Chapter 76: Hereditary Platelet Disorders

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.

• 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 does not correlate with the degree of abnormality of the laboratory findings, and the severity of bleeding symptoms can vary significantly during the life of an individual patient.

• Carriers are usually asymptomatic and have normal platelet function.

Laboratory Features

• Normal platelet count and morphology.

• Prolonged bleeding time.

• Decreased or absent clot retraction.

• Abnormal platelet aggregation to physiologic stimuli (e.g., to ADP).

• Many other abnormalities of platelet function of research interest.

Differential Diagnosis

• Bleeding with normal platelet count.

• Other qualitative platelet disorders: specific laboratory findings.

• von Willebrand disease, afibrinogenemia, hemophilia, and related disorders: specific laboratory findings.

• Autoantibodies to GP IIa/IIIb: demonstrate inhibitor of platelet function by mixing studies using normal plasma and platelets.

Therapy

• Preventive measures: dental hygiene, avoid antiplatelet drugs, hepatitis vaccination early in life, hormone therapy to avoid menorrhagia.

• Iron and folic acid therapy may be required in patients with continued bleeding.

• For management of bleeding, local therapy is given as appropriate, such as pressure dressings, Gelfoam, dental splints, etc; antifibrinolytic therapy may be helpful.

• Epistaxis may be particularly difficult to control.

• Platelet transfusions are given for serious hemorrhage, and packed red cell transfusions are often needed to correct blood loss anemia. All transfusions should be delivered through leukocyte-depletion filters.

• Antifibrinolytic agents (e.g., ε-aminocaproic acid) are useful in patients with gingival bleeding or who are undergoing tooth extractions.

• Treatment of patients with Glanzmann thrombasthenia with recombinant factor VIIa (rFVIIa) has produced considerable, but not universal success, but rare thromboembolic complications have been reported in association with this therapy.

• With repeated platelet transfusion, alloimmunization occurs to platelet proteins such as HLA and GPIIb and/or GPIIIa.

• A few patients with severe bleeding have had allogeneic marrow hematopoietic stem cell transplantation, with some success.

Prognosis

• Bleeding problems may be severe and frequent, but prognosis for survival is good.

• Bernard-Soulier syndrome (BSS) is characterized by moderate thrombocytopenia, giant platelets, and failure of platelets to undergo selective von Willebrand factor (VWF) interactions as a result of abnormalities of the GP Ib/IX complex.

• The mechanisms leading to the thrombocytopenia and the giant platelets are not known.

• The abnormal platelet reactions with VWF and thrombin and the abnormalities of coagulant activity are related to the glycoprotein abnormalities.

Etiology and Pathogenesis

• Patients with BSS are deficient in GP Ib, GP IX, and GP V.

• Several qualitative abnormalities of GP Ib and GP IX have been identified. No defective forms of GP V have been identified.

• Inherited as an autosomal recessive trait; an autosomal dominant form and acquired forms have also been reported.

• Six features contribute to the hemorrhagic diathesis: thrombocytopenia, abnormal platelet interactions with VWF, abnormal platelet interactions with thrombin, abnormal platelet coagulant activity, abnormal platelet interactions with P-selectin, and abnormal platelet interactions with leukocyte integrin αMβ2.

Clinical Features

• Epistaxis is the most common symptom. Ecchymoses, menometrorrhagia, gingival bleeding, and gastrointestinal bleeding also occur frequently.

• Symptoms vary considerably among patients, even those in a single family.

Laboratory Features

• Thrombocytopenia is found in nearly all patients, ranging from about 20 × 10⁹/L to nearly normal levels.

• More than one-third of platelets are large; some are larger than lymphocytes.

• The bleeding time is nearly always prolonged.

• Platelets do not aggregate in response to ristocetin. In contrast to von Willebrand disease, this abnormality is not corrected by addition of normal plasma.

• Platelet coagulant activity may be reduced, normal, or increased.

Differential Diagnosis

• This is discussed under Glanzmann thrombasthenia.

Treatment and Prognosis

• These are similar to Glanzmann thrombasthenia.

• Desmopressin (DDAVP) has been variably effective in decreasing the bleeding time.

• A heterogenous group of patients with mild to moderate bleeding symptoms, variable thrombocytopenia, variably enlarged platelets, and diminished plasma levels of high-molecular-weight multimers of VWF.

Etiology and Pathogenesis

• GP Ib/IX is the receptor for VWF.

• Abnormal forms of GP Ib cause enhanced binding of VWF, leading to reduction in high-molecular-weight multimers in plasma, and perhaps reduction in platelet survival time.

• Specific mutations have been demonstrated in some patients.

