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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 abnormal platelet aggregation or prolongation of the closure time in an automated platelet function analyzer. There is little or no clinical value of the bleeding time because of lack of reproducibility and poor correlation with clinical bleeding, and it should not be used.

  • 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. Integrin αIIbβ3 (glycoprotein IIb/IIIa; CD41/CD61): Glanzmann thrombasthenia

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

    3. Glycoprotein Ibα (CD42b,c): Platelet-type (pseudo-) von Willebrand disease

    4. Integrin α2β1 (glycoprotein Ia/IIa; 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

    5. Hermansky-Pudlak syndrome

  3. 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, 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 extra-large Gαs, Gαi1 deficiency, CaLDAG-GEFI 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 sythase-1] deficiency, thromboxane synthase deficiency)

  4. Abnormalities of platelet coagulant activity (Scott syndrome)

  5. Abnormalities of a cytoskeletal structural protein: β1 tubulin, filamin A

  6. Abnormalities in cytoskeletal linking proteins

    1. Wiskott-Aldrich syndrome protein (WASP)

    2. Kindlin-3: Leukocyte adhesion defect (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 α granules and thrombocytopenia; Paris-Trousseau/Jacobsen syndrome)

    4. GFI1B

ABNORMAL GLYCOPROTEIN (GP) IIB/IIIA (INTEGRIN AIIBB3, 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 GPIIb and/or GPIIIa (also termed integrin α2b/β3; 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 abnormalities have been described that affect expression or various functions of the two molecules.

  • Inheritance of the disorder is autosomal recessive, but about 40% 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.

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