Thrombosis: the relationship of hemostatic mechanisms to drug therapy.

The mechanism of action and present clinical role of drugs affecting hemostasis in the therapy of spontaneous, postoperative, and posttraumatic arterial thrombosis, arterial embolism, venous thrombosis, pulmonary embolism, and intracranial aneurysm have been reviewed. Both the management of neurosurgical problems and the development of antithrombotic regimens are improving. In regard to the use of drug therapy, discussed herein, each surgeon will reach his own decision based on his findings in the individual patient, and may wisely elect in specific situations not to employ drug therapy.

Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass.

The activated clotting time (ACT) with a Hemochron system for determining heparin requirements during cardiopulmonary bypass surgery, (CPB) accompanied by hemodilution and hypothermia was evaluated using plasma heparin levels as a standard. In 28 patients who were administered a standard heparin regimen (300 units/kg prebypass, 8000 units in the pump prime and 100 units/kg hourly during CPB) mean prebypass plasma heparin was 4 units/ml, and ACT was 493 seconds. During CPB mean plasma heparin decreased significantly (p < 0.

leu operon of Salmonella typhimurium is controlled by an attenuation mechanism.

The nucleotide sequence of the control region of the leu operon of Salmonella typhimurium was determined. A prominent feature of this region is a signal for termination of transcription. In vitro, transcription does terminate at this site, yielding a leader RNA of about 160 nucleotides as a major product.

The antithrombotic effects of warfarin and heparin following infusions of tissue thromboplastin in rabbits: clinical implications.

An animal model for the production of stasis thrombi was employed to obtain the data reported in this study. Rabbits treated with warfarin (1.5 mg/kg/day) exhibited a maximal increase in prothrombin time and decreases in factor VII, factor X, and prothrombin within 48 hr with no additional changes occurring after 10 days of drug administration.

The effect of total hip replacement and general surgery on antithrombin III in relation to venous thrombosis.

This investigation was undertaken to identify and correlate one factor that makes patients undergoing total hip replacement more susceptible to venous thrombosis and pulmonary embolism than those who have almost any other elective orthopaedic procedure, and to determine why the operation of total hip replacement has proved to be relatively resistant to antithrombotic prophylaxis compared with general surgical procedures. Using the depletion of antithrombin III as a marker of activation of the coagulation system, two groups of patients were compared: twenty-one who were subjected to hip arthroplasty and fourteen who underwent general surgical procedures. Both during and after operation the decrease in the quantity of antithrombin III in hip-arthroplasty patients was significantly greater (p less than 0.

Heparin and warfarin therapy. Recommendations concerning efficacy and safety.

Heparin and warfarin are antithrombotic agents effective against venous thrombosis as well as pulmonic and systemic emboli. They can exert a favorable effect on mortality and morbidity in a diverse group of illnesses associated with thrombosis. Proper use of these agents will increase their efficacy and diminish the risk of serious hemorrhage.

The thrombogenicity of 6-azouridine.

The antimetabolite 6-azauridine blocks the de novo synthesis of pyrimidines and causes increased serum levels of several amino acids including homocystine. 6-Azauridine was was withdrawn from clinical use for the treatment of psoriasis because of the occurence of arterial and venous thromboembolic episodes in some psoriatic patients. Utilizing a standard animal model for the recognition of venous and arterial thrombosis, 6-azauridine was demonstrated in this study to cause thrombosis without producing homocystinemia when administered orally or intravenously.

The activated factor X-antithrombin III reaction rate: a measure of the increased thrombotic tendency induced by estrogen-containing oral contraceptives in rabbits.

Estrogen-containing compounds are thrombogenic in man. The extent of thrombosis is dose-related, but a measure of this thrombogenicity is not currently available. Evidence is presented, using an animal model of venous thrombosis, that impaired Xa inhibitory activity (the rate of reaction between Xa and antithrombin III) correlates with the development of thrombosis initiated by thrombin in rabbits receiving an oral contraceptive compound.

