Oral anticoagulant therapy--50 years later.

The year 1991 marked the 50th anniversary of the first clinical use of oral anticoagulant therapy as a means of preventing thromboembolic disease. Despite long-term physician familiarity with oral anticoagulants, this mode of therapy still suffers from a relatively high-risk/safety profile. This review briefly highlights important historical and pharmacokinetic points of interest but focuses predominantly on aspects of the day-to-day management of anticoagulant therapy aiming to enhance physician performance in this therapeutic milieu. Emphasis is placed on therapeutic monitoring, understanding the prothrombin time, managing complications, and assessing future innovations for the management of a growing population of patients treated with orally administered anticoagulants.

Long-term patient self-management of oral anticoagulation.

BACKGROUND: The management of oral anticoagulation is fraught with difficulties. This study assessed a new model of anticoagulation management regarding the ability, safety, and efficacy of patients to self-monitor and self-adjust the dose of their oral anticoagulants guided by a capillary whole-blood prothrombin time (PT) monitor. METHODS: This investigation is a retrospective cohort study of 20 patients compared with 20 matched control patients receiving oral anticoagulation at a tertiary medical institution. RESULTS: Study patients monitored their PTs 2153 times during a mean interval of 44.7 months compared with 1608 PTs in matched control patients during a mean interval of 42.5 months. Study patients made an average of 11.5 dosage changes per patient, contrasted with 22.7 changes per control patient (P < .001). The PTs in study patients were within the recommended therapeutic range in 88.6% (95% confidence interval, 87.2 to 89.9) of the determinations compared with 68.0% (95% confidence interval, 65.7 to 70.3; P < .001) of the determinations made by the matched control patients. In response to the 2153 PTs, study patients made 67 (3.1%) dosage decisions that were considered incorrect based on physician guidelines. None of these changes led to adverse outcomes. There was no significant difference in complication rates between the two groups. CONCLUSIONS: Results from what is the first long-term study of patient self-monitoring of PTs and self-adjustment of the warfarin sodium dosage for oral anticoagulation suggest that patients can successfully measure their own PTs, adjust their own warfarin dosage, and achieve a degree of therapeutic effectiveness at least as good, if not better than patients managed in an anti-coagulation clinic. Larger, prospective, randomized trials are needed to confirm the efficacy and safety of this new approach to therapy and to assess its cost-effectiveness.

Heparin-induced thrombocytopenia. What is its real frequency?

A prospective study of 104 patients was undertaken to determine the frequency of severe heparin-induced thrombocytopenia in patients receiving either bovine lung or porcine mucosal heparin. One of 54 patients randomized to receive bovine heparin and two of 50 patients randomized to receive porcine heparin developed heparin-induced thrombocytopenia (platelet count less than 100,000/microliters). Although three previous studies suggest a remarkably high frequency of bovine heparin-induced thrombocytopenia, or a high frequency compared to porcine heparin, our study supports other evidence that clinically important, severe heparin-induced thrombocytopenia (platelet count less than 100,000/microliters) occurs in 10 percent of patients or less receiving heparin, and that there is no significant difference of occurrence between bovine and porcine heparin.

The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double-blind randomized study.

Sixty patients scheduled for elective coronary artery bypass graft operations were randomly assigned to receive epsilon-aminocaproic acid or placebo to test whether antifibrinolytic therapy would decrease postoperative bleeding. A small but significant decrease in bleeding was observed in the treated group without complications resulting from treatment with epsilon-aminocaproic acid.

Gelfoam and autologous clot embolization: effect on coagulation.

An episode of disseminated intravascular coagulation following therapeutic gelfoam embolization to control bleeding from esophageal varices in a patient with liver disease is presented. We have since followed 13 patients prospectively (six control and seven gelfoam/autologous clot) to determine the effect of this procedure on clotting. We were unable to show significant differences between the two groups as measured by the prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen and platelet count. However, fibrin (ogen) degradation products were significantly elevated (p less than .01) in the gelfoam/autologous clot group. We suspect this occurred secondary to clot lysis at the site of embolization. No subsequent bleeding diathesis attributable to this abnormality occurred in any of the patients.

Imprecision of prothrombin time monitoring of oral anticoagulation. A survey of hospital laboratories.

