Functional Platelet Disorders

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Lifelong history of
    • Easy bruisability
    • Frequent ecchymoses
  • Family history of bleeding disorders
  • Unexplained thrombocytopenia in infants and children

Laboratory Testing

  • Rule out more common causes of platelet-type bleeding (eg, VWD, acquired platelet dysfunction)
  • Initial testing – CBC with platelet count and peripheral smear to evaluate platelet morphology and size indices; basic coagulation tests (PT, PTT, fibrinogen)
    • Bleeding time not recommended – invasive, highly dependent on operator, lacks sensitivity and specificity
  • Further testing using platelet aggregation studies when functional disorders are suspected
    • Platelet aggregation studies must be performed locally due to requirement for fresh patient platelets and limited sample stability (~4 hours stability)
    • Prior to testing, the patient should have discontinued any medications that affect platelet function (eg, aspirin, other NSAIDs) to assure that any abnormalities observed are due to an underlying intrinsic qualitative platelet disorder and not medication effect
More Common Inherited Platelet Disorders – Diagnosis
Disorder Diagnosis

Bernard-Soulier syndrome

Platelet count – decreased

Peripheral smear – giant platelets (similar in size to red blood cells)

Aggregation studies – failure to aggregate with high-dose ristocetin; normal aggregation with other agonists (note: patients with severe von Willebrand disease may have a similar aggregation profile)

Platelet flow cytometry – glycoprotein (GP) Ib/IX/V (CD42b) is absent or dysfunctional; flow cytometry may be normal with qualitative defects of GP Ib/IX/V

von Willebrand disease (VWD)

Platelet count and morphology – normal in most subtypes

Aggregation studies – may be normal, have reduced aggregation with high-dose ristocetin, or have abnormally increased aggregation with low-dose ristocetin, depending on subtype. Platelet aggregation is not considered first-line testing for VWD

VWD due to quantitative or qualitative defects in von Willebrand factor (VWF) rather than an intrinsic platelet defect

Initial testing for VWD includes VWF antigen, VWF activity (ristocetin cofactor activity), and factor VIII activity

Multimeric analysis used for subtyping after initial diagnosis; ristocetin-induced platelet aggregation useful in certain cases for subtyping but is not sensitive to mild forms of VWD

Pseudo-VWD (platelet-type) has similar clinical and laboratory features to type 2B VWD; they are differentiated by VWF:PB (platelet binding) assay (also called type 2B binding) or molecular studies

Glanzmann thrombasthenia

Platelet count and platelet morphology – normal

Aggregation studies – absent or markedly decreased response to epinephrine, adenosine diphosphate (ADP), collagen, arachidonic acid, or thrombin; aggregation to ristocetin present (Note: Patients with afibrinogenemia will have a similar aggregation profile)

Platelet flow cytometry – GP IIb/IIIa (CD41/CD61) is absent or dysfunctional; flow cytometry may be normal with qualitative defects of GP IIb/IIIa

Abnormal clot retraction (testing not widely available)

Oculocutaneous albinism (Hermansky-Pudlak syndrome)

Platelet count and morphology – normal

Electron microscopy – decreased or absent dense granules

Aggregation studies – see delta storage pool deficiency below

Chediak-Higashi syndrome

Platelet count and morphology – normal

Peripheral blood/marrow smears – abnormal granules in blood and marrow leukocytes

Electron microscopy – decreased or absent dense granules

Aggregation studies – see delta storage pool deficiency below

Wiskott-Aldrich syndrome

Platelet count and morphology – decreased number and abnormal platelets (small)

Gray-platelet syndrome (alpha granule deficiency)

Platelet count – decreased number

Peripheral smear – large gray (agranular) platelets; must be distinguished from acquired agranular platelets due to ongoing platelet activation

Aggregation studies – variable aggregation abnormalities; tend to have abnormal platelet secretion induced by ADP/collagen, modified thrombin responses

Electron microscopy – decreased alpha granules

Delta storage pool deficiency (dense granule deficiency)

Platelet count and morphology – normal

Aggregation studies – absent secondary wave in response to ADP and epinephrine; possible decreased aggregation to collagen and ristocetin; can stimulate secondary wave response to ADP by using high concentrations of ADP; aggregation studies may be normal in some patients

