An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation

Asakura, Hitoshi; Ontachi, Yasuo; Mizutani, Tomoe; Kato, Minori; Saitô, Masanori; Kumabashiri, Ichiro; Morishita, Eriko; Yamazaki, Masahide; Aoshima, Keiji; Nakao, Shinji

doi:10.1097/00003246-200106000-00015

Cited by 78 publications

(57 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The pathophysiology of DIC involves both the initiation of a fibrin thrombus and the inhibition of fibrinolysis, resulting in the persistence of intravascular thrombi (Levi et al, 1999). Both the coagulation and fibrinolysis phases are equally important in the development of DIC (Asakura et al, 2001). The main mechanism by which the body lyses fibrin thrombi involves plasmin, the activated form of plasminogen.…”

Section: Introductionmentioning

confidence: 99%

Impaired Fibrinolysis and Traumatic Brain Injury in Mice

Morales

McIntosh

Conte

et al. 2006

Journal of Neurotrauma

View full text Add to dashboard Cite

Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a result of thromboplastin released following brain injury. Clots thus formed are lysed by plasmin, which is activated by tissue-type and urokinase-type plasminogen activators (uPA). To evaluate the association between traumatic intravascular coagulation and post-traumatic outcome, uPA knockout (uPA-/-) transgenic mice (n=12) or wild-type littermates (WT; n=12) were anesthetized and subjected to controlled cortical impact (CCI) brain injury. A second group of uPA-/- (n=12) and WT mice (n=12) were subjected to sham injury. Motor function was assessed over 2 weeks using the composite neuroscore test and cognition (learning) was assessed with the Morris Water Maze (MWM) at 2 weeks post-injury, whereupon the animals were sacrificed for cortical lesion volume analysis. Motor function was significantly worse in the brain-injured uPA-/- mice when compared to brain-injured WT mice at 48 h (p<0.05) and one week post-injury (p<0.05). These differences resolved by 2 weeks post-injury. There was no significant difference in post-injury cognitive function between uPA-/- mice and WT mice. However, at 2 weeks post-injury, the brain-injured uPA-/- had a significantly larger volume of cortical tissue loss than their WT counterparts (p<0.05). These results demonstrate that the absence of uPA in mice aggravates acute motor deficit and exacerbates cortical tissue loss following CCI brain injury, and suggests a neuroprotective role of the fibrinolytic process following TBI.

show abstract

Section: Introductionmentioning

confidence: 99%

Impaired Fibrinolysis and Traumatic Brain Injury in Mice

Morales

McIntosh

Conte

et al. 2006

Journal of Neurotrauma

View full text Add to dashboard Cite

show abstract

“…22 Inhibition of fibrinolysis by treatment with antifibrinolytic agents in this condition promotes microvascular thrombosis, resulting in organ failure. 23 In survivors of severe sepsis, markers of coagulation and fibrinolytic activation correlate, whereas in nonsurvivors coagulation activation is not balanced by activation of fibrinolysis.…”

Section: Discussionmentioning

confidence: 99%

“…23 In survivors of severe sepsis, markers of coagulation and fibrinolytic activation correlate, whereas in nonsurvivors coagulation activation is not balanced by activation of fibrinolysis. 22 In animal experiments, homozygous FVL provides no survival benefit in endotoxemia. 7 A possible explanation is that homozygous FVL exaggerates fibrin formation to a level that is above the threshold for effective clearance.…”

