Changes In Fibrinogen Levels Research Articles

The beneficial effects of lipid-lowering drugs beyond lipid-lowering effects: A comparative study with pravastatin, atorvastatin, and fenofibrate in patients with type IIa and type IIb hyperlipidemia

Hyperlipidemia is an important risk factor for atherosclerosis. Hemorheological factors contribute to morbidity and mortality in patients with dyslipidemia. We evaluated the effects of 3 antihyperlipidemic drugs (pravastatin, atorvastatin, and fenofibrate), which have different mechanisms of action and different patterns of action on lipid profiles, on erythrocyte deformability and fibrinogen levels in patients with type IIa and type IIb hyperlipidemia. Twenty-one patients ( 4 men and 17 women) with type IIa and IIb hyperlipidemia were randomized to 3 drugs (pravastatin 20 mg/d, atorvastatin 10 mg/d, fenofibrate 250 mg/d) for 8 weeks. Plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) analysis were performed on a BM-Hitachi 747-200 autoanalyzer (Hitachi-Roche, Tokyo, Japan). Fibrinogen analysis was performed according to Clauss method. Erythrocyte deformability was assessed with cell transit analysis device. There was no significant difference in body mass index, lipid profile, fibrinogen level, and erythrocyte deformability index values among the groups before treatment ( P > .05). In all groups, there were statistically significant reductions in total LDL-C levels ( P < .05). The triglyceride levels were significantly reduced in the atorvastatin and fenofibrate groups ( P < .05), but not in the pravastatin group ( P > .05). There was no significant change in HDL-C levels during the treatment with statins ( P > .05), but there was a significant increase in the fenofibrate group ( P < .05). Mean erythrocyte deformability index was improved in all the groups ( P < .05). There was no significant change in fibrinogen levels during the treatment of pravastatin and atorvastatin ( P > .05), but in fenofibrate group, fibrinogen levels were significantly decreased ( P < .05). The 3 groups of antihyperlipidemic drugs have beneficial effects on the erythrocyte deformability index. Only fenofibrate has significant beneficial effects on the fibrinogen levels.

ＳＡＨ術後管理における低分子デキストランのピットフォール

Low molecular dextran is often used in post-operative management of subarachnoid hemorrhage (SAH) to induce hypervolemia and hemodilution; however, its associated complications are not well-known. We retrospectively analyzed prothrombin time (PT%), activated partial thromboplastin time (APTT%), and fibrinogen level as coagulation markers in patients with subarachnoid hemorrhage who developed delayed intracranial hemorrhagic complications after undergoing craniotomy for clipping to examine the effect of long-term use of low molecular dextran on bleeding tendencies. Fifty-two patients with SAH who underwent craniotomy were divided into 2 groups: 26 without post-operative use of low molecular dextran (Group 1) and 26 to whom low molecular dextran was administered for more than 5 consecutive days (Group 2). Group 2 was further divided into 2 subgroups: those who developed hemorrhagic complications (Group 2A) and those without complications (Group 2B). The frequency of complications in Group 2A was 19% (5/26; 3 with subdural hematoma and epidural hematoma, 1 with epidural hematoma, and 1 with intracerebral hematoma). Complications appeared 7.6 days on average after starting low molecular dextran. Compared with Group 1, PT% and APTT% as well as pre-and post-low molecular dextran administration fibrinogen levels significantly decreased in Group 2A. Low molecular dextran is known to decrease fibrinogen levels, and patients' clinical conditions and changes in fibrinogen levels should be closely monitored to detect bleeding tendencies when low molecular dextran must be used for long periods.