• Inherited as an autosomal dominant trait.

Clinical Features

• Patients have mild to moderate mucocutaneous bleeding.

Laboratory Features

• Bleeding time usually prolonged.

• Some patients have thrombocytopenia and large platelets.

• Plasma VWF concentration is reduced, especially the high-molecular-weight multimers.

• Enhanced platelet aggregation in response to low concentrations of ristocetin is not corrected by normal plasma. (In type II von Willebrand disease, this abnormality is corrected by normal plasma.)

Therapy

• Administration of VWF, or DDAVP to increase endogenous release of VWF, may be beneficial in low doses but can cause thrombocytopenia because of increased binding to platelets.

• Patients should be specifically instructed to avoid aspirin or other antiplatelet agents.

• Platelet transfusion may be beneficial if thrombocytopenia is severe.

• A mild bleeding disorder has been described in association with decreased platelet content of GP Ia and GP IIa.

• Deficiency of GP IV occurs in a small number of people who have no bleeding disorder.

• Deficiency of GP VI has been found in patients with mild bleeding disorders.

• Wiskott-Aldrich syndrome is characterized by small platelets, thrombocytopenia, recurrent infections and eczema, although only a minority of patients have all features of the disorder.

Etiology and Pathogenesis

• Wiskott-Aldrich syndrome is inherited as an X-linked trait. In fact, if the eczema and immunodeficiency are minimal, the condition is termed X-linked thrombocytopenia. Female carriers of Wiskott-Aldrich syndrome have normal platelet counts and normal platelet size as they select against mutant X-chromosome WAS gene.

• Mutations of a Wiskott-Aldrich syndrome protein (WASP) occur in many, but not all, patients with the Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

• WASP is a cytoplasmic protein, expressed in all hematopoietic stem cell–derived lineages. It plays a major role in organization and regulation of the actin cytoskeleton.

• A defect has also been found in sialophorin (CD43), a glycoprotein found on lymphocytes, monocytes, neutrophils, and platelets, but its role in pathogenesis is not clear.

• Deficiencies in GP Ia, Ib, IIb/IIIa, and IV have been found in some, but not all, patients.

• Deficiency of the platelet storage pool of adenine nucleotides and abnormal platelet energy metabolism are found in some patients.

• The thrombocytopenia is believed to be a result of diminished platelet survival, but ineffective thrombopoiesis may also play a role.

• The cause of the small platelets is unknown.

Clinical Features

• Mucocutaneous bleeding.

• Recurrent infections.

• Eczema.

• Increased risk of development of lymphoma, even in childhood.

• Autoimmune diseases, including hemolytic anemia and thrombocytopenia, may occur.

Laboratory Features

• Thrombocytopenia, often with counts of 20 × 10⁹/L or less, and with reduced platelet volume, may occur.

• The bleeding time is usually prolonged.

• Platelet aggregation and release of dense body contents are variably abnormal.

• Defects in both humoral and cellular immunity, especially deficiency in immune response to polysaccharide antigens.

Treatment

• Patients should be specifically instructed to avoid aspirin or other antiplatelet agents.

• Splenectomy improves thrombocytopenia, and may lead to increased platelet size and improved function.

• Marrow hematopoietic stem cell transplantation may be curative.

δ-Storage Pool Deficiency

• A usually mild bleeding disorder with abnormalities in the second wave of platelet aggregation and deficiencies in the contents of the dense granules of platelets.

• There is predisposition to hematologic malignancies in some families.

• It occurs as a primary disorder or in association with inherited multisystem disorders:

  — Hermansky-Pudlak syndrome.

  — Chédiak-Higashi syndrome.

  — Wiskott-Aldrich syndrome (see above).

  — Others less frequently.

• The mode of inheritance of the primary disorder is not well defined, but autosomal dominance has been reported. The forms associated with other disorders are inherited following the pattern of the primary disease.

Clinical Features

• Severe bleeding may occur in patients with Hermansky-Pudlak syndrome; in others bleeding is mild to moderate.

• Mucocutaneous bleeding, excessive bruising, and epistaxis are common.

• Excess bleeding after surgery or trauma also may occur.

Laboratory Features

• The results of platelet function tests vary from patient to patient, and may vary in the same patient over time.

• The bleeding time is usually prolonged.

• Variable abnormalities of second wave of platelet aggregation are characteristic.

Differential Diagnosis

• See "Glanzmann Thrombasthenia," above.

Treatment

• Avoid antiplatelet drugs.

• The bleeding associated with surgery may be decreased by therapy with glucocorticoids.

• Bleeding time may be decreased by therapy with DDAVP or cryoprecipitate.

