Ning Tang writes, Dear George, In China, a categary of hemostatic agents from snake venom named “Haemocoagulase” are widely used, basically they are the generic drugs of Reptilase®, which is produced by a Swiss company. We find that intravenous injection of this drug can cause severe hyperfibrinolysis and hypofibrinogenemia. It seems that Reptilase has been withdrawm from many western countries, do you know the reason? Whether is it due to some side effects? Looking forward to your reply.
Hello, Ning Tang and thank you for your question. Pentapharm, located in Switzerland, as you indicate, isolates Reptilase® from the venom of the Brazilian pit viper, Bothrox atrox. Hemostasis reference laboratories offer the Reptilase time assay, which we use sparingly. Reptilase is a serine protease whose function resembles thrombin as it cleaves fibrinogen and supports fibrin formation. Reptilase’s action differs from thrombin, as thrombin cleaves the ends of fibrinogen’s alpha and beta chain to produce fibrinopeptides A and B, whereas Reptilase cleaves only the end of the alpha chain, releasing only fibrinopeptide A. The action of thrombin is reduced by heparin-activated antithrombin, but antithrombin has no effect on the Reptilase reaction. Thus we can use the Reptilase time and thrombin time assays to confirm presence of therapeutic heparin. The Reptilase time assay uses the same protocol as the thrombin time, merely substiting the venom-based reagent for thrombin. The Reptilase time may also help identify hypofibringenemia and dysfibrinogenemia.
Intravenous therapeutic Reptilase, which Pentapharm named Haemocoagulase in 1954, is used in China, Japan, and Korea as a procoagulant to control operative and traumatic bleeding. While it appears to be effective, it has been used sparingly in other countries. I’ve contacted experts who may have access to studies indicating risks of hyperfibrinolysis and hypofibrinogenemia in Reptilase therapy. There is a recombinant Reptilase reported in You WK, et al. Functional characterization of recombinant batroxobin, a snake venom thrombin-like enzyme, expressed from Pichia pastoris. FEBS Letter 2004, 571: 67–73.
Pentapharm also markets Aprotinin, extracted from bovine lung, that acts as a protease inhbitor and suppresses fibrinolysis. Aprotinin may be used to control bleeding during surgery and has been used as a fibrin sealant.
Pentapharm also markets Defibrase®, (batroxobin), a similar protease isolated from a Bothrops family member, Bothrops moojeni. Batroxobin digests fibrinogen and fibrin, and may be used to treat venous thromboembolic embolization and arterial ischemia. Again, as you noted, Defibrase is employed as a therapeutic only in China. Click or tap Ding J, Zhou D, Hu Y, et al. The efficacy and safety of batroxobin in combination with anticoagulation on cerebral venous sinus thrombosis. J Thrombois Thrombolys 2018;46:371–8 to read a comprehensive study of batroxobin employed with low molecular heparin to treat venous sinus thrombosis.
Again, thank you for your discussion, and please watch here for additional comments regarding Reptilase efficacy and safety.
Added same day, July 22, 2019: Thank you to Dr. Vadim Kostousov for his comments below elucidating the risks of envenomation. Click or tap the following citation to the 2013 article Dr. Kostousov references. Vu TT, Stafford AR, Leslie BA, et al. Batroxobin binds fibrin with higher affinity and promotes clot expansion to a greater extent than thrombin. J Biol Chem 2013.
Some experimental evidence
From Vadim Kostousov, MD: Some experimental evidence suggests that batroxobin could be a procoagulant that contribute to microvascular thrombosis. That is why the majority of snake venoms are gone from the pharmaceutical market. The same story happened to ancrod (Viprinex), marketed in Austria and Germany until it was withdrawn in the 1980s. The failure of ancrod in the 6-hour window for ischemic stroke trial in 2008 led to this drug being discontinued for future research.
“… the procoagulant activity of fibrin-bound batroxobin may contribute to the microvascular thrombosis observed in patients envenomated with Bothrops atrox moojeni (26,27)… Our results suggest that treatment with these agents may be complicated by microvascular thrombosis, which may explain the disappointing results of studies that explored the use of fibrinogen-depleting snake venom enzymes for treatment of acute ischemic stroke (51,52).” Vu TT et al. Batroxobin binds fibrin with higher affinity and promotes clot expansion to a greater extent than thrombin. http://www.jbc.org/content/early/2013/04/23/jbc.M113.464750.full.pdf