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Incidence of emboli with cloth-covered Starr-Edwards valve without anticoagulation and with varying forms of anticoagulation. Analysis of 183 patients followed for 3 1/2 years.

One hundred eighty-three patients with cloth-covered valves were studied from 1 1/2 to 8 years after operation, with an average follow-up time of 3 1/2 years. Over the total period, patients taking Coumadin sustained a 4 percent embolic incidence (1.2 per 100 patient-years); those taking aspirin had a 7 percent incidence (2.6 per 100 patient-years); and those taking Persantine had a 43 percent incidence (10 per 100 patient-years). Patients on no regimen of anticoagulation had a 16 percent embolic rate (four per 100 patient-years), whereas another group of patients who stopped anticoagulants after a year incurred a 13 percent embolic incidence in the subsequent 2 years (6.4 per 100 patient-years). These data showed a significantly lowered embolic rate with anticoagulation and suggest that all patients with cloth-covered valves should be taking anticoagulants. That these valves become epithelialized and do not form thrombus after a year was not borne out by this study. Persantine alone is not a satisfactory anticoagulant. Coumadin appears to be the superior anticoagulant, but if careful monitoring of its use is in question or if serious bleeding complications ensue, aspirin may provide satisfactory protection.

Anticoagulants

Management of anticoagulation in outpatients: experience with an anticoagulation service in a municipal hospital setting.

In 66 months, a general hospital's outpatient Anticoagulation Service (ACS) monitored 263 patients who received 280 courses of warfarin sodium totalling 254 patient treatment years. Major hemorrhagic morbidity was 4% of courses and there was no mortality attributable to warfarin therapy. Major hemorrhage occurred in patients with increased anatomic risk of bleeding (diverticulosis, hemorrhoids, cystitis), and was not a function of patient age, sex, anticoagulation control, or medications administered concurrently with warfarin. Control of anticoagulation was not correlated with age or other medications, but was worsened significantly by the presence of congestive heart failure. We attribute a favorable experience with outpatient ACS to careful patient selection, patient education and monitoring, attention to duration of anticoagulation, and continuing communication with primary physicians who retained responsibility for medical care. An ACS offers safety, consistency, efficiency, and a unified approach to outpatient anticoagulation in the general hospital setting.

Aged

Structural basis for the anticoagulant activity of heparin. 2. Relationship of anticoagulant activity to the thermodynamics and fluorescence fading kinetics of acridine orange-heparin complexes.

Complexing heparin or dermatan sulfate with the fluorescent probe acridine orange provides a means of studying electrostatic as well as static and dynamic conformational aspects of these glycosaminoglycans via the thermodynamic and photochemical (fluorescence fading) properties of these complexes. The cooperative binding constants (Kq), fluorescence fading rate parameters (r''), and anticoagulant activities of heparins fractionated according to anionic density all showed qualitatively the same dependence upon anionic density. When Kq and r'' were plotted against anticoagulant activity, empirical relationships were observed. Interestingly, the corresponding values for unfractionated dermatan sulfate fell on the lines defined by the heparin fractions. Temperature-dependence, studies demonstrated that differences in fading rate observed for heparins of different anionic densities are entropic in origin and reflect differences in the ability to assume a special configuration. Differences in activation entropy for fluorescence fading can be empirically correlated with anticoagulant activity. The latter correlation suggests a physical similarity in the roles played by anionic density in both fluorescence fading and anticoagulant activity.

Acridine Orange

[The anticoagulant property of a lipoid anticoagulant and the mechanism of its influence on hemocoagulation].

A lipoid anticoagulant (LA) from human brain tissue was shown to possess a higher anticoagulant activity than previously obtained preparations. It has been established that out of four phospholipids present in LA, only phosphatidyl serine inhibits the coagulant activity of plasma. In isolated hemocoagulating systems LA and phosphatidyl serine were shown to inhibit prothrombin conversion catalyzed by thrombokinase and to exert the antithrombic action in the system thrombin--fibrinogen. Kinetic study of phosphatidyl serine- and LA-induced inhibition of thrombine formation and the thrombine--fibrinogen reaction by conjugated inhibition. Similar kinetic behaviour, observed upon inhibition of both processes by phosphatidyl serine and LA suggest that phosphatidyl serine is a main anticoagulant agent of LA.

