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Tracking Fibrinolysis of Chandler Loop-Formed Whole Blood Clots Under Shear Flow in An In-Vitro Thrombolysis Model
Published on: April 19, 2024
New treatment strategies for disseminated intravascular coagulation based on current understanding of the
Marcel Levi1, Evert de Jonge, Tom van der Poll
1Department of Internal Medicine/Vascular Medicine, Intensive Care, Laboratory of Experimental Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. m.m.levi@amc.uva.nl
Insights
Disseminated intravascular coagulation (DIC) involves systemic coagulation activation, leading to organ failure and bleeding. Novel therapies targeting coagulation pathways show promise for patients with sepsis and coagulation disorders.
Area of Science:
- Hematology
- Pathophysiology
- Critical Care Medicine
Background:
- Systemic coagulation activation, ranging from mild laboratory changes to severe disseminated intravascular coagulation (DIC), can arise from various clinical conditions.
- DIC is characterized by widespread coagulation activation, leading to fibrin deposition in small and midsize vessels, contributing to microvascular dysfunction and organ failure.
- Coagulation activation can deplete platelets and factors, causing bleeding, while impaired fibrinolysis due to plasminogen activator inhibitor-1 (PAI-1) enhances fibrin deposition.
Purpose of the Study:
- To review the pathogenesis of DIC, focusing on the interplay between coagulation, inflammation, and fibrinolysis.
- To discuss novel preventive and therapeutic strategies for DIC, particularly in the context of sepsis.
Main Methods:
- Review of clinical and experimental studies on DIC pathogenesis.
- Analysis of the roles of tissue factor/factor VIIa, antithrombin III, protein C system, and PAI-1 in DIC.
- Examination of the cross-talk between inflammation and coagulation.
Main Results:
- DIC pathogenesis involves the extrinsic pathway of thrombin generation, suppressed anticoagulant mechanisms, and impaired fibrinolysis.
- Inflammatory mediators and activated coagulation proteases/inhibitors modulate each other through cellular interactions.
- Supportive strategies inhibiting coagulation activation, such as targeting tissue factor or restoring anticoagulant pathways (e.g., recombinant activated protein C), show potential.
Conclusions:
- Understanding DIC pathogenesis has led to new therapeutic approaches.
- Inhibition of coagulation activation or restoration of anticoagulant pathways are promising strategies for managing DIC.
- Further research and clinical studies are needed to optimize these novel treatments for DIC and related conditions.
Abstract:
A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may result in depletion of platelets and coagulation factors, which may cause bleeding. Recent understanding of important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of the fibrinolytic inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular fibrin deposition. Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C.
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