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Blood Transfusion = Trasfusione Del... Sep 2022Acquired platelet function disorders (PFD) are rare bleeding diseases that should be suspected in all patients with unexplained mucocutaneous bleedings of recent onset,... (Review)
Review
Acquired platelet function disorders (PFD) are rare bleeding diseases that should be suspected in all patients with unexplained mucocutaneous bleedings of recent onset, with no previous history of haemorrhages, and with normal coagulation test and platelet count. Drug-induced platelet function bleeding disorders are the most frequent PFDs and can easily be identified on the basis of recent administration of platelet-inhibiting drugs. Apart from these, the most challenging acquired PFDs are those caused by autoimmune mechanisms. In fact, demonstration of autoantibodies inhibiting platelet function may be difficult in most non-specialised centres. Among autoimmune PFDs (aPFDs), acquired Glanzmann thrombasthenia (aGT), which is caused by autoantibodies that bind to platelet αIIbβ3 integrin, inhibiting its function, is the most frequent. aGT can be associated with underlying haematological malignancies or autoimmune diseases but can also be idiopathic. More rarely, other immune-mediated PFDs can occur, such as acquired delta storage pool disease (aδSPD). Treatment of aPFDs must rely on the control of acute and chronic bleedings, treatment of the underlying disease in secondary forms, and immunosuppressive treatment for autoantibody reduction or eradication. aPFDs may completely resolve upon treatment of any underlying disease that may be present. In primary aPFDs, and in the majority of secondary forms, treatment relies on immunosuppressive therapies.Here we present a systematic review of previously described immune-mediated aGT and aδSPD cases. Clinical and laboratory characteristics, treatments for the control of bleedings and for the eradication of autoantibodies, and responses to treatments are also discussed. Although no guidelines are available for the management of these very rare conditions, presentation of all cases reported so far can help clinicians in the diagnosis and treatment of these life-threatening diseases.
Topics: Albinism; Autoantibodies; Autoimmune Diseases; Hemorrhagic Disorders; Hermanski-Pudlak Syndrome; Humans; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombasthenia
PubMed: 34369869
DOI: 10.2450/2021.0119-21 -
Journal of Thrombosis and Haemostasis :... Aug 2005Qualitative disorders of platelet function and production form a large group of rare diseases which cover a multitude of genetic defects that by and large have as a... (Review)
Review
Qualitative disorders of platelet function and production form a large group of rare diseases which cover a multitude of genetic defects that by and large have as a common symptom, excessive mucocutaneous bleeding. Glanzmann thrombasthenia, is enabling us to learn much about the pathophysiology of integrins and of how alphaIIb beta3 functions. Bernard-Soulier syndrome, an example of macrothrombocytopenia, combines the production of large platelets with a deficit or non-functioning of the major adhesion receptor of platelets, the GPIb-IX-V complex. Amino acid substitutions in GPIb alpha, may lead to up-regulation and spontaneous binding of von Willebrand factor as in Platelet-type von Willebrand disease. In disorders with defects in the MYH9 gene, macrothrombocytopenias are linked to modifications in kidney, eye or ear, whereas other inherited thrombocytopenias variously link a low platelet count with a propensity to leukemia, skeletal defects, learning impairment, and abnormal red cells. Defects of secretion from platelets include an abnormal alpha-granule formation as in the gray platelet syndrome (with marrow myelofibrosis), and of organelle biogenesis in the Hermansky-Pudlak and Chediak-Higashi syndromes where platelet dense body defects are linked to abnormalities of other lysosomal-like organelles including melanosomes. Finally, defects involving surface receptors (P2Y(12), TPalpha) for activating stimuli, of proteins essential for signaling pathways (including Wiskott-Aldrich syndrome), and of platelet-derived procoagulant activity (Scott syndrome) show how studies on platelet disorders are helping unravel the pathways of primary hemostasis.
