الفهرس 
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Abstract
Inherited platelet disorders are rare bleeding diseases. They can be classified as hereditary macro thrombocytopenias /micro thrombocytopenia, and disorders of platelet signaling defects, platelet granules, platelet membrane, and defective platelet coagulant function. (Swieringa, 2018).
The main role of platelets is to maintain vascular system integrity and normal haemostasis. These functions rely on the ability of the platelets to provide particular receptors to interact with the exposed extracellular matrix such as type 1 collagen and von Willebrand Factor (VWF) in order to activate signaling pathways. Platelets are generated and activated by locally produced agonists to induce a change in their shape from discs to tiny spheres with reorganized cytoskeleton and filopodia (Van der and Heemskerk, 2018).
Platelet activation is stimulated and results in the aggregation of platelets that eventually form platelet plugs at injury sites to arrest bleeding (Berna Erro et al., 2013).
Thrombin plays an important role in platelet activation via GPIbα binding of thrombin to position it for efficient cleavage of the N-terminal end of protease activated receptor (PARs) molecules particularly PAR-1 in humans. This induces G-protein coupled receptor signaling pathways that are essential in platelet activation (Quach et al., 2018).
IPD diagnosis is straightforward in the major platelet function disorders such as BSS and GT, which often present with severe bleeding symptoms early in life and are easily recognized by the pattern of platelet aggregation defects.
In some IPDs, the platelet function defect and impaired hemostasis are part of well-defined syndromes, e.g. Chediak Higashi Syndrome (CHS) and HPS, where the platelet granule defect is typically associated with immune deficiency or ocular albinism, respectively (Turro et al., 2016).
Diagnosis is further complicated by the fact that for many IPDs, the platelet count is within normal ranges and the disorder may only become apparent after a hemostatic challenge or if cases present with accompanying pathologies in other organ systems, including malignancies (Turro et al., 2016).
Inherited platelet disorders are associated with a wide range of bleeding symptoms. However, as a rule, there is no specific therapy for the vast majority and only severe cases need to be treated. The management of patients with inherited platelet diseases usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control haemorrhagic episodes. However, as the type and severity of bleeding vary in different patients, therapeutic approaches must be personalized (Abbonante, 2017).
The aim of this work was to review genetics, pathobiologic features and their clinical implications in management of inherited platelet disorder.
Platelet reactivity for different disease pathogenesis is widely dependent upon some biologically active markers like CD36, CD41, CD42a, CD42b, and CD61. These include some active surface receptors and platelet secretory products. Platelet tends to alter the expression and signaling of these markers in different disease diagnosis and prognosis, providing a huge field to explore disease progression (Zhu et al., 2016).
Platelets are completely different from endothelial cells and can interact in multiple ways when exposed to endothelial surface. These interactions can be of cross talk over a distance also known as paracrine signaling via transient interactions or through receptor mediated cell- cell adhesion. Platelets are also able to release or transfer many substances as discussed earlier that also interact with endothelial cell (Bianchi et al., 2016).
Platelet starts to change its shape by the formation of pseudopods when intracellular Ca2+ concentration exceeds a specific threshold (Freson and Turro, 2017).
Platelet factor-4 is a 70-amino acid protein that is released from the alpha-granules of activated platelets and binds with high affinity to heparin. Its major physiologic role appears to be neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin III activity and promoting coagulation (Nagy et al., 2018).
The platelets are abnormally large defined by an increased mean platelet volume and an additional peak in the white blood cell analysis. Some of these syndromes also have symptoms of nephritis or sensory problem of deafness.
Platelet storage pool diseases (SPD) are a heterogeneous group of disorders associated with an abnormal presence or contents of intracytoplasmic platelet granules, causing a mild to moderate bleeding (Kroll and Afshar-Kharghan, 2012).
The management of patients with inherited platelet diseases usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control haemorrhagic episodes. However, as the type and severity of bleeding vary in different patients, therapeutic approaches must be personalized (Alamelu and Liesner, 2010). The heritable platelet disorders are a heterogeneous group of disorders, but for clinical purposes can usefully be divided into severe or mild. Treatment options for bleeding can therefore be generalized. Stem cell transplantation is an option for the most serious disorders. The state of the art is advancing rapidly with the discovery of new molecular interactions that, in future, will lead to better understanding of platelet physiology. Most of our recommendations are not able to be based on the highest level of evidence, but nevertheless can act as a basis from which to audit future practice.
Growing evidence suggests that inherited diseases of platelets are more frequent than previously thought. Efforts are being made to distinguish FT from ITP to avoid diagnosis after patients have received medications for controlling an immune-mediated process. Recent progress in diagnosis will not only be valuable for the patients, but will also continue to identify targets, such as new treatments for patients with ischaemic disease, for controlling platelet functions clinically. In summary, our knowledge of platelet and megakaryocyte biology has significantly increased over the past several years due in large part to increased understanding of the pathobiology of the inherited platelet disorders. So, it should be considered as one of differential diagnosis in any case of life long bleeding tendency.Rational use of next-generation or targeted sequencing after careful phenotyping has led to significant advances in our understanding of biology and surprises and novel avenues of investigation. We will need to continue to carefully apply insights gained from whole exome/genome studies to be sure we do not erroneously assign disease to normal variants as all of these studies have shown careful biological follow-up of variants to demonstrate biological plausibility.