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PubMed1990

Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion.

The prevention of graft occlusion by aspirin (100 mg/day) or heparin followed by phenprocoumon was investigated in a randomized trial in 235 patients after aortocoronary bypass operation. Aspirin treatment started 24 hours before, and heparin 6 hours and phenprocoumon 2 days after surgery. The results of the vein graft angiography and the clinical outcome 3 months postoperatively did not differ: 22% of 218 vein graft distal anastomoses in the aspirin group and 20% of 272 in the anticoagulant group were occluded. At least 1 occluded distal anastomosis was present in 38% of 74 patients in the aspirin-treated group and in 39% of 86 in the anticoagulant group. Worst-case analysis of all randomized patients showed graft occlusions, cardiovascular complications or lost to follow-up in 42% of 122 aspirin-treated patients compared with 41% of 113 patients treated with anticoagulants. For grafts with endarterectomy the occlusion rate was lower in the aspirin (12% of 49) than in the anticoagulant (22% of 41) group (p less than or equal to 0.05). Increased perioperative blood loss in the aspirin group (1,211 +/- 814 ml in the first 48 hours vs 874 +/- 818 ml in the anticoagulant group [p less than or equal to 0.001]) without a higher reoperation rate indicates effective platelet inhibition with low-dose aspirin. Because occlusion rates were equal but high in these patients with advanced stage of coronary artery disease, a combination of low-dose aspirin and anticoagulation should be investigated to reduce graft occlusion rates further.

Aspirin↗
PubMed1994

In vitro model to test the thrombogenicity of coronary stents.

Thrombotic occlusion is a major complication limiting the application of stents in coronary arteries. In an in vitro model we investigated the thrombogenicity of different stent materials and several medical regimens to prevent thrombotic occlusion. Experiments were conducted in a closed system of silicon tubing with circulating citrated platelet rich plasma of healthy volunteers (n = 7) and of patients (n = 7 for each condition). Patients were either treated with phenprocoumon or with high or low dose heparin in combination with aspirin alone (100 mg) or aspirin (990 mg) plus dipyridamole (225 mg). After placement of tantalum wire stents into the system platelet aggregates were visible after 13.5 +/- 3.0 min, and occlusion occurred after 15.0 +/- 3.5 min. Similarly, with implanted stainless steel stents aggregation was seen after 13.0 +/- 3.5 min and thrombosis occurred after 14.5 +/- 3.5 min (p < 0.001 vs control without stent). Microscopic examination revealed combined platelet fibrin thrombi occluding the lumen. Platelet components predominately covered stent wires, particularly at crossing points. In all experiments high-dose heparin prevented platelet aggregate formation and stent occlusion independently of additional aspirin or aspirin plus dipyridamole; perfusion time > 60 min (p < 0.001 vs no heparin). Low-dose heparin could not prevent clotting. With aspirin alone aggregates were visible after 16.0 +/- 4.0 min and clotting occurred after 23.0 +/- 5.0 min. In combination with dipyridamole aggregates were visible after 15.5 +/- 5.0 min and clotting after 21.0 +/- 4.0 min (NS vs aspirin alone). Phenprocoumon prevented platelet aggregate formation and stent occlusion; perfusion time > 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Thermospray and particle beam liquid chromatographic-mass spectrometric analysis of coumarin anticoagulants.

Positive ion mass spectra were obtained from several coumarin oral anticoagulants (phenprocoumon, warfarin, acenocoumarol and dicoumarol) and derivatives by liquid chromatography-thermospray mass spectrometry (LC-TSP-MS) and liquid chromatography-electron impact mass spectrometry (LC-EI-MS) to assess the use of LC-MS methods for the determination of these compounds in biological materials. LC-TSP mass spectra showed a single [M + 1]+ ion with no fragmentation; LC-EI mass spectra showed fragment ions which were similar in mass and relative intensities to those obtained by conventional EI-MS. These data should serve as a basis for the development of LC-MS methods for the qualitative and quantitative analysis of coumarin anticoagulants in biological samples. LC-TSP-MS was applied to the determination of phenprocoumon in a plasma extract from an anticoagulated patient.

Anticoagulants↗
PubMed2005

Selective binding of coumarin enantiomers to human alpha1-acid glycoprotein genetic variants.

