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Biomedical subjects

G Dickneite

Publications and source records attributed to G Dickneite.

At least 19 recordsLinked to original sources
PubMed2003

Fibrin sealants in supporting surgical techniques: strength in factor XIII.

Factor XIII has a well-established role in natural coagulation and clot stabilization. It is often added back to fibrin sealants that are used in a wide range of surgical settings to achieve successful hemostasis, tissue adhesion and wound healing. Factor XIII is the final enzyme to be activated in the blood coagulation cascade. It plays an important role in maintaining the balance between coagulation and fibrinolysis. Factor XIII facilitates the formation of covalent cross-links within the fibrin network, forming a loose mesh after activation by thrombin. It adds significant resilience to fibrin clots, augmenting strength by as much as 5-fold. Both fibrin cross-linking and the factor XIII-catalyzed ligation of the fibrinolysis inhibitor alpha(2)-antiplasmin to the fibrin clot contribute to the increased proteolytic resistance of factor XIII-stabilized clots. Preclinical studies indicate that the inclusion of factor XIII in fibrin sealants used for vascular grafting significantly reduces suture-hole blood loss. This has important implications for the successful control of bleeding in comparable clinical situations. The advantages of factor XIII stabilized clots (increased strength, resistance to proteolysis, promotion of wound healing) suggest that the presence of factor XIII in fibrin sealants may optimize their performance in the clinical setting. The aim of this paper is to review preclinical data that provide evidence for a potentially positive role for factor XIII in fibrin sealants.

Animals↗
PubMed2001

The potentiation of human C1-inhibitor by dextran sulphate is transient in vivo: studies in a rat model.

C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions because it is a potent inhibitor of the contact and complement system. C1-Inh application in inflammatory disease is, however, restricted because of the high doses required. The glycosaminoglycan-like molecule dextran sulphate (DXS) enhances C1-Inh function in vitro. Hence, we investigated whether co-administration with dextran sulphate reduces the amount of C1-Inh required, through enhancement in vivo. C1-Inh potentiation was measured in a newly developed C1s-inactivation assay that is based on activation of C4 by purified C1s. Activated C4 in rat plasma was quantified with a newly developed ELISA. Human C1-Inh (2.5 microM) inhibited C1s in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 microM). To study the stability of the complex in vivo, rats were given a mixture of C1-Inh (10 mg/kg) and dextran sulphate (3 mg/kg). C1-Inh activity during 5 h was analyzed ex vivo with the C1s inactivation assay. The noncovalent C1-Inh-dextran sulphate complex resulted in a transient enhancement of the inhibitory capacity of C1-Inh, lasting for 60-90 min. Dextran sulphate did not affect plasma clearance of C1-Inh. We conclude that the enhanced inhibitory capacity of C1-Inh complexed to dextran sulphate is transient in vivo. Hence, co-administration of these compounds seems a feasible approach to achieve short-term inhibition of complement in vivo.

Animals↗
PubMed2001

Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding.

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.

Animals↗
PubMed2000

Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII.

BACKGROUND: Suture hole bleeding is a frequent complication in vascular surgery. The use of fibrin sealants (FSs) during surgery is reported to reduce blood loss by enhancing hemostasis. OBJECTIVES: Using a pig vascular graft model we investigated: (1) the use of FSs in vascular surgery and measured blood loss with and without the use of FSs; (2) the effect of factor XIII in FSs on hemostasis and blood loss; and (3) the effect of increasing FS incubation time on hemostasis and blood loss. MATERIALS AND METHODS: During surgery, a 3-cm incision was made in the carotid artery wall. Incisions were covered with a Gore-Tex (PTFE) patch sutured with Ethicon monofil 5/0 or 3/0. The resulting suture holes were treated according to study protocol. Study 1: Nine pigs received either FS treatment (n = 5) or no treatment (n = 4). Study 2: Twenty pigs underwent bilateral surgery; right (n = 20) and left (n = 20) patches received either FS with factor XIII (FS + FXIII) or FS depleted of factor XIII (FS - FXIII). Study 3: Bilateral surgery was carried out on 24 pigs; PFTE patches secured with Ethicon 3/0 were treated with FS and allowed to polymerize for 120 s (n = 12), 180 s (n = 12), or 240 s (n = 12) or with solid support/thrombin (n = 12). RESULTS: Study 1: Mean blood loss was significantly lower in the FS-treated group compared with untreated controls (9.2 +/- 10.6 mL vs 178.8 +/- 125.5 mL, mean +/- SD, P = 0.016). Study 2: Significantly less blood was lost in the FS + FXIII group than in the FS - FXIII group (Delta = 9.6 mL, P = 0. 02). Study 3: Blood loss was significantly higher from patches treated with solid support/thrombin compared with those treated with FS (P < 0.01). CONCLUSIONS: FSs containing factor XIII, such as Beriplast P, are effective in reducing suture hole bleeding and improving hemostasis during vascular graft procedures. The presence of factor XIII contributes to the efficacy of FSs and reduces the time to hemostasis. During vascular surgery, blood loss can be reduced significantly by the use of fibrin sealant compared with absorbable gelatin sponges coated with thrombin.

