Skin necrosis due to fluindione treatment: a rare but serious complication.

In the setting of protein C deficiency, skin necrosis, which occurs most often at the initial phase of oral anticoagulants therapy, is a rare side effect. Six cases have previously been reported in the literature. In this case report, we present a protein C deficient 42-year-old woman who was being treated for venous thrombosis. Five days after the initiation of oral anticoagulant treatment, she developed extensive skin necrosis on her left calf, followed by a painful leg ulcer. The pathogenesis underlying skin necrosis caused by anticoagulation therapy is still not clear. Despite only a few cases being reported in the literature, it is important to recognise this complication since adequate therapeutic approaches leading to a stable anticoagulation state may prevent it.

[Two new anticoagulants available in 2010--Dabigatran Etexilate and Rivaroxaban: expected progresses--raised problems]. / Deux nouveaux anticoagulants disponibles en 2010--Dabigatran Etexilate et Rivaroxaban: progrès attendus--problèmes posés.

After having been used for decades, heparins (unfractionated heparin [UFH] or low molecular weight heparins [LMWH]) and vitamin K antagonists (VKA), which are only parenterally active or which are responsible for frequent iatrogenicity respectively, have to face the competition of new anticoagulant drugs targeting either factor Xa or factor IIa (thrombin). Rivaroxaban (Xarelto(®)) and Dabigatran Etexilate (Pradaxa(®)) are the two leading components. They are more convenient to use and do not require routine coagulation monitoring. They are already marketed for venous thromboembolism prevention in major orthopaedic surgery. Although manufacturers claim that no biological monitoring is required, these two compounds may interfere in routine coagulation tests such as PT or aPTT, and in esoteric assays such as anti-Xa activity (the results of which are usually expressed in international anti-Xa units either UFH or LMWH unit) for Rivaroxaban or anti-IIa activity for Dabigatran Etexilate. Noteworthy is the fact that, in the case of these new anticoagulant drugs, results should be expressed in active product units (nanogram per millilitre of Rivaroxaban or Dabigatran). The new anticoagulants are associated with a bleeding risk comparable to that of VKA and heparins.

[Arterial and venous thrombosis in lung cancer]. / Thrombose artérielle et veineuse et cancer bronchique.

We report the case of a 61-year old man in whom a deep venous thrombosis was the presenting feature of disseminated lung carcinoma. A few days later, an arterial thrombosis occurred necessitating amputation. Within a few weeks, the lung cancer progressed dramatically and the patient died. While the association between venous thrombosis and cancer is well known, the relationship between cancer and arterial thrombosis has been less explored. This observation allows discussion of the pathophysiological and clinical aspects of this association, as well as the implications for patient care.

The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum.

BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.

[Hormonal contraception and risk of venous thromboembolism: When to ask for an assessment of hemostasis? Which parameters?]. / Contraception hormonale et risque thromboembolique veineux : quand demander une étude de l'hémostase ? Et laquelle ?

One of the deleterious effects of the combined oral contraceptives is venous thromboembolism (VTE) and it is the most frequent. VTE is potentially serious because it is sometimes responsible for fatal pulmonary embolism. Because of the large use of hormonal contraception among healthy women and often for long durations, it is fundamental to target the prescriptions and detect women at high risk of VTE. It has been demonstrated that some congenital or acquired coagulation anomalies are associated with an increase of thromboembolic risk. In addition, combined oral contraceptives modify some parameters of the hemostasis, whatever the route of administration. In order to optimize the benefit-risk balance of oral contraception, the search for a biological thrombophilia is essential in some clinical situations such as in young women with a history of venous thromboembolic event or with a family history of thrombosis at a relatively young age. A thorough questioning must be performed. On the other hand, this biological research is not systematically recommended before any prescription of hormonal contraception in patients having neither previous personal nor family history of venous thrombosis.

[Therapeutic management of menometrorrhagia in hemostasis disorders]. / Prise en charge thérapeutique des ménométrorragies liées aux coagulopathies et traitement anticoagulant.

Numerous epidemiological studies have confirmed an association between disorder of hemostasis and menorrhagia with an incidence of von Willebrand factor deficiency of 13%, the most common underlying bleeding disorder. In this context, a multidisciplinary approach is the best model. Similarly, women using anticoagulant treatment are exposed to menorrhagia or metrorraghia. The research of both gynaecological disease and therapeutic overdose is necessary.

[Venous thromboembolism and pregnancy]. / Maladie thrombo-embolique veineuse et grossesse.

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during or early after pregnancy. Prior VTE or family history of VTE, clinical or biological risk factors increased the risk of pregnancy-related VTE. Defining the risk of VTE before or at the beginning of pregnancy is necessary to propose the best prevention. However, the management is not standardized between physicians, centres and countries. Current guidelines for prophylaxis and treatment of VTE are discussed in this review.

