Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ 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. The clinical value of the bleeding time is questionable because of lack of reproducibility and poor correlation with clinical bleeding and should not be used. ++ Hereditary qualitative platelet disorders classified according to the responsible abnormalities are presented in Table 75–1. ++Table Graphic Jump LocationTABLE 75–1INHERITED DISORDERS OF PLATELET FUNCTIONView Table||Download (.pdf) TABLE 75–1INHERITED DISORDERS OF PLATELET FUNCTION Abnormalities of glycoprotein adhesion receptors Integrin αIIbβ3 (glycoprotein IIb/IIIa; CD41/CD61): Glanzmann thrombasthenia Glycoproteins Ib (CD42b,c)/IX (CD42a)/V: Bernard-Soulier syndrome Glycoprotein Ibα (CD42b,c): Platelet-type (Pseudo-) von Willebrand disease Integrin α2β1 (glycoprotein Ia/IIa; VLA-2; CD49b/CD29) CD36 (glycoprotein IV) Glycoprotein VI Abnormalities of platelet granules δ-Storage pool deficiency Gray platelet syndrome (α-storage pool deficiency) α,δ-Storage pool deficiency Quebec platelet disorder Abnormalities of platelet signaling and secretion 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) Defects in guanosine triphosphate (GTP)–binding proteins (Gαq deficiency, Gαs hyperfunction and genetic variation in extra-large Gαs, Gαi1 deficiency, CaLDAG-GEFI deficiency) Phospholipase C (PLC)-β2 deficiency and defects in PLC activation Defects in protein phosphorylation protein kinase C (PKC)-θ deficiency Defects in arachidonic acid metabolism and thromboxane production (phospholipase A2 deficiency cyclooxygenase [prostaglandin H2 sythase-1 deficiency], thromboxane synthase deficiency) Abnormalities of platelet coagulant activity (Scott syndrome) Abnormalities of a cytoskeletal structural protein: β1 tubulin, filamin A Abnormalities in cytoskeletal linking proteins Wiskott-Aldrich syndrome protein (WASP) Kindlin-3: Leukocyte adhesion defect (LAD)-III; LAD-1 variant; integrin activation deficiency disease defect (IADD) Abnormalities of transcription factors leading to functional defects RUNX1 (familial platelet dysfunction with predisposition to acute myelogenous leukemia) GATA-1 FLI1 (dimorphic dysmorphic platelets with giant α granules and thrombocytopenia; Paris-Trousseau/Jacobsen syndrome) GFI1B Source: Williams Hematology, 9th ed, Chap. 120, Table 120–1. + ABNORMAL GLYCOPROTEIN (GP) IIB/IIIA (INTEGRIN AIIBB3, CD41/CD61): GLANZMANN THROMBASTHENIA Download Section PDF Listen +++ ++ 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 75–1). +++ 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. 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. 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 ++ Patients have normal platelet count and morphology. They have abnormal platelet aggregation to physiologic stimuli (eg, to ADP). Clot retraction is decreased or absent. There are many other abnormalities of platelet function of research interest. Autoantibodies to GPIIb/GPIIIa inhibits the function of normal platelets studied in plasma. +++ Differential Diagnosis ++ Specific laboratory findings can distinguish other qualitative platelet disorders. von Willebrand disease, afibrinogenemia, hemophilia, and related disorders can be distinguished by specific laboratory tests. +++ Treatment ++ Preventive measures include dental hygiene, avoidance of antiplatelet drugs, hepatitis vaccination early in life, and 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, and dental splints, and so on. 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 (eg, 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, and rare thromboembolic complications have been reported in association with this therapy. With repeated platelet transfusion, alloimmunization occurs to platelet proteins such as human leukocyte antigen and GPIIb and/or GPIIIa. A few patients with severe bleeding have had allogeneic marrow hematopoietic stem cell transplantation, with success in some cases. +++ Prognosis ++ Bleeding problems may be severe and frequent, but prognosis for survival is good. + GLYCOPROTEIN IB (CD42B, C), GP IX (CD42A), AND GP V: BERNARD-SOULIER SYNDROME Download Section PDF Listen +++ ++ 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. BSS is 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. 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 in “Glanzmann Thrombasthenia.” +++ Treatment and Prognosis ++ These are similar to those for Glanzmann thrombasthenia. + ABNORMAL GP IB (CD42B, C): PLATELET-TYPE OR PSEUDO-VON WILLEBRAND DISEASE Download Section PDF Listen +++ ++ A heterogenous group of patients have 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. The condition is inherited as an autosomal dominant trait. +++ Clinical Features ++ Patients have mild to moderate mucocutaneous bleeding. +++ Laboratory Features ++ 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.) +++ Treatment ++ Administration of VWF or desmopressin (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 instructed to avoid aspirin or other antiplatelet agents. Platelet transfusion may be beneficial if thrombocytopenia is severe. + OTHER GLYCOPROTEIN DEFICIENCIES Download Section PDF Listen +++ ++ 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 Download Section PDF Listen +++ ++ 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 Possibly autoimmune diseases, including hemolytic anemia and thrombocytopenia +++ Laboratory Features ++ Thrombocytopenia, often with counts of 20 × 109/L or less, and with reduced platelet volume, may occur. 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. Allogeneic hematopoietic stem cell transplantation may be curative. + PLATELET GRANULE DEFICIENCY STATES Download Section PDF Listen +++ +++ δ-Storage Pool Deficiency ++ This is 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 discussion) — 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. 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. 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. This syndrome causes 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. Epinephrine-induced platelet aggregation is normal. 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. + ABNORMALITIES OF PLATELET COAGULANT ACTIVITY (SCOTT SYNDROME) Download Section PDF Listen +++ ++ 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 ++ Serum prothrombin time is abnormal. Assays for “platelet factor 3” are abnormal. +++ Differential Diagnosis ++ The abnormal serum prothrombin time distinguish patients with abnormalities of platelet coagulant activity. +++ Treatment ++ Platelet transfusions have been effective for prevention and treatment. Prothrombin complex concentrates may be effective but may induce thrombosis. + ABNORMALITIES OF PLATELET AGONIST RECEPTORS, SIGNAL TRANSDUCTION, AND SECRETION Download Section PDF Listen +++ ++ 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 PLCθ. ++ For a more detailed discussion, see A. Koneti Rao and Barry S. Coller: Hereditary Qualitative Platelet Disorders, Chap. 120 in Williams Hematology, 9th ed.