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In patients with chronic nonrheumatic atrial fibrillation, prophylaxis of peripheral arterial embolism is strongly indicated. LMWHs may be an alternative regimen if contraindications for oral anticoagulants are present. In the present study the effect of LMWH on the incidence of embolism in atrial fibrillation has been studied in 75 consecutive patients in comparison to no specific treatment. Patients received one daily injection of the LMWH CY 216 (n = 35) subcutaneously over a period of 6 months. Patients of the control group (n = 40) were observed over the same period of time. In the group treated with CY 216, three embolic events (8.6%) occurred, of which two were localized in the cerebrum. One of these two cerebral embolic events was fatal. In the control group, eight embolic events (20%) occurred, six of these were intracerebral and, of these, five were fatal. An even more pronounced difference between the groups was observed on evaluation of the patients with preceding cerebral embolism. Of 15 patients treated with LMWH, one extracerebral nonfatal embolism occurred. In the control group three of the seven patients (43%) experienced fatal reembolism. The results show that in patients with atrial fibrillation one daily subcutaneous injection of LMWH reduces the incidence of arterial embolism to about one third. No adverse effects were observed during the 6-month treatment period with LMWH.

Fractionated and unfractionated heparins are widely used as antithrombotic agents. Because of their heterogeneous composition, it is difficult to study the pharmacokinetics of these drugs. We now report on a new method for labeling low molecular weight heparins with 131I by binding tyramine to the anhydromannose end of the molecules. We examined the pharmacokinetics of the compound by intravenous injection of 131I-tyramine-heparin into Wistar rats. About 18% of the activity was found in the liver, whereas 33% was detected in urine. Biological activity in terms of Factor Xa inhibition was measurable. Since evidence from cell culture experiments implies that reticuloendothelial cell system receptors might be involved in heparin metabolism, maleylated BSA, a substance known to block scavenger receptors, was injected before the radiolabeled heparin compound. The liver uptake was reduced from 17.4 to 4.8%. Injection of unfractionated heparin before tracer application caused a considerable increase in urine excretion of the tracer substance. To our knowledge, this is the first report that liver uptake of heparins is linked to scavenger receptor mediated mechanisms in vivo. This interaction of heparins with scavenger receptors might play an important role in the biology of the vessel wall.

The risk factor patterns for coronary heart disease in China, Japan and Germany were studied. 6,025 Germans, 7,580 Japanese and 2,047 Chinese aged 30-59 were investigated following the protocol of the Göttingen Risk, Incidence, and Prevalence Study carried out in West Germany in 1982. It is concluded that in China, the risk factor intervention focuses mainly on smoking and hypertension; smoking also remains the most important risk factor in Japan; while in Germany the major targets are obesity and hyperlipidemia. However, about 38% of the participants from West Germany showed 3 or more risk factors accumulated per person. Thus the multifactorial risk factor reduction might be necessary in Germany.

Ileocecal resection was performed in two female patients with stenosis of the terminal ileum. Histological findings confirmed the clinical diagnosis of Crohn's disease in the first case, although focal intestinal endometriosis was detected. The resection specimens of the other patient exclusively showed lesions of endometriosis extending from the subserosa to the mucosal tissue. Typical lesions of Crohn's disease were totally absent in this case. Although not very frequent, endometriosis is an important differential diagnosis of Crohn's disease in young females.

A sensitive, reproducible and rapid quantitative microtiter assay for factor XIII activity is described. The assay is based on incorporation of a soluble amine substrate into casein attached to polystyrol microtiter plates and detection of bound substrate with a monoclonal antibody-enzyme conjugate. Defibrination of plasma samples is not required. The assay shows strong correlation with the immunologic assay for factor XIII catalytic subunit a (r = 0.94), the factor XIII dansylcadaverine assay (r = 0.83), and the factor XIII clot solubility test. Normal values detected in healthy blood donors were in the range of 74% to 117%, with a mean value of 96.9% and a median value of 97.8%; pooled normal plasma was used as a reference. Since the assay is performed in a single microtiter plate and requires few reagents and short incubation periods, it can be easily adapted for clinical use.

Coagulation studies were performed in a patient who had been bitten by a snake of the species Bothrops neuwiedi. The patient presented with hemorrhagic necrosis at the envenomization site and considerable bleeding from venous puncture sites. He developed a severe defibrination syndrome with a clottable fibrinogen level of approximately 0.1 g/l. Fibrinogen was not measurable by clotting time assay. Fibrin degradation products were greatly elevated. Treatment with antivenom caused an anaphylactic reaction within ten minutes and serum sickness after three days. In vitro experiments revealed that B. neuwiedi venom directly activates Factors II and X, but does not activate Factor XIII. In vivo consumption of Factor XIII after B. neuwiedi envenomization is ascribed to the action of Factor IIa. At low venom concentrations clotting is initiated by activation of prothrombin by the venom either directly or via Factor X activation. Treatment with heparin might be beneficial in coagulopathy secondary to snake bite by reducing circulating active thrombin. The venom contains thrombin-like proteases which cause slow clotting of fibrinogen, and plasmin-like components causing further proteolysis of fibrinogen and fibrin. Antivenom has no effect on the proteolytic action of the snake venom. The in vivo effects of antivenom are presumably caused by acceleration of the elimination of venom components from the circulation. Intravenous administration of antivenom caused normalization of blood coagulation parameters within 48 h.