• Platelet transfusion may be helpful if bleeding is severe.

Hermansky-Pudlak Syndrome

• Hermansky-Pudlak syndrome is unusually common in patients from northwest Puerto Rico, affecting 1 in 1800 individuals, causing variable oculocutaneous albinism and the absence of dense platelets.

• Linkage analysis of patients from areas where Hermansky-Pudlak syndrome is relatively common led to the identification of the abnormal gene in these patients, then termed HPS1.

• The HPS1 gene encodes a 700 amino acid protein that, along with HPS4, comprises BLOC-3 component of the granule exocytosis machinery.

Gray Platelet Syndrome (α-Granule Deficiency)

• α-Granule membranes form abnormal vesicular structures rather than granules.

• Platelets are deficient in α-granule contents, including fibrinogen and VWF.

• α-Granule deficiency (gray platelet) may be diagnosed by measuring platelet factor-4 and/or β-thromboglobulin in platelets.

Clinical Features

• Mild hemorrhagic manifestations are usual, but severe bleeding has been reported.

Laboratory Features

• Platelets on blood films are pale, gray, ghost-like, oval, and larger than normal.

• Thrombocytopenia is common, and the platelet count may be below 50 × 10⁹/L.

• Platelet aggregation is often normal or nearly so, but may be abnormal.

Differential Diagnosis

• See "Glanzmann Thrombasthenia," above.

• Degranulated platelets may also be seen in myelodysplastic and myeloproliferative disorders.

Treatment

• General measures should be used as in Glanzmann thrombasthenia.

• DDAVP or antifibrinolytic therapy may be beneficial.

• Platelet transfusion is indicated for serious hemorrhage.

• Thrombocytopenia may be improved by glucocorticoid therapy.

α, δ-Storage Pool Deficiency

• There are moderate to severe defects in both α and δ granules.

• Clinical and laboratory features are similar to δ-storage pool deficiency.

Quebec Platelet Disorder

• The early description of this autosomal dominant disorder included severe bleeding after trauma, mild thrombocytopenia, decreased functional platelet factor V, and normal plasma factor V.

• The bleeding time is abnormal, as is epinephrine-induced platelet aggregation.

• Subsequent studies demonstrated that the platelets of these patients had markedly reduced levels of multimerin and thrombospondin, and both reduced levels and proteolysis of a number of α-granule proteins, including factor V, fibrinogen, VWF, fibronectin, and osteonectin.

• The defect in these patients' platelets appears to be excessive plasmin generation as a result of increased expression of urokinase-type plasminogen activator (uPA); increased megakaryocyte expression of the uPA gene due to an abnormality in a cis regulatory element may be the primary abnormality.

• Patients whose platelets fail to facilitate thrombin generation are defined as having defects in platelet coagulant activity. Only a few patients with isolated defects in platelet coagulant activity have been described.

• There is decreased translocation of platelet phosphatidyl serine to the outer membrane leaflet, which results in decreased binding of factors Va-Xa and VIIIa-IXa and hence, a diminished rate of blood clotting.

Clinical Features

• Bleeding, sometimes severe, occurs after trauma, dental extractions, delivery, or surgery. Epistaxis and menorrhagia also occur.

• Bleeding is not primarily mucocutaneous, in contrast to other qualitative platelet disorders.

Laboratory Features

• Bleeding time is usually normal.

• Serum prothrombin time is abnormal.

• Assays for "platelet factor 3" are abnormal.

Differential Diagnosis

• The normal bleeding time and abnormal serum prothrombin time distinguish patients with abnormalities of platelet coagulant activity.

Therapy

• Platelet transfusions have been effective for prevention and treatment.

• Prothrombin complex concentrates may be effective but may induce thrombosis.

• A number of defects in the complex process of platelet activation that cause usually mild hemostatic disorders with rare episodes of severe clinical expression have been described.

• The most common pattern is blunted platelet aggregation with absence of the second wave of aggregation on exposure to ADP, epinephrine, or collagen, and decreased release of dense granule contents. Such patients have been lumped together, more out of convenience than because of an understanding of the mechanism, under the rubric of primary secretion defects, activation defects, or signal transduction defects.

• Occasional patients demonstrate defects in the thromboxane receptor, one of the ADP receptors (P2Y₁₂, P2Y₁ and P2X₁), the epinephrine receptor or the GTP binding proteins that mediate signaling for these heptahelical G-protein coupled receptors, or the signaling intermediates that mediate these platelet activation pathways, such as cyclooxygenase, thromboxane synthase, phospholipase (PL) Cβ or PLC0 Θ.