QUALI DISORDERS OF PLATELETS

• Qualitative platelet disorders


  Disorders that result from abnormalities of each of the major phases of platelet function (adhesion, secretion, and aggregation)
• Glanzmann thrombasthenia (GT)


  Bleeding disorder associated with abnormal in vitro clot retraction and a normal platelet count
• Glanzmann thrombasthenia


  • Inherited as an autosomal recessive disorder
  • Seen most frequently in populations with a high degree of consanguinity
  • Heterozygotes are clinically normal, whereas homozygotes have serious bleeding problems
  • Manifests itself clinically in the neonatal period or infancy, occasionally with bleeding after circumcision and frequently with epistaxis and gingival bleeding
  • Hemorrhagic manifestations include petechiae, purpura, menorrhagia, gastrointestinal bleeding, and hematuria
  • Severity of bleeding episodes seems to decrease with age
• Biochemical lesion in Glanzmann thrombasthenia


  Deficiency or abnormality of the platelet membrane glycoprotein (GP) IIb/IIIa (integrin αẞ3) complex
• Binding of fibrinogen to the GP IIb/IIIa complex mediates normal platelet aggregation responses
• Type 1 and type 2 Glanzmann thrombasthenia


  • Type 2 disease has more GP IIb/IIIa complexes (10% to 20% of normal) than type 1 disease (0% to 5% of normal)
  • Patients with type 2 disease are less affected by abnormal clot retraction and fibrinogen binding
• Genetic mutations in Glanzmann thrombasthenia


  • Distributed widely over the ITGA2B and ITGB3 genes present on chromosome 17, which code for GP IIb/IIIa
  • More than 70 mutations are known to give rise to Glanzmann thrombasthenia
• Both proteins of the GP IIb/IIIa complex must be produced and assembled into a complex in order to be expressed on the platelet surface
• Defects that interfere with or prevent complex formation or affect complex stability lead to absence of the complex on the platelet surface
• Variants of Glanzmann thrombasthenia


  αдb and ẞ3 are produced, form a complex, and are processed normally, but one or more functions of the complex (e.g., fibrinogen binding or signal transduction) are abnormal
• Patients who have ẞ3 gene defects that result in the absence of αшbẞ3 integrin also lack the vitronectin receptor, but do not seem to have a more severe form of Glanzmann thrombasthenia
• Acquired thrombasthenia-like state


  • Can be caused by development of autoantibodies against GP IIb/IIIa, multiple myeloma in which the paraprotein is directed against GP IIIa, and afibrinogenemia
  • Can also be induced by a variety of therapeutic antiplatelet drugs
• Laboratory features of Glanzmann thrombasthenia

  • Normal platelet count and morphology
  • Lack of platelet aggregation in response to all platelet activating agents (including ADP, collagen, thrombin, and epinephrine)
  • Normal ristocetin-induced binding of VWF to platelets and resulting platelet agglutination
  • Diminished platelet procoagulant activity
• Thrombasthenia is one of the few forms of platelet dysfunction in which hemostatic management with platelet transfusions can be effective
• Glanzmann thrombasthenia


  Defect in platelet glycoprotein IIb/IIIa complex, leading to impaired platelet aggregation
• Activation with strong agonists (e.g., thrombin) will induce the release/secretion reaction, even in the absence of aggregation
• Ristocetin-induced binding of VWF to platelets and the resulting platelet agglutination are normal
• Tests for platelet procoagulant activity, such as the platelet factor 3 test, usually show diminished activity
• Reasons for diminished platelet procoagulant activity in Glanzmann thrombasthenia


  • Markedly fewer microvesicles are produced when platelets are activated
  • Prothrombin binds directly to GP IIb/IIIa, which is missing on platelets from patients with Glanzmann thrombasthenia, resulting in less thrombin generation
  • Glanzmann thrombasthenia platelets are activated by thrombin to a lesser degree than normal platelets
• Treatment for bleeding in Glanzmann thrombasthenia


  • Transfusion of normal platelets
  • Use of pre-storage, leukocyte-reduced apheresis platelets or HLA-matched donor platelets to minimize/prevent alloimmunization
• Patients with Glanzmann thrombasthenia should avoid anticoagulants and antiplatelet agents
• Other treatments used to control or prevent bleeding in Glanzmann thrombasthenia


