warfarin and Substance-Withdrawal-Syndrome

The occurrence of a "rebound hypercoagulable state" in patients after dicontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: 2/3 of initial dose the 1st week, 1/3 the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p < 0.001); at the 2nd week F1+2 levels remained higher (p < 0.05) though INR values were not different from those of group B. After baseline, higher than normal F1+2 levels were recorded in 32/66 (48%) controls in group A vs 15/60 (25%) in group B (p < 0.01); at the 2nd week, 10/17 (59%) patients in group A vs 1/15 (7%) in group B still had higher than normal F1+2 levels (p < 0.01). The values of areas under curve (AUC) and maximum concentrations of all variables were not statistically different in the two groups; however, very high levels were observed in a few cases of group A. Thrombotic events (one DVT recurrence and one thrombophlebitis in a varicose vein) occurred in 2 pts of group A, both with high F1+2 and TAT AUC values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Blood Coagulation Tests; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Prospective Studies; Prothrombin; Recurrence; Substance Withdrawal Syndrome; Thromboembolism; Thrombophlebitis; Warfarin

Recent studies have evidenced an association between the time of heparin discontinuance and coronary artery reocclusion. Some investigators have concluded that inadequate heparinization was responsible, and further heparin infusion or an increase in dose would have been indicated. However, several investigators (Rao: Thrombosis Research 24:181-186, 1981; Marciniak and Gockerman: Lancet September 17:581-584, 1977; Fisken et al.: Lancet December 10: 1231, 1977; Conard et al.: Thrombosis Research 22:507-511, 1981; Kakkar et al.: Lancet January 12:103-104; Green: Lancet February 16:374, 375; Harborne and Nicolaides: Thrombosis Research 43:657-662, 1986; Bonen et al.: Thrombosis Research 27:123-124, 1982; Blomback et al.: Acta Physiologica Scandinavica 58:306-318, 1963; Holm et al.: Scandinavian Journal of Haematology 35:564-569, 1985; Andersson et al.: Thrombosis Research 34:333-340, 1984) have demonstrated that antithrombin III levels are reduced in patients on intravenous heparin. Both reduced antithrombin III levels and reduced rate of antithrombin inhibition of thrombin at the time of heparin discontinuance may increase the risk of coronary rethrombosis. If this theory is correct, increasing heparin infusion may exacerbate this risk. We propose an investigation that will provide evidence for or against the decreased antithrombin III theory, and in doing so, test an experimental therapy designed to prevent coronary reocclusion upon heparin discontinuance. In a randomized, placebo-controlled double-blinded study, we will determine whether simultaneous administration of warfarin with heparin initiation provides more time to increase antithrombin III levels and prevent coronary reocclusion upon heparin discontinuance, compared to heparin without warfarin therapy.

Topics: Antithrombin III; Coronary Disease; Coronary Thrombosis; Double-Blind Method; Heparin; Humans; Randomized Controlled Trials as Topic; Recurrence; Substance Withdrawal Syndrome; Time Factors; Warfarin

We report a case of three severe embolic complications due to warfarin withdrawal. An 83-year-old man with hypertension, angina pectoris and atrial fibrillation underwent bladder biopsy under spinal anesthesia after 13 days of warfarin withdrawal. On the second postoperative day, the patient complained of chest pain and was diagnosed as acute myocardial infarction. Embolus was successfully removed by suctioning. Warfarin and heparin therapy was started after that. On the 6th postoperative day, the patient complained of abdominal pain and was diagnosed as superior mesenteric artery embolism. After suctioning of the thrombus and monteplase injection, symptoms disappeared. On the 9th postoperative day, paralysis on the right side of his body and aphasia appeared. Stroke was suspected. Coma advanced day by day and he died due to brain herniation on the 16th postoperative day. In this patient we should have assessed the risk of the thromboembolic complication and planned the appropriate anticoagulation with closer cooperation with his attending physicians.

Topics: Aged, 80 and over; Anticoagulants; Humans; Male; Mesenteric Artery, Superior; Myocardial Infarction; Stroke; Substance Withdrawal Syndrome; Thromboembolism; Warfarin

This paper describes the circumstances of a patient who had been receiving long-term warfarin treatment, but ceased it prior to surgical operation, sustained a transient ischemic heart attack post-operatively, which eventuated in delayed extubation and locked-in syndrome. For patients at low risk of perioperative bleeding, anticoagulation with oral vitamin K antagonist can probably be able to maintain the therapeutic range (INR ≤ 2.0) extreme. For patients with a high risk of bleeding, the international normalized ratio (INR) should be kept ≤ 1.5. Within this range, patients at low risk of thrombosis can discontinue warfarin treatment for 2-5 days pre-operatively; patients at high risk for thrombosis can stop warfarin but should probably be treated with intravenous or subcutaneous heparin when the INR is subtherapeutic.