Section: Discussionmentioning

confidence: 99%

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

Elmas

Suvajac

Jilma

et al. 2010

Blood

View full text Add to dashboard Cite

Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activatorinduced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogenand fibrin-degradation products. (Blood. 2010;116(5):801-805) IntroductionReplacement of Arg506 with Gln in coagulation factor V (the factor V Leiden [FVL] mutation) 1 results in the loss of an important cleavage site for activated protein C (aPC). Factor Va carrying the FVL mutation is less sensitive to inactivation by aPC. In addition, FVL may display an impaired cofactor function in the degradation of factor VIIIa by aPC. FVL predisposes for the development of venous thrombosis. 2 The high prevalence of FVL in the European population 3 indicates some survival advantage, which might be related to less blood loss on injury or childbirth or to improved wound healing. 4 This may be a consequence of enhanced fibrin formation due to the impaired inactivation of factor Va.Presence of disseminated intravascular coagulation (DIC) in sepsis is associated with an adverse outcome. 5 DIC may lead to microvascular thrombosis, causing multiple organ dysfunctions, and it is conceivable that a prothrombotic disposition such as FVL would be associated with an increased rate of fibrin disposition, causing organ dysfunction and death in sepsis.Astonishingly, data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) and Extended Evaluation of Recombinant Human Activated Protein C in Severe Sepsis (ENHANCE) trials indicate that the FVL mutation might be associated with improved survival in severe sepsis. 6,7 In the PROWESS trial, mortality of patients with severe sepsis with heterozygous FVL was 15.6%, compared with 31.0% in patients without FVL in the patient group not treated with recombinant aPC (Drotrecogin alfa [activated]). In patients treated with Drotrecogin alfa (...

show abstract

“…Although activation of blood coagulation is a hallmark of DIC, the degree of this activation appears not to be related to the development of MOF. 78 In fact, suppressed fibrinolysis is believed to be one of the most important forebodes of MOF during DIC; low levels of a2 antiplasmin-plasmin complex and high values of PAI-1 could therefore function as markers of aggravating disease. 78,79 Various reports have especially recommended PAI-1 as a strong prognostic factor [80][81][82] and the level of the inhibitor may in part be genetically determined by the PAI-1 4G/5G polymorphism, which itself is associated with clinical outcome in meningococcal sepsis.…”

Section: Disseminated Intravascular Coagulationmentioning

confidence: 99%

“…78 In fact, suppressed fibrinolysis is believed to be one of the most important forebodes of MOF during DIC; low levels of a2 antiplasmin-plasmin complex and high values of PAI-1 could therefore function as markers of aggravating disease. 78,79 Various reports have especially recommended PAI-1 as a strong prognostic factor [80][81][82] and the level of the inhibitor may in part be genetically determined by the PAI-1 4G/5G polymorphism, which itself is associated with clinical outcome in meningococcal sepsis. 83 In spite of these candidate risk markers, a study by Leithauser et al 84 showed that at the onset of sepsis none of the haemostatic parameters TAT, antithrombin, protein C antigen and PAI-1 were associated with MOF.…”

Section: Disseminated Intravascular Coagulationmentioning

confidence: 99%

Disseminated intravascular coagulation

Slofstra¹,

Spek²,

Cate³

2003

Hematol J

View full text Add to dashboard Cite

Disseminated Intravascular Coagulation (DIC) is an acquired syndrome representing a hypercoagulable state, haemorrhagic symptoms and multiple organ failure. The clinical relevance of this syndrome is complicated since there is no established way of diagnosing DIC and it is difficult to distinguish whether clinical features are attributable to the underlying disease or DIC. Experimental studies, based on models of gram-negative sepsis and the Generalized Shwartzman Reaction, show that DIC is characterized by strongly enhanced inflammatory activity, activated coagulation and impaired fibrinolysis. In this review we propose that activated neutrophils play a pivotal role in the pathophysiology of DIC, particularly by contributing to inflammation and vascular injury. Additionally, a distinct role for granulocytes in fibrinolysis has also been suggested. Although the underlying procoagulant pathways of DIC and the important role of tissue factor have been unravelled, therapeutic interventions counteracting the mediators of these pathways proved mainly unsuccessful (with the positive exception of activated protein C). Dissecting the molecular interactions at the onset and progression of DIC might therefore help to elucidate the fundamental consequences of DIC, possibly contributing to better diagnostic tools and more effective therapeutic options.

show abstract

An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation

Cited by 78 publications

References 18 publications

Impaired Fibrinolysis and Traumatic Brain Injury in Mice

Impaired Fibrinolysis and Traumatic Brain Injury in Mice

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

Disseminated intravascular coagulation

Contact Info

Product

Resources

About