What is the differential diagnosis (Ddx) of platelet aggregation disorder?

Differential Diagnosis of Platelet Aggregation Disorders

Platelet aggregation disorders encompass both inherited and acquired defects affecting platelet function, which can be systematically categorized based on the underlying pathophysiologic mechanism: glycoprotein receptor defects, granule storage deficiencies, signaling pathway abnormalities, and arachidonic acid metabolism defects.

Major Categories of Platelet Aggregation Disorders

Glycoprotein Receptor Defects

• Glanzmann thrombasthenia is caused by quantitative or qualitative defects in integrins αIIb and β3 (GPIIb/IIIa), presenting with severe mucocutaneous bleeding and absent platelet aggregation to all agonists except ristocetin 1
• Bernard-Soulier syndrome results from defects in GPIb/IX complex, identifiable through flow cytometry screening using antibodies against GPIb and GPIb/IX (CD42b and CD42a) 2
• Flow cytometry screening should be performed using antibodies against major platelet glycoproteins (GPIIb/IIIa, GPIIIa, GPIb, GPIb/IX) to identify these specific receptor defects 2

Storage Pool Disorders (SPD)

• δ-storage pool disease (δ-SPD) involves dense granule deficiency and can be rapidly detected by flow cytometry using mepacrine labeling, with affected patients showing significantly reduced labeling (5-23%) compared to normal controls (32-64%) 3
• Gray Platelet Syndrome presents with α-granule deficiency, requiring assessment of granule release (α and δ granules) to detect these secretion defects 2
• Combined α-δ granule defects represent a distinct entity requiring specific diagnostic evaluation through transmission electron microscopy for counting α-granules and dense-granules 2

Signaling Pathway Defects

• P2Y12 receptor defects impair ADP-mediated platelet activation and require expanded light transmission aggregometry (LTA) with additional agonists for diagnosis 2
• These defects may show normal platelet counts but abnormal platelet function, necessitating functional testing beyond simple platelet enumeration 2

Arachidonic Acid Pathway Defects

• Aspirin-like defect (ALD) is caused by defects in intraplatelet arachidonic acid metabolism, diagnosed by absent aggregation to arachidonic acid (maximal aggregation ≤10%) 4
• Cyclooxygenase-1 deficiency and thromboxane synthase deficiency represent specific enzymatic defects in the arachidonic acid pathway 2
• Serum thromboxane B2 measurement by ELISA or RIA can detect these arachidonic acid pathway defects 2

Acquired Platelet Aggregation Disorders

• Drug-induced platelet dysfunction from aspirin, NSAIDs, quinidine, heparin, sulfonamides, sulfonylureas, dipiridamol, and salicylates must be excluded through careful medication history 2, 5
• Myeloproliferative and myelodysplastic disorders (MPD/MDS) frequently cause acquired δ-SPD, with 7/15 patients showing reduced mepacrine staining in one study, though platelet aggregation patterns may be normal 3
• Uremia, liver disease, and paraproteinemias can cause acquired platelet dysfunction requiring clinical correlation 6

Syndromic Platelet Disorders

• Wiskott-Aldrich syndrome presents with small (not large) platelets and thrombocytopenia, distinguishing it from other inherited platelet disorders 2
• Other syndromic disorders may have non-blood phenotypic features and increased predisposition to myelodysplasia and leukemia 6

Critical Diagnostic Pitfalls

• EDTA-induced pseudothrombocytopenia occurs in approximately 0.1% of adults due to platelet agglutinins causing aggregation in EDTA anticoagulant, requiring peripheral blood smear examination to identify platelet clumping 5
• Abnormal platelet aggregation patterns are not specific for storage pool deficiency—3/7 patients with normal aggregation had δ-SPD, while 4/8 with abnormal aggregation had normal dense granules 3
• The bleeding time test should be explicitly excluded from diagnostic algorithms due to insufficient specificity and sensitivity 2
• Repeat platelet studies should be separated by at least 1 month to allow disappearance of acquired interfering factors 2

Diagnostic Algorithm Priority

First-line testing should combine light transmission aggregometry (LTA) with standard agonists (ADP, collagen, epinephrine, ristocetin, arachidonic acid) and flow cytometry screening on resting platelets using antibodies against GPIIb/IIIa, GPIIIa, GPIb, and GPIb/IX, which can diagnose up to 40% of inherited platelet function disorders 2

Second-line testing for undiagnosed cases includes expanded LTA panel, mepacrine labeling by flow cytometry for dense granule assessment, serum thromboxane B2 measurement, and transmission electron microscopy 2, 3