Functional Platelet Disorders

Diagnosis

Indications for Testing

  • Easy bruisability
  • Frequent ecchymoses
  • Family history of bleeding disorders

Laboratory Testing

  • 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
  • First rule out more common causes of platelet-type bleeding (eg, VWD, acquired platelet dysfunction)
  • Further testing with platelet aggregation studies
    • 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 be free of any medications that affect platelet function (eg, aspirin, NSAIDs) to be sure that any abnormalities observed are due to an underlying intrinsic qualitative platelet disorder and not medication effect

Inherited Platelet Disorders – Diagnosis

Disorder

Diagnosis

Bernard-Soulier syndrome

Platelet count – decreased; giant-sized platelets (increased mean platelet volume [MPV])

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

Aggregation studies – failure to aggregate with ristocetin; normal aggregation with other agonists (except low concentrations of thrombin – abnormal)

Platelet flow cytometry – decreased expression of GPIb/IX/V (CD42b); flow cytometry may be normal with qualitative defects of CD42b

Genetic sequencing of GPIb/IX

von Willebrand disease (VWD)

Platelet count and morphology – normal in most subtypes

Aggregation studies – normal

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

Initial testing for VWD includes VWD 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 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 – no response to epinephrine, adenosine 5'-diphosphate (ADP), collagen, arachidonic acid, or thrombin; normal aggregation to ristocetin (Note: Patients with afibrinogenemia will have a similar aggregation profile)

Platelet flow cytometry – decreased expression of GPIIb/IIIa (CD41/CD61); flow cytometry may be normal with qualitative defects of GPIIb/IIIa

Abnormal clot retraction (testing not widely available)

Oculocutaneous albinism (Hermansky-Pudlak syndrome)

Platelet count and morphology – normal

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

Aggregation studies – see delta storage pool deficiency below

Wiskott-Aldrich syndromePlatelet count and morphology – decreased number and abnormal platelets

Gray-platelet syndrome (alpha granule deficiency)

Platelet count and morphology – decreased number and abnormal morphology

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 secretin 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 dense granules

Differential Diagnosis

  • Other causes of platelet-type bleeding
    • Thrombocytopenia
    • Antiplatelet medications – non-steroidal anti-inflammatory drugs (NSAIDs), acetyl salicylic acid (ASA), Plavix
    • Myeloproliferative neoplasms or lymphoproliferative disorders
    • Macrothrombocytopenias with neutrophilic inclusions (MYH9 disorders)
      • May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome
    • Thrombocytopenia with small platelets (X-linked thrombocytopenia)
  • Oculocutaneous albinism
    • Griscelli syndrome
    • Waardenburg syndrome II

Clinical Background

Platelet dysfunction is frequently associated with excessive bleeding (frequently mucosal) and 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 a life span of 5-10 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

Inherited Platelet Disorders – Clinical Presentation

Disorder

Defect

Clinical Presentation

Bernard-Soulier syndrome

Autosomal recessive

Deficiency or dysfunction of platelet GPIb-IX-V complex (adhesion disorder)

Epistaxis, ecchymoses, menorrhagia, gingival hemorrhage, gastrointestinal bleeding

Pseudo-von Willebrand disease (VWD) (platelet-type VWD)

Autosomal dominant

Gain of function of platelet GPIb-IX-V complex – resembles VWD type 2B (adhesion disorder)

Epistaxis, ecchymoses, menorrhagia, gingival hemorrhage

Glanzmann thrombasthenia

Autosomal recessive

Deficiency of dysfunction of platelet glycoprotein IIb-IIIa (aggregation disorder)

Menorrhagia, ecchymoses, epistaxis, gingival hemorrhage

Hermansky-Pudlak syndrome (plus oculocutaneous albinism)

Autosomal recessive

Scarce or absent granules (storage pool disorder)

Oculocutaneous albinism, excessive mucosal bleeding, deposition of ceroid lipofuscin in organs, pulmonary fibrosis

Chediak-Higashi syndrome (plus oculocutaneous albinism, neutropenia, increased infections)

Autosomal recessive

Scarce or absent granules (storage pool disorder)

Oculocutaneous albinism, recurrent infections, loss of pigment in hair and skin, central nervous system ataxia common, excessive mucosal bleeding
Wiskott-Aldrich syndrome X-linkedDecreased small platelets, few alpha granules, lack delta granulesEczema, recurrent infections, severe bleeding

Gray-platelet syndrome (alpha storage pool disease)

Usually autosomal recessive

Decreased alpha granules (storage pool disorder)

Mild mucosal bleeding, myelofibrosis, splenomegaly

Delta storage pool deficiency (dense granule deficiency)

Autosomal dominant; autosomal recessive in association with some syndromes listed above

Abnormal or decreased dense granules (storage pool disorder)

May occur alone or as a component of other hereditary disorders (see above)

Mucosal bleeding

If part of a hereditary syndrome, features of the syndrome will also be present

Other disordersOther potential functional platelet disorders include defects of glycoprotein IV, glycoprotein Ia/IIa, glycoprotein VI, adenosine 5'-diphosphate or other surface receptors, signal transduction, or platelet procoagulant activityRange from mild mucosal bleeding to more severe bleeding problems

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count 0040002
Method: Automated Cell Count

Identify thrombocytopenia

   
Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Identify other potential causes for bleeding disorder

   
Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Identify other potential causes for bleeding disorder

   
Platelet Aggregation Studies 0030160
Method: Aggregation

Evaluate patients with suspected inherited qualitative platelet disorders and with normal CBC

Evaluate patients with lifelong platelet-type bleeding

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 Panel 0030137
Method: Electromagnetic Mechanical Clot Detection/Radial Immunodiffusion

Identify other etiologies for bleeding

   
von Willebrand Panel 0030125
Method: Clotting/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Rule out VWD

Panel includes VWD antigen, ristocetin cofactor activity and factor VIII activity