What are the causes of thrombocytopenia in a general adult population?

Causes of Thrombocytopenia

Major Mechanistic Categories

Thrombocytopenia results from four primary mechanisms: decreased platelet production, increased platelet destruction, splenic sequestration, and dilution. 1, 2, 3

Decreased Platelet Production

• Bone marrow disorders including myelodysplastic syndromes, leukemias, lymphomas, and other malignancies directly impair megakaryocyte function and platelet production. 1, 2, 3
• Aplastic anemia and megaloblastic anemia (from B12 or folate deficiency) reduce platelet production through global marrow failure or ineffective hematopoiesis. 2
• Bone marrow suppression occurs with chronic alcohol use, certain medications (chemotherapy, antibiotics, diuretics), viral infections (HIV, hepatitis C, EBV, CMV), and iron overload. 4, 1
• Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome cause congenital platelet production defects. 1, 2, 3

Increased Platelet Destruction

Immune-Mediated Destruction

• Primary immune thrombocytopenia (ITP) is an autoimmune disorder with antibody-mediated destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes. 1, 2, 3
• Secondary immune thrombocytopenia occurs with:
  • Autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome) 1, 3
  • Viral infections (HIV, hepatitis C, which may precede other symptoms by years) 1, 3
  • Lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas) 1, 3
  • Common variable immune deficiency 1
  • H. pylori infection 1
  • Drug-induced thrombocytopenia (heparin, quinine, sulfonamides, many others) 4, 1, 3
  • Recent vaccinations or bone marrow transplantation 1, 2

Non-Immune Destruction

• Heparin-induced thrombocytopenia (HIT) typically presents with moderate thrombocytopenia (30-70 G/L, rarely <20 G/L) occurring 5-10 days after heparin initiation, paradoxically associated with thrombosis rather than bleeding. 4, 1
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC) cause platelet consumption through microvascular thrombosis. 4, 1, 3
• Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding. 4, 1
• Sepsis and trauma are the most common causes of thrombocytopenia in ICU patients, with platelet consumption from systemic inflammation and microvascular injury. 5

Pregnancy-Related Causes

• Gestational thrombocytopenia is the most common cause in pregnancy, presenting with mild thrombocytopenia (platelet count >70,000/μL) without other complications. 1
• Preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) causes severe thrombocytopenia requiring emergency management. 1, 6

Splenic Sequestration

• Liver disease with portal hypertension causes splenomegaly and pooling of up to 90% of circulating platelets in the enlarged spleen. 1, 7
• Cyanotic congenital heart disease triggers thrombocytopenia through polycythemia and hyperviscosity, with platelet counts inversely correlating with hematocrit levels. 1

Dilutional Thrombocytopenia

• Massive transfusion or fluid resuscitation dilutes circulating platelets without affecting production or destruction. 6, 8

Critical Diagnostic Distinctions

Pseudothrombocytopenia

• EDTA-dependent platelet agglutination falsely lowers automated platelet counts and must be excluded first by examining the sample tube for clots, reviewing the peripheral smear for platelet clumps, and repeating the count in citrate or heparin tubes. 4, 1, 3

Red Flags for Alternative Diagnoses

• Splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for lymphoproliferative disorders, liver disease, or infections. 1, 3
• Constitutional symptoms (fever, weight loss, bone pain) suggest underlying malignancy, infection, or systemic disease rather than primary ITP. 1, 3
• Abnormalities beyond isolated thrombocytopenia (anemia not from blood loss, leukopenia, abnormal white cell morphology, schistocytes) require bone marrow examination to exclude myelodysplasia, leukemia, or thrombotic microangiopathy. 1, 3

Essential Diagnostic Algorithm

Initial Evaluation

• Confirm true thrombocytopenia by peripheral blood smear review to exclude pseudothrombocytopenia and identify platelet clumping, large platelets, or abnormal cells. 1, 2, 3
• Complete blood count with differential distinguishes isolated thrombocytopenia from pancytopenia, which suggests bone marrow failure or infiltration. 1, 2, 3
• Detailed medication history identifies potential drug-induced causes, including over-the-counter medications, herbal supplements, and recent heparin exposure. 4, 1, 3

Mandatory Testing for Secondary Causes

• HIV and hepatitis C testing is recommended in all adults with suspected ITP, as these infections can be clinically indistinguishable from primary ITP and may precede other symptoms by years. 1, 2, 3
• H. pylori testing should be considered, as eradication therapy can resolve thrombocytopenia in infected patients. 1
• Coagulation studies (PT, aPTT, fibrinogen, D-dimers) evaluate for DIC, which can coexist with severe thrombocytopenia. 4, 1

When Bone Marrow Examination Is Mandatory

• Age >60 years requires bone marrow examination to exclude myelodysplastic syndromes, leukemias, or other malignancies regardless of other features. 1
• Systemic symptoms (fever, weight loss, bone pain) necessitate bone marrow evaluation to exclude underlying disorders. 1
• Abnormal blood count parameters beyond isolated thrombocytopenia (unexplained anemia, leukopenia, abnormal white cell morphology) mandate bone marrow examination. 1
• Atypical peripheral smear findings (schistocytes, leukocyte inclusion bodies, dysplastic features) require bone marrow evaluation. 1
• Treatment-refractory cases with minimal or no response to first-line ITP therapies warrant bone marrow examination to exclude alternative diagnoses. 1

Special Considerations for HIT

• 4T score assessment evaluates clinical probability based on: degree of thrombocytopenia (typically 30-70 G/L, rarely <20 G/L), timing (5-10 days after heparin initiation), presence of thrombosis (venous or arterial), and absence of other causes. 4, 1
• Anti-PF4 antibody testing should be performed immediately when clinical probability is intermediate or high based on the 4T score. 4, 1

Common Pitfalls to Avoid

• Missing pseudothrombocytopenia by failing to review the peripheral smear leads to unnecessary workup and treatment. 1, 3
• Overlooking drug-induced thrombocytopenia by not obtaining a comprehensive medication history, including over-the-counter drugs and herbal supplements. 1, 3
• Assuming elevated immature platelet fraction (IPF) confirms ITP, as severe ITP can present with low IPF, and age >60 years mandates bone marrow examination regardless of IPF. 1
• Delaying bone marrow examination in older patients (>60 years) based on typical ITP features, as the mortality risk of missed myelodysplasia or leukemia outweighs procedural morbidity. 1
• Failing to test for HIV and hepatitis C in all adults with suspected ITP, as these infections require specific treatment and alter prognosis. 1, 2, 3