Platelet-vessel Wall Interactions Research Articles

GANGGUAN HEMOSTASIS PADA PENYAKIT GINJAL KRONIK DERAJAT 5

Patients with chronic kidney disease (CKD) develop hemostatic disorders mainly in the form of bleeding diatheses. Platelet dysfunction is the main factor responsible for hemorrhagic tendencies in advanced kidney disease. Anemia, dialysis, the accumulation of medications due to poor clearance, and anticoagulation used during dialysis have some role in causing impaired hemostasis in CKD patients. Platelet dysfunction occurs both as a result of intrinsic platelet abnormalities and impaired platelet-vessel wall interaction. The normal platelet response to vessel wall injury with platelet activation, recruitment, adhesion, and aggregation is defective in advanced renal failure. Dialysis may partially correct these defects, but cannot totally eliminate them. The hemodialysis process itself may in fact contribute to bleeding. Hemodialysis is also associated with thrombosis as a result of chronic platelet activation due to contact with artificial surfaces during dialysis.

Vascular mechanisms and manifestations of COVID-19

Vascular mechanisms and manifestations of COVID-19

Assessing bleeding risk in 18 children with Osteogenesis imperfecta

Assessing bleeding risk in 18 children with <i>Osteogenesis imperfecta</i>

Antiplatelet Agents and Anticoagulants in Patients with Chronic Kidney Disease - from Pathophysiology to Clinical Practice.

Progressive impairment of renal function can lead to uremia, which is associated with an increased risk of bleeding as well as thrombosis. Furthermore, many patients with chronic kidney disease (CKD) have an indication for an anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin-K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOACs) inhibiting factor Xa or thrombin activity represent an alternative for heparins and VKAs. However, DOACs can further aggravate the bleeding risk in CKD patients. This is related to a combination of an accumulation of the substance due to the reduced renal clearance, an inhibition of thrombin-mediated platelet activation, and uremia associated factors such as impaired coagulation, platelet function, and platelet-vessel wall interactions. Furthermore, platelet aggregation inhibitors can also influence the bleeding risk, particularly if they are administered in combination with anticoagulants in patients with advanced CKD. In this review we discuss the different mechanisms leading to the increased risk of bleeding and thrombosis as well as the different options and problems related to an antiplatelet or anticoagulation therapy in CKD patients.

An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet–platelet and platelet–vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10−5–10−4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.

Platelet–vessel wall interactions and drug effects

Abstract Platelet–vessel wall interaction is necessary for hemostasis and vascular repair, but also plays a fundamental role in the early and late development of atherosclerosis and atherothrombotic vascular events. A plethora of adhesion molecules, biological mediators and receptors are engaged in the regulation of platelet function in hemostasis and thrombosis. Currently available antiplatelet drugs act on targets that are critical for both, physiological hemostasis and pathological intravascular thrombosis. Consequently, their major disadvantage is bleeding complications, especially when different antiplatelet drugs are combined or applied together with anticoagulants, such as in antithrombotic therapy of acute coronary syndromes. Aspirin, clopidogrel and GPIIb/IIIa antagonists are commonly used inhibitors of platelet aggregation or secretion. In addition, they modify platelet interactions with the vessel wall, which may contribute to or modulate their antithrombotic action. Some commonly used drugs without primary antiplatelet effects, such as heparins or statins, also appear to modify platelet interaction with the vessel wall. Present research on antithrombotic drug targets aims to identify new pharmacological concepts which more specifically address the pathophysiological mechanisms leading to intravascular thrombosis, thus intending to reduce interference with hemostasis. This review article summarizes the biological and pathological mechanisms involved in thrombogenic platelet–vessel wall interaction, describes the current knowledge on the clinically available drugs in this field and gives an outlook on emerging concepts and innovative pharmacological compounds, which may improve efficacy and safety of antiplatelet therapy in the future.

Liver Disease and Hemostatic (Dys)function.

Cirrhosis presents with decreased procoagulant factors as a consequence of the impaired synthetic capacity of the liver. This was taken as evidence to explain the abnormalities of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (aPTT) and the bleeding events that occur in these patients. It was for long time (and probably is still) common practice to test patients with the PT and to treat those with predefined (but arbitrary) cutoff values with plasma or prohemostatic agents to prevent or stop bleeding. However, anticoagulant factors that contrast the procoagulants are also decreased in cirrhosis. It was therefore postulated that the coagulation balance (i.e., the net result between the action of pro- and anticoagulants) is somewhat rebalanced. Subsequent studies supported this view showing that plasma from cirrhotic patients generates normal amounts of thrombin. In addition, primary hemostasis (i.e., platelet-vessel wall interaction) is rebalanced notwithstanding cirrhosis present with thrombocytopenia. It was shown that increased levels of the adhesive protein von Willebrand factor (a typical feature of cirrhosis) compensate for the low number (function) of platelets. The earlier considerations have been instrumental to help dismantle the old paradigms of cirrhosis as the epitome of the acquired hemorrhagic coagulopathies and the traditional coagulation tests PT and aPTT as suitable predictors of bleeding risk. The demise of the old paradigms and the rise of the new one may have important practical implications for the management of patients with cirrhosis and will be discussed in this chapter.

