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PubMed1995

Desmin 370, a low molecular weight dermatan sulfate, reduces the weight of preformed thrombi in rats made afibrinogenemic by ancrod.

Desmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to induce a marked reduction of the weight of preformed venous thrombi in rats and rabbits by mechanisms that appeared largely independent of inhibition of thrombus accretion. In order to provide further support for such a mechanism, we exploited the defibrinating capacity of ancrod to obtain a thrombosis model characterized by the lack of thrombus growth and thus sensitive only to agents promoting thrombus lysis. Thrombus formation in anesthetized rats was induced by vena cava ligature. Injection of ancrod (5 U/kg) 5 h after induction of venous stasis caused a more than 95% reduction in plasma fibrinogen and prevented thrombus accretion as indicated by the lack of thrombus weight increase during the 3 h experimental period (12.2 +/- 0.6 vs 14.5 +/- 1 as compared to 12.6 +/- 0.6 vs 19.6 +/- 0.8, p < 0.01, in control rats) and by the almost complete (> 90%) inhibition of 125I-fibrin(ogen) binding to thrombi. Moreover, when ancrod was given 1 h before vena cava ligature, no thrombi were formed within 2 h whereas at the same time interval visible thrombi were present in all control rats. Administration of D370 (10 mg/kg) to thrombus bearing rats, 1 h after induction of afibrinogenemia, resulted in a significant reduction in thrombus weight (43% after 2 h, p < 0.01) which was only slightly lower than that recorded in normofibrinogenemic rats (54%). Enhancement of plasma fibrinolytic activity by ancrod had no influence on thrombus lysis and was not all affected by administration of D370.(ABSTRACT TRUNCATED AT 250 WORDS)

Ancrod↗
PubMed1995

Inhibition of arterial thrombus formation in two canine models: comparison of ancrod, a fibrinogen-depleting agent, the thrombin-inhibitor r-hirudin, and the glycoprotein 11b/IIIa-receptor antagonist Ro 43-8857.

Inhibition of arterial thrombus formation by ancrod, a fibrinogen depleting agent isolated from a snake venom, r-hirudin, an inhibitor of thrombin-mediated fibrinogen cleavage, or the glycoprotein (GP)IIB/IIIa-receptor antagonist Ro 43-8857 interfering with fibrinogen binding to platelets, was evaluated in two canine models. As a marker of platelet-dependent thrombus formation, cyclic blood flow reductions (CFR) were induced in the left coronary artery (LAD) of mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. In the second model CFRs were induced by thrombolysis of a copper coil-induced thrombus in the carotid artery. Blood flow rate during the reocclusion phase was used as an additional parameter of efficacy. The frequency of CFRs used a indicator of platelet aggregation and adhesion was significantly diminished by all treatments in both the carotid artery- and the LAD-model. In the LAD-model, following ancrod treatment, CFRs were correlated with plasma fibrinogen concentrations. Carotid artery blood flow after reperfusion, used as indicator of occlusive thrombus formation, rapidly declined to zero in the control group but remained at a high level after treatment with ancrod or r-hirudin. Ro 43-8857 at the selected dose improved flow rate only to a minor degree but prolonged the bleeding time from a mean value of 87.2 +/- 10.9 s (n = 24) to values > 300 s in 50% of the animals. Our results indicate that CFRs as indicator of platelet aggregation and adhesion are inhibited by either treatments. Blood flow as indicator of occlusive thrombus formation, however, is effectively improved by ancrod and r-hirudin only. Inhibition of fibrinogen binding to platelet GPIIb/IIIa receptors alone was found to be less potent antithrombotic principle in this model.

Acetates↗
PubMed1974

Low-dosage ancrod for prevention of thrombotic complications after surgery for fractured neck of femur.