Prothrombin time monitoring of oral anticoagulation is highly dependent on the tissue thromboplastin used. In the United States, patients have received a higher level of anticoagulation because of the use of a less sensitive thromboplastin. Many advocate the use of an International Normalized Ratio to rectify this problem. Laboratory supervisors from all acute care hospitals in Massachusetts were surveyed to determine the disparity in thromboplastin use and reporting practices for prothrombin time testing. Eighty-eight of 103 (86%) hospitals responded. Fifty-eight lots from six manufacturers of thromboplastin were in use. The International Sensitivity Index of these lots ranged from 1.89 to 2.74. Ninety-nine percent of hospitals reported prothrombin times in raw seconds. Only 5% reported an International Normalized Ratio. Sixteen different coagulation instruments were in use. Close to 70% of laboratory supervisors had little or no understanding of the significance of an International Sensitivity Index or an International Normalized Ratio. The management of oral anticoagulation appears far less precise than had been believed. Prothrombin times in the same individual from different laboratories may have poor correlation. Based on the level of understanding of laboratory supervisors, extensive education will be necessary to change practices and improve accuracy and comparability of prothrombin time testing.

Clinical trial of a new bleeding-time device.

The authors report a clinical trial comparing a new bleeding time device (Simplate II) with the Mielke Template. Bleeding times were determined at the same time on the same arm using the two devices. Subjects of the study were 24 healthy volunteers, before and two hours after ingestion of 975 mg aspirin, and 28 patients. For the normal subjects the mean pre-aspirin bleeding times were 4.75 +/- 1.42 minutes (1 SD) with the Simplate II and 3.65 +/- 1.22 minutes with the Mielke Template. The mean bleeding times two hours after ingestion of aspirin were 7.86 +/- 2.76 minutes with the Simplate II and 7.84 +/- 2.94 minutes with the Template. The pre- and the post-aspirin values with the two devices were not significantly different from each other, nor were the bleeding times obtained in the patients with the two devices. The extents of scarring were similar with the two devices. The results were highly reproducible by both methods. The new device was simpler and more rapid to use.

Cost effectiveness of monitoring warfarin therapy using standard versus capillary prothrombin times.

The authors assessed the cost effectiveness of monitoring warfarin therapy guided by standard plasma prothrombin times performed on blood samples obtained by venipuncture versus prothrombin times performed on capillary whole blood samples obtained by fingerstick. Twenty patients receiving long-term oral anticoagulation had either standard or capillary prothrombin times determined every other week for eight weeks in a cross-over design. All time intervals were monitored, including receptionist, secretarial, nursing, phlebotomy, etc., and costs for all materials, procedures, and labor were calculated. The total cost per test by the capillary whole blood prothrombin time method was significantly less than by standard prothrombin time methods ($7.55 vs. $15.64) even though the nurse-patient encounter time was greater per test for the capillary method (12.4 minutes vs. 8.3 minutes). The management of oral anticoagulation guided by prothrombin times performed on instrumentation designed to sample capillary whole blood should result in a significant cost savings, and because of the immediate availability of results, provide the potential for improved health care.

Vitamin B12 levels and age.

Vitamin B12 concentration was determined by radioassay in 179 healthy volunteers between the ages of 20 and 93 years in order to determine whether vitamin B12 levels decline with advancing age. The authors found no statistically significant decline in vitamin B12 levels in older individuals, nor a difference between males and females. A review of previous reports identifies potential reasons for controversy regarding the normal concentration of vitamin B12 in the elderly.

In vivo survival of red blood cells processed by a bubble or membrane oxygenator during cardiopulmonary bypass surgery.

A dual radioisotope labeling technique was utilized to assess red cell survival differences between cells processed by either a bubble oxygenator (eight patients) or membrane oxygenator (eight patients) in 16 patients undergoing cardiopulmonary bypass surgery. Cells processed by a bubble oxygenator consistently had a shortened survival. The 30-minute recovery of cells was not significantly different between oxygenators in contradiction to some previous studies using plasma hemoglobin as an indicator of hemolysis. The results of this investigation confirm previous studies that a membrane oxygenator provides a survival advantage to red cells during cardiopulmonary bypass surgery.

Oral anticoagulants for the treatment of venous thromboembolism.

