Current Strategies in Diagnosis of Inherited Storage Pool Defects

Abstract

Inherited platelet defects lead to bleeding symptoms of varying severity. Typically, easy bruising, petechiae, epistaxis, and mucocutaneous bleeding are observed in affected patients. The platelet defects are classified into disorders affecting either platelet surface receptors or intracellular organelles of platelets. The latter are represented by platelet storage pool diseases (SPD) which share a defect of platelet granules. Platelet a-granules, d-granules, or both may be affected resulting in the clinical picture of a-SPD (e.g. Gray platelet syndrome, Quebec platelet disorder, arthrogryposis, renal dysfunction, and cholestasis syndrome), d-SPD (e.g. Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome), or ad-SPD (e.g. X-linked thrombocytopenia, Wiskott-Aldrich syndrome). Diagnosis of SPD is very extensive and requires platelet aggregation and flow cytometry analyses with interpretation from a specialist. Many of these disorders share common treatments, however, efficacy can vary between different patients. Therapy regiments with tranexamic acid, DDAVP, activated FVIIa, and platelet transfusions have been published. Stem cell or bone marrow transplantations are preserved for severe defects. Here, we describe the pathophysiology, clinical manifestations, and diagnosis of the major human SPDs.

Multiscale prediction of patient-specific platelet function under flow

“…3,4 Similarly, platelet dysfunction or antiplatelet therapy can be associated with bleeding risks. [5][6][7] Furthermore, the function of blood is highly dependent on hemodynamic forces; examples include shear-induced platelet activation at Ͼ 5000/s shear rate, 8,9 requirement of VWF in arterial thrombosis, [10][11][12] shear effects on VWF structure/function and GPIb-VWF A1 domain-bonding dynamics, [13][14][15][16][17] RBC-dependent platelet migration toward the wall, 18,19 and convection-enhanced mass transfer to and from local zones of clotting or bleeding. 20,21 Defining, quantifying, and linking a patient's unique platelet phenotype or coagulation phenotype under hemodynamic conditions to clinical risk remains a diagnostic challenge.…”

Sodobni pristop za diagnosticiranje prirojenih motenj delovanja trombocitov

“…"storage-pool" disease) v gostih trombocitnih zrncih (sindrom Hermansky-Pudlak (17,18), sindrom Che di ak-Higashi (17,(19)(20)(21), in Grisellijev sindrom (17)), motnje skladiščenja substanc v zrncih alfa (sindrom ARC (angl. arthrogryposis, renal tubular acidosis, cholestasis) (17,22)) in motnje izločanja substanc iz zrnc trombocitov. Slednje predstavljajo največjo heterogeno skupino PMDT.…”

Bernard Soulier Syndrome: A Genetic Bleeding Disorder

“…All HPS proteins are associated in multi-protein complexes essential for biogenesis and intracellular trafficking of intracellular vesicles of lysosomal lineage (Li et al, 2004). Mutations within particular HPS genes can lead to dysfunction of the corresponding protein complex and thus to defective maturation of melanosomes and platelet dense bodies (Sandrock & Zieger, 2010).…”

“…In addition, CHS patients showed severe immunologic defects and progressive neurological dysfunction making this disease lethal. If patients survive until adulthood, they develop neurological defects including neuropathies, autonomic dysfunction, atrophy, sensory deficits, seizures, and cognitive defects (Sandrock & Zieger, 2010). Only hematopoietic stem cell transplantation can improve the health status of patients (Eapen et al, 2007).…”

“…This rare hereditary disease is characterized by a bleeding tendency, moderate thrombocytopenia and decrease or absence of platelet -granules and their contents probably due to the failure of maturation during megakaryocyte differentiation (White, 1979). GPS platelets are unsuitable to get and store endogenously synthesized proteins such as platelet factor-4, -thromboglobulin, Von Willebrand Factor (vWF) as well as exogenous proteins such as fibrinogen, albumin, or factor V (Sandrock & Zieger, 2010).…”