Acquired hemophilia due to factor VIII inhibitors in 34 patients.

BACKGROUND: Acquired hemophilia is a rare disease caused by the development of auto-antibodies against factor VIII. SUBJECTS AND METHODS: We studied the characteristics and outcomes of 34 patients (19 women and 15 men) with acquired hemophilia from 1980 to 1997. RESULTS: The mean age of the patients was 61 years (range, 22-93 years). An underlying disease was observed in 18 (53%) patients: 5 patients had cancer, 4 an autoimmune disorder, 2 a dermatologic disorder, 3 asthma, 3 were postpartum, and 1 had an adverse reaction to ampicillin. Factor VIII level was <5% in 30 (90%) patients; factor VIII antibodies were elevated (>10 Bethesda units) in 23 (69%) patients. Bleeding requiring transfusions was reported in 25 (75%) patients. Human factor VIII was given to 14 patients and porcine factor VIII to 5. Six patients received prothrombin complex concentrates and one desmopressin. Several immunosuppressive treatments were used, mainly corticosteroids, cyclophosphamide, and intravenous immunoglobulin. Bleeding stopped in all but one patient within 2 weeks. Most patients achieved complete remission, although two relapses were observed subsequently. CONCLUSION: This large study helps to clarify the presentation and clinical course of acquired hemophilia. Prospective studies are needed to determine the efficacy of treatment.

Intra-coronary thrombolysis with streptokinase or lys-plasminogen/urokinase in acute myocardial infarction: effects on recanalization and blood fibrinolysis.

Forty-two patients with total occlusion of a coronary vessel were treated with intracoronary fibrinolytic agents. Four therapeutic protocols were compared: group I received streptokinase (SK) as a continuous infusion; group II and III received SK as a bolus at different doses and group IV received lysplasminogen (Pg) plus urokinase (UK); maximal doses were 350,000 IU of SK and 250,000 IU of UK plus 75 microK of Pg. Thrombolysis was assessed by coronary angiography. Coagulation studies were performed prior to, 15 min and 6 hr after the end of the thrombolytic treatment. Recanalization was achieved in 27 of the 31 SK-treated patients (87%) and in 7 of the 11 Pg-UK-treated patients (63.6%). The recanalization frequency was the same in the three SK-treated groups, even though when SK was administered as a bolus, the dose was significantly less than when administered on a continuous infusion. Although systemic fibrinolysis occurred in all 4 groups of patients, this effect was less pronounced in the UK-treated patients than in the three SK-treated groups. This study also shows that recanalization can be achieved with a dose of SK lower than the anti-SK antibody level. Haemorrhagic side effects were minimal in all patients studied. Severe defibrination is usually considered a risk of haemorrhage. These preliminary results suggest that bolus injection of SK or the use of UK plus lys-Pg can reduce the level of defibrination and thus the haemorrhagic risk.

Monitoring heparin therapy using activated partial thromboplastin time--results of a multicenter trial establishing the therapeutic range for SILIMAT, a reagent with high sensitivity to heparin.

APTT is widely used for laboratory monitoring of treatment with unfractionated heparin (UFH). However, since its sensitivity to heparin varies significantly from one reagent to another, the therapeutic range had to be defined for each brand of APTT reagent. As an example, SILIMAT (bio-Mérieux) is a new APTT reagent containing rabbit brain phospholipids and micronized silica as an activator. Since its high sensitivity to heparin has been previously reported, a multicenter trial was carried out in an attempt to define the therapeutic range of APTT performed using this new reagent. For that purpose, 170 blood samples drawn for routine coagulation testing from 170 different patients treated with UFH were analyzed. A single batch of two different APTT reagents were used on KC10 coagulometers: SILIMAT and Automated APTT (Organon-Teknika) whereas the anti-Xa activity was evaluated by a chromogenic substrate-based assay. The same methodology was used in all the centers. In order to obtain a plasma anti-Xa activity within the therapeutic range i.e. between 0.30 and 0.70 IU/ml, the APTT ratios were found between 1.90 and 5.40 for SILIMAT, which corresponded to clotting times of the patients plasma between 63 and 178 s. The APTT ratios were significantly lower when evaluated using Automated APTT (between 1.70 and 4.10), with clotting times between 53 and 127 s. In addition, a good correlation was found between the Anti-Xa activity and APTT for both reagents (r > 0.65). However, it is not possible to make recommendations regarding the therapeutic ranges without restrictions. Although about 70% of the patients with an anti-Xa activity between 0.30 and 0.70 IU/ml had an APTT in the above defined ranges, the degree of concordance between the two assays is not absolute. Actually more than 30% of the patients had discordant anti-Xa activity and APTT and more than a quarter of the patients included in the above defined therapeutic range for APTT had an anti-Xa activity outside the 0.30-0.70 IU/ml range, whatever the reagent used. In conclusion, to define the therapeutic ranges of APTT using the recommended method is practicable but some critical points could be raised, suggesting that a better method is awaited in order to improve the standardization.

