[Anticoagulants (heparin, antivitamins K, principles and rules of use)].
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Biomedical subjects
Publications and source records attributed to M H Horellou.
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High-dose intravenous immunoglobulins (ivIG) were used in a 57-year-old patient with acquired von Willebrand disease in order to correct a hemostatic defect before pneumonectomy for lung carcinoma. IvIG induced a rapid and complete correction of factor VIII (F VIII) and von Willebrand factor (vWF) and allowed surgery without additional factor coverage. F VIII and vWF returned to baseline values within 10 days after ivIG.
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Primary lymphoma of the spleen is characterized by predominant splenomegaly. Lymphoplasmacytic malignant lymphoma of the spleen, of low malignancy in the Kiel classification, low and intermediate grade in the National Cancer Institute Working Formulation (NCIWF), is rare. It is often associated with a monoclonal immunoglobulin M (IgM). Four patients presenting with primary splenic lymphoma of plasmacytic type associated with a high level of monoclonal IgM and a lupus anticoagulant (LA) are described. This association has not previously been reported. In contrast with the usual heterogeneity of LA, this LA is relatively homogeneous with an important prolongation of the prothrombin time (greater than 18 sec for a control of 12), more prolonged partial thromboplastin time (PTT) of the mixture patient + control plasma than PTT of the patient plasma. Despite the important coagulation abnormalities, none of these four patients has presented any hemorrhagic or thrombotic complications, even during major surgery such as splenectomy. The lupus-like anticoagulant effect ran parallel with the monoclonal IgM. Survival, after splenectomy and chemotherapy, appears to be favourable: three patients are alive with survivals of greater than or equal to 7 years. The follow-up is as yet too short for the last patient.
A prospective open study was performed in a series of 547 patients undergoing gynecologic surgery. A dose of 20 mg of enoxaparin was administered to all patients 2 hours before surgery. Then patients at high risk of thrombosis (mostly oncologic surgery) received 40 mg of enoxaparin daily whereas those at moderate risk received 20 mg of enoxaparin daily. The principal aim of this prospective open study was to monitor amidolytic anti Xa activity and to study the inhibition of intrinsic prothrombinase using prothrombin consumption measurement as a simple and global test. A second aim was to investigate efficacy and tolerance of these regimens. Treatment tolerance was satisfactory with both regimens since the total incidence of bleeding was 1.8%. A single patient developed a clinically significant thrombosis during hospital stay. The results confirm and extend previous reports regarding a dose effect relationship between the dose of Enoxaparin and plasma Anti Xa activity 3 hours after s.c. injection. A significant relationship was found between Anti Xa activity and patients body weight. Interestingly a dose dependent inhibition of intrinsic prothrombinase was observed when using a one stage prothrombin consumption assay in whole blood. This test in whole blood can be considered as closer to physiological conditions than assays performed in citrated platelet rich or platelet poor plasma samples. The mechanism of intrinsic prothrombinase inhibition during prophylactic treatment with enoxaparin requires further investigation.
Standard nonfractioned heparin has been used for fifty years in the treatment of thromboembolic accidents, and for fifteen years, since Kakkar's works, in the prevention of thromboembolic complications in a surgical and medical context [5]. The antithrombotic efficacy of nonfractioned heparin (NFH) is accompanied by hemorrhagic complications occurring in about 10% of the patients receiving a "curative" treatment at hypocoagulating doses and in about 5% of the patients receiving the low-dose "preventive" treatment. The interest raised by low molecular weight heparins (LMWH), prepared as early as 1970, was based on a concept that is currently called into question: their anti-Xa activity, accounting for the antithrombotic activity, is high, while the anti-IIa (antithrombin) activity, producing the hemorrhagic risks, is lower. The pharmacokinetic properties, including longer-lasting action and better bioavailability with subcutaneous delivery relative to standard heparin, have greatly facilitated their use in the clinical field by allowing the reduction of the daily number of injections. Extensive clinical trials have confirmed that the antithrombotic efficacy of the LMWH is at least equal, if not superior, to that of nonfractioned heparin, though without reducing the frequency of hemorrhagic complications in the prevention of postoperative phlebitis. A limited number of randomized clinical trials suggests that the LMWH might also be as effective as NFH, as expected at doses about 3 times as high as those used for prophylaxis.
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The prothrombin time test (PT) is the most common method used for monitoring oral anticoagulant therapy. As a consequence of the variability in responsiveness of different thromboplastins, PT results obtained from patients on oral anticoagulant therapy may not be interchangeable between laboratories and as consequence could produce potential problems for anticoagulant control. The conversion of PT in INR (International Normalized Ratio) has been introduced recently to standardise the PT used for anticoagulant control. 127 determinations of prothrombin time and INR with 2 different thromboplastin reagents (Thromboplastin C Dade and Owren reagent) have been performed in 73 patients. This study confirm the usefulness of the INR (INR discrepancy in 10% of the cases) despite the imperfections concerning the choice of the control plasma and the need of a precise measurement of the ISI, International Sensitivity index. In parallel, changes in therapeutic ranges for anticoagulant therapy occurred, based on results of the international literature: less intense anticoagulant treatment (INR 2-3) is effective against recurrent venous thromboembolism with reduced bleeding. Different therapeutic ranges must be recommended for oral anticoagulant therapy according to the indication of the treatment.
We report the case of a 57-year old woman whose severe protein C deficiency was revealed soon after oral anticoagulants were introduced into her treatment. Two previous episodes of deep leg vein thrombosis followed by a third episode with suspicion of embolus migration had led to treatment with heparin later replaced by oral anticoagulants. On the 4th day of anticoagulant therapy, she developed skin necrosis of the left calf. A protein C assay showed severe deficiency (19% level as compared with the 70-120% normal levels). The main causes of acquired protein C deficiency were excluded. The first results of a family study demonstrated moderate protein C deficiency in a 30-year old, asymptomatic daughter.