Topics: Aged; Anticoagulants; Female; Humans; Ischemic Attack, Transient; Perioperative Period; Substance Withdrawal Syndrome; Warfarin

Microparticles (MPs) are blebs released from cellular surfaces during activation/apoptosis. They are procoagulant, pro-inflammatory and could contribute to pathogenesis of deep venous thrombosis (DVT). This study compared the number, cellular origin and procoagulant activity of MPs on DVT patients in different clinical situations: at diagnosis (n = 9, 5F/4M; mean age = 41.11), 1-3 years after warfarin withdrawal (n = 10, 7F/3M; mean age = 32.90), associated to antiphospholipid syndrome (APS; n = 11, 9F/2M; mean age = 33.82), or asymptomatic carriers of Factor V Leiden (FVL; n = 7, 7F/0M; mean age = 34.00) vs healthy controls (CTR). The quantification and characterization were performed by flow cytometry using CD235, CD61, CD45, CD31, CD14, CD45, anti-TF and Annexin V. The plasmatic procoagulant activity was investigated by prothrombin fragment 1 + 2 (F1 + 2) determination. The MPs procoagulant activity was analyzed by D-dimer (DD2) and Thrombin Generation Test (TGT) on a healthy pool of plasmas adjusted or not by their number (10,000 MPs). The MPs percentages were not different between the groups, but absolute number was increased in patients 1-3 years after warfarin withdrawal vs CTR (P = 0.02). There was no difference of the MPs cellular origin comparing patients to controls. TGT using 10,000 MPs was lower on these patients (P = 0.01). APS patients showed a reduction of plasmatic procoagulant activity (P = 0.004), but they were under warfarin therapy. DD2 in the presence of MPs, independently of its number, was higher in patients with DVT at diagnosis (P < 0.0001). MPs of patients with spontaneous DVT at diagnosis can promote coagulation activation demonstrated by increased DD2. Even the increased MPs from patients 1-3 years after thrombotic episode generated lower amount of thrombin, they can have a protective effect by activation of Protein C anticoagulant pathway.

Topics: Adult; Antiphospholipid Syndrome; Blood Coagulation Tests; Case-Control Studies; Factor V; Female; Fibrin Fibrinogen Degradation Products; Flow Cytometry; Humans; Lipoproteins; Male; Particle Size; Substance Withdrawal Syndrome; Thrombin; Thrombosis; Venous Thrombosis; Warfarin

Patients with mechanical heart valves are treated with oral anticoagulant therapy in order to minimize the risk of thromboembolism. During invasive procedures it is recommended to temporarily discontinue the oral anticoagulant therapy and substitute with injections of low-molecular-weight heparin. We describe a case where a patient discontinued the oral anticoagulant therapy and had no substitution with low-molecular-weight heparin. The patient had an embolism to the coronary arteries causing progressive heart failure, and the patient was subsequently heart transplanted.

Topics: Adult; Anticoagulants; Aortic Valve Insufficiency; Coronary Thrombosis; Heart Transplantation; Heart Valve Prosthesis; Humans; Male; Substance Withdrawal Syndrome; Thromboembolism; Warfarin

Although hyperhomocysteinemia is an established risk factor for venous thromboembolism there is no consensus for routine determination of circulating homocysteine in the UK, either at the beginning or end of oral anticoagulation therapy. The purpose of this study was to evaluate the prevalence of hyperhomocysteinemia and its relationship to folate and vitamin B12 status in subjects with venous thromboembolism 4 weeks after discontinuation of warfarin therapy. In 78 consecutively recruited patients, plasma homocysteine was significantly higher (p < 0.001) and red cell folate significantly lower (p = 0.03) than in controls. Plasma vitamin B12 was similar in both groups. Strikingly, 38.5% of patients had hyperhomocysteinemia (> 15 micromol/l). Retrospective analysis revealed a significant positive association between plasma total homocysteine and duration of warfarin therapy (p < 0.001) but a negative, though non-significant (p = 0.06), trend with warfarin dose. The results do not suggest any direct interaction between warfarin and plasma homocysteine but raise the possibility of reduced intake of a common food source of folate and vitamin K. One possibility is the shortage of green-leafy vegetables since patients are often advised to limit their intake of this major source of vitamin K. On the basis of this study we suggest that homocysteine screening should be carried out at the time that patients begin warfarin therapy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Folic Acid; Genotype; Homocysteine; Humans; Hyperhomocysteinemia; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Retrospective Studies; Substance Withdrawal Syndrome; Thromboembolism; Vitamin B 12; Warfarin

We sought evidence for thromboembolic sequelae after the transient withdrawal of chronic anti-coagulation because of acute GI bleeding.. Our Gastrointestinal Bleeding Team endoscopic database was reviewed over a 5-yr period to identify patients who underwent a transient withdrawal from chronic anticoagulation as a result of acute GI bleeding. Long term follow-up records were available for all study patients and were carefully scrutinized for any symptomatic thromboembolic events.. Twenty-seven patients were included in the study, of which 17 (63%) were on chronic anticoagulation for prosthetic heart valves. Chronic anticoagulation was withheld for a median period of 3 days (range = 2-7 days) for patients with prosthetic heart valves and 7 days (range = 2-15 days) for patients on chronic anticoagulation for other indications. Over a median follow-up period of 8 months (range = 1-54 months), one patient developed documented lower extremity thromboembolism.. We conclude that symptomatic thromboembolism can occur after the transient withdrawal of chronic anticoagulation for acute GI bleeding but that it does not occur frequently.