Control of oral anticoagulation in patients with the antiphospholipid syndrome--influence of the lupus anticoagulant on International Normalized Ratio. Groupe Méthodologie en Hémostase du Groupe d'Etudes sur l'Hémostases et la Thrombose.

The recommended therapeutic range of International Normalized Ratio (INR) for oral anticoagulant treatment in patients with the antiphospholipid syndrome remains controversial. As a part of this controversy, it has been suggested that lupus anticoagulants (LA) could interfere with the determination of prothrombin time, thus questioning the validity of monitoring the treatment of these patients using INR. To clarify this point, we compared the values of INR obtained in the plasmas of two groups of patients, one without LA (n = 47), and the other with LA (n = 43). INR were determined using 8 different thromboplastin reagents on the same automated coagulation instrument. Chromogenic factor X, which is supposed to be insensitive to the presence of LA, was also measured. The results are the following: provided INR was calculated using calibrated reference plasmas, there was no significant difference between INR values obtained with the 8 reagents, both in the non-LA and in the LA groups (CV: 5.9 and 6.7%. respectively). Closer examination revealed that INR results obtained with one reagent (the recombinant thromboplastin Innovin) diverged from those of the 7 others, leading to an overestimation of INR, to a very large extent in some instances. However this effect was restricted to a subset of the patient population with LA (6 out of 43). Finally, the relationship between INR (average value obtained using the 8 reagents) and factor X was identical in non-LA and in LA patient groups. We conclude that, provided the reagents which display the LA interference are identified and excluded for this purpose, the INR system is valid for monitoring oral anticoagulant treatment in patients with LA.

Treatment of hereditary protein C deficiency with stanozolol.

Five type I protein C deficient male patients received 5 mg stanozolol b.i.d. during 4 weeks. After four weeks of treatment plasma protein C activity increased from 0.42 to 0.74 U/ml and protein C antigen from 0.49 to 0.75 U/ml. This approximately 1.6 fold increase in plasma protein C was accompanied by an increase in factor II antigen (1.5 fold), factor V activity (1.6 fold), factor X antigen (1.1 fold), antithrombin III antigen (1.3 fold) and heparin cofactor II antigen (1.5 fold), while the concentration of factor VII, factor VIII, and factor IX activity, and of protein S antigen remained unchanged. Prothrombin fragment F1+2, measured in two patients, increased 1.3 fold. In addition to its effect on procoagulant and anticoagulant factors stanozolol had profibrinolytic effects, reflected in an increase in tPA activity and in the concentration of plasminogen. These data indicate that in type I protein C deficient patients stanozolol increases the concentrations of both procoagulant and anticoagulant factors and favours fibrinolysis. The efficacy of stanozolol in preventing thrombotic disease in type I protein C deficient patients, however, remains to be established. During the four weeks of stanozolol treatment no thrombotic manifestations were observed in the protein C deficient patients.

Prevalence and patient profile in activated protein C resistance.

Activated protein C resistance (APC-R) is a recently defined abnormality of the coagulation system predisposing to the development of a hypercoagulable state. The authors have attempted to evaluate the prevalence and clinical manifestation of APC-R by studying a population of 183 patients with a history of venous thromboembolic episodes. Laboratory evaluation of APC-R was performed using the test initially described by Dahlbäck and colleagues based on the activated partial thromboplastin time (APTT) with the Coatest APC resistance kit (Chromogenix, Sweden) on KC10 coagulometer (Amelung, Germany). These results showed a 13% prevalence of APC-R as demonstrated by an APC ratio below 2.0. The male-to-female ratio was 1:7. Most of the thrombotic episodes were deep venous thromboses (50%).

Peripheral-T-cell lymphoma with hemophagocytic histiocytosis localised to the bone marrow associated with inappropriate secretion of antidiuretic hormone.

A patient with high fever, loss of weight and profound pancytopenia is reported. Peripheral T-cell lymphoma with hemophagocytosis was diagnosed. Bone marrow was the only localisation of the lymphoma. At presentation there were (i) a coagulopathy consistent with hemophagocytic histiocytosis (ii) the features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). These different abnormalities disappeared after chemotherapy and reappeared during each of the 2 periods of disease progression. The patient died 6 months after diagnosis without ever achieving complete remission. As far as we are aware this is the first case report of T-cell lymphoma with hemophagocytic syndrome localised to the bone marrow and associated with SIADH.

At III content and antithrombin in activity in oestrogen-progestogen and progestogen-only treated women.

