Coumarin Therapy Research Articles

Influence of Storage Time and Temperature on International Normalized Ratio (INR) Levels and Plasma Activities of Vitamin K Dependent Clotting Factors

We designed this study to assess the effect of storage time and temperature on the international normalized ratio (INR) levels and plasma activities of vitamin K-dependent, clotting factors. A total of 100 subjects, comprising 34 healthy controls, 33 patients with liver cirrhosis and 33 patients on long-term coumarin therapy were enrolled. After centrifugation of collected specimens, aliquots of plasma were stored at room temperature (20 −22°C), refrigerated at 2-6°C and frozen at −40°C. Determinations of INR and plasma activities of clotting factors II, VII, IX and X were performed immediately after sampling (0 time) and after 6, 12 and 24 h. We found no significant change of either INR levels or plasma activity of any of the studied clotting factors up-to 24 h at different studied temperatures ( p >0.05). Our data demonstrates that clinical specimens for determination of INR levels and plasma activities of factors II, VII, IX and X are acceptable for testing for up-to 24 h whatever may be the temperature of storage.

Adherence to a guideline for coumarins in pregnancy

To asses the adherence in daily clinical practice to a guideline for anticoagulation during pregnancy. The Dutch anticoagulation clinics developed a pregnancy guideline for anticoagulant therapy in order to avoid foetal exposure to coumarins between the 6th and 9th week of gestation. Anticoagulation was studied in 282 prospectively-registered pregnant women, who were treated by 26 different anticoagulation clinics. The guideline was adhered to in 93% of treated women. Conforming to the guideline, the majority of patients commenced anticoagulation with heparin in the first trimester (n = 81) or started treatment from the second trimester onwards (n = 168). At the time of conception, 31 anticoagulated women were on coumarin treatment. In 13 of these patients (42%), coumarins were withdrawn before the 6th gestational week. In two pregnant women coumarin therapy started unintentionally during the first trimester of gestation. The present study shows that the guideline under study is useful in daily clinical practice. A careful instruction of women of child-bearing age who need medication remains important.

Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI)

Prothrombin Time (PT) clotting tests are widely used to monitor oral anticoagulation therapy and to screen for clotting factor deficiencies. The active ingredient in PT reagents (thromboplastins) is tissue factor, the integral membrane protein that triggers the clotting cascade through the extrinsic pathway. Several years ago, a system for calibrating and using thromboplastin reagents, known as the International Sensitivity Index (ISI) and the International Normalized Ratio (INR), was developed to standardize monitoring of oral anticoagulant therapy. The ISI/INR method, while revolutionizing the monitoring of coumarin therapy, has been criticized for a number of perceived shortcomings. We have undertaken a series of studies aimed at achieving a detailed understanding of which parameters influence the ISI values of thromboplastin reagents, with an ultimate goal of creating 'designer thromboplastins' whose sensitivities to the various clotting factors can be individually tailored. In this study, we demonstrate that ISI values of thromboplastin reagents based on relipidated, recombinant human tissue factor can be controlled by a combination of changes in the phospholipid content (in particular, the levels of phosphatidylserine and phosphatidylethanolamine) and ionic strength. The sensitivity of a given thromboplastin reagent can be increased (i.e. its ISI value decreased) by decreasing the content of phosphatidylserine and/or increasing the ionic strength. The molar ratio of phospholipid to tissue factor, on the other hand, had essentially no impact on ISI value.

An overview of the heparin-induced thrombocytopenia syndrome.

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)-endothelial-leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reflects the "hypercoagulability state" of HIT interacting with diseased or injured arteries, or whether arterial "white clots" reflect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing overlapping coumarin therapy.

Oral anticoagulation in surgical procedures: risks and recommendations.