The impact of third-generation Beta-blocker antihypertensive treatment on endothelial function and the prothrombotic state: Effects of smoking

Background The significance of β-blockers in the treatment of cardiovascular diseases is well established. The effect of vasodilating β-blockers on endothelial function and prothrombotic state has not been investigated. Methods The study comprised 550 consecutive patients with uncomplicated essential hypertension. They were treated with celiprolol, carvedilol or nebivolol monotherapy (171, 179, and 200 patients, respectively), achieving comparable blood pressure reduction. Plasma levels of fibrinogen and homocystine and serum levels of plasminogen activator inhibitor–1 (PAI-1) were obtained before and 6 months after initiation of treatment. Results The three drugs differentiated in regard to homocystine ( P < .00001) and fibrinogen level changes ( P = .00003), but not ( P = NS) in PAI-1 change. In smokers, differentiation was found in all three parameters ( P = .0002, P = .001, and P = .006 for fibrinogen, PAI-1, and homocystine, respectively), but in nonsmokers differentiation was found only in homocystine change ( P = .00003). In smokers, fibrinogen, PAI-1, and homocystine were reduced more ( P = .002, P = .0009, and P <.0001, respectively) than in nonsmokers in the whole study cohort. The effect of nebivolol was more prominent in smokers than nonsmokers in reducing all three parameters ( P = .0001, .003, and .003, respectively), whereas in celiprolol and carvedilol-treated groups, differentiation between smokers and nonsmokers was significant ( P = .00003 and .01, respectively) only in homocystine level change. Conclusions In hypertensive smokers, nebivolol resulted in a significant decrease of plasma PAI-1, fibrinogen and homocystine. Celiprolol also significantly affected these parameters but to a lesser degree, whereas carvedilol had no significant favorable action. In nonsmokers, homocystine was reduced significantly by nebivolol. We conclude that smoking status should be a determinant of antihypertensive treatment choice.

Pharmacomechanical Thrombolysis and Early Stent Placement for Iliofemoral Deep Vein Thrombosis

To evaluate an approach to the treatment of iliofemoral deep vein thrombosis (DVT) that included pharmacomechanical catheter-directed thrombolysis with reteplase and the Helix mechanical thrombectomy device, followed by early stent placement. During 3-year period, 23 symptomatic limbs in 18 patients with iliofemoral DVT were treated with reteplase catheter-directed thrombolysis. After an initial infusion of 8 to 16 hours, any residual acute thrombus over a long segment (> 10 cm) was treated by maceration with use of the Helix thrombectomy device. Residual short-segment (< 10 cm) iliac vein thrombus and/or stenosis were treated with stent placement. Technical success, clinical success, complications, thrombolytic infusion time, total thrombolytic agent dose, fibrinogen level changes, and late limb status were retrospectively analyzed. Technical success was achieved in 23 of 23 limbs (100%). Clinical success was achieved in 22 of 23 limbs (96%). Complete or partial thrombolysis was observed in 19 of 23 limbs (83%). Major bleeding was observed in one patient (6%) and necessitated blood transfusion. Mean per-limb thrombolytic infusion time and total dose were 19.6 hours +/- 8.1 and 13.8 U +/- 5.3 reteplase, respectively. Mean serum fibrinogen nadir and percentage drop in serum fibrinogen were 282 mg/dL +/- 167 and 47% +/- 24%, respectively. Late (mean, 19.8 +/- 11.6 months) modified Venous Disability Scores were 0 (none) for six limbs, 1 (mild) for 10 limbs, 2 (moderate) for two limbs, and 3 (severe) for no limbs. In a preliminary experience, pharmacomechanical catheter-directed iliofemoral DVT thrombolysis with early stent placement was safe and effective.