166 patients aged 40-80 years were included in a controlled, randomized, double-blind study to determine the efficacy and safety of a single daily injection of a low molecular weight (LMW) heparin for prevention of deep-vein thrombosis compared to low dose conventional heparin. Patients received 1 x 1.500 aPTT units of a LMW heparin fraction (plus 2 x placebo injection) or 3 x 5.000 IU of an unfractionated heparin. During 10 days of treatment, patients underwent repeated clinical investigation, serial impedance plethysmography, and Doppler sonography for detection of thrombosis of the lower limbs. Combined application of these methods revealed evidence of thrombosis in 4.5% of patients on unfractionated heparin and 3.6% of patients on LMW heparin. Subcutaneous hematomas were significantly smaller in diameter upon treatment with LMW heparin (p less than 0.001). Antithrombin III levels were significantly higher at the end of the observation period in the LMW heparin group (p less than 0.005). Thrombocyte count, transaminases, creatinine, and haemoglobin did not change in either group. The results indicate that LMW heparin administered by a single s.c. dose daily may be as effective as low dose heparin in prevention of deep venous thrombosis in medical inpatients.

A study was performed to investigate if protamine covalently attached to CNBr-activated agarose is a useful tool for the purification of fibrinogen from human plasma samples. One chromatography step yielded a preparation with a clottability greater than 90% from platelet-poor plasma with a yield of 65-80% of fibrinogen applied. The preparation is free of plasminogen, immunoglobulins, fibronectin, albumin, antithrombin III, alpha 2-macroglobulin, and alpha 1-antitrypsin, as determined by immunological and functional methods. 6.5 mg of fibrinogen were adsorbed to 1.0 ml of protamine-agarose. Protamine-agarose chromatography can be applied to plasma samples as small as 200 microliters.

The anticoagulant, lipolytic and protamine reversible effects of high doses of low molecular weight (LMW) heparin 21-23 and unfractionated heparin were compared in man. 7,500 units of each heparin were applied, which corresponds to 90 mg LMW heparin and 48 mg unfractionated heparin. The anticoagulant properties of the LMW heparin are characterized by a doubled half life of factor Xa activity, smaller influence on aPTT and thrombin after intravenous (i.v.) and subcutaneous (s.c.) injection, and higher bioavailability of factor Xa activity after s.c. administration (90% versus 15%). Protamine chloride completely neutralizes the effect on aPTT and thrombin and reduces the anti factor Xa activity by 60%. The bleeding time is prolonged by both normal and LMW heparin by 20%. This effect is normalized by protamine chloride, too. Thrombelastography with recalcified whole blood demonstrates that protamine chloride shortens but not completely normalizes the coagulation time in presence of either unfractionated or LMW heparin. The half life of lipoprotein lipase (LPL) activity is 60 min after i.v. administration of unfractionated heparin and 120 min with LMW heparin. Although the release of lipases (LPL and HTGL) is higher after i.v. and s.c. administration of the LMW heparin they do not induce higher releases of free fatty acids. This indicates that the lipolytic activity of this LMW heparin and unfractionated heparin is similar. The results show an improved anticoagulant pharmacological profile of this LMW heparin as compared to unfractionated heparin. Protamine normalizes the anticoagulant effects of LMW heparin with exception of a residual anti factor Xa activity and normalizes the changes of bleeding time and thrombelastography.

The major constituents of the hemostatic potential, i.e., platelets and the plasma factors of coagulation and fibrinolysis, guarantee the integrity of the vessel wall and provide effective hemostasis in case of vascular damage. The equilibrium between anticoagulant and procoagulant forces which is essential for the maintenance of the fluidity of blood is controlled by inhibitors, the fibrinolytic system, and the clearance of activated components by the reticuloendothelial system. The proper function of this humoral balance is essentially dependent on hemodynamic factors such as adequate circulation and capillary perfusion.

To assess the role of the fibrinolytic system in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we determined the components of this system in a retrospective study, including 16 patients with restenosis (gr. A) and 19 patients with long-term success (gr. B). In both groups at baseline fibrinolytic activity (FA) is unchanged, whereas tissue plasminogen activator antigen (tPA-Ag) is significantly increased (gr. A: 147.0%; gr. B: 139.8%; p less than 0.01). Fibrinolytic capacity (FC) and tPA-Ag release are significantly reduced in the restenosis group (FC: 46.5%, p less than 0.05; tPA-Ag release: 48.3%, p less than 0.01) compared to normal controls as well as to gr. B (FC: 84.3%, p less than 0.05; tPA-Ag release: 79.0%, p less than 0.05). Relating to the contact activation system, F XII (79.5%, p less than 0.05) is significantly, and F XI (82.3%) is clearly reduced in gr. A. Protein C (PC) is significantly elevated in gr. B (117.5%, p less than 0.05). There is a negative correlation between plasminogen activator inhibitor (PAI 1) and HDL-cholesterol (r = 0.37, p less than 0.05). It appears, that there is a typical pattern of defective fibrinolysis in patients with restenosis after PTCA and that this might be a pathogenetic factor in the development of restenosis.