The anticoagulant dilemma--a prescription for its resolution.

Despite the fact that heparin and the coumarins are effective drugs in the prevention of venous thromboembolism and of systemic embolism and have been in use for more than one quarter of this century, there has been no recognized decrease in overall deaths attributable to these agents. Several factors contribute to this paradox: (1) the disparity between the high prevalence of thromboembolic events and the low incidence of associated mortality or disability has rendered the required size of trial populations exceedingly large, cumbersome, and costly; (2) the major use of anticoagulants has occurred after a thromboembolic event rather than as an instrument of primary prophylaxis; (3) the difficulties in regulating drug dosage persist and serious hemorrhage remains in infrequent but real complication of therapy; and (4) the physician is invariably apprised of clinical failure (further thrombosis or hemorrhage) but rarely of success (no thrombosis). Recent advances in our understanding of the mechanism of intravascular coagulation, of the pathophysiology of thromboembolism, and of the molecular basis of anticoagulant action have begun to permit more effective use of the classical drugs and to suggest the potential value of other agents and modalities for the prevention of the thromboembolism in different segments of the vasculature.

The rabbit as an animal model for the activated factor X-antithrombin III-heparin reaction.

When activated factor X (Xa) inhibitory activity of serially diluted human and rabbit plasma is determined in a low salt assay, a lineare plot is obtained for human, but not for rabbit plasma. When a high salt assay is used, the dilution curves for both human and rabbit plasma are linear, and qualititive as well as quantitative differences are essentially eliminated. On Sephadex G-200 chromatography Xa inhibitory activity of human and rabbit plasma appears in two peaks.

In vitro and in vivo correlation of clotting protease activity: effect of heparin.

The thrombogenicity of three highly purified proteases (thrombin, activated Factor X, and activated Factor IX) was determined quantitatively in an animal model. The minimal amounts required to produce a standard score 4 thrombus were 1.1 nmol for thrombin, 0.

Antithrombotic agents are indicated in the therapy of acute myocardial infarction.

Although there is no statistical proof of the efficacy of coumarin drugs in the therapy of acute myocardial infarction, the numbers of patients at risk from thromboembolism are sufficiently great and the favorable clinical and pathologic impressions are sufficiently strong that, conversely, the possibility of benefit cannot be excluded. This delicate balance is indeed a Hobson's Choice. In this therapeutic dilemma, we would interpret one acceptable course in regard to the use of anticoagulants among patients with acute myocardial infarction as follows: all patients with proved acute myocardial infarction should be treated with anticoagulants while hospitalized unless there are relative or absolute contraindications to the therapy or deficiencies in laboratory facilities.

Current dilemmas in the clinical use of heparin.

The more widespread use of heparin as an effective antithrombotic agent would be greatly facilitated by resolution of the following issues: Clarification of the biological differences between beef and hog heparin. The development of a standard heparin molecule. The modification of heparin for oral use.

Estrogen-containing oral contraceptive agents. A basis for their thrombogenicity.

The mechanism whereby estrogen-containing contraceptives facilitate thrombosis is obscure, and published data concerning their effect on antithrombin III are conflicting. Plasma samples were examined for the quantity of antithrombin III and activated factor X (Xa) inhibitory activity among 57 women receiving oral contraceptives and 48 controls. The quantity of antithrombin III in both groups was normal.

Heparin as an antithrombotic agent. Low-dose prophylaxis.

Presently available data indicate that low-dose heparin prophylaxis will significantly diminish massive postoperative pulmonary emboli in patients more than 40 years of age subjected to major elective abdominothoracic surgery. The schedule is 5,000 USP units of heparin sodium subcutaneously, beginning two hours before surgery and continued every 12 hours (10,000 units/day) until the patient is discharged. Patients receiving this therapy should have a preoperative screening that includes a hematocrit reading, prothrombin time, partial thromboplastin time, and a platelet count.