What are the non-immune causes of thrombocytopenia?

Non-Immune Causes of Thrombocytopenia

Non-immune thrombocytopenia results from decreased platelet production, sequestration, consumption, or dilution—distinct from antibody-mediated platelet destruction seen in immune thrombocytopenia.

Classification Table of Non-Immune Causes

Mechanism	Specific Causes	Key Clinical Features
Decreased Production	Bone marrow disorders: myelodysplastic syndromes, leukemias, malignancies [1]	Pancytopenia, abnormal blood smear, age >60 years [1]
	Viral infections suppressing marrow [1]	Constitutional symptoms, hepatomegaly [2]
	Inherited thrombocytopenias: thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease [1]	Family history, large platelets on smear [1]
	22q11.2 deletion syndrome [1]	Large platelets, reduced platelet quality [1]
Sequestration	Splenomegaly from any cause [3]	Palpable spleen, portal hypertension [4]
	Liver cirrhosis with portal hypertension [5,4]	Hepatomegaly, ascites, decreased thrombopoietin production [4]
Increased Consumption	Disseminated intravascular coagulation (DIC) [1,5]	Elevated PT/aPTT, low fibrinogen, elevated D-dimer [1]
	Thrombotic microangiopathies (TTP, HUS) [1]	Schistocytes on smear, hemolysis, renal dysfunction [1]
	Heparin-induced thrombocytopenia (HIT) [1]	Moderate thrombocytopenia (30-70 G/L), 5-10 days post-heparin, thrombosis [1]
	Sepsis [2]	Most lethal cause, requires immediate antibiotics [2]
Pregnancy-Related	Gestational thrombocytopenia [1]	Mild (>70,000/μL), most common in pregnancy [1]
	HELLP syndrome [1,6]	Hemolysis, elevated liver enzymes, preeclampsia [1]
	Preeclampsia [1]	Hypertension, proteinuria [1]
Dilutional	Massive transfusion [5]	Recent large-volume blood product administration [5]
Multifactorial	Chronic alcohol abuse [3]	Direct marrow toxicity, folate deficiency, liver disease [3]
	Cyanotic congenital heart disease [1]	Polycythemia, hyperviscosity, platelet count inversely correlates with hematocrit (100,000-150,000/μL) [1]

Diagnostic Algorithm for Non-Immune Thrombocytopenia

Step 1: Exclude Pseudothrombocytopenia

• Repeat platelet count in heparin or sodium citrate tube 6
• Review peripheral blood smear for platelet clumping 1

Step 2: Assess Acuity and Severity

• Obtain previous platelet counts to distinguish acute from chronic 6
• Platelet count >50 × 10³/μL: generally asymptomatic 6
• Platelet count 20-50 × 10³/μL: mild bleeding (petechiae, purpura) 6
• Platelet count <10 × 10³/μL: high risk of serious bleeding 6

Step 3: Emergency Causes Requiring Immediate Hospitalization

• Sepsis: Most lethal, requires immediate empiric antibiotics 2
• HIT: 4T score assessment, anti-PF4 antibodies, stop heparin 1
• Thrombotic microangiopathies: Schistocytes, hemolysis, urgent plasmapheresis consideration 1
• HELLP syndrome: Pregnant patients with hemolysis and elevated liver enzymes 1, 6

Step 4: Identify Mechanism Through Targeted Testing

• Complete blood count with differential: Isolated thrombocytopenia vs. pancytopenia 1
• Peripheral blood smear: Schistocytes (TMA), large platelets (inherited), abnormal white cells (leukemia) 1
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer): Evaluate for DIC 1
• Liver function tests: Assess for cirrhosis and decreased thrombopoietin production 4

Step 5: Bone Marrow Examination Indications

• Age >60 years to exclude myelodysplastic syndromes or leukemia 1
• Systemic symptoms (fever, weight loss, bone pain) 1
• Abnormal blood count beyond isolated thrombocytopenia 1
• Splenomegaly, hepatomegaly, or lymphadenopathy 2
• Atypical peripheral smear findings 1

Critical Pitfalls to Avoid

• Missing sepsis: The most lethal cause requires immediate treatment while completing diagnostic evaluation 2
• Overlooking HIT: Moderate thrombocytopenia 5-10 days post-heparin with thrombosis, not bleeding 1
• Confusing thrombotic conditions with pure bleeding disorders: Antiphospholipid syndrome, HIT, and DIC cause both thrombosis and thrombocytopenia 1, 6
• Assuming isolated thrombocytopenia excludes marrow disorders: Patients >60 years require bone marrow examination regardless of presentation 1
• Delaying bone marrow examination in pancytopenia: Abnormalities beyond isolated thrombocytopenia mandate immediate marrow evaluation 1

Treatment Principles Based on Mechanism

• Platelet transfusion indications: Active hemorrhage or platelet count <10 × 10³/μL 6
• Pre-procedure threshold: Platelet count <50 × 10³/μL requires transfusion before invasive procedures 6
• Activity restrictions: Patients with counts <50 × 10³/μL should avoid trauma 6
• Treat underlying cause: Antibiotics for sepsis 2, stop heparin for HIT 1, antiviral therapy for HCV-related thrombocytopenia 4
• Avoid platelet transfusion in: HIT (worsens thrombosis) 1 and thrombotic microangiopathies (ineffective and potentially harmful) 1