Animals↗
PubMed1999

Influence of antithrombin III on coagulation and inflammation in porcine septic shock.

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.

Animals↗
PubMed1998

Antithrombin III in animal models of sepsis and organ failure.

Antithrombin III (AT III) is the physiological inhibitor of thrombin and other serine proteases of the clotting cascade. In the development of sepsis, septic shock and organ failure, the plasma levels of AT III decrease considerably, suggesting the concept of a substitution therapy with the inhibitor. A decrease of AT III plasma levels might also be associated with other pathological disorders like trauma, burns, pancreatitis or preclampsia. Activation of coagulation and consumption of AT III is the consequence of a generalized inflammation called SIRS (systemic inflammatory response syndrome). The clotting cascade is also frequently activated after organ transplantation, especially if organs are grafted between different species (xenotransplantation). During the past years AT III has been investigated in numerous corresponding disease models in different animal species which will be reviewed here. The bulk of evidence suggests, that AT III substitution reduces morbidity and mortality in the diseased animals. While gaining more experience with AT III, the concept of substitution therapy to maximal baseline plasma levels (100%) appears to become insufficient. Evidence from clinical and preclinical studies now suggests to adjust the AT III plasma levels to about 200%, i.e., doubling the normal value. During the last few years several authors proposed that AT III might not only be an anti-thrombotic agent, but to have in addition an anti-inflammatory effect.

Animals↗
PubMed1998

Development of an anti-bleeding agent for recombinant hirudin induced skin bleeding in the pig.

Recombinant hirudin (rH) is a highly specific thrombin inhibitor which is under clinical investigation for various thrombotic disorders. However, one of its potential risks during clinical use might be hemorrhage, especially when combined with other agents interfering with the coagulation system like antiplatelet or fibrinolytic agents. In this experimental study we investigated whether Haemate, a von Willebrand Factor (vWF) and factor VIII containing product, could correct rH/aspirin induced bleeding in an experimental pig study. Skin bleeding time was evaluated in three open, placebo-controlled, randomized studies following comparable designs. A total of 62 animals were given a short-term infusion of aspirin (20 mg/kg) followed by a three-hour infusion of a high or low dose (0.3 or 0.5 mg/kg/h) of rH. At cessation of rH infusion, animals were allocated to treatment with either Haemate (30 FVIII U/kg) or the recombinant factor VIII, Helixate, which is devoid of vWF. The skin bleeding time (SBT, given as times of baseline) as measured four hours after the start of the rH infusion was defined as the prospective endpoint. In study 1 (low dose rH + Haemate) 4 h SBT was 2.18 (placebo) and 1.61 (Haemate, p = 0.0111). In study No. 2 (high dose rH + Haemate) SBT was 2.58 in placebo and 1.73 in Haemate (p = 0.0001). No significant difference between placebo and treatment were detected in study No. 3 (low dose rH + Helixate). Haemate but not Helixate significantly decreased bleeding time as compared to placebo at termination of the study (7 hours) which was defined as the secondary endpoint. No effect on either aPTT nor rH plasma levels were observed with any of the study drugs. It was concluded that Haemate decreases excess bleeding induced by rH/aspirin treatment without altering rH's anticoagulant effect.

Animals↗
PubMed1997

Combined treatment with C1 esterase inhibitor and antithrombin III improves survival in severe acute experimental pancreatitis.