Oral anticoagulation has been the mainstay of therapy for the long-term treatment of venous thromboembolism since the 1940s. The rationale for the use of oral anticoagulation is based on the results of both empirical clinical evidence and animal models of thrombosis in the 1950s and 1960s. Higher-quality studies emerged in the 1970s and 1980s demonstrating the benefit of initial heparinization for venous thromboembolism followed by long-term oral anticoagulation. Good clinical outcomes with oral anticoagulation are highly dependent on the quality of dose management. Excellent management is best achieved in a programme of focused and co-ordinated care, often referred to as an anticoagulation clinic. Such programmes achieve better outcomes at reduced costs because of fewer adverse events. New models of anticoagulation management are emerging with the development of point-of-care testing that enables patients to do their own prothrombin time monitoring and anticoagulation dose adjustment. These models have the potential to improve care further, to increase patient satisfaction and to reduce costs.

Anticoagulation management clinics for the outpatient control of oral anticoagulants.

Oral anticoagulant therapy has a high risk-benefit profile and is labor intensive to manage. A better understanding of the indications for anticoagulation and of prothrombin time monitoring has led to improved outcomes. The development of anticoagulation management services has also improved the overall management of anticoagulation and the resulting clinical outcomes. By reducing adverse events, anticoagulation management services also result in more cost-effective therapy. Although these results have been generated by mostly nonrandomized observational studies, until better quality investigations are available, the preponderance of current clinical evidence strongly supports the value of a coordinated approach to care by an anticoagulation management service.

Oral anticoagulant therapy: practical considerations.

The key to safe and effective oral anticoagulation is to have an understanding of the rationale for dosing guidelines and therapeutic ranges; an appreciation of the imprecision of prothrombin time testing and its standardization; knowledge of the factors influencing prothrombin time response; and awareness of the importance of patient empowerment via ongoing patient education. This review focuses on the routine management of oral anticoagulant therapy to provide these practical insights and to promote safe and effective therapy.

Coagulation abnormalities associated with the use of anabolic steroids.

According to a number of recent reports, persons using anabolic steroids may be subject to an increased risk of thromboembolism. We evaluated the effect of anabolic steroid use on the coagulation and fibrinolytic systems of 16 male bodybuilders to determine whether alterations occurred that would predispose them to a hypercoagulable state. No attempt was made to regulate or guide steroid use. Paired blood samples, both with and without steroid use, were obtained from six individuals, and the remaining subjects provided single samples obtained either during steroid use or nonuse. No differences were noted in most parameters, but we did find a significant increase in protein C antigen (p = 0.008) and free protein S antigen (p = 0.015), with a decreased euglobulin lysis time (p = 0.021) during steroid use. We also found a reduction in total cholesterol levels (p = 0.035) during steroid use. At least some of these findings suggest an activated fibrinolytic state, a known effect of anabolic steroids. The results do not support the presence of a hypercoagulable state. If anabolic steroids do produce a thrombotic tendency, they may do so through alterations in other hemostatic mechanisms or changes in lipid fractions, or more sensitive coagulation assays may be required for detection.

The spectrum of vitamin K deficiency.

The coagulopathy induced by vitamin K deficiency commonly results from our lack of awareness of the clinical setting associated with vitamin K deficiency. Thirteen cases are reviewed to illustrate the clinical correlates most frequently observed. Dietary deficiency was always present, but concomitant antibiotic therapy was not an absolute requirement. The postoperative patient is at high risk, as is the patient with cancer or renal failure. Abnormal bleeding was common, but significant hemorrhage occurred only in postoperative patients. Factor assays were helpful and occasionally necessary to make the diagnosis, but a therapeutic trial with parenteral vitamin K was often enough to provide the right diagnosis. Greater awareness of this deficiency syndrome is necessary to avoid the serious morbidity that often results.

Leukemia cutis in blastic transformation of chronic myelocytic leukemia: TdT positive blasts and response to vincristine and prednisone.

A patient with chronic myelocytic leukemia (CML) in blast transformation with extensive involvement of the skin is reported. The leukemic infiltrates consisted of blasts with lymphoblastoid morphology which were positive for terminal deoxynucleotidyl transferase (TdT) by fluorescent assay. The infiltrates rapidly resolved with vincristine and prednisone therapy. Similar recurrence 4 and 8 months later responded as dramatically to the same therapy and to cytosine arabinoside. This unusual case of extensive leukemia cutis supports the evidence that patients in blast crisis with TdT positive cells are responsive to vincristine and prednisone. The implications of this case in terms of the origin of these cells based upon morphology and TdT content, as well as the diagnosis and therapy, are discussed.

