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

Causes of Low Platelets (Thrombocytopenia)

Low platelet counts result from four primary mechanisms: decreased production, increased destruction, splenic sequestration, or dilution, with immune thrombocytopenia (ITP) and drug-induced thrombocytopenia being the most common causes in otherwise healthy patients with isolated thrombocytopenia. 1

Primary Mechanisms of Thrombocytopenia

Thrombocytopenia is defined as a platelet count below 150 × 10⁹/L and occurs through distinct pathophysiologic processes 2, 3:

Decreased Platelet Production

• Bone marrow failure or suppression from aplastic anemia, myelodysplastic syndromes, or leukemia 4
• Chemotherapy or radiation exposure causing myelosuppression 5
• Nutritional deficiencies including vitamin B12 or folate deficiency 3
• Viral infections affecting bone marrow function 3

Increased Platelet Destruction

Immune-mediated destruction:

• Primary immune thrombocytopenia (ITP) - autoimmune destruction of platelets with platelet counts typically <100 × 10⁹/L in the absence of other identifiable causes 1
• Secondary ITP associated with autoimmune diseases (particularly antiphospholipid antibody syndrome), viral infections (hepatitis C, HIV), and certain drugs 1
• Drug-induced thrombocytopenia from medications including heparin, antibiotics, diuretics, and chemotherapy agents 1, 2
• Heparin-induced thrombocytopenia (HIT) - a prothrombotic condition with thrombocytopenia typically occurring 5-10 days after heparin initiation, with platelet counts usually between 30-70 × 10⁹/L and rarely below 20 × 10⁹/L 1

Non-immune destruction:

• Disseminated intravascular coagulation (DIC) with consumption of platelets and coagulation factors 1, 3
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) 1, 2
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnancy 2

Splenic Sequestration

• Portal hypertension and cirrhosis causing splenomegaly with platelet sequestration 1
• Hypersplenism from any cause of splenic enlargement 3

Dilution and Other Causes

• Massive transfusion diluting existing platelet counts 3
• Pregnancy-related thrombocytopenia 1

Critical Diagnostic Considerations

Exclude Pseudothrombocytopenia First

In stable outpatients, the initial step is to exclude pseudothrombocytopenia by collecting blood in heparin or sodium citrate tubes and repeating the platelet count 2. Laboratory artifacts from EDTA-induced platelet clumping can falsely lower platelet counts 2.

Distinguish Acute from Chronic

Review previous platelet counts to determine if thrombocytopenia is acute or chronic, as this fundamentally changes the differential diagnosis and urgency of evaluation 2:

• Acute thrombocytopenia (developing over days): Consider HIT, thrombotic microangiopathies, HELLP syndrome, acute ITP, or drug-induced causes 2, 6
• Chronic thrombocytopenia (present >6 months): More likely chronic ITP, liver disease, or bone marrow disorders 1

Essential Initial Testing

• Complete blood count with differential to identify isolated thrombocytopenia versus other cytopenias 1, 2
• Peripheral blood smear examination to assess platelet size, identify schistocytes (suggesting microangiopathy), evaluate red and white cell morphology, and confirm true thrombocytopenia 1, 2, 4

Key smear findings in ITP: Normal to large platelets, normal red cell morphology, normal white cell morphology (though atypical lymphocytes and eosinophilia may occur in children) 1

Findings NOT consistent with ITP: Red cell schistocytes, giant platelets approaching red cell size, leukocytosis/leukopenia with immature cells 1

Clinical Presentation by Severity

Bleeding risk correlates with platelet count 2:

• >50 × 10⁹/L: Generally asymptomatic 2
• 20-50 × 10⁹/L: Mild skin manifestations (petechiae, purpura, ecchymosis) 2
• <10 × 10⁹/L: High risk of serious bleeding including intracranial hemorrhage 2

Important Caveat

Some conditions present with both thrombocytopenia AND thrombosis rather than bleeding, including antiphospholipid syndrome, heparin-induced thrombocytopenia, and thrombotic microangiopathies 2. Do not assume all thrombocytopenic patients are at bleeding risk only.

Specific Causes Requiring Emergency Recognition

Heparin-Induced Thrombocytopenia (HIT)

Use the 4T score to assess pretest probability 1:

• Thrombocytopenia: >50% drop from peak (2 points); 30-50% drop or nadir 10-19 × 10⁹/L (1 point)
• Timing: 5-10 days after heparin start or <1 day if recent heparin exposure (2 points)
• Thrombosis: New thrombosis or skin necrosis (2 points)
• Other causes: No other explanation (2 points); possible other cause (1 point)

Score interpretation: 6-8 = high probability; 4-5 = intermediate; 0-3 = low probability 1

Thrombotic Microangiopathies

Look for the pentad of thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on smear), neurologic changes, renal dysfunction, and fever 2.

HELLP Syndrome

Consider in any pregnant or recently postpartum patient with thrombocytopenia, elevated liver enzymes, and hemolysis 2.

Special Populations

Pediatric Considerations

In children with typical ITP features (isolated thrombocytopenia, normal smear), bone marrow examination is unnecessary 1. Bone marrow is also not required before corticosteroid treatment, after IVIg failure, or before splenectomy in children with typical features 1.

Patients with Liver Disease

Thrombocytopenia in cirrhosis results from multiple mechanisms: splenic sequestration from portal hypertension, decreased thrombopoietin production, and potentially increased platelet destruction 1. The platelet count often reflects disease severity rather than bleeding risk 1.

Cyanotic Heart Disease

Thrombocytopenia occurs in cyanotic congenital heart disease through multiple mechanisms: polycythemia-induced consumption, DIC-like states, and decreased platelet survival 1. Platelet counts inversely correlate with hematocrit levels 1.

Treatment Principles Based on Cause

Immune Thrombocytopenia (ITP)

Treatment is indicated only for patients with active bleeding, severe thrombocytopenia with bleeding risk, or need for invasive procedures—not to normalize platelet counts 5, 7.

First-line therapy for pediatric ITP requiring treatment: Single dose IVIg (0.8-1 g/kg) or short course of corticosteroids 1. IVIg produces more rapid platelet increase 1.

Children with no bleeding or only mild bleeding (skin manifestations) should be observed regardless of platelet count 1.

Second-line options for refractory ITP: Thrombopoietin receptor agonists (romiplostim, eltrombopag), rituximab, fostamatinib, or splenectomy 1, 7. Splenectomy should be delayed at least 12 months unless severe disease is present 1.

Drug-Induced Thrombocytopenia

Discontinue the offending agent immediately 2. Recovery typically occurs within days to weeks after drug cessation.

Heparin-Induced Thrombocytopenia

Stop all heparin immediately and initiate alternative anticoagulation with a non-heparin agent 1. Do not use warfarin alone initially due to increased thrombosis risk 1.

Platelet Transfusion Indications

Transfuse platelets for:

• Active hemorrhage regardless of platelet count 1
• Platelet count <10 × 10⁹/L even without bleeding 1, 2
• Before high-risk procedures when platelets <50 × 10⁹/L 1

Important limitation: In liver disease, prophylactic platelet transfusions to prevent procedural bleeding lack evidence of benefit and carry transfusion-related risks 1. Many procedures can be performed safely at lower platelet counts with on-demand management of bleeding if it occurs 1.