Role Of Platelets In Pathophysiology Research Articles

Antiplatelet Therapy in Acute Coronary Syndromes. Lights and Shadows of Platelet Function Tests to Guide the Best Therapeutic Approach.

The key role of platelets in pathophysiology of Acute Coronary Syndromes (ACS) has been well recognized. Platelet activation and aggregation, together with tissue factor-pathway activation, lead to acute thrombus formation in the coronary vessels at sites of plaque rupture. Thus, antiplatelet therapy with drugs able to interfere with platelet activation/aggregation represents a cornerstone of ACS treatment in intensive care units and catheterisation labs. Several observational studies have described that residual high platelet reactivity, despite antiplatelet therapy, is associated with increased risk of nonfatal Myocardial Infarction (MI), definite/probable stent thrombosis and cardiovascular mortality. Thus, assessment of platelet function with reliable and reproducible platelet function tests might be crucial to identify patients at high risk of thrombosis or not responding to ongoing antiplatelet strategies. However, despite this promising background, some randomized clinical trials have failed to demonstrate improvement in outcomes when using platelet function tests for clinical decision-making. This review, after describing platelet biology and pathophysiology of ACS, briefly considers the drugs currently approved for use in patients with ACS or treated by the percutaneous coronary intervention (PCI). Finally, we provide an updated overview of the current methods to evaluate platelet reactivity in the clinical setting of ACS illustrating their potential advantages/limitations in current clinical practice.

Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on ‘Bleeding-Free Antithrombosis’

The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.

Coagulopathy in trauma patients: importance of thrombocyte function?

Trauma-induced coagulopathy results from a complex interplay between shock resuscitation and impaired clotting protease function. A pathophysiological role of platelets in this condition remains as yet undefined. This review examines our current knowledge of platelet function in haemostasis, possible mechanisms for aberrant activity in trauma and the role of platelet transfusions in exsanguinating haemorrhage. Platelet adhesion and aggregation enable a haemostatic plug to form at the site of vessel injury. As described within cell-based models of thrombin generation, platelet membranes provide a platform to amplify clot formation. There is evidence to suggest platelet activity may be of greater importance than platelet number for clot integrity. Analysis of platelet function is limited by currently available devices. Therefore, the precise role and triggers for platelet transfusion in trauma have yet to be fully characterized. Retrospective studies show that early high-volume platelet transfusion in trauma may be associated with similar outcome benefits observed in high ratio plasma: red blood cell replacement. Platelets undoubtedly play a pivotal role in haemostasis and trauma-induced coagulopathy. However, their specific dysfunction in trauma remains to be elucidated. Further research to characterize the dysfunctional pathways of the platelet response is required, together with clinical trials of the optimal timing and dose of platelet transfusions.

Antiplatelet strategies in patients undergoing interventions with acute coronary syndrome: introduction

This supplement presents the proceedings of a scientific and clinical expert panel that was held on 8 March 2008 in Amsterdam, The Netherlands. The charge to the panel was to review and discuss the current and future challenges in the use of antiplatelet therapy in patients with acute coronary artery disease (CAD) who are undergoing percutaneous coronary intervention (PCI). This supplement will also review the currently available information on three of the antiplatelet agents in clinical development. In the first article, Meinrad Gawaz reviews the evolving science of atherothrombotic disease with a focus on the physiology and pathophysiological role of platelets. We know that once platelets adhere to vessel walls, they become activated and start to degranulate proaggregation substances including adenosine diphosphate (ADP). The ability of ADP to stimulate platelet receptors expedites platelet aggregation and thrombus formation. This process can be inhibited by reversible and irreversible binding of antiplatelet …

Pathophysiological role of platelets in acute experimental pancreatitis: influence of endothelin A receptor blockade

The potential pathophysiological role of platelet-endothelium interactions was investigated during ischemia/reperfusion (I/R), and the effect of a selective endothelin(A) receptor antagonist (ET(A)-RA) was evaluated in an acute pancreatitis model. Acute pancreatitis was induced by warm ischemia (60 min) in Wistar rats, and its effects with and without antagonist treatment were investigated. Equivalent sham-operated animals were also studied. Microcirculatory changes were assessed by in vivo microscopy, and serum levels for lipase/amylase and histological specimens were investigated. Capillary constriction to 83.7 +/- 6.7% of sham-operated diameters was observed after 60 min of ischemia. A capillary density of 56.8 +/- 9.3% of the sham-operated group (396.3 +/- 15.8 mm(-1)) was measured after reperfusion. Stagnant leukocytes (329.5 +/- 30.4%) and platelets (337.5 +/- 32.3%) increased in postcapillary venules (P < 0.05). Administration of the ET(A)-RA significantly reduced I/R injury. Capillary diameters were maintained (101.4 +/- 4.5%), and capillary density was improved to 73.3 +/- 7.6% of sham-operated animals (P < 0.05). Stagnant leukocytes (152.3 +/- 10.6%) and platelets (207.1 +/- 19.8%) in sinusoids and postcapillary venules were reduced (P < 0.05). The extent of acute pancreatitis was reduced in the therapy group as indicated by serum lipase/amylase values and histological tissue damage (P < 0.05). Thus, ET(A)-RA therapy was effective in reducing I/R-induced pancreatitis in this experimental model.

Platelet function in acute experimental pancreatitis induced by ischaemia–reperfusion

Ischaemia-reperfusion (IR)-associated microcirculatory changes play a major role in acute post-transplantation pancreatitis. The pathophysiological role of platelets in these events is unknown. The aim of this study was to examine platelet adhesion and function during early reperfusion after pancreatic ischaemia. Rats were subjected to warm pancreatic ischaemia by cross-clamping of the pancreatic vessels for 1 h. After 1 h of reperfusion, platelet-endothelium interaction was evaluated after platelet separation and staining by fluorescence microscopy. Amylase levels and pancreatic histology were evaluated 24 h after reperfusion. Animals treated according to an identical protocol, but without ischaemia, served as controls. Mild pancreatitis had developed by 24 h after IR; serum amylase levels were significantly higher than those in control animals. The numbers of adherent platelets in capillaries and venules were significantly increased, and platelet velocity in capillaries was significantly decreased, in the IR group compared with controls. There was significantly more oedema and inflammation in pancreatic tissue after IR. Warm ischaemia for 1 h followed by reperfusion for 24 h caused mild pancreatitis in this experimental model. The pancreatic microcirculation was characterized by pronounced platelet-endothelium interaction in capillaries and venules. These results suggest that platelet activation may play an important role in acute post-transplantation pancreatitis.