1. Date of download: 7/1/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. Evaluation of patients for inherited abnormalities in platelet number or function. A reduced platelet count occurs in patients with purely quantitative platelet disorders (inherited or acquired) as well as in patients who have inherited qualitative platelet disorders associated with thrombocytopenia. Platelet size (determined from the blood film and/or the mean platelet volume) helps to separate the inherited quantitative platelet syndromes from the acquired thrombocytopenias and the inherited combined quantitative and qualitative thrombocytopenias (see Chap. 119). Very small platelets are characteristic of the Wiskott-Aldrich syndrome. The Paris- Trousseau/Jacobsen syndrome is a rare inherited thrombocytopenia with giant α granules in only a fraction of circulating platelets and deletion of chromosome 11q23.3–24 affecting the transcription factor FLI1. Transcription factor RUNX-1 mutations are associated with familial thrombocytopenia, abnormal platelet function, and a predisposition to leukemia. Large platelets that lack purple granules are observed in the gray platelet syndrome (α-storage pool deficiency), but one needs to be certain that the stain is working properly. Confirmation of the diagnosis of gray platelet syndrome is obtained with biochemical analysis of α-granule contents. Patients with platelet-type (pseudo-) von Willebrand disease (VWD) and type 2b VWD have moderate thrombocytopenia and large platelets. Studies of glycoprotein (GP) Ib function and biochemistry described below establish the diagnosis. Patients who are hemizygous for GPIbβ because of deletion of 22q11.2, those with mutations in transcription factor GATA-1 or β1 tubulin (R318W), and some patients who are heterozygous for defects in GPIb/IX associated with Bernard-Soulier syndrome have variable thrombocytopenia and large platelets. The platelets in Bernard-Soulier syndrome itself are truly giant; the diagnosis is confirmed with biochemical and functional analyses of the GPIb/IX/V complex. A variety of methods have been developed to assess platelet function and new instrumentation continues to be developed.564,799–805 The bleeding time is prolonged in most patients with qualitative platelet disorders (although to various extents) except in the disorder of platelet coagulant activity (Scott syndrome), where the serum prothrombin time is the preferred screening assay. Other tests of platelet coagulant activity, microvesiculation, and phospholipid transfer are used to establish the diagnosis. Platelet aggregation can separate patients into those with defects in the primary wave of platelet aggregation (dependent on either fibrinogen, von Willebrand factor, their respective receptors, or agonist receptors for collagen or adenosine diphosphate [ADP]) and those with defects in the secondary wave of aggregation. Enhanced ristocetin-induced platelet aggregation at low doses of ristocetin is characteristic of patients with platelet-type VWD (who have a defect in the GPIb receptor that facilitates von Willebrand factor binding) and patients with type 2b VWD (who have an intrinsic defect in von Willebrand factor; see Chap. 127). These two diseases can be separated by analyzing the binding of the patient’s von Willebrand factor to normal platelets, or the ability of purified von Willebrand factor, cryoprecipitate or asialo-von Willebrand factor to aggregate patient platelets; confirmation of the diagnosis of platelet-type VWD requires genetic analysis of GPIb. Neither ristocetin nor the snake venom botrocetin induces platelet aggregation if the plasma lacks functional von Willebrand factor, as in most cases of VWD (see Chap. 127), or if the platelets lack functional GPIb/IX complexes, as in Bernard-Soulier syndrome. The defect in VWD, but not Bernard-Soulier syndrome, can be corrected by adding normal plasma or purified von Willebrand factor. Direct analysis of von Willebrand factor and the platelet GPIb/IX complex805a are used to confirm the diagnosis. Patients whose plasma lacks fibrinogen (afibrinogenemia; see Chap. 126) or whose platelets cannot bind fibrinogen because of abnormal αIIbβ3 receptors (Glanzmann thrombasthenia; Glanzmann Thromb) will have no primary wave of platelet aggregation in response to ADP or epinephrine. Analysis of plasma fibrinogen and platelet αIIbβ3 receptors can differentiate between these two groups. Isolated defects in the primary response to collagen have been observed in patients with abnormalities in platelet α2β1 (GPIa/IIa) or GPVI. Platelet glycoprotein analysis can separate these from each other. Because antibodies to GPVI can result in receptor depletion from circulating platelets, a search for an antibody to GPVI should be undertaken in patients with reduced levels of platelet GPVI. Other isolated defects in one or more of the ADP receptor or the thromboxane A2 (TXA2) receptor will result in decreased platelet aggregation in response to ADP or the thromboxane analogue U46619, respectively; isolated defects in the receptor for epinephrine will lead to a defect in primary aggregation in response to this agonist. A heterogeneous group of platelet defects can result in an abnormal secondary wave of platelet aggregation in response to ADP and epinephrine, and diminished responses to low doses of collagen and thrombin. They can be broadly separated into granule defects and defects in the platelet secretion or release reaction. Operationally, these two groups can be separated on the basis of their release of dense granule contents in response to high doses of thrombin. Thrombin activation can overcome most or all of the release reaction abnormalities, so platelets from patients with these disorders will release normal amounts of granule contents; in contrast, patients with reduced granule contents have abnormal release responses even when using high doses of thrombin. α- Granule contents and dense body contents can be measured immunologically and biochemically; electron microscopy can confirm the diagnosis of granule defects. Analysis of the genes or proteins implicated in the different granule defect abnormalities (Wiskott- Aldrich syndrome [WASP], Hermansky-Pudlak syndrome [HPS], Chédiak-Higashi syndrome [LYST], Paris-Trousseau/Jacobson syndrome [FLI1], and inherited platelet disorder with predisposition to leukemia [RUNX1]) can establish the diagnosis. The Quebec platelet disorder is characterized by increased urokinase plasminogen activator (uPA) in α granules and degradation of several α- granule proteins. The diagnosis can be established by immunoblot analysis or analysis of uPA activity. Secretion abnormalities arise due to defects in mechanisms that regulate the release of granule contents, and include abnormalities at the level of guanosine triphosphate (GTP)-binding proteins that link surface receptors to intracellular enzymes, phospholipase C activation, and protein phosphorylation (protein kinase C [PKC]-θ). They also arise from defects in thromboxane A2 synthesis because of deficiencies of phospholipase A2 (PLA2), cyclooxygenase, or thromboxane synthase. Specific studies on signal transduction mechanisms, phosphoinositide metabolism, Ca2+ mobilization, protein phosphorylation, and thromboxane production are needed to define these defects. Legend : From: Chapter 121. Hereditary Qualitative Platelet Disorders Williams Hematology, 8e, 2010 From: Chapter 121. Hereditary Qualitative Platelet Disorders Williams Hematology, 8e, 2010