What is the diagnosis and treatment approach for thrombocytopenia (low platelet count)?

Differential Diagnosis of Thrombocytopenia

The differential diagnosis of thrombocytopenia requires systematic evaluation starting with confirmation of true thrombocytopenia by peripheral blood smear to exclude pseudothrombocytopenia from platelet clumping, followed by categorization based on whether thrombocytopenia is isolated or associated with other abnormalities. 1

Initial Diagnostic Steps

Confirm True Thrombocytopenia

• Examine the peripheral blood smear immediately to exclude pseudothrombocytopenia, which occurs in approximately 0.1% of adults due to platelet clumping in EDTA tubes 1
• If pseudothrombocytopenia is suspected, redraw blood in heparin or sodium citrate tubes and repeat the platelet count 2
• Obtain a complete blood count with differential to assess for other cytopenias that narrow the differential diagnosis 1

Assess Clinical Context

• Determine if thrombocytopenia is isolated or associated with other abnormalities (cytopenias, coagulation disorders, abnormal renal/liver tests), as this fundamentally changes the differential diagnosis 3
• Evaluate bleeding symptoms including petechiae, purpura, ecchymosis, mucosal bleeding, and severity of hemorrhage 1
• Patients with platelet counts >50 × 10³/μL are generally asymptomatic; counts between 20-50 × 10³/μL may show mild skin manifestations; counts <10 × 10³/μL carry high risk of serious bleeding 2

Major Diagnostic Categories

Immune-Mediated Thrombocytopenia

Primary Immune Thrombocytopenia (ITP)

• Most likely diagnosis in patients with isolated thrombocytopenia in the absence of systemic illness 2
• Diagnosis remains one of exclusion after ruling out other causes 4
• Characterized by accelerated platelet destruction and suppressed platelet production due to multiple humoral and cellular immune abnormalities 4
• Bone marrow examination should be performed in patients with persistent thrombocytopenia lasting >6-12 months or those unresponsive to IVIG, but is not required before initiating IVIG therapy 5

Drug-Induced Immune Thrombocytopenia

• Second most common cause in patients with isolated thrombocytopenia 2
• Critical to obtain detailed medication history including heparin, quinidine, sulfonamides, GPIIb-IIIa inhibitors, and chemotherapy agents 5, 1
• GPIIb-IIIa glycoprotein inhibitors in acute coronary syndromes can cause early and often profound thrombocytopenia 5

Post-Transfusion Purpura

• Linked to alloimmunisation with typically major and sudden decrease in platelets in hemorrhagic context 5
• Diagnosis is urgent given risk of severe bleeding and need for specific treatment 5

Heparin-Induced Thrombocytopenia (HIT)

Apply the 4T Score for Clinical Probability Assessment 5, 1

The 4T score assigns 0-2 points for each of four criteria:

1. Thrombocytopenia severity: Platelet count typically 30-70 × 10⁹/L, rarely <20 × 10⁹/L; ≥50% drop from baseline scores 2 points; <30% drop or count <10 × 10⁹/L scores 0 points 5

2. Timing: Onset 5-10 days after heparin initiation scores 2 points; earlier onset if heparin exposure within previous 3 months scores 1 point 5

3. Thrombosis: Presence of venous/arterial thromboembolic events or other clinical events associated with thrombocytopenia; some practitioners recommend systematic Doppler ultrasound of lower limbs as thromboses may be asymptomatic 5

4. Other causes: Most difficult to evaluate; non-heparin drug-related or transfusional thrombocytopenia is often more severe than HIT and complicated by bleeding rather than thrombosis 5

Total score interpretation: ≤3 = low probability; 4-5 = intermediate probability; ≥6 = high probability 5

Special consideration: In cardiac surgery patients with cardiopulmonary bypass, a "biphasic" evolution profile of platelet count is equivalent to a 4T score of 6 with high HIT probability 5

Thrombocytopenia with Thrombosis

When thrombocytopenia is associated with venous or arterial thrombotic complications, consider these aetiologies beyond HIT: 5