This study reports on the biological activity and safety of high dose low molecular weight (LMW) heparin therapy administered by two subcutaneous (s.c.) injections daily for 8 days in healthy human volunteers. Group 1 received 2 x 30 aPTT units LMW heparin/kg bodyweight, and group 2 received 2 x 50 aPTT units/kg per day. In group 1, activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) were uniformly prolonged by 3-5 sec 4 hrs after s.c. administration of heparin. Heptest coagulation time values were prolonged consistently as well by 57 sec on day 1 to 68 sec on day 8. Factor Xa inhibition measured by the S 2222 chromogenic substrate method continuously increased from 0.16 units/ml on day 1 to 0.28 units/ml on day 8. In group 2 prolongation of a aPTT and TCT values increased from 6 sec on day 1 to 15 sec on day 8 and of Heptest time from 70 sec on day 1 to 110 sec on day 8. S 2222 method showed factor Xa inhibitory activity which increased from 0.5 units/ml on day 1 to 0.75 units/ml on day 8. The clinical tolerance of the treatment was good. No changes in clinical chemistry parameters were detected, except for a reversible increase of serum transaminases. The coagulation studies demonstrate accumulation of LMW heparin when high doses are given twice daily. The half life of LMW heparin of factor Xa inhibition increases with increasing doses. Heptest coagulation values were prolonged to 4-6 times the normal values during administration of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Protamine-agarose chromatography is introduced as a rapid and efficient method for the isolation of fibrinogen/fibrin degradation products from biological fluids such as human plasma. All fibrinogen/fibrin fragments above a MW of 35000, including fragments D and E are quantitatively adsorbed to insolubilized protamine and can be eluted with a buffer containing 0.2 M sodium citrate/citric acid pH 5.3, following previous elution of non-fibrinogen proteins with a buffer containing 0.8 M NaCl at neutral pH. Fragments D and E are separated by stepwise elution. The efficiency of the method is - evaluated by applying it to plasma samples obtained from healthy donors and from patients with clinical and laboratory evidence of disseminated intravascular coagulation.

A method for determination of antifactor Xa-like activity in capillary whole blood obtained from the fingertip is described, which employs the Heptest coagulation assay. Values obtained with capillary whole blood are compared to values of corresponding plasma and venous whole blood samples. Normal values in plasma, venous whole blood, and capillary blood from the fingertip were 17.1 +/- 2.1, 10.0 +/- 1.3 and 10.4 +/- 1.3 sec, respectively. The intraindividual coefficients of variations range from 0.4 to 1.8% in all assays. The day to day coefficient of variation of normal values ranged between 0.8 and 2.0% for all assays. The within assay coefficients of variation ranged from 3.0 to 7.7% for whole blood samples and from 1.5 to 2.2% for plasma samples after addition of no, 0.2 or 1.0 units of normal or LMW heparin to the samples. After administration of heparin or LMW heparin in healthy persons the coagulation values of the different coagulation assay systems displayed coefficients of correlation between r = 0.87 and r = 0.95. Correlation coefficients between the coagulation tests and the S 2222 chromogenic substrate method ranged from r = 0.77 to r = 0.92. In patients, who received LMW heparin for prophylaxis of thromboembolism the coagulation assay correlated between r = 0.78 and 0.92. The coagulation assays and the S 2222 method displayed coefficients of correlation between r = 0.74 and r = 0.83. The data indicate that Heptest sensitively measures antifactor Xa-like activity in capillary whole blood as well as venous whole blood samples containing low quantities of heparin or LMW heparin.

A total of 70 outpatients with previous severe haemorrhages and other side effects on conventional oral anticoagulants given for prophylaxis of tromboembolism, were treated with low molecular weight (LMW) heparin fraction Kabi 2165. Anticoagulation was necessary in all patients because of recurrent venous thromboembolism (n = 39), artificial heart valve replacement (n = 12), atrial fibrillation with peripheral embolism (n = 10), and cardiomyopathy (n = 9). LMW heparin was injected sc at doses ranging from 2,500 to 15,000 antifactor Xa (aXa) units once daily by the patients themselves. The dose was adjusted on the basis of body weight, of bleeding risk, and risk of developing thromboembolism. Five of 70 patients with poor compliance, 3 experienced non fatal embolism during the treatment period. Two of 65 patients with good compliance experienced repeat embolism. No fatal embolism occurred. One major episode of gastrointestinal bleeding occurred in a patient with an undetected colon carcinoma. Nine minor hemorrhages were observed in all patients. The present experience suggests that LMW heparin may be used safely and effectively as an alternative anticoagulant in patients who have experienced bleeding and other complications with oral anticoagulants or conventional heparin.