Historical background More than 80 years after the first description of thrombotic thrombocytopen... more Historical background More than 80 years after the first description of thrombotic thrombocytopenic purpura (TTP) by Eli Moschcowitz [1,2], the pathogenesis of this syndrome is still a mystery and in spite of improved modalities of therapy mortality rate of around 15% presents a great challenge for the medical team. The originally described pentad, including fever, thrombocytopenia, microangiopathic hemolytic anemia, renal failure and neurological abnormalities, is no longer required for establishing the diagnosis of TTP. Thus, the association of thrombocytopenia and microangiopathic hemolytic anemia is sufficient for a TTP alert [3]. It was only in the early 1980s when ultra-large VWF (ULVWF) multimers were found in plasma of TTP patients, suggesting a defect in VWF multimers processing, yielding an increased platelet clumping as a basis for the various clinical manifestations of TTP [4]. In 1997 8 two different groups have described for the first time the lack of a cleaving protease activity among inherited as well as acquired TTP patients, and a serum IgG fraction was identified to induce this effect in the latter group, establishing the autoimmune nature of acquired TTP [5,6]. At that time it was established that a level of <5% of the cleaving protease is required for induction of increased platelet adhesion and TTP symptoms. In 2001 2 the VWF cleaving protease has been characterized as the 13th member of the ADAMTS (A Disintegrin and Metalloprotease with Thrombospondin type motifs) metalloprotease family; the gene was sequenced and mutations responsible for inherited TTP were identified [7 9]. Later studies have clarified in greater detail the mechanism of action of ADAMTS 13, its binding site on the A3 domain of the VWF molecule, and the cleavage site on the A2 domain (Tyr 842 843 Met) [10]. It was also discovered that optimal cleavage of ULVWF is executed under high shear flow conditions, when ULVWF is attached to the surface and stretched due to the flow effect, thus exposing the different sites of interaction with ADAMTS 13 [11 13]. These later discoveries opened the road to the development of new diagnostic as well as therapeutic approaches. Thus different new tests have been developed for diagnosis and monitoring of ADAMTS-13 activity, including the testing of the cleavage products of VWF by collagen binding assays, by electrophoretic as well as by ELISA methods. The latter method was based on the identification of the minimally 73 AA peptide required for cleavage by ADAMTS 13 [14]. In addition, physiological testing of ADAMTS 13 has been developed, based on platelet adhesion under flow as a function of ADAMTS-13 activity in the tested plasma [15]. Treatment of TTP is still a great challenge due to the stormy nature of the disease and the relatively high mortality rate of around 15%. Since 1991 it was established that plasma exchange (PE) is indeed the treatment of choice, yielding reduction in both the ULVWF multimers and the inhibitor of ADAMTS 13, and providing an active ADAMTS 13 and normal-size VWF multimers [16]. The role of other treatment modalities, including steroids, IVIG, aspirin and rituximab, is still a matter for future investigations. Treatment of inherited cases of TTP is based on replacement of the missing ADAMTS 13, routinely by plasma transfusion, and potentially by a recombinant product which is now available. In spite of these advancements there are still many open questions regarding the pathogenesis of TTP and its family of Thrombotic MicroAngiopathies (TMAs). Thus, although a <5% activity level of ADAMTS 13 was found to be necessary for the development of TTP, not all patients with such a low level will develop clinical symptoms. Pathogenesis of other TMAs, including HUS and those associated with bone marrow transplantation, with HIV and those which are drug induced is not yet established. The potential effect of PE in this group of disorders is also not established [17].
CNS & Neurological Disorders - Drug Targets, 2012
Stroke is a leading cause of mortality and chronic disability. Therapies aimed at reducing stroke... more Stroke is a leading cause of mortality and chronic disability. Therapies aimed at reducing stroke related morbidity are currently limited. Therefore it is very important to develop effective treatments that will maximize rehabilitation after stroke. Current efforts in the field of cellular therapy focus on stem cell transplantations. This approach involves biological and ethical complications and therefore, the use of endogenous neural stem cells (eNSC) for repairing damage in various neurological disorders has been suggested. eNSCs reside in specialized vascular niches in defined regions, such as the subventricular zone (SVZ) of the lateral ventricle. These cells have an unlimited potential to create newborn cells. Interrelations between newborn neural and endothelial cells have an important role in eNSC survival, maturation, migration and differentiation and neurogenesis occurs in close spatio-temporal association with vessel growth in these niches. Previous studies have shown that application of external factors can boost long-term endogenous repair mechanisms in the cerebral cortex. Activated platelets and their microparticles contain a variety of growth and trophic factors essential to angiogenesis and neurogenesis and may therefore serve as novel therapeutic agents for brain injury. Specifically, factors from platelets and their microparticles may promote neurogenesis by stimulating eNSC proliferation, migration and differentiation, and by stimulating niche angiogenesis and the release of neurogenic signals from endothelial cells and astrocytes. In this review we will show that combined augmentation of angiogenesis, neurogenesis and neuroprotection using platelets and their microparticles is feasible and results in improved functional gain after stroke.
Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary event... more Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur. Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 ( P <0.01 for all). In addition, epinephrine-induced platelet aggregation and pla...
1. Am J Med. 1989 Mar;86(3):347-8. Primary amyloidosis with unusual bone involvement: reversibili... more 1. Am J Med. 1989 Mar;86(3):347-8. Primary amyloidosis with unusual bone involvement: reversibility with melphalan, prednisone, and colchicine. Schattner A, Varon D, Green L, Hurwitz N, Bentwich Z. Department of Medicine C, Kaplan Hospital, Rehovot, Israel. ...