BACKGROUND: Patients with severe acute pancreatitis die of complications closely related to the systemic activation of protease cascades. AIM: To examine the effects of human C1 esterase inhibitor (C1 INH) and antithrombin III (AT III) on two experimental models of acute pancreatitis. METHODS: Oedematous pancreatitis was induced by continuous intravenous infusion of caerulein and haemorrhagic pancreatitis by retrograde injection of sodium taurocholate into the biliopancreatic duct. C1 INH and AT III were given intravenously, either before or after the induction of pancreatitis. Treatment with C1 INH and AT III had no beneficial effect on oedematous pancreatitis. On the other hand, combined C1 INH and AT III therapy improved the survival in haemorrhagic pancreatitis compared with treatment with human serum albumin. This reduction in mortality was found regardless of whether the treatment was given prophylactically or therapeutically. CONCLUSIONS: Treatment with C1 INH and AT III represents a promising therapeutic concept for patients with severe haemorrhagic pancreatitis.

Acute Disease↗
PubMed1996

First-pass elimination of a peptidomimetic thrombin inhibitor is due to carrier-mediated uptake by the liver. Interaction with bile acid transport systems.

CRC 220 (4-methoxy-2, 3, 6-trimethylphenylsulfonyl-L-aspartyl-D-4-amidinophenylalanyl -piperidide) is a competitive peptide-based trombin inhibitor with high affinity to human alpha-thrombin (Ki 2.5 nM). The amphiphilic compound exhibits virtually no systemic bioavailability despite proteolytic stability and proven enteral absorption. After intravenous application (V. jejunalis) in rats CRC 220 is almost completely excreted into bile. Simultaneous administration of bile acids considerably decreases this first-pass elimination. CRC 220 is extensively taken up in isolated rat hepatocytes by a saturable carrier-mediated transport with Km 23.7 microM and Vmax 775 pmol x mg-1 x min-1. A large part of this transport is energy-dependent. At temperatures above 20 degrees C, the uptake is accelerated exponentially. The activation energy amounts to 82 kj/mol. A minor portion of CRC 220 uptake occurs by physical diffusion with a permeability coefficient of 7.83 x 10(-7) cm/sec at 12 degrees C. Sodium ions energize CRC 220 uptake. Replacement of sodium by choline or lithium decreases the transport rate of 23-40%. In addition, a negative membrane potential facilitates the uptake. CRC 220 transport is only observed in hepatocytes: it is absent in BHK, FAO, HepG2, HPCT 1E3, and HPCT 1E3-TC cells. In the presence of 4-amidinophenylalanine derivatives, CRC 220 uptake is considerably decreased. Inhibition also occurs with bile acids and bromosulfophthalein, but less with bumetanide. Because CRC 220 inhibits bile acid uptake into hepatocytes and vice versa, the results suggest that the first-pass elimination of this amphiphilic thrombin inhibitor is due to an active carrier-mediated transport process in the basolateral plasma membrane of rat hepatocytes, and that this transport occurs via a bile acid transport system.

Adolescent↗
PubMed1996

The peptide-based thrombin inhibitor CRC 220 is a new substrate of the basolateral rat liver organic anion-transporting polypeptide.

The peptidomimetic thrombin inhibitor CRC 220, 4-methoxy-2,3,6-trimethylphenylsulfonyl-L-aspartyl-D-4-amidinop henylalanyl- piperidide, is taken up into isolated rat hepatocytes through active, carrier-mediated transport. This uptake is inhibited by bile acids. Functional expression in Xenopus laevis oocytes was performed to identify the transport system responsible for the hepatocellular CRC 220 uptake. Injection of poly(A)+RNA in X. laevis oocytes resulted in a two- to three-times higher uptake of CRC 220, compared with uninjected or water-injected control oocytes. Taurocholate (200 mumol/L) inhibited this uptake completely. No uptake of the peptidomimetic thrombin inhibitor was observed, when X. laevis oocytes were injected with complementary RNA (cRNA) encoding either the cloned rat liver Na(+)-dependent taurocholate transporter Ntcp, the renal oligopeptide carrier rhaPT or the intestinal oligopeptide transporter PepT1. However, after injection of cRNA of the cloned rat liver Na(+)-independent organic anion transporting polypeptide oatp, a specific and saturable CRC 220 uptake was observed (Michaelis-Menten constant 29.5 mumol/L). Cis-inhibition with known oatp-substrates, e.g., 20 mumol/L Bromsulphalein (BSP), 2007 mumol/L taurocholate and 2007 mumol/L cholate, occurred in oatp-expressing X. laevis oocytes, whereas substrates of the two peptide carriers as well as dipeptide- and single-amino acid constituents of the thrombin inhibitor itself lacked any significant inhibitory effects. These data show that the modified dipeptide CRC 220 is a highly selective substrate of the organic anion transporting polypeptide oatp in the basolateral plasma membrane of rat hepatocytes.