Comparative study of HMG-CoA reductase inhibitors on fibrinogen

Statins have a variable response on fibrinogen, and these changes may have implications on cardiovascular events. In this randomized placebo-controlled crossover study, we evaluated whether changes in fibrinogen levels were different between atorvastatin and other statin-treated patients. Adult coronary heart disease (CHD) patients aged 39–83 years with LDL cholesterol levels ≥130 mg/dl were randomized to atorvastatin 80 mg ( n=84) and one of the following statins: fluvastatin 80 mg ( n=23), lovastatin 80 mg ( n=20), pravastatin 40 mg ( n=22) or simvastatin 40 mg ( n=20) each for 12 weeks in either order. Fibrinogen was analyzed by an automated method of Clauss. Three independently acquired samples were obtained within 1 min of tourniquet application, and each specimen was measured in duplicate. Statistical analyses were performed using a mixed model repeated measures analysis of variance procedure with SAS version 6.12. There were no significant changes in fibrinogen between treatment groups. This study evaluated changes in fibrinogen with established pre-analytical and analytical procedures known to minimize variability in fibrinogen measurement, and we did not observe any differences in fibrinogen levels in the treatment groups.

Hemorheological Profile in Chronic Venous Insufficiency after Surgery

In recent years, there have been rheological abnormalities reported in chronic venous insufficiency (CVI), mainly an increase of erythrocyte aggregability (EA), which probably take part in the pathophysiology of the disease. The aim of this study was to analyze the hemorheological profile after stripping in 45 patients suffering from CVI. Follow-up included laboratory tests on the 7th, 60th and 180th day after surgery. EA was assessed with a photometric aggregometer (MA1, Myrenne) in stasis and low shear (3 s^–1). The results show an increase of EA on the 7th day after surgery (p < 0.001). Two and 6 months later, EA values returned to those found prior to surgery. The plasma fibrinogen level changes in a way parallel to EA. The association between rheological disturbances and thrombogenesis is well known, so the hyperaggregability found supports the antithrombotic prophylaxis in the early postsurgical period. On the other hand, the hemorheological abnormalities persist after stripping, so postsurgical treatment to inhibit EA may be beneficial.

Plasma fibrinogen concentration is increased following depletion of vitamin K-dependent clotting factors by the indirect anticoagulant difenacoum in norway rats (Rattus norvegicus)

Difenacoum, a 4-hydroxycoumarin anticoagulant rodenticide with the same mode of action as warfarin, was fed to four strains of rat in medium oatmeal at 0.005% (w/w) for five days. The four rat strains had differing degrees of resistance to the anticoagulant difenacoum. Prothrombin time, factor X and fibrinogen concentration were monitored daily throughout the feeding period, and for a further 8 days following feeding. After 24 h factor X had been reduced in susceptible rats to 25% and fibrinogen had increased to 110% of resting levels. By 48 h prothrombin times were so extended that it was impossible to estimate the levels of fibrinogen in rats of this susceptible strain beyond that time point. As factor X levels reduced, fibrinogen levels increased in the plasma of rats with medium resistance levels. Feeding of difenacoum to highly resistant rats caused little, if any, extension of prothrombin time and enabled further comparison of fibrinogen and factor X levels in these animals. Fibrinogen levels did not increase significantly in the highly anticoagulant-resistant rats which had normal concentrations of factor X levels throughout the experiment. It is, therefore, unlikely that increased levels of fibrinogen resulted from direct effects of difenacoum. Changes in fibrinogen levels may be caused by a feedback mechanism in response to changes in the plasma concentration of factor X and/or other vitamin K-dependent clotting factors. These changes appeared to partially reduce the effect of factor X loss on the prothrombin time and may be a secondary mechanism of resistance of potential importance in the survivorship of rats on farms during a control treatment.

Effect of niacin supplementation on fibrinogen levels in patients with peripheral vascular disease

This study demonstrates that niacin supplementation decreases plasma fibrinogen and low-density lipoprotein cholesterol in subjects with peripheral vascular disease randomized to receive niacin, warfarin, antioxidants, or placebo. Changes in fibrinogen levels are highly correlated with changes in low-density lipoprotein cholesterol (r = 0.61; p < 0.009) in subjects taking niacin.