Surgery in anticoagulated patients is problematic. Coumarin therapy is often discontinued or reversed to reduce the perioperative bleeding risk. Meanwhile, the thromboembolic risk is enhanced. We sought to determine the frequency of bleeding and thromboembolism in anticoagulated patients undergoing routine surgery and to investigate the role of patient characteristics and the level of anticoagulation. We studied patients who attended the Leiden Anticoagulation Clinic for treatment relating to mechanical heart valve prostheses, atrial fibrillation or myocardial infarction and underwent surgery at the Leiden University Medical Centre between 1994 and 1998. Outcome events were bleeding and thromboembolism in the perioperative period. Seventy-two complications occurred in 603 interventions, yielding an overall frequency of 11.9% [95% confidence interval (CI): 9.3-14.9], 9.5% (n = 57) for haemorrhage and 2.5% (n = 15) for thromboembolism. Younger patients tended to have more complications [odds ratio (OR) for >65 years of age: 0.5, 95% CI 0.3-1.0] as did patients with atrial fibrillation (OR for atrial fibrillation versus mechanical heart valve prostheses: 1.8, 95% CI 0.8-4.2). High postoperative levels of anticoagulation were associated with a slightly increased risk of complications [OR international normalized ratio (INR) > 3 vs. INR < 2: 1.3, 95% CI 0.6-3.0]. We conclude that routine surgery in anticoagulated patients yields a high perioperative bleeding and thromboembolic risk. While neither patient characteristics nor the level of anticoagulation appeared to play a major role in the occurrence of complications, the risk was clearly associated to the type of surgery, with the highest risk in thoracic surgery.

A multicentre assessment of the endogenous thrombin potential using a continuous monitoring amidolytic technique.

This study assessed the inter-laboratory imprecision associated with the measurement of the endogenous thrombin potential (ETP). The initial studies used techniques that had evolved in each of the participating laboratories. Samples from normal healthy subjects (n = 10), two patients receiving coumarin therapy [International Normalized Ratio approximately 2.0 and approximately 4.0] and a further two subjects receiving treatment with unfractionated heparin (anti-Xa 0.07 i.u./ml and 0.31 i.u./ml) were assayed relative to a lyophilized normal plasma that had arbitrarily been assigned a potency of 100%. Considerable variation in potency estimates was observed between the centres, although individual laboratories using fully automated techniques achieved acceptable levels of imprecision as assessed by the coefficient of variation (CV) (intra-assay CV < 9.5%, inter-assay CV < 12.5%). A second study to assess a similar range of samples, using a standardized assay protocol and incorporating appraisal of two chromogenic substrates, CBS.0068 or Pefachrom TG, demonstrated markedly improved agreement in potency estimates between centres and good correlation (r > 0.96) between the chromogenic substrates. Our data demonstrates that an automated ETP method can be standardized between laboratories and suitable levels of imprecision achieved, using different analysers (COBAS Mira at two centres and an ACL-300R) and two thrombin substrates. This indicates that more widespread use of ETP measurements in clinical laboratories is feasible.

Concomitant Coumarin–NSAID Therapy and Risk for Bleeding

OBJECTIVETo investigate the risk of bleeding complications during the combined use of coumarin derivatives and nonsteroidal antiinflammatory drugs (NSAIDs) compared with the use of coumarin derivatives alone.SUBJECTS AND METHODSIn this 1-year observational study, the local outpatient anticoagulation office detected all coumarin users with bleeding complications. These patients were sent questionnaires regarding the type and consequences of the bleeding as well as previous NSAID use. The local pharmacists detected patients with concomitant coumarin and NSAID prescriptions (but no bleeding). The relative risk for bleeding due to concomitant coumarin and NSAID use was estimated.RESULTSDuring 1 year, 738 hemorrhages were identified in 681 coumarin users. In 12.2% of these cases, an NSAID was involved. In contrast, in the whole population of coumarin users, 2.5% were prescribed an NSAID. Therefore, the relative risk of NSAID use with regard to bleeding complications was 5.8 (95% CI 2.3 to 13.6).CONCLUSIONSNSAID use during coumarin therapy considerably increases the bleeding risk compared with coumarin therapy alone. Although in daily practice these medications are frequently prescribed concomitantly, our results underscore the contraindication of concomitant use of NSAIDs and coumarin derivatives.