Anticoagulants

[Hemarthroses complicating anticoagulant therapy (heparin, oral anticoagulants)].

Three patients with hemarthrosis complicating anticoagulant therapy are described. Two had acute hemarthrosis of the knee joint occurring during long term oral anticoagulant therapy for cardiovascular disorders. Joint symptoms disappeared rapidly after arthrocentesis and diminution of the dose of oral anticoagulant medication. The third patient has been on chronic hemodialysis for the last three years. After 2 years of this therapy he developed periarthritis of the right shoulder, followed suddenly by hemarthrosis of the right shoulder which remained symptomatic for 9 months in spite of several joint aspirations and reduction in the dosage of heparin administered during hemodialysis. Resolution of the hemarthrosis of the right shoulder occurred only when the vascular access for the dialysis sessions was displaced from the right to the left forearm. It is assumed that there was communication in the venous draining territories of the arterio-venous fistula and the shoulder articulation.

Acenocoumarol

Comparative pharmacokinetics of coumarin anticoagulants XXIX: Elimination kinetics and anticoagulant activity of (S)-(-)-warfarin in rats before and after chronic administration.

The kinetics of elimination and the anticoagulant effect of (S)-(-)-warfarin were determined in adult male rats before and after daily drug administration for 13 days. There was a small but statistically significant (p less than 0.05) decrease in the body clearance of (S)-(-)-warfarin (from 4.84 to 4.37 ml/hr/kg) and an increase in the serum free fraction of racemic warfarin (added to serum in vitro) from 0.00850 to 0.0107 (p less than 0.05). The concentration of (S)-(-)-warfarin in serum at which the synthesis rate of prothrombin complex activity is one-half of the pre-warfarin rate increased from 0.532 to 0.655 microgram/ml on the average (p less than 0.05).

Animals

[Comparative studies with various anticoagulant stabilizer combinations for the preservation of blood specimen in leukosis diagnosis. II. Testing the application possibilities of new anticoagulant stabilizer combinations for the hematologic diagnonsis of leukosis].

The anticoagulant Chelaplex III in aqueous solution with two new stabilizers (methenamine and tannin) was tested for the preservation of blood samples, together with another combination composed of oxalic acid and methenamine solution. The eventual aim was to test their suitability for use with blood specimens dried in the tube, but this was not done in the present experiments. It was shown that a combination of 5% oxalic acid with 36% methenamine was at least as good as the conventional Chelaplex III-formaldehyde combination for inhibiting coagulation, and it was relatively cheap.

Animals

Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis.

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Anticoagulants

Oral anticoagulant therapy in patients undergoing dental surgery.

The literature on dental surgery in patients receiving oral anticoagulants is reviewed, and methods of managing anticoagulant therapy to minimize the risk of complications are discussed. Although blood loss during and after oral surgery in patients receiving oral anticoagulant drugs can be substantial, research indicates that most bleeding incidents are not serious and can be controlled by local measures. Studies of 241 anticoagulant-treated patients undergoing more than 500 dental extractions during the 1950s and 1960s showed that only 9 had postoperative bleeding. More recent studies indicate that continued anticoagulation can increase the frequency of prolonged bleeding and delay wound healing. An antifibrinolytic mouthwash containing tranexamic acid can effectively suppress postoperative bleeding. Gelatin sponges, oxidized cellulose, and microcrystalline collagen are other useful hemostatic agents. A reduction in the intensity of anticoagulation therapy has been recommended; the prothrombin time should be measured shortly before the procedure in such patients. In many patients the duration of subtherapeutic anticoagulation must be minimized to reduce the possibility of thromboembolism. An option for high-risk patients is to switch them to heparin. Each patient must be evaluated individually, and the level of risk of the dental procedure and the risk of thromboembolism should be taken into account. In patients taking oral anticoagulants who must undergo dental surgery, careful control of the intensity of anticoagulation and improved methods of local hemostasis can minimize the risk of hemorrhagic complications and thromboembolism.

