Thrombosis, resulting in occlusive blood clots, blocks blood flow to downstream organs and causes life-threatening conditions such as heart attacks and strokes. The administration of tissue plasminogen activator (t-PA), which drives the enzymatic degradation (fibrinolysis) of these blood clots, is a treatment for thrombotic conditions, but the use of these therapeutics is often limited due to the time-dependent nature of treatment and their limited success. We have shown that clot contraction, which is altered in prothrombotic conditions, influences the efficacy of fibrinolysis. Clot contraction results in the volume shrinkage of blood clots, with the redistribution and densification of fibrin and platelets on the exterior of the clot and red blood cells in the interior. Understanding how these key structural changes influence fibrinolysis can lead to improved diagnostics and patient care. We used a combination of mathematical modeling and experimental methodologies to characterize the process of exogenous delivery of t-PA (external fibrinolysis). A three-dimensional (3D) stochastic, multiscale model of external fibrinolysis was used to determine how the structural changes that occur during the process of clot contraction influence the mechanism(s) of fibrinolysis. Experiments were performed based on modeling predictions using pooled human plasma and the external delivery of t-PA to initiate lysis. Analysis of fibrinolysis simulations and experiments indicate that fibrin densification makes the most significant contribution to the rate of fibrinolysis compared with the distribution of components and degree of compaction (p < 0.0001). This result suggests the possibility of a certain fibrin density threshold above which t-PA effective diffusion is limited. From a clinical perspective, this information can be used to improve on current therapeutics by optimizing timing and delivery of lysis agents.

血栓形成会导致闭塞性血凝块，阻碍血液流向下游器官，并导致心脏病和中风等危及生命的疾病。施用组织纤溶酶原激活剂 (t-PA) 可以驱动这些血栓的酶促降解（纤维蛋白溶解），是治疗血栓性疾病的一种方法，但由于治疗的时间依赖性，这些疗法的使用通常受到限制以及他们有限的成功。我们已经证明，在血栓前条件下发生改变的凝块收缩会影响纤溶的功效。凝块收缩导致血凝块体积收缩，凝块外部的纤维蛋白和血小板以及内部的红细胞重新分布和致密化。了解这些关键的结构变化如何影响纤维蛋白溶解可以改善诊断和患者护理。我们结合数学模型和实验方法来表征 t-PA 的外源性递送（外部纤溶）过程。使用外部纤维蛋白溶解的三维 (3D) 随机多尺度模型来确定凝块收缩过程中发生的结构变化如何影响纤维蛋白溶解机制。实验是根据模型预测进行的，使用汇集的人血浆和外部递送 t-PA 来启动裂解。纤溶模拟和实验分析表明，与成分分布和压实程度相比，纤维蛋白致密化对纤溶速率的贡献最为显着（p < 0.0001）。该结果表明可能存在一定的纤维蛋白密度阈值，高于该阈值时 t-PA 的有效扩散受到限制。从临床角度来看，这些信息可用于通过优化裂解剂的时间和递送来改进当前的治疗方法。