  • Hormonal therapy (norethindrone acetate) for menorrhagia
  • Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) for gingival hemorrhage or excessive bleeding after tooth extraction
  • Recombinant factor VIIa for severe bleeding, especially in patients with isoantibodies to GP IIb/IIIa or undergoing invasive procedures
• Bernard-Soulier syndrome


  Rare disorder of platelet adhesion due to defect in platelet glycoprotein Ib/IX/V complex, leading to inability to bind von Willebrand factor and adhere to exposed subendothelium
• Bernard-Soulier syndrome usually manifests in infancy or childhood with hemorrhage characteristic of defective platelet function: ecchymoses, epistaxis, and gingival bleeding
• Hemarthroses and expanding hematomas are rarely seen in Bernard-Soulier syndrome
• Heterozygotes in Bernard-Soulier syndrome


  Have about 50% of normal levels of GP Ib, GP V, and GP IX and have normal or near-normal platelet function
• Homozygotes in Bernard-Soulier syndrome


  • Have enlarged platelets, thrombocytopenia, and usually decreased platelet survival, leading to a moderate to severe bleeding disorder
  • Platelet counts generally range from 40,000/μL to near normal
  • Platelets are 5 to 8 µm in diameter (normal 2 to 3 μm), but can be as large as 20 μm
• Glycoproteins required to form the GP Ib/IX/V complex

  GP Iba, GP Ibẞ, GP IX, and GP V, present in the ratio of 2:2:2:1
• Synthesis of GP Iba, GP Ibẞ, and GP IX is required for surface expression of the GP Ib/IX complex
• The most frequent forms of Bernard-Soulier syndrome involve defects in GP Iba synthesis or expression
• Variants of Bernard-Soulier syndrome


  Can have normal surface expression of the GP Ib/IX/V complex but impaired functionality due to mutations affecting binding domains or resulting in truncation of a specific protein in the complex
• Antibody to GP Ib/V can cause a Bernard-Soulier-like syndrome (pseudo-BSS), in which the GP Ib/IX/V complex is nonfunctional
• Gain-of-function mutations in the GP Ib/IX/V complex can result in platelet-type von Willebrand disease (pseudo-VWD)
• Laboratory features of Bernard-Soulier syndrome

  Platelets have normal aggregation responses to ADP, epinephrine, collagen, and arachidonic acid, but do not respond to ristocetin and have diminished response to thrombin
• Treatment for Bernard-Soulier syndrome


  • Avoid antiplatelet therapy
  • Antifibrinolytic therapy may be useful for mucosal bleeding
  • Platelet transfusions are the therapy of choice, but patients develop alloantibodies limiting further transfusions
  • Use pre-storage, leukoreduced apheresis platelets or HLA-matched donor platelets to minimize alloimmunization
  • Other treatments include desmopressin acetate (DDAVP) and recombinant factor VIIa
• In addition to Bernard-Soulier syndrome, there are several other inherited syndromes with large platelets and thrombocytopenia, usually with mild bleeding tendency
• Inherited giant platelet syndromes

  • Giant platelets with velocardiofacial syndrome
  • Giant platelets with abnormal surface glycoproteins and mitral valve insufficiency
  • Familial macrothrombocytopenia with GP IV abnormality
  • Montreal platelet syndrome
  • May-Hegglin anomaly
  • Fechtner syndrome
  • Sebastian syndrome
  • Hereditary macrothrombocytopenia
  • Epstein syndrome
  • Mediterranean macrothrombocytopenia
• Storage pool disorders


  Defects related to dense granules or α-granules in platelets, leading to mucocutaneous hemorrhage and hematuria, epistaxis, and easy/spontaneous bruising
• Dense granule deficiencies


  • Can be associated with albinism or occur in otherwise normal individuals (nonalbinos)
  • In nonalbinos, evidence suggests an inability to package the dense granule contents, rather than a deficiency in dense granule membranes
• As an isolated abnormality, dense granule deficiency does not typically result in a serious hemorrhagic problem, usually just causing mild bleeding like easy bruising