Systems Analysis of Thrombus Formation

Abstract

The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient-specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. Additionally, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs.

Slow Collateral Flow Is Associated with Thrombus Extension in Patients with Acute Large-Artery Occlusion

“…Slow collateral flow represents the stasis of blood flow at the occlusion site, which may cause platelet aggregation, local accumulation of inflammatory mediators, leukocyte activation, and endothelial dysfunction. 9 Moreover, slower collateral flow can result in low shear stress to the thrombus because collateral flow velocity is a surrogate for the pressure drop across the collateral vessels and the occlusion site. 5 These hemodynamic changes thus create an environment conducive to the formation of a new clot and are therefore associated with the ex- tension of the thrombus.…”

Thrombosis of popliteal artery aneurysm with cutaneous microembolism of toes

“…Moreover, with the enlargement of aneurysmal sac, there will a turbulent blood flow through the lumen, resulting in clot formation; which can ultimately lead to thrombosis and/or embolism. 4,6,7 Acute thrombosis of PAA can result in acute critical limb ischemia; while repeated thromboembolic events can cause chronic ischemia and is seen in 85% of asymptomatic PAA. 8,9 Patients may present with worsening claudication pain, rest-pain, ulceration or blue toe syndrome.…”

Emerging anticoagulant strategies

“…2,3 Platelets predominate in arterial thrombi, which usually form under high-shear conditions at sites of atherosclerotic plaque disruption. In contrast, fibrin is the major component of venous thrombi, which form under low-shear conditions.…”