The effect of a low-dosage regimen of ancrod in the prevention of postoperative deep vein thrombosis was assessed in 24 patients having surgical repair of fractured neck femur and compared with 25 control patients who did not receive therapy. The objective of the therapy was to lower the preoperative fibrinogen level and produce a low concentration of fibrin degradation products yet avoid the haemorrhagic complications of total defibrination. Ancrod therapy proved feasible to carry out, was not associated with haemorrhagic complications, and produced sustained, predictable reductions in fibrinogen concentration. There were seven thromboembolic complications in the control patients compared to one such complication in the ancrod-treated patients. Five deaths occurred in the control group and one in the treated group. Though the incidence of deep vein thrombosis was not apparently affected by ancrod it appeared on venography that the thrombi in the treated patients were less extensive than those in the control patients. Finally, some discrepancies in the diagnosis of deep vein thrombosis by the three techniques of clinical examination, (125)I-fibrinogen scanning, and ascending venography were identified.

Aged↗
PubMed1992

Amino acid sequence determination of ancrod, the thrombin-like alpha-fibrinogenase from the venom of Akistrodon rhodostoma.

The thrombin-like serine protease and antithrombotic agent, Ancrod, was rapidly purified from the crude venom of Akistrodon rhodostoma by agmatine-Sepharose affinity chromatography followed by MonoQ anion exchange chromatography. N-Terminal sequencing and analysis of overlapping proteolytic fragments of purified Ancrod by automated Edman degradation in combination with tandem mass spectroscopy allowed the determination of the 234 amino acid sequence of the protease. Glycosylation sites at all five canonical N-linked glycosylation sites were inferred from the appearance of blank sequencer cycles in the amino acid sequence and were confirmed by mass spectroscopic analysis of the N-glycanase-treated peptides. Monoclonal antibodies raised against the denatured protein and HF-deglycosylated protein recognized Ancrod on Western blots. Sequence comparison to other thrombin-like serine proteases and reptilian fibrinogenases revealed a number of similarities, most notably the catalytic triad and many conserved cysteine positions.

Amino Acid Sequence↗
PubMed1998

Cardiopulmonary bypass with danaparoid sodium and ancrod in heparin-induced thrombocytopenia.

Heparin is the standard anticoagulant for patients undergoing cardiopulmonary bypass. There are some patients for whom heparin is unsuitable and ancrod (a defibrinogenating enzyme) has been used as an alternative. We present a patient with heparin-induced thrombocytopenia in whom treatment ancrod was ineffective. The addition of danaparoid sodium (a heparinoid) allowed safe cardiopulmonary bypass. We discuss the reasons for this and suggest that the combination of ancrod and danaparoid sodium is a logical one in such cases.

Ancrod↗
PubMed1976

Comparison of ancrod and heparin as anticoagulants following endarterectomy in the dog.

An experimental model of surgically-induced arterial thrombosis was devised using the femoral arteries of dogs. Within 7 days, 67% of the arteries became completely thrombosed and only 12% remained compeletly patent. In the group of dogs that received low-dose heparin, 69% of the vessels were completely thrombosed and 6% remained completely patent. In the group of dogs treated with low-dose Ancrod to induce partial defibrination, 75% remained completely patent while only 19% of their femoral arteries were completely thrombosed. Although the ancrod was effective in preventing arterial thrombosis, 88% of the wounds showed moderate to severe separations. Most likely the absence of a fibrin lattice, necessary for the securement and growth of fibroblasts as the wound heals, explains this latter effect. Thus while Ancrod may become useful as an anticoagulant in certain clinical situations, it should not be used in proximity to surgery. Finally, in these studies of acute arterial thromboses, low-dose heparin therapy offered no protective effect.

Ancrod↗
PubMed1991

Experimental ancrod (Arvin) for acute ischemic stroke: nursing implications.