Topics: Bernard-Soulier Syndrome; Blood Platelet Disorders; Blood Platelets; Coagulants; Genetic Therapy; Humans; Integrins; Megakaryocytes; Models, Biological; Platelet Aggregation; Protein Binding; Signal Transduction; Thrombasthenia; Thrombocytopenia; Up-Regulation; von Willebrand Factor
PubMed: 16102044
DOI: 10.1111/j.1538-7836.2005.01428.x -
Pathophysiology : the Official Journal... Dec 2018Thrombocytopenia (TCP) and Glanzmann thrombasthenia (GT) are typical platelet disorders characterized by mild to severe bleeding. This study aims to create in vitro...
Thrombocytopenia (TCP) and Glanzmann thrombasthenia (GT) are typical platelet disorders characterized by mild to severe bleeding. This study aims to create in vitro models of TCP and GT and to correct the impaired clot formation by fibrinogen and coagulation factor XIII. The TCP model (mean platelet count, 16 × 10 L) was produced by differential centrifugation of normal blood followed by mixing plasma with packed cells. The GT model was created by treating normal blood with 50 μg/mL eptifibatide, an inhibitor of platelet integrin αIIbβ3. Clot formation was evaluated in whole blood by rotation thromboelastometry. In both models, the extent of clot strength was two-three times lower compared to normal blood. Fibrinogen and, to a lesser extent, factor XIII stimulated the propagation phase of clot formation both in TCP and GT models. Clot strength in TCP was increased by both agents, while in GT by fibrinogen only. Similar results were obtained in blood from patients with primary immune thrombocytopenia and Glanzmann thrombasthenia. In conclusion, the created models may be useful in the development of new ways to correct the impaired coagulation potential in TCP and GT.
PubMed: 29805054
DOI: 10.1016/j.pathophys.2018.05.005 -
Clinical Genetics Aug 2018Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by spontaneous mucocutaneous bleeding. The disorder is caused by quantitative or qualitative...
Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by spontaneous mucocutaneous bleeding. The disorder is caused by quantitative or qualitative defects in integrin αIIbβ3 (encoded by ITGA2B and ITGB3) on the platelet and is more common in consanguineous populations. However, the prevalence rate and clinical characteristics of GT in non-consanguineous populations have been unclear. We analyzed 97 patients from 93 families with GT in the Han population in China. This analysis showed lower consanguinity (18.3%) in Han patients than other ethnic populations in GT-prone countries. Compared with other ethnic populations, there was no significant difference in the distribution of GT types. Han females suffered more severe bleeding and had a poorer prognosis. We identified a total of 43 different ITGA2B and ITGB3 variants, including 25 previously unidentified, in 45 patients. These variants included 14 missense, 4 nonsense, 4 frameshift, and 3 splicing site variants. Patients with the same genotype generally manifested the same GT type but presented with different bleeding severities. This suggests that GT clinical phenotype does not solely depend on genotype. Our study provides an initial, yet important, clinical and molecular characterization of GT heterogeneity in China.
Topics: Adolescent; Adult; Blood Platelets; Child; Child, Preschool; China; Female; Frameshift Mutation; Genetic Predisposition to Disease; Genotype; Hemorrhage; Humans; Infant; Integrin alpha2; Integrin beta3; Male; Middle Aged; Mutation, Missense; Platelet Aggregation; Thrombasthenia; Young Adult
PubMed: 29675921
DOI: 10.1111/cge.13366 -
Blood Coagulation & Fibrinolysis : An... Apr 2024As bleeding disorders are a worldwide health concern, Saudi Arabia is experiencing a notable prevalence of such disorders. Studying the frequency and cause of hemostatic... (Review)
Review
As bleeding disorders are a worldwide health concern, Saudi Arabia is experiencing a notable prevalence of such disorders. Studying the frequency and cause of hemostatic disorders is the key to successful clinical interventions and instigating effective public policies that limit the spread of such disorders. The current review aims to highlight the major findings of the body of literature that has investigated the causes, prevalence, and major challenges associated with bleeding disorders in the country. The current review summarizes the major findings of different studies that have been conducted in Saudi Arabia regarding different bleeding disorders. Multiple causes and symptoms of bleeding disorders have been reported by different studies. Some studies investigated the genetic aspect of bleeding disorders and revealed specific mutations in coagulation factor genes influencing the symptoms of different bleeding disorders. Moreover, rare bleeding disorders such as Glanzmann thrombasthenia and Henoch-Schönlein purpura, have been reported in different regions of Saudi Arabia. Combining clinical presentations, genetic factors, and epidemiological data, the current review of the literature provides a comprehensive insight into bleeding disorders in the kingdom. This will help in advancing the diagnostic capabilities and genetic counseling enhancing management strategies and therapeutic interventions benefiting bleeding disorder patients and the kingdom.
