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Chapter 76: Hereditary Platelet Disorders

INTRODUCTION

Abnormalities of platelet function are expressed primarily by mucocutaneous bleeding. The most frequent laboratory abnormality is prolongation of the bleeding time, although the clinical value of the bleeding time is questionable because of lack of reproducibility and poor correlation with clinical bleeding.

  • Hereditary qualitative platelet disorders classified according to the responsible abnormalities are presented in Table 76–1.

TABLE 76–1INHERITED DISORDERS OF PLATELET FUNCTION
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TABLE 76–1 INHERITED DISORDERS OF PLATELET FUNCTION

  1. Abnormalities of Glycoprotein Adhesion Receptors

    1. αIIbβ3 (Glycoprotein IIb/IIIa; CD41/CD61): Glanzmann thrombasthenia

    2. Glycoproteins Ib (CD42b,c)/IX(CD42a)/V: Bernard-Soulier syndrome

    3. Glycoprotein GPIbα (CD42b): platelet-type (pseudo-) von Willebrand disease

    4. α2β1 (Glycoprotein Ia/IIa; very-late antigen [VLA]-2; CD49b/CD29)

    5. CD36 (Glycoprotein IV)

    6. Glycoprotein VI

  2. Abnormalities of Platelet Granules

    1. δ-Storage pool deficiency

    2. Gray platelet syndrome (α-storage pool deficiency)

    3. α,δ-Storage pool deficiency

    4. Quebec platelet disorder

  3. Abnormalities of Platelet Coagulant Activity (Scott syndrome)

  4. Abnormalities of Platelet Signaling and Secretion

    1. Defects in platelet agonist receptors or agonist-specific signal transduction (thromboxane A2 receptor defect, adenosine diphosphate [ADP] receptor defects [P2Y12, P2Y1, P2X1], epinephrine receptor defect, platelet-activating factor receptor defect)

    2. Defects in guanosine triphosphate (GTP)-binding proteins (Gαq deficiency, Gαs hyperfunction and genetic variation in extralarge Gαs, Gαi1 deficiency)

    3. Phospholipase C (PLC)-β2 deficiency and defects in PLC activation

    4. Defects in protein phosphorylation: protein kinase C (PKC)-θ deficiency

    5. Defects in arachidonic acid metabolism and thromboxane production (phospholipase A2 deficiency, cyclooxygenase [prostaglandin H2 synthase] deficiency, thromboxane synthase deficiency)

  5. Abnormalities of a Cytoskeletal Structural Protein: β1 Tubulin

  6. Abnormalities in Cytoskeletal Linking Proteins

    1. Wiskott-Aldrich syndrome protein (WASP)

    2. Kindlin-3: Leukocyte adhesion defect-III (LAD-III); LAD-1 variant, integrin activation deficiency disease defect (IADD)

  7. Abnormalities of Transcription Factors Leading to Functional Defects

    1. RUNX1 (familial platelet dysfunction with predisposition to acute myelogenous leukemia)

    2. GATA-1

    3. FLI1 (dimorphic dysmorphic platelets with giant αgranules and thrombocytopenia; Paris-Trousseau/Jacobsen syndrome)

Source: Williams Hematology, 8th ed, Chap. 121, Table 121–1, p. 1934.

ABNORMAL GLYCOPROTEIN (GP) IIb/IIIa (αIIBβ3, CD41/CD61): GLANZMANN THROMBASTHENIA

  • Glanzmann thrombasthenia is characterized by severely reduced or absent platelet aggregation in response to many physiologic agonists because of abnormalities of platelet GP IIb and/or IIIa (see Table 76–1).

Etiology and Pathogenesis

  • GPIIb/IIIa functions as receptor for fibrinogen and other adhesive glycoproteins.

  • It is required for platelet aggregation induced by all agonists believed to function in vivo.

  • Both GPIIb and GPIIIa are required for normal function, and defects in either component may cause thrombasthenia.

  • Many different molecular biologic abnormalities have been described that affect expression or various functions of the two molecules.

  • Inherited as an autosomal recessive disorder, but about 40 percent of patients are compound heterozygotes rather than homozygotes.

Clinical Features

  • The most frequent bleeding symptoms in patients with Glanzmann thrombasthenia are menorrhagia, easy bruising, epistaxis, and gingival bleeding.

  • Clinical expression ...

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