Fibrinolysis as a feature of disseminated intravascular coagulation (DIC) after envenomation

Masci, Paul P.; Rowe, E.; Whitaker, A N; Jersey, John de

doi:10.1016/0049-3848(90)90399-w

Cited by 24 publications

(19 citation statements)

References 20 publications

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“…These procoagulant enhancements likely provide this snake with a selective advantage by facilitating massive disseminated coagulation after envenomation of prey. 3,28 Our data support the conclusion that pt-FV is synthesized in an active state and, unlike human FV, does not require proteolytic removal of the B-domain to express procoagulant activity. This represents the first reported example of a constitutively procoagulant form of FV in nature.…”

Section: Discussionsupporting

confidence: 78%

Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations

Bos

Boltz

Pierre

et al. 2009

Blood

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Venomous snakes produce an array of toxic compounds, including procoagulants to defend themselves and incapacitate prey. The Australian snake Pseudonaja textilis has a venom-derived prothrombin activator homologous to coagulation factors V (FV) and Xa (FXa). Here we show that the FV component (pt-FV) has unique biologic properties that subvert the normal regulatory restraints intended to restrict an unregulated procoagulant response. Unlike human FV, recombinant pt-FV is constitutively active and does not require proteolytic processing to function. Sequence comparisons show that it has shed a large portion of the central B-domain, including residues that stabilize the inactive procofactor state. Remarkably, pt-FV functions in the absence of anionic membranes as it binds snake-FXa with high affinity in solution. Furthermore, despite cleavage in the heavy chain, pt-FV is functionally resistant to activated protein C, an anticoagulant. We speculate this stability is the result of noncovalent interactions and/or a unique disulfide bond in pt-FV linking the heavy and light chains. Taken together, these findings provide a biochemical rationale for the strong procoagulant nature of venom prothrombinase. Furthermore, they illustrate how regulatory mechanisms designed to limit the hemostatic response can be uncoupled to provide a sustained, disseminated procoagulant stimulus for use as a biologic toxin. IntroductionThe circulation of blood coagulation factors as precursors and their localization to the site of vascular injury after activation are important factors that maintain normal hemostasis and restrict indiscriminate clotting. 1 Bypassing these regulatory paradigms can be life-threatening, yet organisms have evolved strategies that exploit these systems for a selective advantage. For example, the venom of numerous snake species comprises a diverse array of proteases that activate and overwhelm the host hemostatic system in an uncontrolled fashion. 2 Some of the most potent venoms come from the Australian elapid family, including Pseudonaja textilis, Oxyuranus microlepidotus, and Oxyuranus scutellatus. 3 Their venom is considered the most toxic in the world and is unusual as it contains 2 coagulation proteins: factor V (FV) and a factor Xa (FXa)-like enzyme. [4][5][6][7][8][9][10] These proteins make up approximately 20% to 40% of the total venom and form a powerful procoagulant complex. 5,7 This complex converts prothrombin to thrombin, and its activity is enhanced, to various degrees, by calcium and phospholipids, but not by the cofactor FVa. [4][5][6][7]11 Venom-derived FV from these snakes share approximately 44% homology with mammalian FV and have a similar domain structure (A1-A2-B-A3-C1-C2). 8,10,12 However, we were surprised to learn that their B-domains are remarkably short, approximately 46 versus approximately 800 residues in mammals. (Amino acid numbering for pt-FV is as follows: the mature sequence starts at ϩ1 and the remaining sequence is numbered consecutively to 1430. The pt-FV B-domain is defined ...

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Section: Discussionsupporting

confidence: 78%

Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations

Bos

Boltz

Pierre

et al. 2009

Blood

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“…A recent study of severe coagulopathy in 167 envenomed patients demonstrated that the coagulopathy was similar irrespective of the snake, characterized by complete consumption of fibrinogen, very high D-dimers and unrecordable international normalized ratio. 5 Importantly, the time course of the recovery of the consumption coagulopathy or VICC was the same for tiger and brown snakes. 5 Therefore, the coagulopathy seen clinically appears to be similar irrespective of the use of human factor Va by the tiger snake group venoms or the presence of brown snake derived factor Va-like toxin and its ability to avoid hemostatic regulation as shown by Bos et al 1 Interestingly, it may be more clinically relevant and unique that the brown snake-derived factor Va-like molecule does not require activation, so that the prothrombin activator (Xa-Va-like toxin) is able to rapidly induce clotting activation in vivo.…”

mentioning

confidence: 91%

“…5 Importantly, the time course of the recovery of the consumption coagulopathy or VICC was the same for tiger and brown snakes. 5 Therefore, the coagulopathy seen clinically appears to be similar irrespective of the use of human factor Va by the tiger snake group venoms or the presence of brown snake derived factor Va-like toxin and its ability to avoid hemostatic regulation as shown by Bos et al 1 Interestingly, it may be more clinically relevant and unique that the brown snake-derived factor Va-like molecule does not require activation, so that the prothrombin activator (Xa-Va-like toxin) is able to rapidly induce clotting activation in vivo. Some recent work by our group on the onset of VICC showed that, in a series of 112 patients, there was a discernible delay in the development of the coagulopathy with tiger snake group envenoming compared with brown snake.…”

mentioning

confidence: 91%

“…[2][3][4] Masci et al made a similar observation investigating the time course of snake bite envenomation by these snakes. 5,6 To a certain extent the observation that there are no differences in the final coagulopathy and time course of recovery is not surprising. Laboratory measurements (Ͼ 3 INR, undetectable fibrinogen, elevated D-dimer) were initially made more than 4 hours after the snake bite, when there has been ample time to exhaust endogenous clotting factors.…”

Section: Responsementioning

confidence: 99%

“…4 Although it would appear that the presence of a factor Va-like toxin in brown snake (Pseudonaja spp) venom that is impervious to regulation by the hemostatic system provides a potent biologic weapon against prey and in human envenoming, clinical research does not fully support this. 4,5 It is useful to compare the effects of Australian tiger snake group (genera Notechis, Tropidechis, and Hoplocephalus) venoms, which all contain factor Xa-like prothrombin activators (without a factor Va-like part), 4 to that of brown snake venom, which contains the factor Xa-Va-like prothrombin activator. A recent study of severe coagulopathy in 167 envenomed patients demonstrated that the coagulopathy was similar irrespective of the snake, characterized by complete consumption of fibrinogen, very high D-dimers and unrecordable international normalized ratio.…”

mentioning

confidence: 99%

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