Treatment of severe hypertriglyceridemia lowers plasma viscosity

Elevated plasma viscosity is a predictor of atherosclerotic vascular disease and is a potential mechanism by which hypertriglyceridemia increases cardiovascular risk. Previous studies of plasma viscosity reduction in hypertriglyceridemic patients used medications that lowered both triglyceride and fibrinogen levels. Because fibrinogen is a major determinant of viscosity, it is unclear whether triglyceride reduction alone is sufficient to reduce plasma viscosity. The purpose of this study was to determine whether triglyceride-lowering therapy reduces plasma viscosity. This was a prospective study of 24 adult patients with severe hypertriglyceridemia (≥5.67 mmol/l). Fasting lipid, total serum protein, fibrinogen, plasma viscosity and serum viscosity levels were measured before and after therapy with 1200 mg/ d of gemfibrozil. Triglyceride levels decreased by 70% ( P<0.001). Mean plasma and serum viscosity levels decreased by 0.082 mPa/s ( P=0.003) and 0.086 mPa/s ( P=0.013), respectively. Fibrinogen levels did not change significantly. Triglyceride-lowering therapy reduced plasma and serum viscosity without changes in fibrinogen levels. Since serum samples are deplete of fibrinogen, the serum viscosity reduction observed is corroborative evidence for an independent effect of triglyceride-lowering therapy on plasma viscosity. This observation provides a physiological rationale for triglyceride-lowering therapy in patients at risk for atherosclerotic vascular disease, the chylomicronemia syndrome and pancreatitis.

Effects of Gemfibrozil and Ciprofibrate on Plasma Levels of Tissue-type Plasminogen Activator, Plasminogen Activator Inhibitor-1 and Fibrinogen in Hyperlipidaemic Patients

Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.

7. Are winter infections responsible for seasonal changes in fibrinogen levels in elderly people?

7. Are winter infections responsible for seasonal changes in fibrinogen levels in elderly people?

Comparison of the effects of gemfibrozil (600 mg twice daily and 900 mg once daily) on lipid and glucose levels in chinese patients with non—insulin-dependent diabetes mellitus

We compared the effects of 600 mg of gemfibrozil twice daily (BID) and 900 mg of gemfibrozil once daily (OD) on lipid and glucose levels in 32 Chinese patients (13 men, 19 women) with non—insulin-dependent diabetes mellitus (NIDDM) using a crossover study design for a total of 16 weeks. Both gemfibrozil 600 mg BID and gemfibrozil 900 mg OD significantly reduced triglyceride levels (from 5.74 ± 0.47 mmol/L to 2.17 ± 0.16 mmol/L [ P < 0.001] and 2.99 ± 0.49 mmol/L [ P = 0.001], respectively) and increased high-density lipoprotein cholesterol levels (HDL-C) (from 0.96 ± 0.04 mmol/L to 1.08 ± 0.03 mmol/L [ P = 0.01] and 1.08 ± 0.04 mmol/L [ P =0.021], respectively). However, fibrinogen levels also were elevated (from 3.31 ± 0.19 g/L to 4.59 ± 0.27 g/L [ P = 0.001] and 4.18 ± 0.22 g/L [ P = 0.01], respectively). Blood pressure, glycemic control (fasting plasma glucose and glycated hemoglobin A 1c), total cholesterol, creatine phosphokinase, lactate dehydrogenase, and alanine aminotransferase levels were not significantly affected by either regimen. There were no differences between the two treatment regimens in the mean percentage changes in levels of triglyceride, HDL-C, and total cholesterol. The changes in fibrinogen levels also were similar in both groups. No major side effects were noted. Gemfibrozil given as a 900-mg OD preparation appears to be as effective as the conventional 600-mg BID regimen in treating Chinese NIDDM patients with dyslipidemia. Elevations in fibrinogen noted with both regimens require further study.