PIP: Serum antithrombin (AT) and AT 3 content in plasma and serum were measured in 204 women taking either 50 or 30 mg of estrogenprogestogen preparations, or a progestogen only pill, to determine the estrogen content on antithrombin levels. AT 3 determination was done with the Mancini technique, and serum AT activity was measured by the van Kaulla method. 140 controls were also observed before oral contraception. Results of the study showed a decrease in serum AT 3 and in serum AT activity with combined pills containing 50 mg of ethinyl estradiol, but the decrease was not time-dependent after the 3rd. month of treatment. A relevant decrease was also observed with pills with a 30 mg. of estrogen content, while progestin only pills did not induce a decrease in either AT 3 or AT activity.^ieng

Markers of activated coagulation in patients with factor V Leiden and/or G20210A prothrombin gene mutation.

The activated protein C (APC) resistance phenotype associated with an abnormal factor V Leiden (FVL), and the G20210A prothrombin gene mutation are the most common findings in patients with venous thromboembolism (VTE). In a group of 210 patients, we compared the levels of markers of coagulation activation in carriers of FVL (71 heterozygous, 30 homozygous), G20210A prothrombin mutation (88 heterozygous) or both mutations combined (21 heterozygous), in order to assess whether these markers allow identification of a group of patients with a higher risk of thrombosis; they were also compared to normal values. A total of 143 patients had a personal history of VTE and 67 were asymptomatic. None of them had other hereditary causes of thrombophilia or an antiphospholipid syndrome. None were currently treated with either anticoagulant or hormonal treatment. Pregnant women were excluded. No significant difference between the four groups of patients could be found in the levels of F1+2, TAT and DDI. Levels were all significantly higher than the control values (p<0.05). The levels of F1+2 and TAT were similar in patients with or without a history of VTE, regardless of the type of mutation. DDI levels were significantly higher in patients with a history of VTE than in asymptomatic subjects (443+/-248 vs. 333+/-222 ng/ml, p=0.02) but with only 57% sensitivity and specificity. In conclusion, our study confirms the hypercoagulable state found in mutation carriers and points out the inability of F1+2 and TAT assays to identify a group of subjects at higher risk of thrombosis, within carriers of genetic risk factors. Although the sensitivity and specificity of DDI assay are low, high DDI concentrations tend to be associated with the risk of VTE.

Central retinal vein thrombosis associated with resistance to activated protein C.

PURPOSE/METHODS: Activated protein C resistance was recently described as a major cause of venous thrombosis. We observed a central retinal vein thrombosis in a woman with activated protein C resistance. RESULTS/CONCLUSION: DNA analysis showed the patient to be heterozygous for the factor V gene mutation, which is related to activated protein C resistance. Patients with retinal vein thrombosis should be examined for activated protein C resistance.

Comparison of thrombolytic, fibrinolytic, and fibrinogenolytic properties of tissue plasminogen activator, streptokinase, single-chain urokinase, high molecular weight and low molecular weight urokinase in human plasma in vitro.

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.

Potential use of D-dimer measurement in patients treated with oral anticoagulant for a venous thromboembolic episode.

AIM: We compared the level of plasma D-dimer in patients with previous venous thromboembolism (VTE), receiving or not oral anticoagulant treatment (OAT) and investigated its predictive value for the risk of VTE recurrence after OAT withdrawal. METHODS: We have studied 149 patients, 81 receiving oral anticoagulants and 68 after treatment interruption. Patients with known causes of D-dimer increase were excluded. D-dimer measurements were performed by Vidas analyzer (bioMérieux, France). RESULTS: A significantly lower D-dimer plasma level was found in patients under OAT than in untreated patients, 197+/-134 ng/ml versus 399+/-239 ng/ml, respectively (p<0.001). This decrease was similar in the different age populations and whether the patient had thrombophilia (n=84) or not. There was no correlation between INR and D-dimer levels. During a mean follow-up of 30 months, no recurrence occurred in patients under OAT versus 7 untreated patients. Among them, 3 had a D-dimer below 500 ng/ml, and 3 others had a level above 500 ng/ml. The last patient was not tested. CONCLUSION: The physician should be informed of the decrease of D-dimer under OAT, since the usual cut-off of 500 ng/ml used for deep vein thrombosis (DVT) exclusion is probably lower in such treated patients. It has been recently proposed that normal D-dimer level had a high negative predictive value for VTE recurrence when this dosage was performed 3 months after OAT interruption. The small number of recurrences observed in our study with an available result of D-dimer measured more than 3 months after OAT discontinuation does not allow a definite

[Biological monitoring of treatment with antivitamin K. Value of INR and definition of new therapeutic ranges. A study of 73 patients]. / Surveillance biologique des traitements par les antivitamines K. Intérêt de l'INR et définition des nouvelles zones thérapeutiques. Etude chez 73 malades.

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.