Nanodiagnostics, nanopharmacology and nanotoxicology of platelet-vessel wall interactions.

In physiological conditions, the interactions between blood platelets and endothelial cells play a major role in vascular reactivity and hemostasis. By contrast, increased platelet activation contributes to the pathogenesis of vascular pathology such as atherosclerosis, thrombosis, diabetes mellitus, hypertension and carcinogenesis. Nanomedicine, including nanodiagnostics and nanotherapeutics is poised to be used in the management of vascular diseases. However, the inherent risk and potential toxicity resultant from the use of nanosized (<100 nm) materials need to be carefully considered. This review, basing on a systematic search of literature provides state-of-the-art and focuses on new discoveries, as well as the potential benefits and threats in the field of nanodiagnostics, nanopharmacology and nanotoxicology of platelet-vessel wall interactions.

Analysis of platelet function and dysfunction.

Although platelets act as central players of haemostasis only their cross-talk with other blood cells, plasma factors and the vascular compartment enables the formation of a stable thrombus. Multiple activation processes and complex signalling networks are responsible for appropriate platelet function. Thus, a variety of platelet function tests are available for platelet research and diagnosis of platelet dysfunction. However, universal platelet function tests that are sensitive to all platelet function defects do not exist and therefore diagnostic algorithms for suspected platelet function disorders are still recommended in clinical practice. Based on the current knowledge of human platelet activation this review evaluates point-of-care related screening tests in comparison with specific platelet function assays and focuses on their diagnostic utility in relation to severity of platelet dysfunction. Further, systems biology-based platelet function methods that integrate global and specific analysis of platelet vessel wall interaction (advanced flow chamber devices) and post-translational modifications (platelet proteomics) are presented and their diagnostic potential is addressed.

Nonsteroidal Anti-Inflammatory Drugs and the Heart

Aspirin has been on the market for 115 years. Beginning with the marketing of indomethacin for the treatment of rheumatoid arthritis in 1963, at least 20 other nonsteroidal anti-inflammatory drugs (NSAIDs) with aspirin-like actions have been developed over the past 50 years,1 culminating with the introduction of a new class of selective inhibitors of cyclooxygenase (COX)-2, the coxibs, approximately 15 years ago.2 The NSAIDs represent the single most crowded family of drugs sharing the same therapeutic activities and mechanism of action, perhaps reflecting the unmet therapeutic need in the area of pain management and the large interindividual variability in response to these agents. NSAIDs provide symptomatic relief of pain and inflammation associated with a variety of human disorders, including the rheumatic diseases. Their shared therapeutic actions (ie, analgesic, anti-inflammatory, and antipyretic) are usually accompanied by mechanism-based adverse effects that can, at least in part, be attenuated as a function of individual pharmacokinetic or pharmacodynamic properties.1 Nuances in the tolerability of different NSAIDs had been described in the precoxib era on the basis of clinical trials of a few hundred patients treated for up to a few months with soft end points. More recently, however, important differences in safety have been demonstrated in head-to-head randomized comparisons of individual coxibs and 1 or more traditional NSAIDs that involved tens of thousands of patients treated for up to a few years with hard end points. Even more significantly, the interpretation of the effects of NSAIDs has been greatly enhanced by the availability, for the first time, of large, placebo-controlled trials that aimed to assess the potential for chemoprevention of colorectal cancer by rofecoxib or celecoxib. As a result of these developments, the whole field of NSAIDs has been illuminated during the past 15 years. Although epidemiological studies had previously associated …

Microvascular platforms for the study of platelet-vessel wall interactions

Platelets interact with the endothelium to regulate vascular integrity and barrier function, mediate inflammation and immune response, and prevent and arrest hemorrhage. In this review, we describe existing tools to study the flow-dependent interactions of platelets with the vessel wall. We also discuss our work on building engineered microvessels to study the roles of platelets on endothelial barrier function, endothelial sprouting, and thrombus formation on both quiescent and stimulated endothelium. In particular, we will show the advantage of using a cell-remodelable system in the studies of platelet-vessel wall interactions.

Systems biology of platelet-vessel wall interactions.