Coumarin-type anticoagulants, warfarin, phenprocoumon and acenocoumarol, were tested for their stereoselective binding to the human orosomucoid (ORM; AGP) genetic variants ORM 1 and ORM 2. Direct binding studies with racemic ligands were carried out by the ultrafiltration method; the concentrations of free enantiomers were determined by capillary electrophoresis. The binding of pure enantiomers was investigated with quinaldine red fluorescence displacement measurements. Our results demonstrated that all investigated compounds bind stronger to ORM 1 variant than to ORM 2. ORM 1 and human native AGP preferred the binding of (S)-enantiomers of warfarin and acenocoumarol, while no enantioselectivity was observed in phenprocoumon binding. Acenocoumarol possessed the highest enantioselectivity in AGP binding due to the weak binding of its (R)-enantiomer. Furthermore, a new homology model of AGP was built and the models of ORM 1 and ORM 2 suggested that difference in binding to AGP genetic variants is caused by steric factors.

Acenocoumarol↗
PubMed2006

Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.

INTRODUCTION: Prothrombin complex concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. MATERIALS AND METHODS: In the acute model, rats received 2.5 mg.kg(-1) phenprocoumon, and reversal of anticoagulation by 4.88 mL.kg(-1) saline, 100 microg.kg(-1) rFVIIa (NovoSeven) or 50 U.kg(-1) PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), prothrombin time (PT) and tail tip bleeding. RESULTS: Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT (p<0.01), fully normalized blood loss (p<0.01) and shortened bleeding time (p=0.008), while rFVIIa was without significant effect on these endpoints. CONCLUSIONS: In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.

Animals↗
PubMed2001

Sustained benefit over four years from an initial combined antiplatelet regimen after coronary stent placement in the ISAR trial. Intracoronary Stenting and Antithrombotic Regimen.

Combined antiplatelet therapy after coronary stent placement is superior to anticoagulation with respect to early outcome. It is unclear if this benefit is maintained during long-term follow-up. This study reports on the 4-year clinical outcome of patients randomized in the Intracoronary Stenting and Antithrombotic Regimen trial. In the Intracoronary Stenting and Antithrombotic Regimen trial, 517 patients were randomized after successful placement of Palmaz-Schatz stents: 257 to aspirin and ticlopidine, and 260 to aspirin and phenprocoumon. Ticlopidine and phenprocoumon were given for 4 weeks. At 30 days, patients with ticlopidine had significantly fewer adverse cardiac events (1.6% vs 6.2%; p = 0.007), nonfatal myocardial infarction (0.8% vs 3.5%; p = 0.034), and target vessel revascularization procedures (1.2% vs 5.4%; p = 0.007). At 4 years, rates for any adverse cardiac events were 22.6% versus 28.5% (p = 0.078), for nonfatal myocardial infarction 0.9% versus 5.8% (p = 0.003), and for target vessel revascularization 18.3% versus 22.7% (p = 0.21). The absolute difference in event rates (4.6% after 30 days) was maintained after 4 years (5.9%). Event rates beyond day 30 were not significantly different (21.1% vs 22.5%; p = 0.78), nor were the rates beyond the first year, which were very low (5.2% vs 3.6%; p = 0.50). This study shows that the benefit of combined antiplatelet therapy evident after 30 days is maintained after 4 years. Independent of the initial regimen, rates of adverse cardiac events are low beyond the first year.

Angioplasty, Balloon↗
PubMed1999

[Recurrent thromboembolisms despite oral anticoagulation in a 76-year-old patient--Trousseau syndrome].

We report the case of a 76-year-old man with recurrent thromboses and low-grade chronic disseminated intravascular coagulation despite therapeutic oral anticoagulation with phenprocoumon. Work-up revealed a bronchial carcinoma (NSCCL) with hilar and mediastinal lymph node metastasis. The clinical condition was consistent with Trousseau's syndrome. Based on reports in the literature, the therapy was changed from phenprocoumon to intravenous unfractionated heparin (UFH), which was effective in controlling the thrombotic coagulopathy. For practical reasons, despite lack of established effectiveness in Trousseau's syndrome, therapy was switched to low-molecular-weight heparin (LMWH, nadroparine) in therapeutic dosage of 100 IU/kg body wt. subcutaneously 12 hourly. The patient remained free from further thromboembolic events during the last 6.5 months of his life. This case suggests that LMWH might be a convenient alternative to the established therapy with UFH in Trousseau's syndrome.

Aged↗
PubMed1977

Oral anticoagulation in the treatment of a spontaneously metastasising murine tumour (3LL).

The effects of long-term anticoagulation with phenprocoumon on growth of the Lewis lung carcinoma (3LL) were studied. Oral anticoagulation initiated at the day of i.m. transplantation of the 3LL into C57BL mice significantly inhibited primary tumour growth and reduced the number of spontaneous metastases to the lungs. Intermittent anticoagulation was without effect on metastasis formation but still retarded primary growth. There was no influence of anticoagulation on the mean survival time (MST) of tumour-bearing animals. Phenprocoumon appears to improve the results of cyclophosphamide of 5-fluorouracil treatment, but there were no statisticially significant differences. In contrast, bleomycin treatment in combination with adjuvant anticoagulation suggested a possible drug synergy. No significant influence of anticoagulation on the response of the primary tumour to irradiattion was found, though the MST of irradiated and anticoagulated animals was greater than in the solely irradiated controls. The present investigations suggest that coumarin derivatives have some direct tumour-inhibiting capacities, but exert their antimetastatic action via deceleration of the blood clotting mechanism.