By increasing local cerebral blood flow to ischemic brain tissue in a timely fashion, impending cerebral infarction can be reversed. Aggressive, early intervention is the key to overall neurological improvement of stroke patients. Ancrod, a purified protein fraction of venom from the Malayan pit viper, has been shown to produce rapid and effective defibrinogenation in humans. A current clinical trial with ancrod in patients with acute or progressing nonhemorrhagic ischemic stroke requires an onset to treatment time of no more than 6 hours. Ancillary hospital personnel, physicians and nurses all play important roles in expediting study treatment. Nurses must assess ancrod study patients for potential bleeding problems. Community awareness and education about the warning signs of impending stroke are factors important to insuring early intervention and improving neurological outcome of stroke victims.

Ancrod↗
PubMed1977

Role of fibrinopeptide B release: comparison of fibrins produced by thrombin and Ancrod.

The gelation time, opacity, light scattering, and elastic moduli of human fibrin gels clotted in the presence of thrombin, Ancrod, and Reptilase have been compared. At low ionic strength lateral association to thick fibers is observed in all cases. At all ionic strengths thrombin fibrin forms thicker fibers than does Ancrod fibrin. We have demonstrated that an increase in the extent of lateral association is linked to an increase in its velocity and to a decrease in the gelation time. One may consider the removal of fibrinopeptide B to act as a switch: after it is removed fibrin assembles rapidly to thick fibers and gelation is fast; but when this peptide is still attached, there is a slow assembly of thin fibers, and gelation, especially of dilute fibrin, is delayed. We believe that this delay is critical for the complete digestion by plasmin of fibrin formed during in vivo defibrination with Ancrod and of fibrin produced by very small amounts of thrombin (which would still contain fibrinopeptide B), and that slow release of fibrinopeptide B is part of a control mechanism for the regulation of fibrin formation and the prevention of intravascular coagulation.

Ancrod↗
PubMed1982

Double-blind controlled clinical trial of ancrod for ischemic rest pain of the leg.

In a randomized double-blind trial, patients with ischemic rest pain of the leg received 8 days of treatment with intravenous injections of the defibrinating agent, ancrod (Arvin) or saline. Plasma fibrinogen, plasma viscosity, and blood viscosity were significantly reduced during ancrod therapy. After 27 patients had completed treatment, sequential analysis showed no preference for either therapy. In each group two-thirds of the patients claimed improvement in pain after treatment. There were no significant differences between treatment groups in analgesic consumption, Doppler systolic pressure ratio, or surgical intervention in the 6 months following treatment. We conclude that in patients with ischemic rest pain, ancrod therapy is not superior to placebo injections, and that the effect of placebo treatment is considerable.

Aged↗
PubMed1989

Anticoagulation by ancrod for carbon dioxide removal by extracorporeal membrane lung in the dog.

Ten dogs were subjected to defibrinogenation with an intravenous perfusion of ancrod (1 unit/kg) (Arvin, Knoll AG, Ludwigshafen, Federal Republic of Germany) over a 2 1/2 hour period. Six of them were subjected to extracorporeal elimination of carbon dioxide with a polypropylene membrane lung by means of veno-venous bypass. The remaining four dogs did not undergo extracorporeal circulation and served as control subjects. In both groups, ancrod administration itself resulted in a marked drop in alpha 2-antiplasmin (33% and 67%, respectively, of the baseline values) and in slight but significant decreases in factor II and plasminogen activities of 25% and 20%, respectively (p less than 0.05), in the group subjected to carbon dioxide removal. There were no significant changes in platelet number or factor V and antithrombin III activities. During the 6-hour bypass period, platelet count and antithrombin III and factor II and V levels decreased significantly. No bleeding was observed. Histologic examination of lung biopsy tissue showed no pathologic features. Analysis of the membrane of the artificial lungs revealed no fibrin deposits. In the control group, except for a drop in alpha 2-antiplasmin levels (54%), no significant changes in hemostatic parameters occurred during the corresponding 6 hours. We conclude that, despite the drop in coagulation factors and in alpha 2-antiplasmin activity during bypass, ancrod can be considered as a valuable alternative anticoagulant for extracorporeal carbon dioxide removal.

