What are the causes of thrombocytopenia (low platelet count)?

Causes of Thrombocytopenia

Major Mechanistic Categories

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

Decreased Platelet Production

Bone marrow disorders are the most critical category to exclude, as they carry the highest mortality risk:

• Myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and require urgent identification, particularly in patients over 60 years 1, 3
• Aplastic anemia and megaloblastic anemia directly affect platelet production 3
• Bone marrow fibrosis disrupts normal platelet generation 3
• Viral infections (HIV, hepatitis C, EBV) suppress bone marrow platelet production 1, 2

Inherited thrombocytopenias include thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome (which characteristically presents with large platelets) 1, 2, 3

Increased Platelet Destruction

Immune-mediated destruction:

• Primary immune thrombocytopenia (ITP) is an autoimmune disorder causing immunologic destruction of otherwise normal platelets—this is a diagnosis of exclusion 1, 2, 3
• Secondary immune thrombocytopenia associates with:
  • Autoimmune diseases (antiphospholipid syndrome, systemic lupus erythematosus) 1, 2, 3
  • Infections (HIV, hepatitis C, H. pylori) 1, 2
  • Lymphoproliferative disorders 1, 2, 3
  • Common variable immune deficiency 1
  • Recent vaccinations 1, 3
  • Bone marrow transplantation 1

Drug-induced thrombocytopenia must always be considered and may be difficult to exclude—blood samples for drug-dependent antibody testing should be collected during the acute episode or within 3 weeks, as antibodies disappear rapidly 1, 2

Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction that typically presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation, and paradoxically causes thrombosis despite low platelets 1, 4

Thrombotic microangiopathies:

• TTP-HUS, disseminated intravascular coagulation (DIC), and antiphospholipid syndrome cause both thrombocytopenia and thrombosis 1, 2
• HELLP syndrome and preeclampsia in pregnancy 1

Splenic Sequestration

Hepatic disease with portal hypertension leads to splenomegaly and platelet sequestration 1, 5

Pregnancy-Related Causes

• Gestational thrombocytopenia is the most common cause in pregnancy, typically mild (>70 × 10⁹/L) 1
• Preeclampsia/HELLP syndrome requires emergency recognition 1
• ITP in pregnancy must be distinguished from gestational thrombocytopenia 1

Special Populations

Cyanotic congenital heart disease causes thrombocytopenia through polycythemia and hyperviscosity, triggering platelet consumption—platelet counts inversely correlate with hematocrit levels, typically resulting in mild thrombocytopenia (100,000-150,000/μL) 1

Critical Red Flags Suggesting Alternative Diagnoses to ITP

The following findings mandate immediate expanded workup:

• Lymphadenopathy, splenomegaly, or hepatomegaly suggest lymphoproliferative disorders, infections, or malignancy 1, 2, 3
• Constitutional symptoms (fever, weight loss, bone pain) indicate underlying infection or malignancy 1, 2
• Abnormal hemoglobin, white blood cell count, or white cell morphology suggest bone marrow pathology 1, 2
• Non-petechial rash points away from ITP 1
• Schistocytes on peripheral smear indicate thrombotic microangiopathy 1

Essential Diagnostic Algorithm

Step 1: Confirm true thrombocytopenia

• Exclude pseudothrombocytopenia by examining peripheral blood smear for EDTA-dependent platelet clumping—collect blood in heparin or sodium citrate tube and repeat count 1, 2, 5

Step 2: Distinguish acute from chronic

• Review previous platelet counts to determine acuity 5

Step 3: Assess bleeding severity

• Platelet count >50 × 10⁹/L: generally asymptomatic 5
• Platelet count 20-50 × 10⁹/L: mild skin manifestations (petechiae, purpura, ecchymosis) 5
• Platelet count <10 × 10⁹/L: high risk of serious bleeding 5

Step 4: Mandatory testing for all adults with suspected ITP

• HIV and hepatitis C testing in all adults with typical ITP presentation 1, 2, 3
• H. pylori screening as eradication therapy can resolve thrombocytopenia 1, 3

Step 5: Determine need for bone marrow examination

Bone marrow examination is mandatory when:

• Age >60 years (to exclude myelodysplastic syndromes, leukemias, malignancies) 1, 2, 3
• Systemic symptoms present (fever, weight loss, bone pain) 1, 3
• Abnormal blood count parameters beyond isolated thrombocytopenia 1, 3
• Atypical peripheral smear findings 1
• Splenectomy is being considered 1, 3
• Minimal or no response to first-line ITP therapies 1

Bone marrow examination is NOT necessary when:

• Typical ITP features in patients <60 years with isolated thrombocytopenia, normal physical exam except bleeding manifestations, and no systemic symptoms 1, 2, 3

Common Diagnostic Pitfalls

• Missing drug-induced thrombocytopenia: Always obtain detailed medication history including over-the-counter drugs, herbal supplements, and recent medication changes 1, 2
• Overlooking HIT: Evaluate with 4T score (degree of thrombocytopenia, timing, thrombosis, other causes) in any patient with heparin exposure in past 100 days 1, 4
• Failing to test for secondary causes: HIV, HCV, and H. pylori testing must be performed even when ITP seems obvious 1, 2, 3
• Relying solely on platelet count in older patients: Age >60 years mandates bone marrow examination regardless of how typical the presentation appears 1
• Missing inherited thrombocytopenias: Family history and platelet size on smear provide critical clues 1