Biomedical subjects
Publications and source records attributed to S Wessler.
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 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of pyrimidines and causes increased serum levels of several amino acids including homocystine. 6-Azauridine was was withdrawn from clinical use for the treatment of psoriasis because of the occurence of arterial and venous thromboembolic episodes in some psoriatic patients.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.
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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 0.05) than the decrease in general surgical patients. Seventy-three per cent of hip-replacement patients had venographic evidence of recent thrombosis, 60 per cent of which were discontinuous femoral-vein thrombi. Femoral-vein thrombosis occurs frequently in hip-arthroplasty patients and is relatively resistant to current antithrombotic prophylaxis. The data presented suggest that during hip surgery there is a strong systemic activation of the clotting cascade that is associated with local vessel injury and local stasis in the femoral vein, an association not found in most general surgical procedures.
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. In contrast, Xa inhibitory activity was unchanged after 48 hr of warfarin treatment but was significantly increased by the tenth day. When thrombosis was induced by infusions of 60 micrograms of tissue thromboplastin, the warfarin regimen produced an antithrombotic effect by the sixth hour, which increased to significance by day 2 and was further significantly increased by day 10. These three stages correspond to the initial depletion of the vitamin K-dependent clotting factors, the maximal depletion of these proteins, and the maximal increase in Xa inhibitory activity, respectively. Thus these experiments separate the antithrombotic potential of warfarin into two components: an early effect related to the decrease in factor VII and a delayed augmentation of Xa inhibitory acticity. Intravenous heparin alone (5 U/kg) did not protect against infusions of 60 micrograms of tissue thromboplastin but did provide an antithrombotic effect against 45 micrograms of the same infusate. Higher doses of heparin, however, did protect against infusion of 60 micrograms of tissue thromboplastin. After 48 hr of warfarin treatment, 5 U/kg heparin increased protection against 60 micrograms of tissue thromboplastin to a degree equivalent to that provided after 10 days of warfarin therapy alone.
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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 responses in the clotting assay and in the extent of thrombosis are dose-related. The hypercoagulable state induced by oral contraceptives can be completely reversed by trace amounts 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, 0.12 nmol for activated Factor X, and 0.018 nmol for activated Factor IX. After the administration of heparin at 5, 10, and 20 units/kg in rabbits, the thrombogenicity of each of these proteases decreased progressively. The heparin-induced inhibition of thrombosis decreased in the order, activated Factor IX > activated Factor X > thrombin at each heparin concentration. These differences were statistically significant. These in vivo data provide support for the following hypotheses originally developed from in vitro experiments: (i) activation of the blood coagulation system, which proceeds through a cascade mechanism, incorporates biochemical amplification; (ii) the inhibition of activated Factor IX by antithrombin III in the presence of heparin is an important reaction in the prevention of thrombosis; (iii) less heparin is required to inhibit thrombosis prior to thrombin generation than afterward; (iv) an increase in the reactivity of antithrombin III reflects a decreased tendency to thrombosis while a decrease in this reactivity reflects an increased tendency to thrombosis.
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. With the low salt assay the first and second peaks for human plasma contain respectively 30%, and 70% of the activity; whereas with rabbit plasma these values are greater than 95% and less than 5% of the activity. With the high salt assay the figures for human plasma are less than 5% and greater than 95%, and with rabbit plasma 65 +/- 3% and 35 +/- 3%, respectively. With the high salt system, rabbit plasma shows a continuous increase in Xa inhibitory activity with increasing heparin concentrations, similar to that obtained with human plasma. In the high salt system the relative contributions of antithrombin III to Xa neutralization in human and rabbit plasma are different. However, in experiments in which Xa inhibitory activity of antithrombin III is altered by heparin, a simple formula, Total activity (%) = 65% + 0.35 x human plasma (%), permits translation of rabbit data on the Xa-antithrombin III-heparin reaction to man. On the basis of these findings, the rabbit model can effectively be used to study the Xa-antithrombin III reaction.
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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. The availability of a standard in vitro assay of the drug's antithrombotic potential. A meaningful assay of plasma heparin together with a determination of whether or not heparin is present in human plasma in normal and diseased states. Establishment of criterions for determining the proper dosage schedules in various pathological conditions. A reconcilation of USP and International units of heparin.
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. Patients with questionable infarcts should be treated with anticoagulants only until the diagnosis is established or rejected. If the latter occurs, the administration of the drug should be discontinued. When, in a patient suspected of having an acute myocardial infarction, there is reason to believe that the pain may be due to pericarditis, dissecting aneurysm, or gastrointestinal abnormalities, anticoagulant therapy should be withheld until this is resolved.
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. In contrast, Xa inhibitory activity was significantly reduced (P less than .001) among patients taking oral contraceptives, compared to controls. Heparin sodium added to plasma from patients taking contraceptives raised Xa inhibitory activity toward or above normal without changing the quantity of antithrombin III. The effect of estrogen is not to decrease the quantity of plasma antithrombin III, but rather to diminish plasma Xa inhibitory activity, an effect that can be abolished by heparin.
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. They should also not be receiving aspirin or other platelet antiaggregating agents for five days prior to surgery. The efficacy of this regimen is complemented by the fact that it is well tolerated by the patient, free of side effects, requires no laboratory monitoring, and produces minimal intraoperative or postoperative bleeding. This low-dose regimen has not proved effective in open prostatectomy or major orthopedic surgery. Data are not available concerning the drug's safety in spinal or epidural anesthesia, nor is it recommended for eye or brain surgery or in patients with an active thrombotic process. Other data are suggestive but still inconclusive that the regimen may reduce the incidence of postoperative acute myocardial infarction. In non-surgical patients hospitalized with acute myocardial infarction and receiving a low-dose heparin regimen, the findings reflect a significant decrease in deep venous thrombosis, though no observations are yet available concerning reductions in pulmonary emboli, mural thrombi, or systemic emboli.
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