Electron microscopy – decreased or absent dense granules

Differential Diagnosis

  • Thrombocytopenia
    • Inherited thrombocytopenias
      • Macrothrombocytopenia with neutrophilic inclusions (MYH9 disorders)
        • May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome
        • Thrombocytopenia with small platelets (X-linked thrombocytopenia)
    • Decreased platelet production due to bone marrow disorders (eg, ALLAMLMDS)
    • Increased platelet destruction
      • Immune causes
      • Nonimmune causes (mechanical destruction)
      • Platelet sequestration in spleen
  • Antiplatelet medications – nonsteroidal anti-inflammatory drugs (NSAIDs), acetyl salicylic acid (aspirin, ASA), clopidogrel bisulfate (Plavix)
  • Myeloproliferative neoplasms or lymphoproliferative disorders
  • Oculocutaneous albinism
    • Griscelli syndrome
    • Waardenburg syndrome II

Platelet dysfunction is frequently associated with excessive bleeding, frequently mucosal or post trauma/surgery. It can be acquired or inherited.

Epidemiology

  • All inherited disorders are rare
  • Age – onset depends on disorder

Risk Factors

  • Acquired conditions
  • Genetics – family history of inherited disorders

Pathophysiology

  • Platelets originate from bone marrow megakaryocytes and have an average life span of ~10 days
  • Normal platelet function
    • Maintain vascular integrity and prevent prolonged bleeding
    • Circulate in close contact with endothelial cells
    • Adhere to blood vessel wall after vascular injury
      • Adhesion activates platelets, causing recruitment of additional platelets to site
      • Recruited platelets aggregate to form temporary platelet plug (the initial seal that stops bleeding)
  • Abnormalities in platelet function involve adhesion defects, release defects (granule deficiency or signal transduction defects) and aggregation abnormalities

Clinical Presentation

  • Acquired disorders include the following

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

CBC with Platelet Count 0040002
Method: Automated Cell Count

Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Platelet Aggregation Studies 0030160
Method: Qualitative Aggregation

Limitations

This is a time-sensitive test – this test is only available for local clients due to 4-hour sample stability

Do not order this test if platelets are decreased (<100,000/μL)

Fibrinogen 0030130
Method: Electromagnetic Mechanical Clot Detection

von Willebrand Panel 0030125
Method: Electromagnetic Mechanical Clot Detection/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Platelet Surface Glycoprotein Expression (PGE) by Flow Cytometry, Whole Blood 2013070
Method: Qualitative Flow Cytometry

Limitations

Dysfunctional platelet defects but normal expression of platelet glycoprotein cannot be detected

General References

Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet. 2012; 131(12): 1821-32. PubMed

Daly ME, Leo VC, Lowe GC, Watson SP, Morgan NV. What is the role of genetic testing in the investigation of patients with suspected platelet function disorders? Br J Haematol. 2014; 165(2): 193-203. PubMed

Favaloro EJ, Lippi G, Franchini M. Contemporary platelet function testing. Clin Chem Lab Med. 2010; 48(5): 579-98. PubMed

Freson K, Wijgaerts A, van Geet C. Update on the causes of platelet disorders and functional consequences. Int J Lab Hematol. 2014; 36(3): 313-25. PubMed

Hayward CP M. Diagnostic evaluation of platelet function disorders. Blood Rev. 2011; 25(4): 169-73. PubMed

Mezzano D, Quiroga T, Pereira J. The level of laboratory testing required for diagnosis or exclusion of a platelet function disorder using platelet aggregation and secretion assays. Semin Thromb Hemost. 2009; 35(2): 242-54. PubMed

Miller JL. Glycoprotein analysis for the diagnostic evaluation of platelet disorders. Semin Thromb Hemost. 2009; 35(2): 224-32. PubMed

Nurden AT, Fiore M, Pillois X, Nurden P. Genetic testing in the diagnostic evaluation of inherited platelet disorders. Semin Thromb Hemost. 2009; 35(2): 204-12. PubMed

Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders. Haemophilia. 2012; 18 Suppl 4: 154-60. PubMed

Nurden AT, Nurden P. Congenital platelet disorders and understanding of platelet function. Br J Haematol. 2014; 165(2): 165-78. PubMed

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014; 36(3): 269-78. PubMed

Medical Reviewers

Last Update: January 2016