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Direct oral anticoagulants (DOAC) are indicated for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism. As any anticoagulant, they are associated with a bleeding risk. Management of DOAC-induced bleeding is challenging. Idarucizumab, antidote for dabigatran, is currently available and is part of the therapeutic strategy, whereas antidotes for anti-Xa agents are under development. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. We propose an update on DOAC-associated bleeding management, integrating the availability of idarucizumab and the critical place of DOAC concentration measurements.

Rivaroxaban is a direct oral anticoagulant targeting factor Xa. Efficacy and safety of rivaroxaban were evaluated through the phase 3 EINSTEIN program, consisting in three clinical trials regarding the treatment of deep vein thrombosis (EINSTEIN DVT), pulmonary embolism (EINSTEIN PE), and in secondary prevention after a first episode of venous thromboembolic disease (EISNTEIN EXT). Rivaroxaban was recently approved both by the European and the French Health agencies for the treatment of DVT and prevention of deep vein thrombosis recurrence. This report addresses the use of rivaroxaban in clinical practice in such indications.

State of the art of antithrombotics and their use recommendations during pregnancy.A reviewAspirin and heparins remain the safest molecules during pregnancy, and oral anticoagulants are still used for mechanical valves. Heparinoids are the methods of choice in case of heparin-induced thrombopenia but other molecules could find their place: fondaparinux at first and possibly the direct thrombin inhibitors. Thrombolysis may be used in case of life-threatening incident. At present, the new oral forms can not be used during pregnancyDuring pregnancy, all antithrombotics, except the oral forms, can be used, but the low molecular weight heparins replacing the unfractionated ones in the treatment and prevention of venous thromboembolism remain the treatment of choice.

Numerous newer anticoagulants are under advanced clinical development for the treatment of venous thromboembolism. These new drugs specifically inhibit activated factors II or X, with predictable effects and no need for dose modification and laboratory monitoring. The main direct activated factor X (FXa) inhibitors are rivaroxaban, apixaban and edoxaban. They are taken orally once or twice per day. Dabigatran is the main inhibitor of activated factor II (IIa) and is administered orally once daily. Dabigatran and rivaroxaban are already licensed for the prevention of thromboembolic events following major orthopedic surgery such as total hip and knee replacement. They will probably soon be authorized for the treatment of venous thromboembolism, if they both confirm their efficacy and safety, and can demonstrate their cost-effectiveness. However, only rivaroxaban has been tested as a stand-alone treatment, whereas dabigatran was compared to vitamin K antagonism after a standard treatment regimen based on heparin or its derivates.

A 36-year-old patient was admitted to our hospital with ischaemic stroke. The initial assessment allowed the diagnosis of an antiphospholipid syndrome (APS) and an intracardiac mass suggestive of a heart tumour. The patient was treated with unfractionated heparin. Type II heparin-induced thrombopenia (HIT) was diagnosed on the 18th day of therapy. Given the risk of stroke recurrence it was decided to remove the cardiac tumour surgically. Cardiopulmonary bypass (CPB) was performed using danaparoid in a state of deep hypothermia, in accordance with the well-established protocol in use in our department. As the CPB and surgical procedure came to an end a massive thrombus began forming in the circuit, requiring immediate displacement of the CPB cannulae. The anti-Xa activity level obtained had been considered effective at an estimated 1.20 IU/ml, although, the level recommended by Magnani is between 1.50 and 2.0 IU/ml. There was no clinical consequence and postoperative recovery was uneventful. The discrepancy between the satisfactory level of anti-Xa activity and the thrombus formation in the CPB circuit raises the issue of the diversity of published anticoagulation protocols, the difficulty to extrapolate within a surgical team, the need for intensive laboratory monitoring within a narrow therapeutic range, as well as the patient profiles variability with concurrent disorders complicating their clinical management.

In the early eighties, following breakthroughs in oligosaccharide chemistry, we achieved the total chemical synthesis of pentasaccharides related to the antithrombin-binding domain in heparin. Selective inhibitors of coagulation factor Xa, thus obtained, represent a new class of efficient antithrombotic drugs. In a further step, we have designed and synthesised oligosaccharides (pentadeca--to eicosasaccharides), comprising an antithrombin binding domain prolonged by a thrombin binding domain. These compounds inhibit both factor Xa and thrombin, in the presence of antithrombin, while they are devoid of undesirable non-specific interactions, particularly with platelet factor 4 (PF4). The efficacy of these new synthetic antithrombotics, with a unique biological profile, will be evaluated in clinical trials.