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A 45 years old woman with AL amyloidosis presented with a hypofibrinogenemia (fibrinogen 100 mg/dl) without severe bleeding. There was laboratory evidence of fibrinolysis with shortened euglobulin lysis time, decreased alpha-2 plasmin inhibitor and decreased plasminogen. The mechanism of this primary fibrinolysis remains unclear, since there is no enhancement of the tissue-type plasminogen activator. Analysis of the 8 cases related in the literature of excessive fibrinolysis associated with amyloidosis demonstrated improvement of bleeding manifestations and abnormal fibrinolysis following the administration of antifibrinolytic agents.
The aim of this retrospective study was to evaluate the efficacy and tolerance of a moderate dose of urokinase (UK : 2000 IU/kg/h) for at least 24 h in a series of 23 patients with massive pulmonary emboli (PE) (mean pulmonary vascular obstruction = 70 +/- 7%). All patients received heparin in conjunction with UK. A control pulmonary angiography, performed at the end of UK therapy, revealed an important decrease in pulmonary obstruction (-50%). One patient died before the end of UK therapy from shock due to PE (early mortality = 4.3%). Severe hemorrhagic complications occurred in 3 patients (13%) and dictated the stoppage of UK administration, but bleeding was never the cause of death or sequelae. Thus, moderate doses of UK associated with heparin appear to effectively induce clot lysis in patients with massive pulmonary emboli. The incidence of hemorrhagic complications should be decreased by strictly respecting all contraindications to the use of thrombolytic agents and by avoiding excessive heparinization.
This is a report of a 62-year-old male patient who had a bleeding disorder due to the presence of a factor VII (proconvertin) inhibitor. After treatment with a high-dose intravenous (IV) immunoglobulin failed and a life-threatening intracranial hemorrhage occurred, plasma exchanges were performed and immunosuppressive therapy was given. The factor VII inhibitor promptly disappeared, and the patient's parameters of hemostasis became normal. Even though a relapse occurred some months later, the patient responded to immunosuppressive therapy. No underlying disorder was evidenced after 17 months of follow-up.
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Thrombolytic, fibrinolytic, and fibrinogenolytic properties of tissue plasminogen activator (t-PA) from melanoma cells (mt-PA), recombinant t-PA (rt-PA), streptokinase (SK), single-chain urokinase plasminogen activator (scu-PA), and high and low molecular weight urokinase (HMW UK, LMW UK) were compared in vitro by means of systems using human plasma. Thrombolytic activities were tested on standard or labeled hanging clots. When compared on the basis of urokinase international units, t-PA appeared to be slightly more active than scu-PA and streptokinase, and about 10-fold more active than both preparations of UK when they were diluted in plasma. Fibrinolytic activity was evaluated by measuring the lysis time of recalcified plasma containing variable amounts of thrombolytic agents. t-PA was shown to be twice as active as HMW UK, which was itself more active than LMW UK. When scu-PA and both types of UK were compared on bovine fibrin plates, they showed similar fibrinolytic activity, but the t-PA calibration curve was not parallel to those obtained with UK and scu-PA. Relative thrombolytic and fibrinogenolytic properties were studied for each thrombolytic agent. For similar thrombolytic activities, fibrinogenolysis provoked by scu-PA was less marked than with t-PA and with both UK, while SK showed the highest activity. Our results demonstrate that the thrombolytic/fibrinogenolytic ratio is much more favorable to t-PA and scu-PA than to both forms of UK. Another observation clearly shows that fibrinogenolysis can be induced in vitro in human plasma by high doses of t-PA. This consequence may be important since the therapeutic use of t-PA can be associated with high concentrations of t-PA, and thus t-PA infusion could lead in vivo to severe fibrinogen breakdown. In addition, the methodology described could be useful in standardizing comparison between different species of thrombolytic agents.
The presence of hereditary protein C deficiency has been shown to predispose patients to the development of venous thrombosis. We used radioimmunoassays for the protein C activation peptide (PCP) and the prothrombin fragment F1 + 2 to quantitate the extent of in vivo activation of protein C by thrombin-thrombomodulin and prothrombin by factor Xa, respectively, in the blood of individuals with this clinical disorder. A total of 46 protein C deficient subjects from 18 kindreds were studied. In 23 nonanticoagulated patients with an isolated deficiency of protein C, the mean level of PCP was substantially reduced while the mean concentration of F1 + 2 was significantly elevated as compared with normal controls (1.10 pmol/L v 1.78 pmol/L, P less than .0005 and 2.54 nmol/L v 1.51 nmol/L, P less than .0005, respectively). The metabolic behavior of 131I-F1 + 2 was found to be similar in protein C deficient patients and normal individuals. However, we were unable to establish a significant correlation between decreased PCP levels and increased F1 + 2 measurements in these 23 patients. This study demonstrates that heterozygous protein C deficient individuals with equivalent plasma levels of the zymogen may have markedly different biochemical profiles when assay techniques are used that quantitate the in vivo activity of the coagulation system. Six individuals from three pedigrees were identified as having combined deficiencies of protein C and either antithrombin III or protein S; the genetic basis for the combined deficiency state was determined in two of the kindreds. Finally we observed that hemostatic system activity as measured by the PCP and F1 + 2 assays is markedly suppressed in protein C deficient patients who are chronically anticoagulated with coumarin derivatives.