Historical background More than 80 years after the first description of thrombotic thrombocytopen... more Historical background More than 80 years after the first description of thrombotic thrombocytopenic purpura (TTP) by Eli Moschcowitz [1,2], the pathogenesis of this syndrome is still a mystery and in spite of improved modalities of therapy mortality rate of around 15% presents a great challenge for the medical team. The originally described pentad, including fever, thrombocytopenia, microangiopathic hemolytic anemia, renal failure and neurological abnormalities, is no longer required for establishing the diagnosis of TTP. Thus, the association of thrombocytopenia and microangiopathic hemolytic anemia is sufficient for a TTP alert [3]. It was only in the early 1980s when ultra-large VWF (ULVWF) multimers were found in plasma of TTP patients, suggesting a defect in VWF multimers processing, yielding an increased platelet clumping as a basis for the various clinical manifestations of TTP [4]. In 1997 8 two different groups have described for the first time the lack of a cleaving protease activity among inherited as well as acquired TTP patients, and a serum IgG fraction was identified to induce this effect in the latter group, establishing the autoimmune nature of acquired TTP [5,6]. At that time it was established that a level of <5% of the cleaving protease is required for induction of increased platelet adhesion and TTP symptoms. In 2001 2 the VWF cleaving protease has been characterized as the 13th member of the ADAMTS (A Disintegrin and Metalloprotease with Thrombospondin type motifs) metalloprotease family; the gene was sequenced and mutations responsible for inherited TTP were identified [7 9]. Later studies have clarified in greater detail the mechanism of action of ADAMTS 13, its binding site on the A3 domain of the VWF molecule, and the cleavage site on the A2 domain (Tyr 842 843 Met) [10]. It was also discovered that optimal cleavage of ULVWF is executed under high shear flow conditions, when ULVWF is attached to the surface and stretched due to the flow effect, thus exposing the different sites of interaction with ADAMTS 13 [11 13]. These later discoveries opened the road to the development of new diagnostic as well as therapeutic approaches. Thus different new tests have been developed for diagnosis and monitoring of ADAMTS-13 activity, including the testing of the cleavage products of VWF by collagen binding assays, by electrophoretic as well as by ELISA methods. The latter method was based on the identification of the minimally 73 AA peptide required for cleavage by ADAMTS 13 [14]. In addition, physiological testing of ADAMTS 13 has been developed, based on platelet adhesion under flow as a function of ADAMTS-13 activity in the tested plasma [15]. Treatment of TTP is still a great challenge due to the stormy nature of the disease and the relatively high mortality rate of around 15%. Since 1991 it was established that plasma exchange (PE) is indeed the treatment of choice, yielding reduction in both the ULVWF multimers and the inhibitor of ADAMTS 13, and providing an active ADAMTS 13 and normal-size VWF multimers [16]. The role of other treatment modalities, including steroids, IVIG, aspirin and rituximab, is still a matter for future investigations. Treatment of inherited cases of TTP is based on replacement of the missing ADAMTS 13, routinely by plasma transfusion, and potentially by a recombinant product which is now available. In spite of these advancements there are still many open questions regarding the pathogenesis of TTP and its family of Thrombotic MicroAngiopathies (TMAs). Thus, although a <5% activity level of ADAMTS 13 was found to be necessary for the development of TTP, not all patients with such a low level will develop clinical symptoms. Pathogenesis of other TMAs, including HUS and those associated with bone marrow transplantation, with HIV and those which are drug induced is not yet established. The potential effect of PE in this group of disorders is also not established [17].
CNS & Neurological Disorders - Drug Targets, 2012
Stroke is a leading cause of mortality and chronic disability. Therapies aimed at reducing stroke... more Stroke is a leading cause of mortality and chronic disability. Therapies aimed at reducing stroke related morbidity are currently limited. Therefore it is very important to develop effective treatments that will maximize rehabilitation after stroke. Current efforts in the field of cellular therapy focus on stem cell transplantations. This approach involves biological and ethical complications and therefore, the use of endogenous neural stem cells (eNSC) for repairing damage in various neurological disorders has been suggested. eNSCs reside in specialized vascular niches in defined regions, such as the subventricular zone (SVZ) of the lateral ventricle. These cells have an unlimited potential to create newborn cells. Interrelations between newborn neural and endothelial cells have an important role in eNSC survival, maturation, migration and differentiation and neurogenesis occurs in close spatio-temporal association with vessel growth in these niches. Previous studies have shown that application of external factors can boost long-term endogenous repair mechanisms in the cerebral cortex. Activated platelets and their microparticles contain a variety of growth and trophic factors essential to angiogenesis and neurogenesis and may therefore serve as novel therapeutic agents for brain injury. Specifically, factors from platelets and their microparticles may promote neurogenesis by stimulating eNSC proliferation, migration and differentiation, and by stimulating niche angiogenesis and the release of neurogenic signals from endothelial cells and astrocytes. In this review we will show that combined augmentation of angiogenesis, neurogenesis and neuroprotection using platelets and their microparticles is feasible and results in improved functional gain after stroke.
Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary event... more Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur. Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 ( P <0.01 for all). In addition, epinephrine-induced platelet aggregation and pla...
1. Am J Med. 1989 Mar;86(3):347-8. Primary amyloidosis with unusual bone involvement: reversibili... more 1. Am J Med. 1989 Mar;86(3):347-8. Primary amyloidosis with unusual bone involvement: reversibility with melphalan, prednisone, and colchicine. Schattner A, Varon D, Green L, Hurwitz N, Bentwich Z. Department of Medicine C, Kaplan Hospital, Rehovot, Israel. ...
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