Topics: Acute Disease; Aged; Aged, 80 and over; Anticoagulants; Chronic Disease; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Male; Middle Aged; Risk Factors; Substance Withdrawal Syndrome; Thromboembolism; Time Factors; Warfarin

Topics: Administration, Oral; Anticoagulants; Factor VIII; Humans; Substance Withdrawal Syndrome; Warfarin

A 61-year-old woman receiving warfarin for postoperative atrial fibrillation and carbamazepine for a peripheral neuropathy had extreme elevation of prothrombin time associated with clinically significant hemorrhage when the carbamazepine therapy was discontinued. The mechanism of this significant drug interaction involves the withdrawal of carbamazepine-induced enhancement of hepatic warfarin breakdown with resultant delay of warfarin excretion and excessive hypoprothrombinemia. The clinically significant hemorrhage associated with warfarin-carbamazepine interaction is an indication for caution when these two agents are prescribed concomitantly.

Topics: Carbamazepine; Drug Interactions; Ecchymosis; Female; Humans; Middle Aged; Prothrombin Time; Substance Withdrawal Syndrome; Warfarin

This study evaluated 44 separate medication withdrawal periods in 17 subjects who were attending a hospital anticoagulation clinic for management of anticoagulation medication. The data suggest that when anticoagulant withdrawal is needed for particular dental procedures, a 2-day hold is an effective period of medication withdrawal. No thromboembolic events were observed after any of the withdrawal periods. Further, no posttreatment hemorrhagic episodes were observed when the anticoagulant medication was reinstituted after dental treatment. Prothrombin time blood levels should be determined in the immediate pretreatment period, however, because the prothrombin time can fluctuate even in the best maintained patients.

Topics: Adult; Aged; Blood Coagulation Factors; Dental Care for Disabled; Female; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Thromboembolism; Time Factors; Warfarin

Sharp decreases in the prothrombin time after discontinuing heparin have been reported in patients undergoing oral anticoagulant therapy. Twenty-five patients receiving continuous intravenously administered heparin and orally or intravenously administered warfarin were studied. All patients had prothrombin times greater than 1.40 times control, and activated partial thromboplastin times 1.5 to three times control before discontinuing heparin therapy. Prothrombin times on the heparin infusion and four to six hours after it was discontinued were compared. The mean change in the prothrombin time was -1.60 s with a range of +0.8 to -5.5 s. Eight (32%) of 25 patients had a decrease of greater than 2 s. The decrease in prothrombin time correlated poorly with heparin dose or activated partial thromboplastin time in patients taking heparin. Since the change in prothrombin time is unpredictable, a repeated prothrombin time is recommended after stopping heparin therapy prior to discharging a patient.

Topics: Adult; Heparin; Humans; Partial Thromboplastin Time; Prothrombin Time; Recurrence; Risk; Substance Withdrawal Syndrome; Thrombosis; Warfarin

1 Free fractions of diazepam, propranolol and warfarin were determined in 15 male chronic alcoholics in alcohol withdrawal. 2 On admission the mean free fraction of diazepam was 25% above and propranolol 44% below the limits of normal range, while the mean warfarin free fraction was in high normal range. One week later mean free fraction of diazepam declined by 20% while propranolol and warfarin increased by 24% and 19% respectively (P less than 0.05). 3 Propranolol free fraction and alpha 1-AGP concentrations were highly correlated (linear r = -0.83, P less than 0.001). In contrast the sources of variation in diazepam and warfarin free fraction were more complex and less certain. 4 Statistically significant changes of drug free fractions in serum of chronic alcoholics were observed during alcohol withdrawal. The extent and direction of these changes differed for various classes of drugs and their potential causes appear to be quite different. 5 Clinically important changes in drug effect may be present acutely, within the dosing interval, as a result of altered drug binding. These are more likely when the clinical response is closely related to drug concentration and will occur within the dosing interval due to larger fluctuations in free drug concentration, even though the average free drug concentration will remain unchanged. 6 Total drug level changes will be observed during alcohol withdrawal even in absence of detectable changes of drug metabolism.

Topics: Adult; Chemical Fractionation; Diazepam; Ethanol; Fatty Acids; Humans; Male; Middle Aged; Orosomucoid; Propranolol; Protein Binding; Regression Analysis; Serum Albumin; Substance Withdrawal Syndrome; Warfarin

Topics: Aspirin; Humans; Ischemic Attack, Transient; Substance Withdrawal Syndrome; Warfarin

Topics: Aged; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Infarction; Male; Preoperative Care; Substance Withdrawal Syndrome; Thromboembolism; Warfarin