Functional Platelet Disorders

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
For diagnosis information based on disorder, see table below

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 syndrome	Platelet 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
  - Idiopathic thrombocytopenias
  - Decreased platelet production due to bone marrow disorders – leukemias (eg, ALL, AML), myelodysplastic syndromes
  - Increased platelet destruction
    - Immune or non-immune causes (lymphoproliferative disorders)
    - Platelet sequestration in spleen
- 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

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-linked	Decreased small platelets, few alpha granules, lack delta granules	Eczema, 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 disorders	Other 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 activity	Range from mild mucosal bleeding to more severe bleeding problems

Acquired disorders include the following
- Antiplatelet medication effects (most common cause)
- Uremia
- Hepatic cirrhosis
- Acquired vWD
- High concentrations of fibrin/fibrinogen degradation products
- Dysproteinemias
- Cardiopulmonary bypass
- Myeloproliferative neoplasms
- Microangiopathic hemolytic anemias (platelet exhaustion from continued platelet activation)

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count

ARUP #: 0040002

Methodology: Automated Cell Count

Use:

Identify thrombocytopenia

Test name: Prothrombin Time

ARUP #: 0030215

Methodology: Electromagnetic Mechanical Clot Detection

Use:

Identify other potential causes for bleeding disorder

Test name: Partial Thromboplastin Time