombocytopenia (HIT) typically presents with moderate thrombocytopenia (30–70 × 10⁹/L) occurring 5–10 days after heparin initiation and is associated with a 30–50% risk of thrombosis. 1, 5, 2
- Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding. 1, 5
- Thrombotic microangiopathies (TTP, HUS) consume platelets through microvascular clotting, producing organ ischemia; untreated TTP carries >90% mortality. 5, 2, 3
- In cancer patients with thrombocytopenia, venous thromboembolism risk is not reduced despite low platelet counts, and prolonged thrombocytopenia (>30 days) is associated with a greater than four-fold increased risk of recurrent VTE. 2
Diagnostic Approach
Initial Evaluation
- Obtain a complete blood count with differential to determine whether thrombocytopenia is isolated or part of pancytopenia. 5, 3, 6
- Peripheral blood smear review by a hematopathologist is mandatory to exclude pseudothrombocytopenia (EDTA-dependent platelet clumping, occurring in ~0.1% of samples), identify giant platelets (suggesting inherited thrombocytopenias), detect schistocytes (indicating thrombotic microangiopathy), and assess red and white cell morphology. 5, 3, 6, 4
Mandatory Testing in Adults with Suspected ITP
- HIV antibody testing in all adults, because HIV-associated thrombocytopenia can be clinically indistinguishable from primary ITP and may precede other manifestations by years. 5
- Hepatitis C virus serology in all adults, as chronic HCV can cause thrombocytopenia that resolves with antiviral therapy. 5
- Helicobacter pylori testing (urea-breath test or stool antigen) in adults, especially in high-prevalence regions, because eradication normalizes platelet counts in a subset of ITP patients. 5
When to Perform Bone Marrow Examination
Bone marrow aspiration and biopsy are not required in patients with typical ITP features but become mandatory in the following situations: 5
- Age ≥60 years (to exclude myelodysplastic syndrome, leukemia, or other malignancies)
- Systemic constitutional symptoms (fever, unexplained weight loss, night sweats, bone pain)
- Abnormal CBC parameters beyond isolated thrombocytopenia (anemia, leukopenia, leukocytosis)
- Atypical peripheral smear findings (schistocytes, immature cells, giant platelets, leukocyte inclusion bodies)
- Splenomegaly, hepatomegaly, or lymphadenopathy on physical exam (these findings exclude primary ITP)
- Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, anti-D)
- Prior to splenectomy in chronic ITP
Common Pitfalls
- Never diagnose thrombocytopenia without reviewing the peripheral blood smear, as automated counters miss pseudothrombocytopenia, giant platelets, and schistocytes. 5
- Never skip HIV and HCV testing in adults with suspected ITP, even in low-risk populations, because these infections can masquerade as primary ITP for years. 5
- Missing HIT, TTP, or DIC carries high mortality risk (untreated TTP >90% mortality; HIT thrombosis risk 30–50%); prompt exclusion of these entities is essential. 5
- Presence of splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes (HIV, lupus, lymphoproliferative disorders, chronic liver disease). 5