Animals↗
PubMed1995

Pharmacological characterization of a new 4-amidinophenyl-alanine thrombin-inhibitor (CRC 220).

The new thrombin inhibitor CRC 220 was characterized in vivo for its antithrombotic effects. CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pigs and monkeys. We evaluated the efficacy of CRC 220 to prevent thrombus formation in arteries and in the microcirculation in different animal models. In a rabbit model of tissue factor-induced coagulation activation, infusion of 0.5 mg/kg x h CRC 220 (3 hours) led to a significant prevention of fibrinogen decrease. In a rat model of lethal LPS-induced DIC CRC 220 significantly prevented the mortality rate after a 4h-infusion of 0.75 mg/kg x h. Thrombin-induced platelet aggregation in rat lungs could be prevented by the i.v. bolus injection of CRC 220. A dose of 0.3 mg/kg leads to a reduction of more than 80% of platelet deposition in the lung, significant inhibition was still observed 90 minutes after CRC 220 administration; at this time the inhibitor had already been cleared from plasma. Arterial thrombosis was induced in rabbits by squeezing and stenosis of the A. carotis. The i.v. bolus administration of CRC 220 dose-dependently prevented thrombus formation, an ED50 of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.

Animals↗
PubMed1995

Modulation of the immunoglobulin dysregulation in GvH- and SLE-like diseases by the murine IL-4 receptor (IL-4-R).

As has been reported previously, models of chronic graft-versus-host (GvH) and systemic lupus erythematosus (SLE)-like diseases are characterized by high IgE and IgG1 immunoglobulin (Ig) levels in the serum. An IL-4 induced pathological expansion of Th2 helper cells has been described for both disease models. Due to the immunopharmacological profile of soluble recombinant interleukin-4 receptor (IL-4-R) to bind specifically the corresponding ligand IL-4 and thereby to modulate biological activity upon exogenous administration in various autoimmune disease models, we investigated the immunoregulatory activity of IL-4-R and anti-IL-4 monoclonal antibody (MAb) 11B11 on the development of SLE-like disease in MRL/lpr autoimmune mice and on chronic GvH reaction in BDF1 hybrid mice. Sensitized GvH-BDF1 hybrid mice and SLE in MRL/lpr autoimmune mice were treated in vivo with the IL-4 antagonists to alter the pattern of serum Ig production and to modulate the disease process. These animals were followed for proteinuria, autoantibody production (anti-dsDNA), serum IgE, IgG1 and IgG2a levels, and the survival was monitored. Treatment of these diseased animals resulted in an improved survival rate, lowered the percentage of animals with lymphadenopathy and hepatosplenomegaly, reduced the levels of autoantibodies and inhibited proteinuria of the developing glomerulonephritis in both mouse strains, even in the established diseases. In both models the increase in total IgE and IgG1 levels in serum was strongly inhibited by the IL-4 antagonists, even under therapeutic conditions. But there was no inhibitory activity observed on the IgG2a serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data.

Peptidomimetic thrombin inhibitors (TI), derived from L-Asp-D-Phe were examined in confluent monolayers of a human colon carcinoma cell line (Caco-2) to elucidate their transepithelial transport properties. Effect availabilities, based on activated partial thromboplastin time (aPTT) measurements in rats, after peroral administration of five TI correlated reasonably well with permeability coefficients obtained from in vitro transport studies in Caco-2 monolayers, whereas physicochemical properties, such as molecular mass, solubilities, pKa and octanol-buffer partition coefficients failed to yield meaningful relationships. Substitution of the beta-carboxylic group of L-Asp leads to analogues which are mainly transported by passive diffusion, while an unsubstituted carboxylic group favours carrier-mediated active transport. The effects of concentration, temperature, competitive inhibitors and direction dependence on in vitro transport were investigated. The results obtained are compatible with a saturable carrier-mediated transport, operating parallel to a passive paracellular route. The Michaelis-Menten parameters for the active transport component (Km = 1.67 mM, Vmax = 26.5 pmol min-1 mg protein-1) indicate an involvement of the intestinal di/tripeptide transport system for one of the TI. The Caco-2 transport model may be helpful for the design of perorally active peptidomimetics.

