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Classification of inherited thrombocytopenias according to platelet size.
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Inherited thrombocytopenias are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. Some of these diseases are exclusive to megakaryocytes and platelets, while in others the pathology extends to other cell types. Although the defective genes, coding for membrane glyoproteins, cytoskeleton components and intr...
Citations
... Congenital amegakaryocytic thrombocytopenia is an autosomal recessive disease characterized by severe thrombocytopenia since birth. 85,86 It may be caused by mutations in the MPL or THPO genes. 87,88 Most patients do not have associated physical abnormalities, although micrognathia, microcephaly, congenital heart disease, growth retardation, and maturation disorders have been described. ...
... 86,90 Mortality is high, in general secondary to intracranial hemorrhage. These patients tend to progress to aplastic anemia (50 % of cases), leukemia or myelodysplasia, 85,86,89,91 so the treatment of choice is hematopoietic stem cell transplantation, which should be done as early as possible; transplantation achieves a survival of more than 90 %. 92,93 Until the procedure is performed, the patient should be managed with PTs. 89,91 Treatment with romiplostim, which has proven to be highly effective in 3 children from an affected family, is under study. ...
... 86,90,95 As of 1 year old, thrombocytopenia tends to resolve, and remission is achieved by 4 years old in 70 % of cases. 91 These patients do not progress to pancytopenia and generally do not tend to a malignant change, 74,85,86,89,97 although isolated cases of leukemia have been reported. [98][99][100] Treatment includes periodic PTs to maintain the PC above 30 x 10 9 /L. ...
Non-immune thrombocytopenia is caused by multiple pathologies; the most common causes are extra- or intrauterine infections, whereas secondary cases result from other pathologies involved in the fetal-placentalmaternal interface. This second article lists its causes and provides details of the different pathologies. Platelet transfusion is widely used in neonatology, both as treatment and as bleeding prophylaxis. However, there is no general consensus about the platelet count threshold that is convenient to indicate a transfusion or actual indications. Recent articles are commented regarding the different proposed strategies. The emphasis is on discussing the multiple adverse effects of platelet transfusions because knowledge about them is changing the paradigm for indications, suggesting that a much more restrictive policy is required.
... The addition of normal plasma doesn't help aggregation, thus differentiating BSS from VWD. However, normal aggregation is seen with epinephrine, adenosine diphosphate, collagen, and arachidonic acid [11]. Testing for genetic mutations can differentiate between functional or synthetic problems of the GPIB-IX-V receptor complex, and this approach greatly improves the diagnosis of rare inherited platelet disorders [12]. ...
Bernard Soulier Syndrome is a genetically inherited platelet disorder that commonly presents with symptoms of impaired blood coagulation, such as epistaxis, menorrhagia, and petechiae formation. Here we present a case of Bernard Soulier Syndrome in which the individual has presented with melena, which is the appearance of black tarry stools due to bleeding from the upper gastrointestinal tract. This presentation is rare and should be discussed so that appearance of the less common symptoms can be caught early, leading to an early diagnosis and consequently earlier and more effective management options.
... The clinical suspicion of BSS has to be confirmed by different laboratory investigations. A variable degree of thrombocytopenia (platelet count range: <30 x 10 9 /L to normal [22,24]) might be observed, with a blood smear revealing abnormally large or irregularly shaped platelets (even in patients with normal platelet count) [32,33]. The closure time measured by the platelet function analyser (PFA-100/200) is increased and the bleeding time prolonged [34,35]. ...
... However, the sensitivity of PFA-100/200 assay depends on the severity of the defect [15,36], which implies further investigations (aggregometry and/or flow cytometry) to establish an accurate diagnosis. The VWF-dependent agglutination measured in the presence of ristocetin by light transmission aggregometry (LTA) is defective in homozygous BSS platelets (but normal in heterozygous form) [33]. Of note, this defect will not be rescued by the addition of normal plasma, which distinguishes BSS from von Willebrand disease (VWD) [35,37]. ...
... Of note, this defect will not be rescued by the addition of normal plasma, which distinguishes BSS from von Willebrand disease (VWD) [35,37]. In vitro aggregation of BSS platelets in response to epinephrine, ADP, collagen, and arachidonic acid is normal, but a slow response is observed with low doses of thrombin [33]. The expression of GPIb-IX-V complex at the platelet surface can be assessed by flow cytometry. ...
Platelets are active key players in haemostasis. Qualitative platelet dysfunctions result in thrombocytopathies variously characterized by defects of their adhesive and procoagulant activation endpoints. In this review, we summarize the traditional platelet defects in adhesion, secretion, and aggregation. In addition, we review the current knowledge about procoagulant platelets, focusing on their role in bleeding or thrombotic pathologies and their pharmaceutical modulation. Procoagulant activity is an important feature of platelet activation, which should be specifically evaluated during the investigation of a suspected thrombocytopathy.
... Transplantation should be considered in severe disorders when the patients have developed antiplatelet antibodies. Patients with BSS should be counseled about the importance of preventing even minor trauma as well as avoiding aspirin-containing medications and other platelet antagonists [52,53,60]. ...
