Inherited Platelet Function Disorders (IPFDs).

BACKGROUND: Inherited platelet function disorders (IPFDs) are a wide spectrum of qualitative platelet disorders with variable bleeding tendency, ranging from mild bleeding to severe life-threatening episodes. Diagnosis and classification of IPFDs is a challenge worldwide. The present study aims to present a proper classification, describe the molecular basis and clinical presentations as well as some diagnostic clues for these disorders. METHODS: All relevant publications were searched using appropriate keywords. RESULTS: IPFDs can be divided into four major groups including defects of platelet surface glycoproteins, platelet granules and secretion disorders, platelet signaling defects, and transcription-related platelet disorders. Some of these disorders, such as Glanzman thrombasthenia, are more common, with severe bleeding, while most of these disorders are extremely rare with mild bleeding. CONCLUSIONS: A proper classification, accompanied by familiarity with diagnostic clinical and laboratory features of IPFDs, can be helpful in in-time and exact diagnosis of these complicated bleeding disorders.

Genetic basis of congenital platelet disorders.

Over the past 4 decades, a better understanding of the genetic origins of inherited platelet disorders has illuminated avenues of investigation in megakaryopoiesis and has identified targets of pharmacologic intervention. Many of these discoveries have been translated into clinical medicine. The success of inherited platelet disorder research is underpinned by broader advances in methodology through the biochemical and molecular revolution of the 20(th) and 21(st) centuries, respectively. Recently, modern genomics techniques have affected platelet and platelet disorders research, allowing for the discovery of several genes involved in platelet production and function and for a deeper understanding of the RNA and miRNA networks that govern platelet function. In this short review, we focus on recent developments in the genetic elucidation of several disorders of platelet number and in the molecular architecture that determines the "genetic makeup" of a platelet in health and disease.

Approach to a child with bleeding in the emergency room.

A bleeding child is a cause of great concern and often, panic, for parents and pediatricians alike. Causes of bleeding could be trivial or secondary to an underlying bleeding disorder or a potentially serious systemic illness. Based on etiology, they can be categorized into disorders affecting platelets or the coagulation cascade and can be inherited or acquired. A systematic approach with relevant clinical history and examination along with appropriate laboratory investigations aid in reaching the diagnosis promptly. Indication and administration of blood products including fresh frozen plasma, cryoprecipitate, random donor and single donor apheresis platelets is elaborated. Management of hemophilia, Von Willebrand disease, disseminated intravascular coagulation and bleeding in cyanotic congenital heart disease, among other causes is outlined. Role of antifibrinolytic therapy, desmopressin and recombinant factor VIIa is briefly described. The review outlines the approach to a bleeding child in the emergency room. Practical points in history, examination, investigations and management are discussed. Management in resource constraint setting of developing countries is addressed.

An update on the platelet dysfunction in chronic myeloproliferative syndromes.

The thrombotic and hemorrhagic diathesis represents a frequent complication in myeloproliferative disorders (CMPD). They are correlated with the number of platelets, but also with their qualitative disorders, such as membrane glycoprotein changes. The latter are revealed by many platelet essays including flow-cytometry and include modified activation, secretion and aggregation patterns. The thrombopoietin platelet receptor (cMPL), affected by the JAK2 V617 mutation encountered in CMPD, may be associated with a prothrombotic status. Its implication reveals the importance of the molecular genetics profile in defining molecular diagnostic hallmarks and makes it a candidate in the early diagnosis of myeloproliferative disorder and a predictor of thrombotic complications in this group of diseases.

Platelet function defects.

Inherited defects of platelet function are a heterogeneous group of disorders that can result in bleeding symptoms ranging from mild bruising to severe mucocutaneous haemorrhage. These defects may be classified according to their effect on the various steps of platelet microthrombi formation including initiation, extension and cohesion, or based on their particular structural or functional deficiency. Platelet membrane receptor deficiencies result in the rare, but well-characterized syndromes of defective clot initiation, such as Bernard-Soulier Syndrome. Platelet storage pool defects are the most common disorders affecting the extension phase of clot formation. Glanzmann thrombasthenia, with absent or dysfunctional alpha IIb beta 3 receptor is the prototypical defect of the cohesion/aggregation phase of microthrombi formation. Many of these disorders share common treatments although some therapies will have greater efficacy for one patient than another and should be individualized so as to provide optimal control of symptoms. Currently much effort is being put into methods to more rapidly and accurately diagnose patients with platelet disorders and to initiate appropriate therapy and prevent life threatening bleeding.

Congenital platelet disorders.

Congenital platelet disorders represent a rare group of diseases classified by either a qualitative or quantitative platelet defect. This article outlines the historical, clinical, laboratory, and genetic features of various inherited platelet disorders with attention given to updated information on disease classification, diagnosis, and genotypes. A separate discussion regarding management addresses the difficulty in treatment strategies, particularly in patients who develop alloimmunization to platelets.