Topics: Humans; Saudi Arabia; Blood Coagulation Disorders; Thrombasthenia; Hemorrhage; Hemostatic Disorders; Prevalence; Rare Diseases
PubMed: 38358894
DOI: 10.1097/MBC.0000000000001286 -
Blood Apr 2022Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and...
Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and delivery are recognized risk periods for bleeding in women with GT. The newborn may also be affected by fetal and neonatal immune thrombocytopenia induced by the transplacental passage of maternal anti-αIIbβ3 antibodies, which can lead to severe hemorrhage and fetal loss. Pregnancy in women with GT thus requires a multidisciplinary approach, including prepregnancy counseling and a treatment plan for delivery for both the mother and child. In this article, we summarize the current knowledge on pregnancy in women with GT and describe how we manage this severe platelet disorder in our clinical practice.
Topics: Female; Fetal Death; Hemorrhage; Humans; Infant, Newborn; Infant, Newborn, Diseases; Platelet Glycoprotein GPIIb-IIIa Complex; Pregnancy; Purpura, Thrombocytopenic, Idiopathic; Thrombasthenia; Thrombocytopenia, Neonatal Alloimmune
PubMed: 35286390
DOI: 10.1182/blood.2021011595 -
Haematologica Aug 2015Standard treatment for Glanzmann thrombasthenia, a severe inherited bleeding disorder, is platelet transfusion. Recombinant factor VIIa is reported to be effective in...
Standard treatment for Glanzmann thrombasthenia, a severe inherited bleeding disorder, is platelet transfusion. Recombinant factor VIIa is reported to be effective in Glanzmann thrombasthenia with platelet antibodies and/or refractoriness to platelet transfusions. We aimed to evaluate recombinant factor VIIa effectiveness and safety for the treatment and prevention of surgical bleeding in patients, with or without platelet antibodies and/or refractoriness, using data from the Glanzmann Thrombasthenia Registry, an international, multicenter, observational, post-marketing study of rFVIIa. Between 2007 and 2011, 96 patients were treated for 206 surgical procedures (minor 169, major 37). History of platelet antibodies was present in 43 patients, refractoriness in 23, antibodies+refractoriness in 17, while 47 had no confirmed antibodies/refractoriness. Treatments analyzed included antifibrinolytics, recombinant factor VIIa, recombinant factor VIIa+antifibrinolytics, platelets±antifibrinolytics and recombinant factor VIIa+platelets±antifibrinolytics. The most frequent treatment for minor procedures was recombinant factor VIIa+antifibrinolytics (n=65), and for major procedures, recombinant factor VIIa+platelets±antifibrinolytics (n=13). In patients without antibodies/refractoriness, recombinant factor VIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for minor and major procedures. The effectiveness of treatment for minor procedures in patients with antibodies and refractoriness was 88.9% for recombinant factor VIIa, 100% for recombinant factor VIIa+antifibrinolytics, 66.7% for platelets±antifibrinolytics and 100% for recombinant factor VIIa+platelets±antifibrinolytics. One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics). For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (±antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients. This trial was registered at clinicaltrials.gov identifier: 01476423.