4-Hydroxycoumarins↗
PubMed2000

Plasma levels of C-reactive protein after coronary stent implantation.

AIMS: This study was designed to investigate the role of inflammation on the occurrence of angiographic restenosis 6 months after coronary stent implantation and the influence of different kinds of antithrombotic and antiplatelet strategies on inflammation. METHODS AND RESULTS: In an open randomized trial, 40 consecutive patients were treated with aspirin (100 mg. day(-1)) and either ticlopidine (2x250 mg. day(-1)) (n=17), or phenprocoumon (INR 2.0-3.0) and dipyridamole (3x160 mg. day(-1)) (n=23) after successful elective coronary stent implantation. Plasma levels of C-reactive protein were determined one day before stent implantation and serially thereafter twice daily up to 120 h. C-reactive protein plasma levels increased significantly (P<0.0001) after stent implantation. Phenprocoumon and dipyridamole or ticlopidine had no effect on C-reactive protein plasma levels (P=0.51) or the occurrence of angiographic restenosis (P=0.48). C-reactive protein plasma levels were significantly higher in patients with lesion type C compared to types A or B (P=0.035), respectively. C-reactive protein plasma levels were significantly higher and mean shoulder levels occurred 48 h later in patients with restenosis compared to patients without restenosis after 6 months (P=0.038). CONCLUSIONS: Elevated C-reactive protein plasma levels still persisting 96 h after stent implantation might reflect a prolonged inflammatory reaction to coronary stent implantation which might causally be involved in pathophysiological mechanisms leading to restenosis.

Angioplasty, Balloon, Coronary↗
PubMed2005

Adverse reactions to anticoagulants and to antiplatelet drugs recorded by the German spontaneous reporting system.

According to their code of professional conduct, German physicians are obliged to report suspected cases of adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (AkdA). On the basis of an agreement between the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) a common pharmacovigilance database within the German spontaneous reporting system was created. A user-friendly application program developed in-house enables the user to conduct searches about reported ADRs covering a wide variety of questions within a short period of time. ADRs caused by anticoagulants and by antiplatelet drugs still belong to the most reported adverse events. The most frequently reported suspected drugs are heparins, followed by ticlopidine, phenprocoumon, acetylsalicylic acid, and clopidogrel. Bleeding complications are the most often described ADR symptoms of any anticoagulation therapy, especially of phenprocoumon and acetylsalicylic acid. Another serious ADR is heparin-induced thrombocytopenia or changes in blood counts (CBC) due to ticlopidine and clopidogrel. During the past few years a reduction in severe reactions, such as cerebral hemorrhage, especially with fatal outcome was detectable because of better clinical management of oral anticoagulant therapy and of adverse events concerning heparin.

Administration, Oral↗
PubMed1999

[Heparin-induced thrombocytopenia as the cause of persistent bleeding after pacemaker implantation].

HISTORY AND CLINICAL FINDINGS: A cardiac pacemaker was to be implanted in a 74-year-old man, known for many years to have cardiac arrhythmias. Lown type IVb, because of the onset of severe bradycardic episodes. After appropriate preoperative preparation the patient's anticoagulant medication was changed over 5 days from phenprocoumon (Marcumar) to heparin. The procedure and the immediate postoperative period were without complication. But two days later he had to be admitted to the intensive care unit because of cardiac failure and bleeding into the operation site. LABORATORY FINDINGS: One week after starting heparin the platelet count had fallen from 154 x 10(9)/l preoperatively to 92 x 10(9)/l. Haemoglobin concentration was 8.9 g/dl, haematocrit 26.7%. The Quick value of 51%, partial thromboplastin time of 54.1 s, thrombin time of 17.6 s and plasma antithrombin level of 61% provided no further diagnostic pointers. An HIPA test and a PF4/heparin immunoassay, performed as heparin-induced type II thrombocytopenia was suspected, subsequently confirmed the diagnosis. TREATMENT AND COURSE: After the cardiac status had stabilized the operative wound was explored, but no bleeding site found. Other causes having been excluded (liver failure, disseminated intravascular coagulopathy, septicemia, dilution thrombocytopenia), heparin was discontinued 2 days later. Recombinant hirudin infusion, 0.025 mg/kg per hour, was begun. After 4 days the platelet count had improved, the other clotting parameters were stable within the therapeutic anticoagulant range and the diffuse bleeding had stopped. CONCLUSION: When changing from phenprocoumon to heparin preoperatively one must be aware of the rare risk of acquired heparin-induced thrombocytopenia. Intravenous recombinant hirudin proved to be a safe treatment until oral anticoagulation had been established, quickly normalizing the platelet count.