Thromboembolic disease and present oral contraception.

Since their introduction, oral contraceptives have been linked to an increased incidence of thromboembolic events. Epidemiologic studies have shown that women who use third-generation oral contraceptives containing desogestrel, gestodene, or norgestimate have a higher risk of venous thrombosis than women who use second-generation oral contraceptives containing levonorgestrel. Women who use oral contraceptives are significantly less sensitive to activated protein C. From January 1996 to December 2001, 17,577 patients were hospitalized in our department, 177 of them (1%) had confirmed diagnosis of venous thromboembolism and 15 of those (177) were women on oral contraceptive therapy. Oral contraceptives were taken from 28 days to 18 months. No other potential congenital or acquired causes of thrombosis were present before thromboembolic events occurred in these women. The discontinuation of the pill combined with usual heparin (in one patient thrombolysis) and coumarin therapy was effective in all cases. After the discontinuation of coumarin (3-6 months), every patient was screened for hereditary thrombophilia. All women on oral contraceptive therapy had confirmed hereditary risk factors for venous thrombosis. Acquired resistance to activated protein C may explain the epidemiologic observation of increased risk of venous thrombosis in oral contraceptive users, especially in women using third-generation oral contraceptives who had other risk factors (hereditary or acquired) for venous thrombosis.

Oral Anticoagulation Therapy During and After Coronary Angioplasty

To the Editor: We read with great interest the recent article by ten Berg et al1 on oral anticoagulant therapy during and after coronary angioplasty. In previous trials on late restenosis after percutaneous transluminal coronary angioplasty (PTCA), oral anticoagulants were not more effective than aspirin as adjunctive treatment after PTCA. However, in those trials, anticoagulant therapy was only started after PTCA. The study by ten Berg et al1 revealed that coumarin therapy started before PTCA decreased the incidence of late thrombotic events and improved 6-month angiographic outcome. Previously, we investigated changes in blood coagulation and platelet activation in the coronary sinus of patients who underwent PTCA.2 Blood samples were drawn from the coronary sinus immediately before and after, as well as 4 and 24 hours after PTCA. Despite adequate …

Reduction in the intensity of abortive migraine drug use during coumarin therapy.

To investigate the impact of coumarin therapy on migraine attack frequency. Sporadic case reports and clinical studies have described beneficial effects of coumarin therapy on migraine severity. A retrospective follow-up study based on a prescription database covering a population of 450 000 was conducted. All patients using an abortive migraine drug (ergotamine or sumatriptan) and subsequently treated with either coumarin (index group) or low-dose acetylsalicylic acid (control group) were analyzed. The impact of coumarin and low-dose acetylsalicylic acid on the frequency of migraine attacks was assessed by measuring the intensity of ergotamine and sumatriptan use, in defined daily doses per month per patient, before and during coumarin or acetylsalicylic acid treatment. In addition, a "therapeutic intensity reduction" was determined for each patient. The study population consisted of 92 patients; 35% had been prescribed coumarin and 65% had been prescribed low-dose acetylsalicylic acid after the initiation of ergotamine or sumatriptan. Two thirds of the study population was treated with ergotamine. Overall, ergotamine and sumatriptan use for the coumarin cohort decreased from 6.4 defined daily doses per month prior to coumarin treatment to 3.0 defined daily doses during coumarin treatment, compared with a reduction from 5.2 defined daily doses per month to 4.4 defined daily doses per month for the low-dose acetylsalicylic acid cohort (P>.05). The therapeutic intensity of ergotamine and sumatriptan use was significantly decreased by 40% for the coumarin cohort, compared with 4.7% for the low-dose acetylsalicylic acid cohort (P=.004). We observed that coumarin treatment was clearly associated with a reduction in the therapeutic intensity of abortive migraine drug use in comparison with low-dose aspirin treatment. This suggests that, overall, the coumarin cohort had experienced a substantial reduction in the frequency of migraine attacks during anticoagulation treatment. Our findings, as well as those of others, justify a controlled clinical trial to further establish the effects of coumarin therapy on migraine severity and its possible role in the prophylactic management of patients suffering from migraine.