Platelets, the smallest cells in the blood, are associated with hemostasis, bowel formation, tissue remodeling, and wound healing. Although the prevalence of inherited platelet disorders is not fully known, it is a rare disease group and is encountered in approximately between 10000 and 1000000. Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are more frequently observed in inherited platelet disorders. In GT, the platelet aggregation stage due to deficiency or dysfunction of the platelet GPIIb/IIIa complex cannot take place. BSS is a platelet adhesion disorder due to the absence or abnormality of GPIb/IX complex on the platelet surface. If there is bleeding after easy bruising, mucous and oral cavities, menorrhagia, tooth extraction, tonsillectomy, or other surgical interventions, inherited platelet dysfunction should be considered if the platelet count is normal while the bleeding time is long. Firstly, other causes should be investigated by making differential diagnosis of GT and BSS. In this chapter, the definition, etiology, historical process, epidemiology, genetic basis, pathophysiology, clinical findings, diagnosis, differential diagnosis, and the follow-up and treatment approach of GT and BSS will be reviewed according to the current medical literature.
... GP9 (chromosome 3q21), and GP5 (chromosome 3q29) that encode GPIbα, GPIbβ, GPIX, and GPV, respectively. Concomitant and proper expression of GPIbα, GPIbβ, and GPIX subunits are required for appropriate and efficient expression of the GPIb-IX-V complex on the cell surface [1,3,9,10,16,19,20]. ...
... In addition, GPIbβ defect can occur in patients with DiGeorge/velocardiofacial syndrome that is caused by microdeletion within chromosome 22q11.2, which in this region contains the GPIBB gene; thus, these patients are obligatory carriers of BSS ( Fig. 15.3) [3,11,17,20,22,23,32,46,53,54]. ...
... Cys5Tyr Arg17Cysfs14 [3,9,12,14,20,34,48,54,55,[57][58][59][60]. ...
Bernard-Soulier syndrome (BSS) is a rare mostly autosomal recessive platelet function disorder that is characterized by variable bleeding tendency, macrothrombocytopenia, impaired platelet agglutination in response to ristocetin, and defect in the glycoprotein (GP) Ib-IX-V complex. This disorder is due to mutations in one of the GPIb-IX-V complex encoding genes. BSS is usually present early in life with different bleeding diathesis including epistaxis, gingival bleeding, and purpura. Although diagnosis of some of severe inherited platelet function disorders (IPFD) such as BSS and Glanzmann thrombasthenia (GT) is straightforward, misdiagnosis is a challenge in BSS such as in many other IPFD. A considerable number of these patients initially are misdiagnosed as immune thrombocytopenic purpura (ITP), but further studies can resolve this issue. In addition to routine laboratory assessments, more specific laboratory studies such as aggregometry assays, flow cytometry, and molecular analysis can help to precise and timely diagnosis of disorder. BSS treatment includes supportive cares as well as specific treatment of bleeding episodes.
... GP9 (chromosome 3q21), and GP5 (chromosome 3q29) that encode GPIbα, GPIbβ, GPIX, and GPV, respectively. Concomitant and proper expression of GPIbα, GPIbβ, and GPIX subunits are required for appropriate and efficient expression of the GPIb-IX-V complex on the cell surface [1,3,9,10,16,19,20]. ...
... In addition, GPIbβ defect can occur in patients with DiGeorge/velocardiofacial syndrome that is caused by microdeletion within chromosome 22q11.2, which in this region contains the GPIBB gene; thus, these patients are obligatory carriers of BSS ( Fig. 15.3) [3,11,17,20,22,23,32,46,53,54]. ...
... Cys5Tyr Arg17Cysfs14 [3,9,12,14,20,34,48,54,55,[57][58][59][60]. ...
Bernard-Soulier syndrome (BSS) is a rare mostly autosomal recessive platelet function disorder that characterized by variable bleeding tendency, macrothrombocytopenia, impaired platelet agglutination in response to ristocetin and defect in the glycoprotein (GP) Ib-IX-V complex. This disorder is due to mutations in one of the GPIb-IX-V complex encoding genes. BSS is usually present early in life with different bleeding diathesis including epistaxis, gingival bleeding and purpura. Although diagnosis of some of severe inherited platelet function disorders (IPFD) such as BSS and Glanzmann thrombasthenia (GT) is straightforward, misdiagnosis is a challenge in BSS such many other IPFD. A considerable number of these patients initially are misdiagnosed as immune thrombocytopenic purpura (ITP), but further studies can resolve this issue. In addition to routine laboratory assessments, more specific laboratory studies such as aggregometry assays, flow cytometry and molecular analysis can help to precise and timely diagnosis of disorder. BSS treatment includes supportive cares as well as specific treatment of bleeding episodes.
... Among the most frequent MYH9 mutations are those affecting S96 and R702 located in the HD, R1165, D1424, E1841 in the coiled coil and R1933 in the NHT (Balduini et al., 2002). About 35% of cases are sporadic with de novo mutations (Balduini and Savoia, 2012) and two cases have been shown to be due to somatic or germinal mosaicism (Kunishima et al., 2005(Kunishima et al., , 2009. ...
Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count resulting in impaired hemostasis. Patients can have spontaneous hemorrhages and/or excessive bleedings provoked by hemostatic challenges as trauma or surgery. To date, ITs encompass 32 different rare monogenic disorders caused by mutations of 30 genes. This review will focus on the major discoveries that have been made in the last years on the diagnosis, treatment and molecular mechanisms of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases. Furthermore, we will discuss the use a Thrombopoietin mimetic as a novel approach to treat the thrombocytopenia in these patients. We will propose the use of a new 3D bone marrow model to study the mechanisms of action of these drugs and to test their efficacy and safety in patients. The overall purpose of this review is to point out that important progresses have been made in understanding the pathogenesis of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases and new therapeutic approaches have been proposed and tested. Future advancement in this research will rely in the development of more physiological models to study the regulation of human platelet biogenesis, disease mechanisms and specific pharmacologic targets.
... [4] Management of BSS includes supportive measures (platelet transfusion) for uncontrolled bleeding/ prophylaxis during surgery. [10] Alloimmunization and platelet refractoriness remain a problem in frequently transfused patients. Desmopressin and recombinant factor VIIa (rFVIIa) are other available alternatives. ...
... Desmopressin and recombinant factor VIIa (rFVIIa) are other available alternatives. [10] Counselling of patients to avoid trauma, aspirin containing medications and other platelet antagonists is paramount in order to avert serious bleeding. [10] In conclusion, BSS is rare bleeding disorder with highly variable clinical phenotype and is likely to be misdiagnosed and mismanaged. ...
... [10] Counselling of patients to avoid trauma, aspirin containing medications and other platelet antagonists is paramount in order to avert serious bleeding. [10] In conclusion, BSS is rare bleeding disorder with highly variable clinical phenotype and is likely to be misdiagnosed and mismanaged. Platelet aggregation studies and more definitely flowcytometry can provide an accurate diagnosis and timely institution of adequate therapy. ...
Bleeding syndromes in the newborn are rare, but they may be life-threatening and demand immediate attention. Congenital bleeding disorders especially pose a diagnostic challenge to the clinician because of their rarity and the need to be differentiated from the other common causes of bleeding in children. We present a case of an infant presenting with bleeding symptoms early in his life (since 5 months of age) which was initially thought to be immune thrombocytopenic purpura (ITP) with low platelet count. No response to steroids and further evaluation by platelet aggregometry and flowcytometry led to the correct diagnosis – Bernard soulier syndrome(BSS). Though, there is no specific treatment available for this rare bleeding disorder, however it is imperative to have arrived at correct diagnosis in order to save unnecessary therapy and to take due precautions for prevention of bleeding.
... Myosin light chains bind the neck region of the heavy chains, and when the light chains are phosphorylated, the complex is activated and can bind actin filaments and initiate the contractile response. The C-terminal assists actin polymerisation and cargo-loading; reviewed in Althaus and Greinacher 45 and Balduini et al. 46 Heterozygous mutations have a dominant negative affect because the WT protein becomes sequestered in intracellular aggregations with mutant protein. 47,48 MK numbers in the marrow may be slightly elevated. ...
... 51,52 This includes MYL9, another component of NMM-II that associates with MYH9 encoded heavy chain. 46 A female patient presented with immunodeficiency and mild thrombocytopenia, caused by homozygous nonsense mutation in MKL1. 53 Whilst the patient's MK were not studied directly, their neutrophils showed impaired migration and podosome formation was impaired in monocyte derived dendritic cells. ...
The actin cytoskeleton plays many important roles in the lifecycle of platelets, from biogenesis from megakaryocytes, to activation and clearance from the circulation. It is therefore unsurprising that mutations in genes regulating the dynamics of this cytoskeleton lead to numerous inherited thrombocytopenias. A diverse array of proteins are affected, including actin nucleators, structural proteins, myosin motors, and transcriptional regulators. This review summarises the current understanding of how genetic dysregulation of the actin cytoskeleton can contribute to the pathogenesis of thrombocytopenia.
... Splenectomy does not seem to be helpful in GPS. Newer therapies such as recombinant activated factor VIIa (rFVIIa) may have a role in some platelet disorders 11,12 . ...
Gri trombosit (platelet) sendromu (GPS), trombositopeni ve ışık mikroskopunda soluk görünen kusurlu trombositlerle karakterize, otozomal resesif geçişli bir hastalıktır. Hastalarda kolay morarma, burun kanaması, menoraji ve uzun kanamalar görülmektedir. GPS için spesifik bir tedavi bulunmamaktadır dolayısı ile hastalığa karşı, riskleri öngörmek ve kanamanın önlenmesi için trombosit fonksiyonunu bozan ilaçlardan kaçınmak gerekmektedir. Bu olgu sunumunda, tekrarlayan anormal kanama atakları olan ve GPS bulgusu bulunan bir vaka sunulmaktadır.