Renal impairment, which is frequently observed in elderly patients, raises the question of low molecular weight heparins treatment dose adjustment in this population. Thus, we conducted a prospective study to determine whether tinzaparin, administered subcutaneously at treatment dose (175 anti-Xa IU/kg) once daily for 10 days, does accumulate in patients older than 70 years of age.Accumulation criteria were an increase of plasma anti-Xa and anti-IIa levels determined prior to the first injection and on days 2, 5, 7 and 10. The characteristics of the 30 consecutive included patients receiving tinzaparin at treatment dose (six men, 24 women) were: age 87.0 +/- 5.9 years (range: 71-96 years), body weight: 62.7 +/- 14.6 kg (range: 38-90 kg) and creatinine clearance 40.6 +/- 15.3 mL/min (range: 20-72 mL/min).None of the patients required a dose adjustment of tinzaparin over the 10-day treatment period. Anti-Xa and anti-IIa activity levels on day 2 were 0.66 +/- 0.20 IU/mL (range: 0.26-1.04 IU/mL) and 0.33 +/- 0.10 IU/mL (range: 0.18-0.55 IU/mL), respectively. These levels did not significantly change over the 10 days. These results favor the absence of the accumulation effect of tinzaparin. There was no correlation between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. Concerning the side-effects, only one minor hematoma at the injection site was reported.Tinzaparin may thus be administered in older patients with renal impairment, at a treatment dose (175 anti-Xa IU/kg/d) for a 10-day treatment period, without accumulation effect nor hemorrhagic side-effect in patients with creatinine clearance greater than 20 mL/min.

In 1990 conflicting views are still being held concerning oral contraception and risks associated with pregnancy in women with systemic lupus erythematosus. As regards oral contraceptives, all authors agree that oestrogen-progestin combination pills are harmful, but the best alternative hormonal contraception remains to be determined. Protein-based "micropills" seem to be harmless; cyproterone acetate appears to be without side-effects, and its usefulness in preventing recurrences is being evaluated. As regards pregnancy, it would be wise not to contemplate having a child until 6 months have elapsed since the onset of remission. Blood pressure, platelet count and serum creatinine and uric acid levels must be closely monitored. Two types of antibodies may be present in the mother and are known to be responsible for foetal complications. These are antibodies to phospholipids (antiprothrombinase, anticardiolipin, antibodies responsible for dissociated treponema serology), which expose to spontaneous abortion or intrauterine death, and the antibody to SS-A (or anti-Ro), which exposes to foetal cardiomyopathy and congenital atrioventricular block.Even in 1990 there are still conflicting views concerning oral contraception (OCs) and risks associated with pregnancy in women with systemic lupus erythematosus. With regard to OCs, all authors agree that estrogen-progestin combinations are harmful, but the best alternative hormonal contraception has yet to be found. Progestin-based micropills seem to be harmless; cyproterone acetate appears to have no side effects and its usefulness in preventing recurrences is being evaluated. With regard to pregnancy, it would be wise not to contemplate having a child until 6 months have passes since onset of remission. Blood pressure, platelet count, and serum creatinine and uric acid levels must be closely monitored. 2 types of antibodies may be present in the mother and may be responsible for fetal complications. These are antibodies to phospholipids (antiprothrombinase, anticardiolipin, antibodies responsible for dissociated treponema serology), which expose patients to spontaneous abortion or intrauterine death, and the antibody to SS-A (or anti-Ro), which exposes patients to fetal cardiomyopathy and congenital atrioventricular block. (author's modified)

The hemorrhagic risk of an association of fractioned heparin (Fraxiparine) injected intravenously at the dose of 7500 AXaICU or of unfractionned heparin (UFH) injected intravenously at the usual dose used for a priming dose for hemodialysis (3750 +/- 1280 IU + 1000 IU after 2 hours of dialysis) to the subcutaneous administration of a thrombo-embolism preventive dose of Fraxiparine (7500 AXaICU) was evaluated on the modifications of the following hemostasis parameters: thrombin time, Activated Partial Thrombin Time (APTT), prothrombin time, anti Xa activity in 13 uremic patients on hemodialysis. The association of intravenous and subcutaneous Fraxiparine prevents efficiently the clotting of the extracorporeal circulation without inducing a detectable antithrombinic activity. In contrast, the association of I.V. UFH to subcutaneous Fraxiparine induces a significant increase of the thrombin time and of the APTT. This latter is exclusively explained by the activity of UFH. It is concluded that subcutaneous Fraxiparine at the thromboembolism preventive dose can be associated as well to I.V. Fraxiparine as to UFH without increasing the antithrombinic activity of the plasma.

Synthetic chromogenic substrates were adapted to KEM-O-MAT 2HP for an automated monitoring of anticoagulant treatments, determination of factor X (S 2337) in oral anticoagulation, anti-Xa (Hepachrom) and anti-lla (S 2238) activities of heparin in prophylactic and curative heparin therapies. In all cases, these methods revealed high sensitivity, reproducibility, and a good correlation of their results with those of classical clotting assays. The present cost of synthetic substrates seriously limits the potential value of chromogenic assays for routine controls. However, the development of automated amidolytic techniques should provide an easier standardization in the laboratory control of anticoagulant treatments.

