The proteolytic action of arvin on human fibrinogen

Ewart, M. R.; Hatton, M. W. C.; Basford, J. M.; Dodgson, K. S.

doi:10.1042/bj1150017p

Cited by 47 publications

(26 citation statements)

References 15 publications

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“…One such protease, Ancrod, derived from Malayan pit viper venom, cleaves Fg␣ and rapidly decreases plasma Fg levels (22). It effectively limited infarct size in acute stroke animal models (21), and two of three randomized controlled clinical trials involving acute stroke patients showed positive results (8a, 54).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Craciun

Ajay

Hoffmann

et al. 2014

American Journal of Physiology-Renal Physiology

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Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

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Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Craciun

Ajay

Hoffmann

et al. 2014

American Journal of Physiology-Renal Physiology

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“…As a-polymerization progresses, the fibrin becomes completely insoluble in the above solvents and is then termed fully cross-linked fibrin. Unlike thrombin, ancrod and reptilase are reported to cleave only fibrinopeptide A from fibrinogen; in addition ancrod partially degrades fibrinopeptide A (22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

“…In vivo such fibrin is rapidly cleared and this has been attributed to lysis by plasmin (30,47), since no further direct proteolytic effect of ancrod on fibrin could be demonstrated (22,24,29), and to phagocytosis of fibrin by the reticuloendothelial system (31). However, it recently has been shown that ancrod itself definitely degrades the a-chains of monomeric fibrin to yield approximately 38,000 and 33,000 mol wt cleavage products (2628), the latter of which appears to undergo further degradation by ancrod.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of ancrod anticoagulation

Pizzo¹,

Schwartz²,

Hill³

et al. 1972

J. Clin. Invest.

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A B S T R A C T Fibrin formed in response to ancrod, reptilase, or thrombin was reduced by P-mercaptoethanol and examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It was found that ancrod progressively and totally digested the a-chains of fibrin monomers at sites different than plasmin; however, further digestion of fibrin monomers by either reptilase or thrombin was not observed. Highly purified ancrod did not activate fibrin-stabilizing factor (FSF); however, the reptilase preparation used in these experiments, like thrombin, activated FSF and thereby promoted cross-link formation. Fibrin, formed by clotting purified human fibrinogen with ancrod, reptilase, or thrombin for increasing periods of time in the presence of plasminogen, was incubated with urokinase and observed for complete lysis. Fibrin formed by ancrod was strikingly more vulnerable to plasmin digestion than was fibrin formed by reptilase or thrombin. The lysis times for fibrin formed for 2 hr by ancrod, reptilase, or thrombin were 18, 89, and 120 min, respectively.Evidence was also obtained that neither ancrod nor reptilase activated human plasminogen. These results indicate that fibrin formed by ancrod is not cross-linked and has significantly degraded a-chains; as expected, ancrodformed fibrin is markedly susceptible to digestion by plasmin.

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“…Ancrod cleaves the A␣ chain of mammalian fibrinogens, releasing only fibrinopeptide A to yield des-A-fibrinogen (or Ancrod-fibrin monomer). 32 In vitro, des-A-fibrinogen polymerizes poorly compared with thrombin-derived fibrin monomer, 33,34 and, for this reason, Ancrod-fibrin clots are believed to be . Each rabbit was exsanguinated at 10 minutes after balloon-catheter injury was induced and the aorta excised and processed as described in the text.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment of Rabbits With Either Hirudin, Ancrod, or Warfarin Significantly Reduces the Immediate Uptake of Fibrinogen and Platelets by the Deendothelialized Aorta Wall After Balloon-Catheter Injury In Vivo

Hatton

Ross

Southward

et al. 1998

ATVB

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Abstract-Fibrinogen and platelets rapidly saturate the exposed subendothelium of a freshly deendothelialized aorta in vivo. As thrombin generated within the site of injury is largely responsible for fibrin(ogen) deposition, we questioned whether various anticoagulant treatments would inhibit uptake of both fibrinogen and platelets in vivo. Rabbits were anticoagulated by pretreatment with either Warfarin, Ancrod, or recombinant hirudin. Each anesthetized, anticoagulated (or saline-injected control) rabbit was injected IV with rabbit 51 Cr-platelets and 125 I-fibrinogen before a balloon-catheter deendothelializing (or sham) injury of the thoracic aorta. At 10 minutes after injury, the rabbit was exsanguinated and the aorta excised. Platelet adsorption by the deendothelialized aorta surface was substantially reduced in anticoagulated rabbits (controls, 2.2ϫ10 5 /mm 2 ; Warfarin-treated, 1.2ϫ10 5 /mm 2 ; Ancrod-treated, 5.3ϫ10 4 /mm 2 ; r-hirudin-treated [5 mg/kg], 5.3ϫ10 4 /mm 2 ), and a significant reduction of fibrinogen associated with the platelet layer (from 5.3 to 1 to 2 pmol/cm 2 ) and within the underlying intima-media layer (from 16.9 to 5 to 6 pmol/cm 2 ) was observed in the r-hirudin-and Warfarin-treated rabbits. The pattern of aorta-deposited 51 Cr-platelets and 125 I-fibrin in the anticoagulated rabbits corresponded well with an assessment by transmission electron microscopy of aortic tissue samples. We conclude that Ϸ70% of fibrinogen uptake is thrombin dependent and that Ϸ80% of platelet adsorption depends on codeposited fibrin(ogen) during the 10-minute interval after balloon injury. Pretreatment with an agent that interferes with either thrombin or fibrin production will inhibit the immediate interaction of fibrinogen and platelets with the freshly exposed subendothelium. (Arterioscler Thromb Vasc Biol. 1998;18:816-824.)

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The proteolytic action of arvin on human fibrinogen

Cited by 47 publications

References 15 publications

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Mechanism of ancrod anticoagulation

Pretreatment of Rabbits With Either Hirudin, Ancrod, or Warfarin Significantly Reduces the Immediate Uptake of Fibrinogen and Platelets by the Deendothelialized Aorta Wall After Balloon-Catheter Injury In Vivo

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