Quantitative Platelet Disorders- Thrombocytosos & Qualitative Platelet Disorders

Disorders of Primary Hemostasis

Quantitative Platelet Disorders

• Types:

  • Thrombocytosis

  • Qualitative Platelet Disorders

Quantitative Thrombocytosis

Essential (Primary)

• Platelet counts > 10,000,000,000

• Result of primary bone marrow disorder

• Characterized by increased number of platelets, clonal disorder affecting all cell lines

• Often presents with bleeding tendencies due to functional abnormalitiesAssociated Conditions:

  • Hodgkin’s disease

  • Polycythemia vera

  • Myelofibrosis

  • Chronic Myelogenous Leukemia (CML)

  • Thrombocythemia

Reactive (Secondary)

• Response to other conditions such as:

  • Iron deficiency associated with chronic blood loss

  • Chronic inflammatory disease

  • Splenectomy associated thrombocytosis

  • Rebound thrombocytosis following massive blood loss (within 1 day due to bone marrow stimulation)

Qualitative Platelet Disorders

Glanzmann’s Thrombasthenia

• Genetic Basis: Autosomal recessive defect (chromosome 17) resulting in a decrease in GPIIb/IIIa and available fibrinogen binding sites

• Lab Findings:

  • Abnormal platelet function but normal number and appearance

  • Abnormal aggregation with a phase of disagglutination

• Symptoms:

  • Range from minor bruises to severe hemorrhages

  • Bleeding predominantly from mucosal surfaces

• Diagnostic Criteria:

  • Autosomal recessive inheritance

  • Normal platelet count and morphology

  • Increased bleeding time

  • No aggregation with ADP, thrombin, collagen, and epinephrine but normal with ristocetin

  • Flow cytometry shows deficiency or absence of GPIIb/IIIa

  • Abnormal clot retraction

• Treatment:

  • Prevent bleeding

  • Good dental care

  • Avoidance of antiplatelet drugs

  • Platelet transfusions as needed

  • Supportive therapy

Bernard-Soulier Syndrome

• Overview: Functional platelet disorder that may resemble Immune Thrombocytopenic Purpura (ITP)

• Genetic Basis: Decrease in GPIb and GPV

• Lab Findings:

  • Aggregation and granular content release are normal with aggregating agents except ristocetin

  • Deficiency of platelet GPIb/IX complex leads to reduced thrombin-induced granular release

  • Normal to decreased platelet count with large, irregular-shaped platelets

  • Increased bleeding time

• Clinical Symptoms:

  • Bleeding gums

  • Nosebleeds

  • Purpura

  • Menorrhagia

  • GI bleeds

• Diagnostic Criteria:

  • Autosomal trait expressed in homozygotes

  • Moderate thrombocytopenia (normal megakaryocytes in bone marrow)

  • Giant/large platelets in peripheral smear

  • Prolonged bleeding time

• Management:

  • Active bleeding management with RBC transfusion and antifibrinolytic agents

  • Estrogen therapy for bleeding control

  • Recombinant factor VIIa for bleeding treatment

Storage Pool Deficiencies (Granule Defects)

• Involve absence of platelet granules or defective enzymatic pathways

• Congenital Deficiencies:

  • Dense granule defects (ADP, ATP, serotonin, Calcium) lead to diminished platelet aggregation

  • Examples:

    • Hermansky-Pudlak Syndrome: Decreased dense granules

    • Chediak-Higashi Syndrome: Giant lysosomes causing dense granule destruction

    • Wiskott-Aldrich Syndrome: Sex-linked decrease in dense granules

• Alpha Granule Deficiencies: Rare functional abnormalities with decreased aggregation and release properties, known as gray platelet syndrome

Chediak-Higashi Syndrome

• Overview:

  • Autosomal recessive immune deficiency due to WBC dysfunction

  • Partial albinism and platelet dysfunction

  • Progressive neurological symptoms

  • Risk for lymphoma-like syndrome (often fatal)

  • Diagnosis: Genetic testing for LYST mutations

Enzymatic Pathway Defects

• Deficiencies in Thromboxane Generation:

  • Genetic deficiency in cyclo-oxygenase enzyme

  • Platelet aggregation tests unresponsive to arachidonic acid

Von Willebrand Disease

• Overview: Inherited deficiency of vWF which affects platelet adhesion

• Genetic Details:

  • vWF is an important adhesive protein synthesized in endothelial cells and megakaryocytes

  • Circulates as a complex with factor VIII and binds to platelets and endothelial cells

• Symptoms:

  • Mucocutaneous bleeding

  • May have autosomal inheritance pattern

  • Severe cases lead to potentially life-threatening bleeding

  • Mild cases may be undetected

• Diagnosis:

  • Difficult due to variabilities; differentiate from Hemophilia A & Bernard-Soulier Syndrome

  • Lab Tests:

    • Bleeding time

    • Platelet count

    • Factor VIII activity

    • Qualitative plasma vWF antigen and activity

    • Multimer analysis

Classification of Von Willebrand Disease Subtypes

• Type 1:

  • Autosomal dominant

  • 70% of cases

  • Quantitative decrease in normal vWF with mild bleeding

  • Treatment: DDAVP (Desmopressin)

• Type 2 (Qualitative Abnormality):

  • 2A: Mutation affecting proteolysis, moderate-severe bleeding

  • 2B: Gain of function mutation, moderate-severe bleeding

  • 2M: Loss of function mutation, moderate bleeding

  • 2N: Mutation in FVIII binding site, infrequent moderate bleeding

• Type 3:

  • Autosomal recessive

  • Absent vWF multimers with severe bleeding akin to Hemophilia A

  • Resistant to DDAVP, treated with FVIII & cryoprecipitate

• Acquired Variants:

  • Associated with diseases such as MGUS, non-Hodgkin's lymphoma, and medication (ciprofloxacin)