Functional Platelet Disorders


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



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

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 – no response to epinephrine, adenosine 5'-diphosphate (ADP), collagen, arachidonic acid, or thrombin; aggregation to ristocetin present (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

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 syndromePlatelet 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
      • Macrothrombocytopenias 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, ALL, AML, MDS)
    • 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

Clinical Background

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


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

Risk Factors

  • Acquired conditions
  • Genetics – family history of inherited disorders


  • 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

  • Inherited platelet disorders – autosomal recessive

    Inherited Platelet Disorders – Autosomal Recessive



    Clinical Presentation

    ADP receptor defect

    Aggregation defect


    Bernard-Soulier syndrome

    Adhesion disorder with deficiency or dysfunction of platelet GPIb-IX-V complex

    GP1BA, GP1BB, GP9

    Epistaxis, ecchymoses, menorrhagia, gingival hemorrhage, gastrointestinal bleeding

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

    Storage pool disorder with scarce or absent granules

    LYST (previously known as CHS1)

    Oculocutaneous albinism, recurrent infections, loss of pigment in hair and skin, central nervous system ataxia common, excessive mucosal bleeding
    Collagen receptor defect

    Aggregation defect


    Normal platelet count

    Congenital amegakaryocytic thrombocytopenia

    Lack of megakaryocyte precursors with elevated thrombopoietin


    Progressive bone marrow failure

    Severe thrombocytopenia

    No physical anomalies

    Cystosolic phospholipase A2α deficiency

    Aggregation defect and delta-storage pool disorder


    Ghosal hematodiaphyseal dysplasia syndrome

    Aggregation defect for arachidonic acid


    Increased bone density
    Glanzmann thrombasthenia

    Aggregation disorder with deficiency of dysfunction of platelet glycoprotein IIb-IIIa


    Menorrhagia, ecchymoses, epistaxis, gingival hemorrhage

    Gray-platelet syndrome (alpha storage pool disease)

    Also autosomal dominant

    Storage pool disorder with decreased alpha granules


    Mild mucosal bleeding, myelofibrosis, splenomegaly

    Hermansky-Pudlak syndrome (types 1 and 9)

    Storage pool disorder with scarce or absent granules

    HPS1, AP3B1, HPS3, HPS4, AIBP63, HPS6, DTNBP1, BLOC1S3, BLOC1S6,

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

    Thrombocytopenia-absent radius syndrome

    Defect is in megakaryocytic differentiation and platelet production

    Elevated thrombopoietin


    Cardiovascular defects (eg, tetralogy of Fallot), absent radii, short stature
    Thromboxane receptor

    Aggregation defect for arachidonic acid


    Nurden, 2014; Freson, 2014
    Inherited platelet disorders – autosomal dominant

    Inherited Platelet Disorders – Autosomal Dominant



    Clinical Presentation

    Autosomal dominant macrothrombocytopeniaTUBB1Normal structure and function of platelets
    Autosomal dominant thrombocytopenia

    Cyroskeletal protein defect


    Normal function and structure to platelets
    Familial platelet disorder with predisposition to acute myelogenous leukemia

    Transcription factor defect


    Predisposition to AML or MDS

    Gray-platelet syndrome (alpha storage pool disease)

    Also autosomal recessive

    Storage pool disorder with decreased alpha granules


    Mild mucosal bleeding, myelofibrosis, splenomegaly
    Gs platelet defect related to bleeding

    Aggregation defect


    Short stature, mental disability, brachydactyly

    May-Hegglin anomaly

    Sebastian syndrome

    Fechtner syndrome

    Epstein syndrome

    Abnormal cytoskeletal proteins


    Nephritis, hearing loss for Fechtner and Epstein syndromes
    Mediterranean macrothrombocytopenia

    Similar defect to Bernard-Soulier syndrome


    Mild bleeding
    Paris-Trousseau syndrome

    Transcription factor defect


    Severe thrombocytopenia psychomotor disability, trigonocephaly, facial dysmorphism, cardiac abnormalities

    Platelet-type von Willebrand disease (VWD)

    Adhesion disorder with gain of function of platelet GPIb-IX-V complex – resembles VWD type 2B


    Epistaxis, ecchymoses, menorrhagia, gingival hemorrhage
    Quebec platelet disorder

    Aggregation defect


    Scott syndrome

    Coagulation pathway protein defect


    Nurden, 2014; Freson, 2014
    Inherited platelet disorders – X-linked

    Inherited Platelet Disorders – X-Linked



    Clinical Presentation


    Cytoskeletal protein defect


    Wide spectrum disorder – skeletal, cardiac, GI dysfunction
    Wiskott-Aldrich syndrome

    Cytoskeletal protein defect with decreased small platelets, few alpha granules, lack delta granules


    Eczema, recurrent infections, severe bleeding, neutropenia, autoimmune disorders
    X-linked macrothrombocytopenia

    Transcription factor defect


    Mild to moderately severe bleeding
    Nurden, 2014; Freson, 2014
  • Acquired disorders include the following

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

Initial test for suspected bleeding  disorder

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Initial test for suspected bleeding  disorder

Platelet Aggregation Studies 0030160
Method: Qualitative Aggregation

Evaluate patients with suspected inherited qualitative platelet disorders

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 0030130
Method: Electromagnetic Mechanical Clot Detection

Determine if fibrinogen deficiency is a potential cause of bleeding

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

Recommended panel for the initial workup of suspected von Willebrand disease

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