C4b-Binding Protein Exacerbates the Host Response to Escherichia coli

Activated protein C is a plasma anticoagulant. For activated protein C to function as an anticoagulant, it must form a complex with protein S. Protein S anticoagulant activity is neutralized by formation of a reversible complex with C4b binding protein (C4bBP). C4bBP is an acute-phase plasma protein. When C4bBP levels increase, mass action forces the level of free protein S to decrease, giving rise to an acquired functional protein S deficiency. It has been proposed that these elevated C4bBP levels and the resultant acquired deficiency of protein S that occurs in inflammation could contribute to a hypercoagulable state. An experimental model to test this hypothesis was suggested by our previous studies that demonstrated that inhibition of protein C activation rendered baboons hypercoagulable in response to sublethal Escherichia coli infusion (J Clin Invest 79:918, 1987). We have extended these studies to examine the effect of inhibition of protein S activity with C4bBP in the host (baboon) response to infusion of sublethal concentrations of E coli organisms. Five sets of animals were studied: (1) those challenged with sublethal concentrations of E coli alone (0.4 x 10(10)/kg); (2) those supplemented only with C4bBP (20 mg/kg); (3) those challenged with the same level of E coli but supplemented with C4bBP (20 mg/kg); (4) those challenged with sublethal E coli and supplemented with C4bBP (20 mg/kg) and sufficient protein S (2.3 mg/kg) to fill the protein S binding sites on C4bBP; and (5) those challenged with lethal concentrations of E coli. Sublethal E coli infusion (group 1 animals) caused only an acute-phase response with no consumption of fibrinogen, detectable organ damage, or detectable tumor necrosis factor (TNF) in the plasma. C4bBP infusion (group 2 animals) resulted in no significant physiologic changes, no detectable plasma TNF, and little change in fibrinogen level. The group 3 animals, receiving both sublethal E coli and C4bBP, exhibited rapid consumption of fibrinogen, systemic organ damage, and detectable circulating TNF ultimately leading to death. The overall response of this group was very similar to the response of the group 5 animals receiving an LD100 dose of E coli. The group 4 animals, which were treated exactly as above except that C4bBP was supplemented with a slight excess of protein S, responded essentially like those that received sublethal E coli alone. These studies suggest that the elevation of C4bBP during an inflammatory response can contribute to fibrinogen consumption and vascular damage. This vascular damage may be associated with enhanced elaboration of cytokines like TNF.(ABSTRACT TRUNCATED AT 400 WORDS)

C4b-binding protein exacerbates the host response to Escherichia coli

Activated protein C is a plasma anticoagulant. For activated protein C to function as an anticoagulant, it must form a complex with protein S. Protein S anticoagulant activity is neutralized by formation of a reversible complex with C4b binding protein (C4bBP). C4bBP is an acute- phase plasma protein. When C4bBP levels increase, mass action forces the level of free protein S to decrease, giving rise to an acquired functional protein S deficiency. It has been proposed that these elevated C4bBP levels and the resultant acquired deficiency of protein S that occurs in inflammation could contribute to a hypercoagulable state. An experimental model to test this hypothesis was suggested by our previous studies that demonstrated that inhibition of protein C activation rendered baboons hypercoagulable in response to sublethal Escherichia coli infusion (J Clin Invest 79:918, 1987). We have extended these studies to examine the effect of inhibition of protein S activity with C4bBP in the host (baboon) response to infusion of sublethal concentrations of E coli organisms. Five sets of animals were studied: (1) those challenged with sublethal concentrations of E coli alone (0.4 x 10(10)/kg); (2) those supplemented only with C4bBP (20 mg/kg); (3) those challenged with the same level of E coli but supplemented with C4bBP (20 mg/kg); (4) those challenged with sublethal E coli and supplemented with C4bBP (20 mg/kg) and sufficient protein S (2.3 mg/kg) to fill the protein S binding sites on C4bBP; and (5) those challenged with lethal concentrations of E coli. Sublethal E coli infusion (group 1 animals) caused only an acute-phase response with no consumption of fibrinogen, detectable organ damage, or detectable tumor necrosis factor (TNF) in the plasma. C4bBP infusion (group 2 animals) resulted in no significant physiologic changes, no detectable plasma TNF, and little change in fibrinogen level. The group 3 animals, receiving both sublethal E coli and C4bBP, exhibited rapid consumption of fibrinogen, systemic organ damage, and detectable circulating TNF ultimately leading to death. The overall response of this group was very similar to the response of the group 5 animals receiving an LD100 dose of E coli. The group 4 animals, which were treated exactly as above except that C4bBP was supplemented with a slight excess of protein S, responded essentially like those that received sublethal E coli alone. These studies suggest that the elevation of C4bBP during an inflammatory response can contribute to fibrinogen consumption and vascular damage. This vascular damage may be associated with enhanced elaboration of cytokines like TNF.(ABSTRACT TRUNCATED AT 400 WORDS)