Ancrod↗
PubMed1978

Subcutaneous ancrod after operation for fractured hip--a dose-ranging and feasibility study.

We have conducted a dose-ranging and feasibility study of daily subcutaneous injections of ancrod (Arvin) as a potential antithrombotic method in 28 patients following operation for fractured neck of femur. Sustained, predictable fibrinogen depletion during the first post-operative week was induced by four different regimes. A total dose of 10 units/kg weight, given in divided doses starting on the day of operation, is suggested as a possible antithrombotic regime. Ancrod treatment produced a rise in fibrinogen/fibrin degradation products, prolongation of the thrombin clotting time, and a fall in plasminogen, plasma fibrinogen and corrected blood viscosity were observed in 14 control patients. Plasma fibrinogen was correlated with plasma viscosity and corrected blood viscosity. No adverse effects of treatment occurred. Subcutaneous ancrod appears to be a simple, safe, and feasible potential antithrombotic method, and merits trials of efficacy in the prevention of post-operative thromboembolism.

Adult↗
PubMed1994

Heparin-induced thrombosis treated with ancrod.

Heparin used in the treatment of thromboembolic disease may produce an immune response in the patient, leading to thrombocytopenia and even thrombosis. These complications may arise at any time after the institution of heparin therapy. The authors report a case of heparin-induced thrombocytopenia with thrombosis in a 70-year-old woman. The complication was treated successfully with thrombectomy and the administration of warfarin and ancrod, which is a natural fibrinolytic agent. The nature of heparin-induced thrombosis and the mechanism of action of ancrod are discussed. The authors emphasize that all patients receiving heparin therapy should be closely monitored to detect hematologic disorders and to prevent their sequelae. Ancrod provides a reasonable therapeutic option if thrombosis does occur.

Aged↗
PubMed1994

Ancrod infusion for anticoagulation during and after PTCA in a patient with heparin-induced thrombocytopenia.

Ancrod is a rapid-acting defibrinogenating agent derived from the venom of the Malayan pit viper which has been used successfully as an alternative to heparin sulfate for anticoagulation during peripheral vascular procedures and coronary artery bypass surgery. We describe the first use of ancrod for anticoagulation before and during percutaneous transluminal coronary angioplasty (PTCA) in a patient with heparin-associated thrombocytopenia.

Ancrod↗
PubMed1994

Isolation of multiple isoforms of alpha-fibrinogenase from the Western diamondback rattlesnake, Crotalus atrox: N-terminal sequence homology with ancrod, an antithrombotic agent from Malayan viper.

Three fibrinogenolytic proteases from the rattlesnake (Crotalus atrox) venom were isolated and purified from multiple-step chromatographies including ion-exchange chromatography, gel permeation and reversed-phase HPLC. The fractions were shown to be homogeneous as judged by SDS-gel electrophoresis. In vitro, they also showed a high and specific proteolytic activity against alpha-chains of fibrinogen molecules. Further characterization of these purified fractions with fibrinogenase activity indicated that they are all single-chain proteins with similar molecular weights of about 33,000-35,000. Their stability at high temperatures was examined and the cleavage specificity of various proteases was studied using oxidized insulin B-chains as substrates. The reactivity toward fibrinogen molecules in the presence of varied protease inhibitors including EDTA, beta-mercaptoethanol, soybean trypsin inhibitor, aprotinin and phenylmethanesulfonyl fluoride was also investigated in order to classify these proteases based on their reaction mechanisms. Amino acid analysis indicates that these purified venom toxins possess closely-similar compositions with regard to most amino acids including cysteine, methionine and tyrosine. N-Terminal sequence analysis of these proteases revealed that they are similar to ancrod, an antithrombotic agent isolated from the Malayan pit viper. This study points to the existence of a family of novel ancrod-like fibrinogenases in crotalid rattlesnakes, which may be useful as effective venom-based anticoagulants.

