Formation, Inhibition and Clearance of Plasmin in vivo

Chandler, Wayne L.; Alessi, Marie‐Christine; Aillaud, M F; Vague, P; Juhan‐Vague, I.

doi:10.1159/000054136

Cited by 24 publications

(29 citation statements)

References 27 publications

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“…Third, the model system is critical since it allows specific assumptions to be defined, tested, and used in analysis and interpretation; allows kinetic processes to be directly compared, such as thrombin versus fibrin generation; and allows kinetic interactions to be studied, as we have done in the fibrinolytic system. 8,9 In this study we determined that the process of open-heart surgery utilizing CPB had different effects on thrombin and fibrin generation. At baseline prior to starting surgery, the average thrombin generation rate was about 0.24 picomoles of thrombin per second.…”

Section: Discussionmentioning

confidence: 99%

“…The vascular model used in this study is a modification of previous models that were used to assess changes in fibrinolytic marker levels and to evaluate the effect massive blood loss has on fibrinolysis during liver transplantation. [8][9][10][11] As a clinical problem we chose to study coagulation during cardiopulmonary bypass (CPB) for several reasons: (1) CPB results in a reproducible stimulation of coagulation that can be used to study the regulation of this system, 12 (2) CPB is an important clinical tool used in the treatment of heart disease that still has significant risk and side effects associated with it, and (3) many new drugs (such as aprotinin) and technologies (such as heparin-coated bypass circuits) are being developed and used to reduce hemostatic activation and side effects, even though their precise mechanism of action is still debated. 13 The long range goal is to use this method of analysis to better understand the regulation of the hemostatic system and to hopefully suggest which new therapies are likely to be the most effective in preventing, suppressing, or eliminating hemostatic disorders.…”

Section: Introductionmentioning

confidence: 99%

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Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass

Chandler

Velan

2003

Blood

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Our objective was to estimate the in vivo rates of thrombin and fibrin generation to better understand how coagulation is regulated. Studied were 9 males undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and soluble fibrin generation in vivo were based on measured levels of prothrombin activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and soluble fibrin, combined with a computer model of the patient's vascular system that accounted for marker clearance, hemodilution, blood loss, and transfusion. Prior to surgery, the average thrombin generation rate was 0.24 ؎ 0.11 pmol/s. Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1% was soluble fibrin. The thrombin generation rate did not change after sternotomy or administration of heparin, then rapidly increased 20-fold to 5.60 ؎ 6.65 pmol/s after 5 minutes of CPB (P ‫؍‬ .000 05). Early in CPB each new thrombin generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin generation rate was 2.14 ؎ 1.88 pmol/s during the remainder of CPB, increasing again to 5.47 ؎ 4.08 pmol/s after reperfusion of the ischemic heart (P ‫؍‬ .000 08). After heparin neutralization with protamine, thrombin generation remained high (5.34 ؎ 4.01 pmol/s, P ‫؍‬ .0002) and total fibrin generation increased, while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and fibrin generation rates were returning to baseline levels. We conclude that cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of nonhemostatic thrombin generation and dysregulated fibrin formation, not just a steady increase in thrombin generation as suggested by previous studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass

Chandler

Velan

2003

Blood

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“…62 Raza et al demonstrated in 303 trauma patients that fibrinolytic activation as detected by elevated PAP levels is common (59% of patients), but hyperfibrinolysis as detected by ROTEM (5%) was not. 63 Given that PAP clearance has a half-life of 3 to 6 hours in healthy individuals, 64 many patients with elevated PAP levels may not have had ongoing elevation of fibrinolytic activity at the time of ROTEM assay. Increasing PAP levels were nonetheless independently associated with increased mortality, with the combination of elevated PAP level and ROTEM lysis being particularly deadly (40% mortality).…”

Section: Trauma-induced Coagulopathy 1045mentioning

confidence: 99%

Advances in the understanding of trauma-induced coagulopathy

Chang

Cardenas

Wade

et al. 2016

Blood

246

225

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Ten percent of deaths worldwide are due to trauma, and it is the third most common cause of death in the United States. Despite a profound upregulation in procoagulant mechanisms, one-quarter of trauma patients present with laboratory-based evidence of trauma-induced coagulopathy (TIC), which is associated with poorer outcomes including increased mortality. The most common causes of death after trauma are hemorrhage and traumatic brain injury (TBI). The management of TIC has significant implications in both because many hemorrhagic deaths could be preventable, and TIC is associated with progression of intracranial injury after TBI. This review covers the most recent evidence and advances in our understanding of TIC, including the role of platelet dysfunction, endothelial activation, and fibrinolysis. Trauma induces a plethora of biochemical and physiologic changes, and despite numerous studies reporting differences in coagulation parameters between trauma patients and uninjured controls, it is unclear whether some of these differences may be “normal” after trauma. Comparisons between trauma patients with differing outcomes and use of animal studies have shed some light on this issue, but much of the data continue to be correlative with causative links lacking. In particular, there are little data linking the laboratory-based abnormalities with true clinically evident coagulopathic bleeding. For these reasons, TIC continues to be a significant diagnostic and therapeutic challenge.

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“…In the absence of tPA, plasminogen bound to macrophage plasma membrane undergoes autoproteolysis generating a 48-kd inactive fragment with surface-binding capacity and small soluble fragments with catalytic capacity 37 that are rapidly inhibited in the fluid phase by anti-plasmins ( Figure 6). 38,39 The timing of AIIt involvement in fibrin degradation is also a crucial factor in promoting or inhibiting fibrinolysis because the presence of AIIt during fibrin polymerization inhibits fibrinolysis. 40 Therefore, limited availability of tPA in MS lesions because of formation of tPA-PAI-1 complexes as previously shown by nonreducing immunoblots of the same set of samples 31,41 reduces the ability of AIIt to generate plasmin and further diminishes the fibrinolytic capacity possibly resulting in increased axonal fibrin deposition and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%