Effectiveness, specificity and safety of intranasal 1-deamino-8-D-arginine vasopressin treatment of normal blood donors.

A study of the absorption of 300 micrograms of 1-deamino-8-D-arginine vasopressin (DDAVP) given intranasally to normal blood donors was carried out to determine (a) the correlation between plasma levels of DDAVP and the percent rise of factor VIII procoagulant activity (VIII:C) and (b) the efficacy, specificity and safety of this treatment in increasing the recovery of factor VIII:C in donated blood. The maximum drug concentration was highly correlated to the maximum percent rise of VIII:C (r = 0.858, p less than 0.01). A differentiated effect of DDAVP on increases of VIII:C, VIII:Ag, vWF:Ag and vWF multimers was observed. A transient rise of fibrinopeptide A from 5 to 16 ng/ml, 30 min post-DDAVP, was not accompanied by changes in fibrinogen levels or generation of detectable factor Xa or thrombin. DDAVP had no effect on the factor XII-dependent pathway of plasminogen activation, or on the donor's vital signs and hematological parameters. Side effects were minor and of short duration. Intranasal DDAVP treatment of blood donors is considered to be a practical means of improving the recovery of VIII:C from normal donors.

Low-dose streptokinase for selective thrombolysis: systemic effects and complications.

The systemic effects and complications associated with the infusion of low-dose (5,000 U/hr) intravascular streptokinase were reviewed in 159 patients. Eighty-two percent of the patients had a 50% decrease in plasma fibrinogen levels during the first 4 hours of treatment, and 100% of the patients showed the same decline following 12 hours of treatment. The thrombin time was prolonged to at least 1 1/2 times the control thrombin time in 42% of the patients at 4 hours of treatment and in 92% at 24 hours of treatment. The rate or degree of change in fibrinogen levels or prolongation of the thrombin time did not correlate with the incidence of complications. Seventeen patients (10.7%) suffered major complications. Thirteen of the 17 had hemorrhagic complications, three had thrombotic or embolic complications, and one had a false aneurysm. In this series, systemic effects occurred in all patients. It is concluded that, despite precautionary measures, hemorrhagic complications may occur. Steps should be taken to minimize complications, including careful observation of the patient and monitoring of plasma fibrinogen levels until adequate regeneration is complete.

Endogenous anticoagulation during extracorporeal perfusion: generation of a heparinlike inhibitor.

Studies were done to define the coagulation defect that develops in hemodynamically stable anesthetized dogs perfused on our arteriovenous extracorporeal system without added heparin. After 45 min, the dogs developed whole blood clotting times (WBCT) greater than 24 h. There was an associated decrease in ADP-induced platelet aggregation and a drop in factor V, VIII, and X levels of 75.8, 33.5, and 46.8%, respectively. Despite an increase in fibrinogen degradation products, there was no significant change in fibrinogen level or platelet count. An inhibitor of thrombin and factor Xa clotting of plasma appeared that was "heparinlike", because it stimulated the inactivation of factor Xa by antithrombin III (ATIII) but not by O-methyl isoureamodified ATIII. Thrombin inhibition by ATIII was also stimulated. The inhibitor was heat stable, adsorbed by BaSO4, and neutralized by protamine. Infusion of protamine sulfate into two perfused dogs neutralized the inhibitor and brought the WBCT from greater than 24 h to less than control. Six dogs developed inhibitor levels equivalent to 0.98 to 6.15 U/ml heparin. Five eviscerated dogs in which the hepatic artery was ligated developed peak plasma inhibitor levels of 3.2 +/- 1.0 U/ml. Thus, the endogenous heparinlike inhibitor is a major contributor to the anticoagulated state induced with our perfusion system and may have an extrahepatic origin.