Amino Acid Sequence↗
PubMed1993

Glycosylation of the thrombin-like serine protease ancrod from Agkistrodon rhodostoma venom. Oligosaccharide substitution pattern at each N-glycosylation site.

In a previous study, we determined the structures of the glycans present in ancrod, a thrombin-like serine protease from the venom of the Malayan pit viper Agkistrodon rhodostoma (Pfeiffer et al. (1992) Eur J Biochem 205:961-78). In order to allocate the various carbohydrate chains to distinct N-glycosylation sites of the molecule, we have now isolated individual glycopeptides. Peptide moieties were identified after deglycosylation with peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase F by amino acid analysis and sequencing. Liberated oligosaccharides were assigned to the previously deduced carbohydrate structures by high performance liquid chromatography. Although only quantitative differences were observed, the results indicate that each glycosylation site of ancrod carries its characteristic oligosaccharide pattern. Furthermore, all potential sites were shown to be substituted by carbohydrates.

Agkistrodon↗
PubMed1985

The effect of cycloheximide, heparin and ancrod on mice given Ehrlich ascites tumour cells intravenously.

Mice injected intra-venously with Ehrlich ascites tumour cells showed a fatal susceptibility to normally-tolerated doses of cycloheximide when the latter was given at the following times after the tumour cells--2 h, 24 h, 48 h, and 72 h. When the interval between tumour cell injection and cycloheximide challenge was extended to 1 week or 3 weeks (at which latter time mice have clinical "metastatic" neoplasia), no such susceptibility was shown. In the case of the 2 h interval between tumour cells and cycloheximide (and also when cycloheximide was given 2 h before tumour cells), the lethal syndrome was prevented by heparin treatment and also by Ancrod defibrination. This strongly suggests that heparin is effective by virtue of its anticoagulant properties, and that fibrinogen-to-fibrin conversion is an essential step in the pathogenesis. Neither heparin nor Ancrod confer any protection when used in the syndrome consequent upon cycloheximide challenge 24 h after tumour cell injection, which indicates that, in this case, the conversion of fibrinogen to fibrin is not an essential step in determining the fatal outcome.

Ancrod↗
PubMed1982

Deficiency of a plasma factor stimulating vascular prostacyclin generation in patients with lupus nephritis and glomerular thrombi and its correction by ancrod: in-vivo and in-vitro observations.

Glomerular thrombi occur frequently in active lupus nephritis. Their presence has been correlated with low platelet counts and with subsequent development of glomerular sclerosis. We have examined the plasma PGI2 generating capacity of 8 patients with active lupus nephritis with thrombi that were to undergo defibrination therapy with ancrod. PGI2 generation by these plasma samples was significantly decreased as compared both to normals and to 6 individuals with lupus nephritis and no glomerular thrombi. Significant improvement in the capacity to generate PGI2 was seen in the post-ancrod treatment plasma samples. the pathogenesis of this defect is discussed.

Ancrod↗
PubMed1986

Primary specificity of ancrod, the coagulating serine proteinase from the Malayan pit viper (Agkistrodon rhodostoma) venom.

Values of steady-state and pre-steady-state parameters for the hydrolysis of ZArgONp and ZLysONp catalysed by ancrod, the coagulating serine proteinase from the Malayan pit viper (Agkistrodon rhodostoma) venom, have been determined, between pH 2.5 and 8 (I = 0.1 M) at 21 +/- 0.5 degrees C, and analysed in parallel with those of bovine alpha-thrombin and porcine pancreatic beta-kallikrein-B. In addition to the well-known coagulating behaviour, ancrod also shows catalytic properties, in the hydrolysis of ZArgONp and ZLysONp, reminiscent of those of porcine pancreatic beta-kallikrein-B.

Ancrod↗