Blood Clot Contraction (Retraction) Is Impaired in Acute Ischemic Stroke

Obstructive thrombi or thrombotic emboli of cerebral arteries are the pathogenic basis of ischemic stroke, which is a leading cause of death and disability worldwide. Blood clots undergo volume shrinkage due to the contractile forces that are generated by platelets and propagated through the clot volume due to platelet-fibrin interactions and elasticity of the fibrin network. This process is designed clot contraction (retraction) which remains one of the least studied steps of blood clotting. Importantly, this phenomenon has been shown to occur not only in vitro but also in in vivo thrombi. Clot contraction has been shown to be important in the volume reduction of otherwise obstructive thrombi and has the potential to reduce occlusion and restore blood flow past emboli or thrombi. Despite the potential medical significance of clot contraction, it has not been examined systemically in a clinical setting. This aim of this work was to examine the potential pathogenic role of clot contraction in ischemic stroke. Here we employed a novel automated method to quantify the time of initiation, extent and rate of clot contraction in vitro to compare clot contraction in the blood of healthy subjects with patients suffering a recent ischemic stroke (<6 hours from the onset of symptoms) who had not yet received any treatment with anticoagulants, antiplatelet drugs or thrombolytics.. Parameters of clot contraction were correlated with the severity and etiological types of stroke as well as with hematological, coagulation, and biochemical tests to examine the clinical significance of clot contraction. The main finding of this work is that clot contraction in blood from patients with acute ischemic stroke is reduced on average by ~60% (p<0.0001) when compared to that of healthy subjects. The reduction in clot contraction is correlated with a lower platelet count and platelet dysfunction, higher fibrinogen level, higher hematocrit, leukocytosis as well as other changes in the blood composition of patients with ischemic stroke that may alter the properties of the blood clot. We propose that these changes in the composition of the blood contribute to the impaired mechanism of clot contraction, which may exaggerate vessel occlusion and brain infarct. While stroke severity is determined mainly by the diameter and location of the obstructed cerebral artery, the ability of the thrombi to contract more or less may augment or ease the course of brain damage. Clinical correlations with respect to severity and stroke etiology indicate that reduced clot contraction has the potential to be a pathogenic factor in ischemic stroke. Paradoxically, the extent of clot contraction marginally improved in patients with a more severe stroke (NIHSS>15 vs. NIHSS<15, p<0.01), while it was still significantly reduced compared to healthy subjects. This finding can be presumably explained by the fact that in severe brain damage a massive amount of tissue factor is released into the systemic circulation, which can induce the activation of blood coagulation. We propose that this release of tissue factor results in a secondary wave of thrombin generation that causes patients with more severe stroke to have hyperactivity of platelets. In combination with a higher platelet count (p<0.01) this can enhance contraction of obstructive clots or thrombi, which may be a compensatory mechanism resulting in the recanalization of an otherwise occluded blood vessel. In support of this hypothetical scenario, it was also found that patients with atherothrombotic strokes have an increased extent of clot contraction compared to patients with cardioembolic stroke (p<0.05), and atherothrombotic patients are reported to have increased tissue factor as a consequence of atherosclerotic lesions. In summary, the clinical pathophysiological importance of clot contraction in a thrombotic state has been examined for the first time and the modulation of the ability of clots or thrombi to shrink in volume may be a novel and unappreciated mechanism that aggravates or alleviates the course and outcomes of thrombosis, such as ischemic stroke. The clinical importance of clot or thrombus remodeling in vivo as well as the diagnostic and prognostic value of this blood test for clot contraction needs further exploration.