Endotoxin induced disseminated intravascular clotting: Evidence that it is mediated by neutrophil production of tissue factor

Cycloheximide is a potent inhibitor of protein synthesis. Its effects on endotoxin induced human neutrophil tissue factor production in vitro and endotoxin induced disseminated intravascular clotting (DIC) in rabbits were examined. Endotoxin added to citrated whole human blood led to the production of tissue factor except when neutrophils were absent from the blood. The production of this tissue factor was inhibited by cycloheximide. Cycloheximide added after the tissue factor was formed had no effect. We concluded that neutrophil production of tissue factor depends on protein synthesis. Eight steroid prepared rabbits were given intravenous cycloheximide prior to and after endotoxin injection. None of the rabbits developed DIC as measured by change in fibrinogen level or development of glomerular capillary thrombi. Six rabbits given endotoxin alone showed a 37% mean drop in fibrinogen level and four showed glomerular capillary thrombi. Rabbits treated with cycloheximide alone did not show any glomerular fibrin or change in fibrinogen level. They were capable of developing DIC since infusion of endotoxin and rabbit brain tissue factor caused a fall in fibrinogen level and development of glomerular fibrin. This adds further evidence that neutrophil production of tissue factor is necessary for endotoxin induced DIC.

Changes in fibrinogen levels, platelet counts, clotting times and fibrinolytic activity in relation to thrombosis in contagious bovine pleuropneumonia

Changes in the packed cell volume, haemoglobin, fibrinogen and total protein levels, in the prothrombin, thrombin clotting and kaolin partial thromboplastin times, platelet numbers and fibrin degradation products were investigated in 7 cattle in which contagious bovine pleuropneumonia (CBPP) was induced by inoculating Mycoplasma mycoides by the endobronchial intubation method. Thrombosis of lung vessels was confirmed in all animals at necropsy. The results of the complement fixation and slide agglutination blood tests indicated that typical lesions of CBPP were present at 7 days. There was a rise in fibrinogen levels soon after inoculation and the difference between the means of the levels of the infected and control animals was significant from the 7th day. Platelet counts in the infected animals were reduced on the 2nd to the 5th day and, although a significant difference between these and the controls could not be demonstrated, this was confirmed by a compensatory rise in the severely affected animals that survived. The kaolin partial thromboplastin time test showed a significant rise in the infected animals from the 8th day, but there was no increase in the prothrombin time nor the thrombin clotting time indicating that depletion of factors in the intrinsic clotting system had commenced by the 8th day and that factors, VIII, IX, XI and XII could have been involved. Fibrin degradation products increased significantly in the infected animals from the 9th day. We conclude that thrombosis is an early event in the pathogenesis of CBPP, it contributes to the subsequent pathology of the lung lesions and platelets are involved to a substantial degree in the formation of the thrombi.

The effect of leukocytic extract on fibrinogen synthesis in rabbits

Crude leukocytic extract (CLE) was prepared from rabbit peritoneal exudates. Injection of CLE to 15 rabbits elicited a mean maximal rise in temperature of 0.8 ± 0.2°C (SE), whereas in 14 controls a mean maximal change of only 0.04 ± 0.18°C (SE) was observed. In 19 rabbits the mean change in fibrinogen level observed within 24 hr following CLE injection was 61 ± 16 mg% (SE) and in 19 controls 40 ± 10 mg% (SE). The observed difference is not significant: t = 1.113, p > 0.1. Thus CLE does not appear to play a significant role in the regulation of fibrinogen synthesis in rabbits.