Consensus guidelines for coordinated outpatient oral anticoagulation therapy management. Anticoagulation Guidelines Task Force.

OBJECTIVE: To provide primary and referring healthcare practitioners with guidelines for the provision of safe and effective anticoagulation management in any venue to standardize and improve quality of care and to permit negotiation for reimbursement from third-party payers. DATA EXTRACTION AND SYNTHESIS: Data on the current practice of anticoagulation providers and outcomes related to anticoagulation clinic care were obtained through the literature, interviews with anticoagulation providers, and a focus group meeting of anticoagulation clinic stakeholders. This information collation process revealed that an anticoagulation service consists of three separate areas for which guidelines should be developed. Based on the consensus opinions of the committee members, the literature review, and the current practice of anticoagulation services providers, a draft guideline was developed and reviewed by an independent multidisciplinary panel of anticoagulation services providers whose comments were incorporated into the final guideline. CONCLUSIONS: Systematic outpatient anticoagulation services are systems of care designed to coordinate and optimize the delivery of anticoagulation therapy by (1) evaluating patient-specific risks and benefits to determine the appropriateness of therapy; (2) facilitating the management of anticoagulation dosages and prescription pick up or delivery; (3) providing ongoing education of the patient and other caregivers about warfarin and the importance of self-care behavior leading to optimal outcomes; (4) providing continuous systematic monitoring of patients, international normalized ratio results, diet, concomitant drug therapy, and disease states; and (5) communicating with other healthcare practitioners involved in the care of the patient. To create a reproducible framework for the provision of these services, guidelines for structure, process, and outcomes of coordinated outpatient anticoagulation management services were developed. Guidelines for organization and management include (1) qualifications for personnel, (2) supervision, (3) care management and coordination, (4) communication and documentation, and (5) laboratory monitoring. Guidelines for the process of patient care include (6) patient selection and assessment, (7) initiation of therapy, (8) maintenance and management of therapy, (9) patient education, and (10) management and triage of therapy-related and unrelated problems. Guidelines for the evaluation of patient outcomes include (11) organizational components and (12) patient outcomes. The impact of these 12 guidelines on patient care and reimbursement procurement will depend on their implementation and the perceived value of their use.

Control of bleeding varices by vasopressin: a prospective randomized study.

From July 1975 to November 1976 25 patients with bleeding esophagogastric varices documented by endoscopy who failed to respond to conservative medical treatment were transferred to the Surgical Service. These patients, who were mainly Child's Class "C" alcoholic cirrhotic patients, were treated with vasopressin infused continuously using a standardized dose into either a peripheral vein or the superior mesenteric artery (SMA) according to a predetermined randomization. No significant difference in efficacy for control of bleeding (average rate = 56%) related to route of administration was found. Because catheter-related complications in the SMA group were significantly greater, we concluded that the method of choice in vasopressin treatment of esophagogastric variceal bleeding is a continuous infusion by way of a peripheral vein.

Characterization of indium-111 labeled recombinant tissue plasminogen activator for the imaging of thrombi.

The in vitro functional properties of recombinant tissue plasminogen activator (rt-PA), its biodistribution in mice, and its pharmacokinetics and clot localization properties in dogs have been investigated after labeling rt-PA with 111In. The rt-PA was coupled with the bicyclic anhydride of DTPA using standard methodology. Amidolytic and fibrinolytic assays showed retention of protein activity when rt-PA was conjugated with an average of one DTPA group or less per molecule. Size exclusion HPLC showed each preparation to be radiochemically pure with 111In bound exclusively to the attached DTPA groups. Biodistribution in mice showed major accumulation of activity in the liver and kidneys. After administration of 0.5-1.0 mg of the labeled protein to dogs, blood activity decreased with a half time of approximately 5 min in agreement with previous reports of rapid blood clearance. Largely because of decreased blood levels, clot: blood ratios of labeled protein increased rapidly, in one study reaching 6.3 after 31 min, and satisfactory images of fibrin thrombi were obtained. The rt-PA may be labeled with 111In without destroying the ability of the protein to localize in clot and images of forming clot can be obtained with this agent within 1 h after administration.