The management of coumarin-induced over-anticoagulation Annotation.

The management of coumarin-induced over-anticoagulation Annotation.

Prospective Study on the Usefulness of Lung Scan in Patients with Deep Vein Thrombosis of the Lower Limbs

Asymptomatic pulmonary embolism (PE) is a common finding in patients with deep venous thrombosis (DVT) of the lower limbs, but the usefulness of seeking for silent PE in patients with acute DVT has not been evaluated. This was a prospective study involving consecutive patients with acute symptomatic proximal DVT (confirmed by objective methods) and no clinical suspicion of PE. All patients underwent chest X-ray, ventilation-perfusion lung scan and arterial blood gases on admission, and received anticoagulant therapy. Those with scintigraphic evidence of PE underwent repeated lung scan and blood gases 7 days later. The aim of the study was to assess how many patients with silent PE develop symptoms while on heparin therapy, and in how many of them such symptoms are due to recurrent PE. 946 consecutive patients with acute, proximal DVT had no contraindications to full-dose anticoagulant therapy. Baseline lung scan revealed high-probability defects (silent PE) in 200 (21%). Seven of these 200 patients had symptomatic recurrences during the 7-day study period, and an inferior vena cava filter was inserted. Besides, 6 patients developed PE symptoms, but no new perfusion defects were found on repeated scan. They switched to coumarin therapy, and they did not develop any further complications. Lung scan in patients with symptomatic DVT and no clinical suspicion of PE may be useful, since some patients with silent PE may develop symptoms while on heparin therapy. Without a baseline scintigraphy all these patients would have been considered to have recurrent PE, and vena cava interruption could have been performed.

Growth until puberty after in utero exposure to coumarins

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.

Growth until puberty after in utero exposure to coumarins

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.

Venographic comparison of subcutaneous low–molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis

Purpose: The primary objective of this study was to evaluate with venography the rate of thrombus regression after a fixed dose of low–molecular weight heparin (LMWH) per day for 3 months compared with oral anticoagulant therapy for deep venous thrombosis (DVT). Secondary endpoints were the comparisons of the efficacy and safety of both treatments. Methods: This study was designed as an open randomized clinical study in a university hospital setting. Of the 165 patients finally enrolled in the study, 85 were assigned LMWH therapy and 80 were assigned oral anticoagulant therapy. In the group randomized to oral anticoagulant therapy, the patients first underwent treatment in the hospital with standard unfractionated heparin and then coumarin for 3 months. Doses were adjusted with laboratory monitoring to maintain the international normalized ratio between 2.0 and 3.0. Patients in the LMWH group were administered subcutaneous injections of fixed doses of 40 mg enoxaparin (4000 anti-Xa units) every 12 hours for 7 days, and after discharge from the hospital, they were administered 40 mg enoxaparin once daily at fixed doses for 3 months without a laboratory control assay. A quantitative venographic score (Marder score) was used to assess the extent of the venous thrombosis, with 0 points indicating no DVT and 40 points indicating total occlusion of all deep veins. The rate of thrombus reduction was defined as the difference in quantitative venographic scores after termination of LMWH or coumarin therapy as compared with the scores obtained on the initial venographic results. The efficacy was defined as the ability to prevent symptomatic extension or recurrence of venous thromboembolism (documented with venograms or serial lung scans). The safety was defined as the occurrence of hemorrhages. Results: After 3 months of treatment, the mean Marder score was significantly decreased in both groups in comparison with the baseline score, although the effect of therapy was significantly better after LMWH therapy (49.4% reduction) than after coumarin therapy (24.5% reduction; P < .001). LMWH therapy and male gender were independently associated with an enhanced resolution of the thrombus. A lower frequency of symptomatic recurrent venous thromboembolism was also shown in patients who underwent treatment with LMWH therapy (9.5%) than with oral anticoagulant therapy (23.7%; P < .05), although this difference was entirely a result of recurrence of DVT. Bleeding complications were significantly fewer in the LMWH group than in the coumarin group (1.1% vs 10%; P < .05). This difference was caused by minor hemorrhages. Coumarin therapy and cancer were independently associated with an enhanced risk of complications. Subcutaneous heparin therapy was well tolerated by all patients. Conclusion: The patients who were allocated to undergo enoxaparin therapy had a significantly greater improvement in their quantitative venographic score, a significantly lower recurrence rate of symptomatic venous thromboembolism, and a significantly lower incidence of bleeding than patients who underwent treatment with coumarin. LMWH can be used on an outpatient basis as a safer and more effective alternative to classical oral anticoagulant therapy for the secondary prophylaxis of selected patients with DVT. (J Vasc Surg 1999;30:283-92.)