Topics: Adolescent; Adult; Antifibrinolytic Agents; Child; Child, Preschool; Factor VIIa; Female; Hemorrhage; Humans; Male; Platelet Transfusion; Recombinant Proteins; Registries; Thrombasthenia; Treatment Failure; Treatment Outcome; Young Adult
PubMed: 26001792
DOI: 10.3324/haematol.2014.121384 -
British Journal of Haematology Apr 2014Genetic defects of platelets constitute rare diseases that include bleeding syndromes of autosomal dominant, recessive or X-linked inheritance. They affect platelet... (Review)
Review
Genetic defects of platelets constitute rare diseases that include bleeding syndromes of autosomal dominant, recessive or X-linked inheritance. They affect platelet production, resulting in a low circulating platelet count and changes in platelet morphology, platelet function, or a combination of both with altered megakaryopoiesis and a defective platelet response. As a result, blood platelets fail to fulfil their haemostatic function. Most studied of the platelet function disorders are deficiencies of glycoprotein mediators of adhesion and aggregation while defects of primary receptors for stimuli include the P2Y12 ADP receptor. Studies on inherited defects of (i) secretion from storage organelles (dense granules, α-granules), (ii) the platelet cytoskeleton and (iii) the generation of pro-coagulant activity have identified genes indirectly controlling the functional response. Signalling pathway defects leading to agonist-specific modifications of platelet aggregation are the current target of exome-sequencing strategies. We now review recent advances in the molecular characterization of platelet function defects.
Topics: Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Blood Platelets; Humans; Platelet Adhesiveness; Purpura, Thrombotic Thrombocytopenic; Receptors, Cell Surface; Signal Transduction; Thrombasthenia
PubMed: 24286193
DOI: 10.1111/bjh.12662 -
TH Open : Companion Journal To... Jul 2019Standard treatment for Glanzmann thrombasthenia (GT), a severe inherited bleeding disorder, is platelet transfusion. Recombinant activated factor VII (rFVIIa) is...
Standard treatment for Glanzmann thrombasthenia (GT), a severe inherited bleeding disorder, is platelet transfusion. Recombinant activated factor VII (rFVIIa) is reported to be effective in GT with platelet antibodies and/or refractoriness to platelet transfusions. We evaluated rFVIIa effectiveness and safety for the treatment and prevention of surgical and nonsurgical bleeding in children <18 years old, with or without platelet antibodies and/or refractoriness, as reported in the GT Registry (GTR). Data were used from the GTR, an international, multicenter, observational, postmarketing study of rFVIIa that prospectively collected data on the treatment and outcomes of bleeds in patients with GT. Only patients with a diagnosis of congenital GT were included in the registry. Between 2007 and 2011, 27 children were treated for 44 surgical procedures (minor: 36; major: 8); nonsurgical bleeds occurred in 104 patients (599 episodes: severe, 145; moderate, 454; spontaneous, 423; posttraumatic, 176). The effectiveness of treatment for minor procedures, major procedures, nonsurgical bleeds was 6/6, 1/1, and 75/84 for rFVIIa, 6/6, 2/2, and 64/76 for rFVIIa + antifibrinolytics (AF), 11/12, 1/1, and 162/214 for platelets ± AF, and 5/6, 0/3, and 33/45 for rFVIIa + platelets ± AF. In all, 25 adverse events were reported in children; no thromboembolic events were reported. For all patients, regardless of platelet antibody or refractoriness status, rFVIIa, administered with or without platelets (± AF), provided effective hemostasis with a low frequency of adverse events in surgical, as well as nonsurgical, bleeding in patients with GT. clinicaltrials.gov identifier: NCT01476423.
PubMed: 31523745
DOI: 10.1055/s-0039-1696657 -
International Journal of Clinical and... Apr 2010Glanzmann's thrombasthenia is a rare congenital bleeding disorder. Patients usually present with mucocutaneous bleeding and excessive bleeding associated with trauma... (Review)
Review
Glanzmann's thrombasthenia is a rare congenital bleeding disorder. Patients usually present with mucocutaneous bleeding and excessive bleeding associated with trauma and/or surgery. Patients have an increased bleeding time and a normal platelet count with abnormal platelet function assays. Genetically, Glanzmann's thrombasthenia is associated with mutations in the genes which encode for glycoproteins, GPIIb or GPIIIa. Defects in these genes lead to a lack of or highly reduced expression of the glycoprotein complex (GPIIb/GPIIIa), resulting in platelet dysfunction. Bleeding is managed by platelet transfusions. Bone marrow transplants have been used successfully in rare cases. With proper supportive care Glanzmann's thrombasthenia has a very good prognosis.
Topics: Fatal Outcome; Female; Humans; Thrombasthenia
PubMed: 20490335
DOI: No ID Found