Platelets are small, anucleated cells that participate in primary hemostasis by forming a hemostatic plug at the site of a blood vessel's breach, preventing blood loss. However, hemostatic events can lead to excessive thrombosis, resulting in life-threatening strokes, emboli, or infarction. Development of multi-scale models coupling processes at several scales and running predictive model simulations on powerful computer clusters can help interdisciplinary groups of researchers to suggest and test new patient-specific treatment strategies.

Toward the Multi-scale Simulation for a Human Body Using the Next-generation Supercomputer

We have developed novel numerical methods for fluid-structure and fluid-membrane interaction problems. The basic equation set is formulated in a full Eulerian framework. The method is based on the finite difference volume-of-fluid scheme with fractional step algorithm. It is validated through a numerical solution to a deformable vesicle problem, and applied to blood flows including red blood cells (RBCs) and platelets. Further, to gain insight into the mechanism of thrombus formation, a stochastic Monte Carlo model to describe the platelet-vessel wall interaction is incorporated into the Eulerian method. The effect of the RBCs on the platelet motion is discussed.

The Potential Therapeutic Benefit of Targeting ADAMTS13 Activity

Platelet-vessel wall interaction is mediated by von Willebrand factor (VWF), which thereby plays a major role in physiological hemostasis and thrombotic disease. VWF is released as ultralarge multimers from endothelial cells, whereupon it is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type I repeats-13). The prohemostatic properties of VWF are dependent of its multimeric size; hence, ADAMTS13 activity is an important determinant in platelet-vessel wall interaction. Deficiency of ADAMTS13 in its most classical form in thrombotic thrombocytopenic purpura can lead to severe thrombotic microangiopathy. However, there is a growing variety of diseases in which ADAMTS13 levels have been found to be decreased and in which reduced cleavage of VWF may play a role. Hence, targeting of VWF cleavage by pharmacological modulation of ADAMTS13 levels is an interesting approach in some of these conditions. This review discusses the available evidence for a role of ADAMTS13 in various disease states and the potential therapeutic benefit of restoration of ADAMTS13 levels.

Endothelial injury in sepsis

Vascular endothelial cells play a pivotal mediatory role in many responses to systemic inflammation including the crosstalk between coagulation and inflammation in sepsis [1, 2]. Endothelial cells respond to the cytokines expressed and released by activated leukocytes but can also release cytokines themselves. Furthermore, endothelial cells are able to express adhesion molecules and growth factors that may not only promote the inflammatory response further but also affect a myriad of downstream responses. It has recently become clear that, in addition to these mostly indirect effects of the endothelium, injured endothelial cells directly interfere with platelet–vessel wall interaction, neutrophil entrapment through formation of extracellular nets, and activation of inflammation and coagulation mediated by microparticles (Fig. 1). Blood cell–vessel wall interaction in sepsis

TREATMENT OF REPERFUSION INJURY WITH RECOMBINANT ADAMTS13 IN A PORCINE MODEL OF ACUTE MYOCARDIAL INFARCTION

Background: No reflow and decreased microvascular perfusion after percutaneous coronary intervention increase morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. No reflow may be mediated by platelet vessel wall interaction that is governed by von Willebrand factor. ADAMTS13 is a metalloprotease that cleaves von Willebrand factor, thereby reducing its prohemostatic properties. There is considerable evidence that ADAMTS13 levels decrease and von Willebrand factor levels increase in STEMI patients. Recombinant ADAMTS13 has been effective in reducing cerebral infarct size in a murine model of stroke. Aims: In this study recombinant ADAMTS13 was tested as a potential treatment of no reflow in a porcine model of cardiac ischemia and reperfusion. Methods: In 23 female swine (median age 83 days, median weight 30 kg) a balloon was inflated in the circumflex coronary artery for 75 min. Fifteen minutes after reperfusion, an intracoronary bolus of either recombinant ADAMTS13 (400 U/kg, Baxter Innovations Vienna, Austria) or vehicle was given. Results: ADAMTS13 activity significantly increased in treated pigs (from median 18%, IQR 14.5-24.0 to median 324%, IQR 117.0- 384.0, P = 0.003) whereas no change was observed in the control group. Animals were sacrificed 7 days later for histopathology. There was no difference in the size of myocardial necrosis as assessed with plasma Troponin T measurements, continuous 12 leads ECG, macroscopical infarct analysis, and histopathology using phosphotungstic acid-hematoxylin staining. Microvascular obstruction as estimated by staining with anti-CD31/Hematoxylin and counting of vessels and microthrombi was similar for both groups. Conclusions: Intracoronary treatment with recombinant ADAMTS13 did not prevent formation of microthrombi and did not decrease infarct size in this porcine coronary model of ischemia and reperfusion.

Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies.

Thrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Frequently, platelet transfusions are given to thrombocytopenic infants in an attempt to decrease the incidence or severity of hemorrhage, which is often intracranial. Whereas there is very limited evidence to guide platelet transfusion practices in this population, preterm infants in the first week of life (the highest risk period for bleeding) are nearly universally transfused at higher platelet counts than older infants or children. To a large extent, this practice has been influenced by the observation that neonatal platelets are hyporeactive in response to multiple agonists in vitro, although full-term infants exhibit normal to increased primary hemostasis. This apparently paradoxical finding is due to factors in the neonatal blood that enhance the platelet-vessel wall interaction and counteract the platelet hyporeactivity. Relatively few studies have evaluated the platelet function and primary hemostasis of preterm infants, the subset of neonates at highest risk of bleeding and those most frequently transfused. Current understanding of platelet production and function in preterm and full-term neonates, how these factors affect their response to thrombocytopenia and their primary hemostasis, and the implications of these developmental differences to transfusion medicine are reviewed herein.

Is my patient a bleeder? A diagnostic framework for mild bleeding disorders.

Congenital mild bleeding disorders (MBDs) are very prevalent and are the source of frequent diagnostic problems. Most MBDs are categorized as disorders of primary hemostasis (ie, type 1 VWD and platelet function disorders), but mild or moderate deficiencies of clotting factors and some rare hyperfibrinolytic disorders are also included. These patients have abnormal bleeding from the skin and mucous membranes, menorrhagia, and disproportionate hemorrhages after trauma, invasive procedures, and surgery. This review addresses the main problems that physicians and hemostasis laboratories confront with the diagnosis of these patients, including: discerning normal/appropriate from pathological bleeding, the role and yield of screening tests, the lack of distinctive bleeding pattern among the different diseases, the inherent difficulties in the diagnosis of type 1 VWD and the most common platelet functional disorders, improvements in assays to measure platelet aggregation and secretion, and the evidence that most of the patients with MBDs end up without a definite diagnosis after exhaustive and repeated laboratory testing. Much research is needed to determine the pathogenesis of bleeding in MBD patients. Better standardization of current laboratory assays, progress in the knowledge of fibrinolytic mechanisms and their laboratory evaluation, and new understanding of the factors contributing to platelet-vessel wall interaction, along with the corresponding development of laboratory tools, should improve our capacity to diagnose a greater proportion of patients with MBDs.

Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies

AbstractThrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Frequently, platelet transfusions are given to thrombocytopenic infants in an attempt to decrease the incidence or severity of hemorrhage, which is often intracranial. Whereas there is very limited evidence to guide platelet transfusion practices in this population, preterm infants in the first week of life (the highest risk period for bleeding) are nearly universally transfused at higher platelet counts than older infants or children. To a large extent, this practice has been influenced by the observation that neonatal platelets are hyporeactive in response to multiple agonists in vitro, although full-term infants exhibit normal to increased primary hemostasis. This apparently paradoxical finding is due to factors in the neonatal blood that enhance the platelet-vessel wall interaction and counteract the platelet hyporeactivity. Relatively few studies have evaluated the platelet function and primary hemostasis of preterm infants, the subset of neonates at highest risk of bleeding and those most frequently transfused. Current understanding of platelet production and function in preterm and full-term neonates, how these factors affect their response to thrombocytopenia and their primary hemostasis, and the implications of these developmental differences to transfusion medicine are reviewed herein.

Is my patient a bleeder? A diagnostic framework for mild bleeding disorders

AbstractCongenital mild bleeding disorders (MBDs) are very prevalent and are the source of frequent diagnostic problems. Most MBDs are categorized as disorders of primary hemostasis (ie, type 1 VWD and platelet function disorders), but mild or moderate deficiencies of clotting factors and some rare hyperfibrinolytic disorders are also included. These patients have abnormal bleeding from the skin and mucous membranes, menorrhagia, and disproportionate hemorrhages after trauma, invasive procedures, and surgery. This review addresses the main problems that physicians and hemostasis laboratories confront with the diagnosis of these patients, including: discerning normal/appropriate from pathological bleeding, the role and yield of screening tests, the lack of distinctive bleeding pattern among the different diseases, the inherent difficulties in the diagnosis of type 1 VWD and the most common platelet functional disorders, improvements in assays to measure platelet aggregation and secretion, and the evidence that most of the patients with MBDs end up without a definite diagnosis after exhaustive and repeated laboratory testing. Much research is needed to determine the pathogenesis of bleeding in MBD patients. Better standardization of current laboratory assays, progress in the knowledge of fibrinolytic mechanisms and their laboratory evaluation, and new understanding of the factors contributing to platelet-vessel wall interaction, along with the corresponding development of laboratory tools, should improve our capacity to diagnose a greater proportion of patients with MBDs.