Secondary Prevention of Venous Thromboembolism: A Role for Low-Molecular-Weight Heparin

Background: After a short initial course of heparin therapy, patients with venous thrombo-embolism (VTE) require continuing anticoagulant therapy for several months after hospital discharge. At present, two small-scale studies have compared the efficacy and safety of low-molecular-weight heparin (LMWH) with warfarin in the secondary prevention of VTE. Patients and Methods: We studied 654 consecutive patients, 202 with pulmonary embolism (PE) and 452 patients with deep vein thrombosis (DVT) of the lower limbs. 220/654 patients (34%) were considered to have some contraindications to coumarin, and were discharged on LMWH (dalteparin, Fragmin^®, 10,000 IU s.c. once daily). The remaining 434/654 patients were asked to choose between either coumarin or LMWH: 190 patients preferred LMWH and 244 coumarin. Patients were followed up for a 3-month (DVT patients) or 6-month (PE patients) period. Results: 14/654 patients (2%) developed recurrent VTE while on anticoagulant therapy. One in every three recurrent episodes was PE (which was fatal in 2/5 patients), and half of the recurrent DVT were located in the contralateral leg. We failed to find any differences between patients receiving LMWH and those on coumarin therapy, but recurrences were more common in patients with cancer (hazard ratio: 17.15; 95% CI: 4.0–73.5; p < 0.001). 21 patients (3.3%) bled (major bleeding 5 patients; minor bleeding 16). Bleeding was more common in patients on coumarin therapy (hazard ratio: 3.14; 95% CI: 1.20–8.22; p = 0.02). Conclusions: Long-term LMWH therapy proved to be both effective and safe in the long-term treatment of VTE. Thus, we suggest long-term LMWH therapy should be considered for patients with contraindications to coumarin, or those with difficulties in coming to laboratory control.

Venöse Thrombosen - eine diagnostische und therapeutische Herausforderung

Venous thrombosis and embolism has been the target of intensive investigation in recent years. The growing importance of mortality and morbidity due to venous thromboembolism led to new diagnostic and therapeutic tools. The clinical diagnosis may be misleading and both false-negative and false-positive diagnoses are common, when only clinical signs and symptoms are considered. A major problem in the care of the patient is to establish the correct diagnosis. Studies show, that only Venography or Duplexsonography can clearify diagnosis. Risk factors for venous thromboembolism, propability calculations and consensus recommendations for diagnosis and therapy are presented. Diagnosis. Diagnosis of deep vein thrombosis must be established by Duplexultrasound and/or venography. Special situations may need further investigation by CT-scan or NMR-tomography. No single clinical sign or combination of signs give enough sensitivity and specificity. In patients with thromboembolism without clear etiology, hypercoagulability, neoplasms, compression syndroms, vascultides and other conditions have to be excluded. Heparins are the standard-therapy. Low-molecular weight heparins may have some benefits over standard heparins in terms of side effects and handling. Coumarin therapy can be started immediately, if no invasive procedures are necessary and have to be continued for 4-12 months, in recurred events and/or hypercoagulability even life-long. Thrombolysis is restricted to very few patients (patients under the age of 50 with large thrombosis not older than 3-7 days and no contraindications). Surgical thrombectomy is even more restricted. Compression therapy should be obligatory in all patients with thromboembolism. Thromboembolism is mainly a diagnostic challenge. The immediate start of the appropriate treatment may reduce embolism and thrombus formation, induce recanalisation and prevent post-thrombotic syndrom.