[Murine models of platelet diseases]. / Modèles murins de pathologies plaquettaires.

Platelet-related diseases correspond to functional defects or abnormal production (thrombopoiesis) of hereditary and immunological origins. Recent progress in the manipulation of the mouse genome (transgenesis, gene inactivation or insertion) has resulted in the generation of numerous strains exhibiting defective platelet function or production. Some strains reproduce known hereditary diseases affecting haemostasis (Glanzmann thrombasthenia, Bernard-Soulier syndrome (BSS) or thrombopoiesis (Wiscott-Aldrich or May-Hegglin syndrome). More often the mutated strains have no human equivalent and represent useful models to study: (i) the role of adhesive or signalling receptors or of signalling proteins in platelet-dependent haemostasis and thrombosis or; (ii) to study the poorly characterized mechanisms of thrombopoiesis, which implicate transcription factors (GATA, Fli1), growth factors and receptors (TPO, cMPL), and cytoskeletal or contractile proteins (tubulin, myosin). Additional mouse strains result from the selection of spontaneous mutants many of which affect intracellular platelet granules, representing models of storage pool diseases (SPD) such as the Gray platelet syndrome (alphaSPD) or Hermansky-Pudlack syndrome (deltaSPD). More recently, a systematic chemical mutagenesis approach has also identified genes involved in thrombopoiesis and platelet survival. Finally, mouse models of auto- or allo-immune thrombocytopenia have been developed to study the mechanisms of platelet destruction or removal.

[First results of the THROMKID study: a quality project for the registration of children und adolescents with hereditary platelet function defects in Germany, Austria, and Switzerland]. / Erste Ergebnisse der THROMKID-Studie: Qualitätsprojekt zur Erfassung von Kindern und Jugendlichen mit angeborenen Thrombozytenfunktionsstörungen in Deutschland, Osterreich und der Schweiz.

THROMKID is a quality project of the Paediatric Group of German Thrombosis and Haemostasis Research Society (GTH). Data from paediatric patients with hereditary thrombocytopathies (HT) treated in Germany, Austria, and Switzerland were obtained between May 2005 and August 2006. By evaluation of results of platelet function tests criteria were determined to assess the diagnosis in each patient into most likely, likely or unlikely. A total of 215 patients treated in 31 centers were identified. In 95 patients (44%) the diagnosis of HT was most likely, in 28 (13%) likely and in 92 (43%) unlikely. Taken the first two groups together (n = 123) the diagnoses were as follows: Glanzmann thrombasthenia (n = 39, 32%), Aspirin-like defect (n = 26, 21%), thrombocyte receptor defects (n = 21, 17%), storage pool disorders (n = 18, 15%), Bernard-Soulier syndrome (n = 10, 8%), Hermansky-Pudlak syndrome (n = 6, 5%) and MYH9-related hereditary makrothrombocytopenia (n = 3, 2%). The low prevalence of these diseases and the high percentage of patients with unclassified HT stresses the necessity for the establishment of a competence network for comprehensive care of these patients in the three German-speaking countries.

Acquired disorders of platelet function.

A qualitative abnormality of platelet function should be considered in patients with mucocutaneous bleeding in the absence of thrombocytopenia or von Willebrand disease. Antiplatelet drugs are the most common cause of acquired platelet disorders leading to bleeding. Uremia, hepatic cirrhosis, myeloma and related disorders, polycythemia vera, essential thrombocythemia, and cardiopulmonary bypass have long been recognized as clinical situations in which platelet dysfunction may contribute to bleeding. When an acquired platelet disorder is suspected, it is useful to examine platelet function by measuring the bleeding time, examining platelet-dependent closure time in a platelet function analyzer and performing platelet aggregometry. When a specific acquired platelet disorder is diagnosed, many treatment options are available including controlling the underlying disease, giving platelet transfusions and administering a hemostatic drug.

[Congenital and acquired platelet function disorders]. / Angeborene und erworbene Thrombozytenfunktionsstörungen.

A survey is given on congenital and acquired platelet functional disorders. Congenital platelet functional disorders are extremely rare. Acquired platelet functional disorders are probably the most frequent disturbances of haemostasis. The knowledge of the defects leading to inherited platelet function disorders much improved our understanding of platelet function in general. Acquired platelet functional disorders are due to various diseases and drugs.

Spectrum of inherited bleeding disorders from Western India.