Aged↗
PubMed1997

[Secondary resistance to coumarin derivatives in a patient with a hypercoagulability syndrome].

HISTORY AND CLINICAL FINDINGS: A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity. INVESTIGATIONS: The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed. TREATMENT AND COURSE: Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died. CONCLUSION: Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

Adult↗
PubMed1983

[Cutaneous coumarin necrosis of the breast].

In a 62-year-old female patient petechial haemorrhages of the right breast were observed after the 4th day of treatment with phenprocoumon. Within a few hours large cutaneous necroses developed. Histology showed lymphocytic vasculitis with vessel wall destruction and erythrocytic extravasates as well as necrobiotic changes of the middle and lower corium. High-dosage treatment with prednisolone was started after withdrawal of phenprocoumon. Progression of the necrosis to the left breast could be prevented. However, necrosis of the haemorrhagic area of the right breast could not be arrested. Aetiology and pathomechanisms of coumarin-induced necrosis have to date not been ascertained. Allergic precipitating mechanisms probably were of no importance in our patient.

4-Hydroxycoumarins↗
PubMed2002

Anticoagulant-related iliopsoas muscle bleeding leading to fatal exsanguination: report of two autopsy cases.

Two cases of massive iliopsoas muscle bleeding leading to fatal exsanguination are presented. Both patients (two women, 61 and 74 years old, respectively) received oral anticoagulation with phenprocoumon. The intramuscular bleeding occurred spontaneously in women of relatively good physical condition. Intriguingly, phenprocoumon concentrations were within the therapeutic range (1.55 microg/ml and 1.26 microg/ml, respectively) as detected by toxicologic analysis. These cases demonstrate that severe bleeding in the iliopsoas muscle has to be considered in all patients receiving anticoagulant medication, even in those who have coagulation parameters within the therapeutic range. Especially in older patients with a high degree of comorbidity or in patients receiving analgesic drugs, the potential of fatal outcome of iliopsoas muscle bleeding seems to be of clinicopathologic relevance.

Aged↗
PubMed2005

Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants.

OBJECTIVE: Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants. METHODS: We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon. RESULTS: To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers. CONCLUSION: The ApoE genotype affects the dose requirements of acenocoumarol.

Acenocoumarol↗
PubMed1993

Regulation of the L-arginine-dependent and tetrahydrobiopterin-dependent biosynthesis of nitric oxide in murine macrophages.

Nitric oxide is a recently discovered biomolecule with a broad range of actions. The present study investigated the regulation of nitric oxide synthase activity by dexamethasone and the cofactor tetrahydrobiopterin in murine macrophages. The influence of the tetrahydrobiopterin biosynthesis inhibitors 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, and phenprocoumon, an inhibitor of sepiapterin reductase, on the synthesis of nitric oxide was investigated. Dexamethasone decreased the nitric oxide production due to direct inhibition of the induction of nitric oxide synthase and of GTP cyclohydrolase. Substitution of tetrahydrobiopterin via sepiapterin could not overcome the dexamethasone-mediated inhibition. 2,4-Diamino-6-hydroxypyrimidine abolished nitric oxide synthesis and synergized with dexamethasone, completely eliminating nitric oxide production. Phenprocoumon inhibited production of nitric oxide via interference with later steps of tetrahydrobiopterin biosynthesis. An exogenous supply of tetrahydrobiopterin through sepiapterin led to a further increase of nitric oxide production, even in fully activated macrophages. The amount of nitric oxide produced by murine macrophages is therefore limited by the amount of tetrahydrobiopterin present in the cells. Inhibitors of tetrahydrobiopterin biosynthesis could provide a novel approach for therapy of pathological conditions mediated by nitric oxide, such as septic shock.

Alcohol Oxidoreductases↗
PubMed1996

Modified oral anticoagulant potency in an amitriptyline-treated patient?

We report the case of a 74-year-old female patient who received the antide-pressant amitriptyline because of a major depression. Incidence of acute lower extremity venous thrombosis required an additional oral anticoagulant therapy with phenprocoumon. During the simultaneous adjustment of both substances, the Quick value displayed great fluctuations which only disappeared after discontinuation of the amitriptyline medication. This finding is discussed as an aspect of a possible drug-drug interaction between amitriptyline and phenprocoumon.

Aged↗
PubMed2006

Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study.

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Abnormalities, Drug-Induced↗