In a prospective study assessing haemostatic functions, the activated partial thromboplastin time was prolonged in 134 out of 10,229 patients studied, without an increase in the prothrombin or thrombin times; this abnormality persisted in only 37 of them on a new blood sample. A retrospective analysis was made of 265 patients who had such an isolated prolongation of the activated partial thromboplastin time on two successive blood samples: the causal abnormality remained unexplained in 135 patients; a well defined coagulation disorder without abnormal bleeding tendency was present in 110 patients (1 severe factor XII deficiency, 58 partial factor XI or XII deficiencies and 51 lupus anticoagulants); a bleeding disorder was diagnosed in 20 patients (8 haemophilias, 8 Von Willebrand's diseases, 4 factor VIII inhibitors). The well-iron efficacy of the activated partial thromboplastin time for detecting coagulation abnormalities is counter-balanced by some disadvantages such as the delay for biologic conclusions. In the preoperative assessment of haemostatic functions, rather than taking a routine approach, it would seem better to determine for each patient the need and the extent of biological testing according to the type of planned surgery, the clinical status of the patient and possible bleeding symptoms.

An anticoagulant with antithrombinase activity was looked for in 49 patients with systemic lupus erythematosus and found to be present in 14 of them. The latter were suffering from severe and progressive lupus, specially with arterial involvement. The presence of an isolated antithrombinase does not contraindicate a renal biopsy provided the platelet count and other coagulation factors are normal.

Using low molecular weight fractions of heparin (HBPM) can be at least potentially useful in pregnant women for certain indications. After animal studies had been carried out for toxic effects, one HBPM, CY216, which has been put on the market under the name of Fraxiparin, was studied to see whether it crosses the placenta in pregnant women by analysing fetal blood directly. Seven women who had fetal indications for terminating their pregnancies in the third trimester received a subcutaneous injection of 17,500 Choay units of Fraxiparin (0.7 ml). The haemostatic state was assessed in the mothers before the injection and three hours after it, and in the fetus approximately three hours after the injection into the mother. The fetal blood was taken in the uterus by direct aspiration using ultrasound guidance techniques. Anti Xa, anti IIa, and cephalin-kaolin time (TCK) were estimated. The anti Xa, anti IIa and the TCK were not changed in the 7 fetuses that were studied, 3 hours after the subcutaneous injection of a large dose of CY 216 although marked changes were noted in the mothers.

The systematic search for a deficiency in antithrombin III must be considered in case of: venous thrombosis in a young patient, recurrent venous thrombosis especially if these occurred under Heparin, venous mesenteric infarction since this type of thrombosis is rare and seems relatively frequent in case of congenital deficiency in antithrombin III, familial past history of venous thrombosis in a woman desiring to undergo estrogen-progesterone therapy. The most often used techniques are: study of antithrombin III activity by amidolytic method and titration by immunodiffusion. Anti-vitamin K treatment is the only effective therapy proposed to patients suffering from a hereditary deficiency in antithrombin III.

Fifteen patients (9 females and 6 males) with the "lupus type" circulating anticoagulant have been studied. The underlying disease was an auto-immune disorder in 11 cases and a malignant hemopathy in 4 cases. The manifestations frequently associated with the lupus inhibitor, such as thrombosis, thrombocytopenia and false-positive VDRL test were analysed. Hemorrhagic syndrome occurred only when thrombocytopenia or acquired abnormality of Willebrand's factor was present. Thrombotic events (8 cases) were frequent. Deep venous thrombosis was complicated with pulmonary embolism in 4 patients. Platelet abnormality, decreased fibrinolytic response or acquired Willebrand's syndrome were found in all patients with a thrombotic event. These different manifestations followed diverging courses in some patients with persistent thrombocytopenia although the anticoagulant had disappeared in 3 cases, negativation of the false-positive VDRL test while the anticoagulant remained unchanged in 1 case, occurrence of a thromboembolic episode although the anticoagulant had disappeared in 1 case.

Five tests were carried out on 15 lupus anticoagulant plasmas: activated partial thromboplastin time with a commercial reagent (APTT); kaolin partial thromboplastin time with a human brain extract (KPTT-H); tissue thromboplastin inhibition test (TTI); Russell's viper venom time without phospholipid (RVVT); assay of phospholipid-related procoagulant activity (PPA). One of our criteria for diagnosis of lupus anticoagulant was a prolonged APTT; hence this test was abnormal in all 15 plasmas. An abnormal TTI was observed for the 15 lupus anticoagulants while PTT-H was abnormal in only 13 cases, RVVT in 11 cases and PPA assay in 12 cases. In another study evaluating the specificity of TTI and PPA assay, the TTI appeared to be influenced by factor II, V, VII, and X deficiencies, but not by factor VIII: C, IX, XI, and XII deficiencies, or by anti-factor VIII: C anticoagulants. Furthermore, the TTI displayed a weak sensitivity to heparin. On the other hand, the PPA assay was influenced by anti-factor VIII: C anticoagulants of high potency and was found to be more sensitive to heparin than the TTI. Our overall results emphasize the value of TTI as a screening test for the lupus anticoagulant.