• Antiphospholipid syndrome 5, 1
• Thrombotic thrombocytopenic purpura (TTP) 5
• Disseminated intravascular coagulation (DIC): Measure D-dimer and fibrinogen assay 1
• Cancer-associated pseudo-HIT: Thrombocytopenia and thrombosis can occur in cancer patients 5
• Vaccine-induced immune thrombocytopenia and thrombosis (VITT): Assess vaccination history, particularly COVID-19 vaccines 1

Perioperative and Critical Care Causes

Common in intensive care and post-surgical patients: 5

• Perioperative haemodilution and platelet consumption in extracorporeal circuits or intra-aortic balloon counterpulsation 5
• Consumption thrombocytopenia at end of cardiac surgery, ventricular assistance, or renal replacement therapy 5
• Sepsis-associated thrombocytopenia 3

Cancer-Associated Thrombocytopenia

Assess etiology systematically: 5

• Chemotherapy-induced: Often transient with predictable nadir 5
• Bone marrow infiltration: Requires bone marrow examination 1
• Immune thrombocytopenia secondary to malignancy 5
• Thrombotic microangiopathy 5
• Myelodysplastic syndrome (MDS): Consider in patients with familial cases of myelodysplasia or acute myeloid leukemia 5

Inherited Platelet Function Disorders

Consider when: 5

• Unexplained or extensive bruising, epistaxis, menorrhagia, bleeding during childbirth or after procedures 5
• Family history of bleeding or thrombocytopenia 1
• Associated syndromic features: hearing loss, heart/face/bone dysmorphisms, ocular involvement, mental retardation, skin discoloration 5
• Use bleeding assessment tool (BAT) to assess symptom severity 5

First-step laboratory tests include: 5

• Blood smear for altered platelet size/structure
• Light transmission aggregometry with epinephrine, ADP, collagen, arachidonic acid, and ristocetin
• Assessment of platelet granule release (ATP/ADP and α-granule markers)
• Flow cytometry for major platelet surface glycoproteins

Pregnancy-Associated Thrombocytopenia

• Occurs in 7-10% of pregnancies 6
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) requires emergency hospitalization 2

Infectious Causes

• HIV testing recommended for patients with risk factors 5, 1
• Various viral and bacterial infections can cause thrombocytopenia 6

Emergency Situations Requiring Immediate Intervention

The following require urgent hospitalization and/or referral to reference center: 3

• Active bleeding 3
• Biological signs of disseminated intravascular coagulation 3
• Acute renal failure 3
• Platelet count <30 × 10⁹/L (or <50 × 10⁹/L if patient on anticoagulation/antiplatelet therapy) 3
• Significant and/or sudden onset pancytopenia 3
• Thrombotic microangiopathy 2, 6
• HELLP syndrome 2

Laboratory Evaluation Algorithm

Initial Laboratory Tests 1

• Complete blood count with differential
• Peripheral blood smear examination
• Prothrombin time and activated partial thromboplastin time

Additional Tests Based on Clinical Suspicion 1

• D-dimer and fibrinogen for suspected DIC
• HIV testing for patients with risk factors
• Bone marrow examination for persistent thrombocytopenia, abnormal cells on peripheral smear, or high suspicion for malignancy
• HIT antibody testing when 4T score indicates intermediate or high probability
• Antiplatelet antibodies when ITP is suspected
• Liver and renal function tests to assess for hepatic disease or renal insufficiency

Common Pitfalls to Avoid

• Never assume thrombocytopenia has a single cause; multiple pathologies may coexist, particularly in intensive care patients 1
• Do not delay bone marrow examination when clinically indicated, especially with high suspicion for malignancy 1
• Do not overlook drug-induced causes, particularly heparin, quinidine, and sulfonamides 1
• Do not assume all thrombocytopenia with low counts requires treatment; many patients, especially children with ITP, can be safely managed with observation alone if asymptomatic 7
• Recognize that thrombocytopenia can paradoxically present with thrombosis in conditions like HIT, antiphospholipid syndrome, and TMA 2