OBJECTIVE: The study was undertaken to assess the magnitude and diversity of different bleeding disorders in Western India. MATERIALS AND METHODS: 768 cases referred to our Institute for evaluation of an underlying bleeding diathesis were investigated appropriately to detect the cause of the abnormal hemostatic function. RESULTS: 630 patients were diagnosed to have hereditary bleeding diathesis. Amongst these, 598 patients had a coagulation disorder while only 32 patients had a platelet function abnormality. Amongst the coagulation disorders, hemophilia A (70.5%) was the most common disorder followed by hemophilia B (14%) and VWD (10.8%). Glanzman's thrombasthenia (84.3%) was the most common platelet function disorder followed by Bernard-Soulier syndrome (12.5%). Some rare disorders have also been diagnosed. CONCLUSION: In spite of their apparent rarity, India has a substantial number of cases of inherited bleeding disorders. A large number of these patients is referred to many tertiary care institutions. It is therefore desirable that district hospitals must develop their laboratories to detect most of these disorders so that the patients need not travel long distances to get an appropriate diagnosis and proper management. All 1st degree female relatives of severe and moderate hemophilia must get factor assays done because some of them may be vulnerable to post-procedural or post-traumatic bleeding.

Trombocitopatías: casos clínicos / Bleeding diseases: clinical cases

Se presentan dos casos de baja prevalencia pero que en algunas ocasiones adquieren gran complejidad en su tratamiento, dado que necesitan el empleo de transfusión de plaquetas sanguíneas como terapia sistémica, un procedimiento que comprende grandes inconvenientes. Las plaquetas deben ser transfundidas dentro de un período no superior a 6 horas, dado que poseen una gran labilidad y pierden el 80 por ciento de su actividad. Estas son afecciones genéticas y hemorrágicas debidas a la ausencia de glucoproteínas de la membrana plaquetaria

Platelet-associated bleeding disorders.

OBJECTIVE: To provide a review of platelet disorders, treatment, and nursing care. DATA SOURCES: Review articles and book chapters pertaining to quantitative and qualitative platelet disorders. CONCLUSIONS: Platelet-associated bleeding disorders are classified as quantitative (abnormal number), qualitative (abnormal function), or hypercoagulable states (errors in hemostasis). The resulting complications include thrombocytosis, thrombocytopenia, hypercoagulation, or bleeding dyscrasias. The administration of drugs, plasma, or platelet therapy may be beneficial to these patients. IMPLICATIONS FOR NURSING PRACTICE: Patients with platelet disorders are at great risk of life-threatening hemorrhage and require close monitoring to prevent unnecessary sequelae. Patient instruction to prevent trauma is required.

Disorders of platelet function.

Qualitative platelet disorders are described and reviewed above. The acquired platelet function defects are very common, and sometimes result in hemorrhage, especially in association with trauma or surgery. However, the specific biochemical defect is absent, and no characterized platelet abnormalities have been recognized. On the other hand, the hereditary qualitative platelet defects are rare, but the platelet abnormalities are characteristic. The study of these patients had led to an increased understanding of the normal primary hemostatic mechanism. Recently, the molecular basis analysis of the platelet defects has been developed. This will help us understand the molecular events involved in platelet adhesion and aggregation.

Laboratory evaluation of platelet dysfunction.

Platelet dysfunction, especially acquired forms, is a common cause of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally rare, hereditary storage pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are very common and should promptly be suspected in patients with easy and spontaneous bruising, mild-to-moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in the patient frankly bleeding, is not reliable, and platelet aggregation or lumi-aggregation should be done in applicable clinical situations. Prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for all of these defects, if bleeding is important, is the liberal infusion of suitable numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.

Inherited diseases of platelet glycoproteins: considerations for rapid molecular characterization.

The characterization of inherited diseases of platelets has provided valuable information about platelet physiology and platelet protein function. Genetic studies on patients with Glanzmann thrombasthenia, the Bernard-Soulier syndrome, and platelet-type von Willebrand disease have been confined to abnormalities of the GPIIb-IIIa and GPIb-IX receptor complexes. The primary molecular technique used in these analyses has been the polymerase chain reaction (PCR). The amplified PCR products are either directly sequenced, or used to screen for abnormal regions of the genes which are then sequenced. This review examines the known mutations in GPIIb-IIIa and GPIb-IX, focusing on those genetic issues which should dictate decisions regarding the approach to identifying molecular defects. The techniques for characterizing mutant alleles in Glanzmann thrombasthenia and Bernard-Soulier syndrome are described and a general strategy is offered. Because mutations resulting in reduced levels of transcripts can be missed when screening RNA, an argument is made for using genomic DNA as the primary material for mutation detection.

Platelet function defects associated with hemorrhage or thrombosis.

Platelet dysfunction, especially acquired forms, is a common cause of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally quite rare, hereditary storage pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are common and should promptly be suspected in patients developing easy and spontaneous bruising, mild-to-moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in a patient frankly bleeding, is not reliable, and platelet aggregation or lumiaggregation should be done in appropriate clinical situations. Also, prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for almost all these defects, if bleeding is significant, is the liberal infusion of appropriate numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.