Administration, Oral

Anticoagulation and high dose liver radiation: a preliminary report.

Two groups of patients were observed for evidence of acute radiation hepatitis during "high dose" radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.

Adult

Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis.

Among 52 cases of prosthetic valve endocarditis, adequate anticoagulant therapy was administered in 38 and discontinued or given in subtherapeutic dosage in 14. Our data suggest that anticoagulant therapy does not appreciably increase morbidity or mortality in patients with prosthetic valve endocarditis. On the contrary, in our patients the incidence of major clinical CNS (central nervous system) complications was increased and the mortality was higher if anticoagulant therapy was discontinued. CNS complications occurred in 10 of the 14 patients without adequate anticoagulant therapy and in three of the 38 with adequate anticoagulant therapy. Mortality was 57% among those treated without adequate anticoagulation and 47% among those with adequate anticoagulation. At autopsy, CNS complications were thought to be the primary cause of five of the eight deaths in cases without adequate anticoagulation.

Adolescent

[Subdural hematoma and anticoagulant therapy].

The authors report a series of 22 cases of subdural hematomas in patients submitted to anticoagulant therapy. A review of the literature finds 150 cases. Subdural hematomas occurs in about one third of the patients presenting hemorrhage of central nervous system related to anticoagulant therapy. Among subdural hematomas of any cause, the possible role of a previous anticoagulant therapy is stressed in 4,8 to 14% of cases. In most cases, long term anticoagulants were indicated for arterial or heart (ischemic) lesions (16/22 cases). In 6 cases, anticoagulants were indicated for prevention or treatment of pulmonary embolies. In 18 cases, anticoagulant drug is from the group of dicoumarol or phenylindanedione. In 3 cases, the only anticoagulant given to patient was heparin. Pathogenic study suggests that hypocoagulability might not always be the only factor of bleeding: high blood pressure, other drugs and head trauma (10 cases) are often associated. Clinical features, in our series, are similar to those encountered in cases of subdural hematoma of any cause. According to the existence of a cranial injury and to the chronology of anticoagulant therapy, the authors divide their 22 patients into 3 groups. The use of protamin sulfate or human plasma fraction PPSB provides in few minutes a normal coagulability. Neurosurgical treatment in all our cases evacuated in 11 patients a chronic subdural hematoma, in 2 cases an acute, and in 9 cases a subacute hematoma. Results were fair in 19 patients with no sequelae. 3 patients died during the immediate post-operative period. The authors conclude by stressing several preventive measures.

Anticoagulants

Purification and properties of the anticoagulant principle of Trimeresurus gramineus venom.

By means of DEAE-Sephadex A-50 column chromatography, Trimeresurus gramineus venom was separated into 12 fractions. Fraction 8 had marked anticoagulant action in the tests of whole blood clotting time, calcium clotting time and plasma prothrombin time. Fraction 8 was rechromatographed on Sephadex G-100, then on DEAE-Sephadex A-50 again, and finally on Sephadex G-100, and a single peak was obtained. The patterns of microzone and disc electrophoresis also showed a single band. A single symmetrical boundary with 1.70 Svedberg units was obtained by ultracentrifugation. The estimated molecular weight was 19 500. The isoelectric point was pH 4.5. Chemical analysis showed that the anticoagulant principle was a glycoprotein and that it was thermolabile. The anticoagulant activity of this purified principle was 3.5 times higher than that of the crude venom. Fraction 5 potentiated its anticoagulant activity to 10 times higher than that of the crude venom. This principle did not possess caseinolytic, tosyl-L-arginine methyl ester esterase, phospholipase A, phosphodiesterase, alkaline phosphomonoesterase, fibrinolytic, hemorrhagic or local irritating activities. The purified anticoagulant principle did not destroy fibrinogen, induce fibrinolysis, inactivate thrombin nor interfere with the interaction between thrombin and fibrinogen. However, a marked inhibition of prothrombin activation was caused by the anticoagulant principle. The inhibition of prothrombin activation was not due to the destruction of prothrombin or its activation factors, but due to an interference in the interaction between prothrombin and its activation factors because of the reversible binding of these factors with the anticoagulant principle of the venom.

Amino Acids