Isolated Iliac Vein Thrombosis During Oral Contraceptive Therapy in Three "Normal" Women

Isolated iliac vein thrombosis appears to be a rare clinical entity. It is usually due to extrinsic compression on the iliac vein with consequent stasis. Diagnosis may be difficult since compression ultrasonography is usually negative. Only phlebography is surely diagnostic. This procedure should be carried out whenever there is a discrepancy between the clinical evaluation and a negative sonography. We report three women on oral contraceptive therapy in whom a diagnosis of isolated iliac vein thrombosis was suspected clinically and confirmed phlebographically. No other congenital or acquired potential cause of thrombosis was present in the propositae but for the oral contraceptives. Oral contraceptives had been taken for 12, 3, and 2 months respectively for three patients before thrombosis occurred. Two of the propositae were 25 years old and the third was 54. The latter patient had been given oral contraceptives to "prevent osteoporosis" after menopause. The discontinuation of the pill together with usual heparin and coumarin therapy were effective in every instance. A specific pathogenic role of the oral contraceptives may be surmised. In fact, no isolated iliac vein thrombosis was found in a control group of 20 women of fertile age we showed to have idiopathic deep vein thrombosis of the legs. This article emphasizes once again the importance of a careful clinical evaluation in the suspicion of deep vein thrombosis. Key Words: Oral contraceptive therapy-Deep vein thrombosis-Iliac vein thrombosis.

Surgery in patients treated with anticoagulation during emergency and elective interventions

Patients under oral anticoagulation with coumarin derivatives have a variable perioperative thromboembolic risk which necessitates continuation of their thromboembolic prophylaxis during elective and emergency surgery. Because of their better handling unfractionated heparin and low-molecular-weight heparins are used most often for this purpose. The overlapping effect of coumarin and heparin therapy requires a close daily monitoring of the clotting inhibition (partial thromboplastin time, thromboplastin time, thrombin time). In elective surgery coumarin therapy is interrupted 2-3 days preoperatively; in emergency cases vitamin K or fresh frozen plasma have to be substituted. Patients under heparin therapy or prophylaxis are easier to handle, because the effect of heparin disappears in a few hours after stopping the treatment. In the immediate postoperative phase the heparin application is interrupted for 6 h because of increased bleeding risk. It is important to take into account additional risk factors like the underlying disease, disturbances of platelet function, liver diseases and renal insufficiency.

Inhibition rather than Enhancement of Hemostatic System Activation during Initiation of Oral Anticoagulant Treatment

Coumarin-induced skin necrosis is believed to be due to a transient hypercoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X during initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a technique that investigates coagulation activation in the microcirculation. We determined in 10 healthy volunteers the concentrations of prothrombin fragment F1 + 2 (f1.2) and thrombin-antithrombin complex (TAT) in blood emerging from an injury of the microvasculature (bleeding time incision) before and after initiation of both high-intensity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F VIIa) and the activities of F II, F VII, F X and protein C were measured in venous blood. A rapid decline of F VII and protein C was observed in venous blood with activities at 24 h of 7 +/- 1% and 43 +/- 2%, respectively, during the high-intensity regimen. A 20 to 30% reduction of f1.2 and TAT was seen in venous blood at 72 h with no major difference between the high- and the low-intensity regimen. F VIIa levels were substantially affected by anticoagulation with a > 90% reduction at 48 h during the high-intensity regimen. Following high-intensity coumarin, a > 50% decrease in the f1.2 and TAT levels was found in shed blood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT levels was seen neither in shed blood nor in venous blood. Our data do not support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-induced skin nekrosis.