Biological Availability↗
PubMed1995

Synthesis and characterisation of novel thrombin inhibitors based on 4-amidinophenylalanine.

Thrombin inhibitors have been thought to play a pivotal role in myocardial infarct and stroke incidences and their aftermath. Quite some time ago potent synthetic thrombin inhibitors became known based on peptide derivatives D-Phe-Pro-Arg and benzamidine. One of them, fairly well characterised was beta-naphthylsulphonylglycyl-D,L-4-amidino-phenylalanylpiperidi de (NAPAP). NAPAP was prone to being administered intravenously due to its short plasma half life. Drawbacks to this compound such as effects on histamine release and blood pressure may have obstructed its clinical use. Long half life and oral bioavailability would be desirable for prophylactic treatment of thrombotic disorders. We have used NAPAP as a template for new synthetic compounds to improve some characteristics of its profile. For screening purposes we have investigated fairly simple surrogate parameters, aspects that were considered to contribute to pharmacological effects. Potency was correlated to thrombin inhibition, side effects were addressed by specificity toward thrombin as well as reduction in basicity, and plasma half life was considered to be modulated by plasma stability of the compound. Oral bioavailability would be affected by instability during the passage through the gut wall. Chemical introduction of a carboxylic group and exchange of the naphthyl group for 4-methoxy-2,3,6-trimethylphenyl led to a compound that when compared to NAPAP, exhibited a 4-fold increase in thrombin inhibitory activity and a 3-fold increase in trypsin specificity. Plasma stability decreased to 22 h, however, sufficient enough not to play a major role in plasma half life. Gut homogenate stability of the compound has not changed. The potency increase did not translate into a reduction in IC50-values for the coagulation assay aPTT and TT, in contrast to the IC50-values for thrombin-induced platelet aggregation.

Antithrombins↗
PubMed1994

Combination of antibiotic treatment with the thrombin inhibitor recombinant hirudin for the therapy of experimental Klebsiella pneumoniae sepsis.

Rats which were infected with the gramnegative pathogen Klebsiella pneumoniae develop disseminated intravascular coagulation (DIC), multi-organ failure (MOF) and finally die in a septic shock. We investigated the therapeutic effect of antibiotic (tobramycin) treatment combined with the infusion of the highly specific thrombin inhibitor rec. hirudin. Although administration of 2 mg/kg tobramycin alone leads to a decrease of the bacterial burden, DIC could not be prevented. Infusion of rec. hirudin (0.25 mg/kg x h) for 4 h (start of treatment 1 h post infection), in addition to a bolus administration of tobramycin, led to an amelioration of DIC parameters as fibrinogen, thrombin-antithrombin complex (TAT) and platelets. Serum transaminase levels (GOT, GPT) as a marker of MOF were significantly improved by rec. hirudin, the T50 value increased from 17 h in the tobramycin group to 42 h in the tobramycin+rec. hirudin group, mortality rates were 90% or 60%, respectively. Combination of heparin (100 U/kg x h) and tobramycin was not effective on survival.

Animals↗
PubMed1994

Formation of fibrin monomers in experimental disseminated intravascular coagulation and its inhibition by recombinant hirudin.

An experimental disseminated intravascular coagulation (DIC) was induced in female CD rats by the intravenous administration of living bacteria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or lethal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 micrograms/kg i.v. bolus or 0.4 micrograms/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by their ability to stimulate the tissue-type (t-PA) plasminogen activator dependent conversion of plasminogen to plasmin by a chromogenic assay. Miniplasminogen was used instead of plasminogen to avoid interference of the assay by alpha 2-antiplasmin. As a marker of DIC, elevated levels of FM were observed with all DIC-inducing agents (plasma levels were up to 90 micrograms/ml). The kinetics of FM formation were similar to the course of thrombin-antithrombin III (TAT) levels (maximal plasma levels 70 ng/ml); however, in the bacterial infection group, both parameters rose after a lag phase of about 1 hr. A 4 hr infusion of the highly specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 micrograms/ml in the LPS group (n = 10) to 27.4 +/- 11.2 micrograms/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 73.1 +/- 19.7 micrograms/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the rec. hirudin group (P < 0.001). Other coagulation parameters, such as platelets, fibrinogen, and fibrin(ogen) degradation products, were ameliorated accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