Elisabeth Mazoyer

Coagulation Disorders in Patients With Venous Malformation of the Limbs and Trunk: A Case Series of 118 Patients

OBJECTIVE To investigate the clinical characteristics of venous malformation of the limbs and trunk and known but poorly appraised associated coagulation disorders. Venous malformations are ubiquitous, slow-flow vascular anomalies known to be occasionally painful because of thrombotic episodes inside the lesion. DESIGN Large case series, with screening of accepted standard coagulation tests. SETTING Ambulatory multidisciplinary clinics for vascular anomalies. PATIENTS This 2-year study (2003-2005) included 118 patients with clinical, radiological, and biological features informative for better defining venous malformation and associated coagulation abnormalities. MAIN OUTCOME MEASURES The primary outcome was coagulation disorders associated with VM. Secondary measures include anatomic location, extent of lesion, localized pain, and impaired motion. RESULTS The mean age of patients was 27 years, and there was a female preponderance of 64%. The venous malformation involved the upper extremity, lower extremity, and trunk in 30%, 58%, and 36% of patients, respectively; it was plurifocal in 22%. Intralesional pain (in 92% of patients) had a higher frequency in female (63%) than in male (47%) patients. Tissular involvement concerned the skin (65%), muscle (73%), bone (13%), joints (12%), and viscera (9%). According to our severity scoring system, cases of less gravity had a score of 2 or 3 (52%), cases of intermediate severity had a score of 4 or 5 (32%), and cases of major severity had a score of 6 to 9 (10%). The most frequent blood coagulation abnormality was a high plasma D-dimer level (> 0.5 microg/mL) (58% of patients), which was correlated with muscle involvement and high severity score and was more frequent in women. The factor VIII-von Willebrand factor complex was documented in 84 patients, and plasma von Willebrand factor level was decreased (<60%) in 23 (27%) of them; 10 of the 84 patients (12%) had more notably decreased levels (<50%). CONCLUSIONS This study of a large case series of patients with pure venous malformation in the limbs and/or trunk highlights muscle involvement and frequency of pain. It validates that coagulation disorders, present in 58% of our patients, create thrombotic painful events. Under certain circumstances, these disorders entail a risk of hemorrhage because of the progression of localized intravascular coagulopathy to disseminated intravascular coagulopathy.

Characterization of an antithrombotic peptide from kappa-casein in newborn plasma after milk ingestion.

Bovine and human kappa-caseinoglycopeptides, two antithrombotic peptides derived from the corresponding kappa-caseins, were detected in physiologically active concentrations in the plasma of 5-d-old newborn infants after ingestion of cows-milk-based formula or human milk respectively. It is suggested that these two bioactive peptides are released from milk proteins during digestion.

Prevalence of factor V Leiden and prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution

Among inherited risk factors for venous thrombosis, the most common are the FV-G1691A and FII-G20210A polymorphisms. The FV-G1691A polymorphism is preferentially observed in Europe, with differences between European countries. The FII-G20210A polymorphism is observed all over the world. The study was designed to compare the prevalence of the FV-G1691A and FII-G20210A polymorphisms in a large French population of unrelated individuals with no thrombotic disease history and to determine the age and geographical distributions. Over a period of 18 months, 6154 individuals were included throughout France and FV-G1691A and FII-G20210A polymorphisms were determined. The FV-G1691A prevalence was 3.84% (95% confidence interval 3.35–4.33) and the FII-G20210A prevalence was 3.07% (95% CI 2.63–3.51). A north-east/south-west gradient was observed in the FV-G1691A geographical distribution. No difference was observed in the geographical distribution of FII-G20210A polymorphism nor in the age distribution of the two polymorphisms. The prevalence of the two polymorphisms was similar whatever the blood group (O or non-O). Plasma D-dimers were significantly higher in healthy individuals with FV-G1691A but not in individuals with FII-G20210A. Thirty percent of variation in plasma prothrombin level was explained by environmental factors (serum cholesterol, age, oral contraception, hormonal replacement therapy, body mass index, sex) and genetic factors (FII-G20210A). As expected, individuals with FII-G20210A displayed higher plasma prothrombin level compared with individuals with wild type. However, this was not associated with a modification of the fibrin clot elastic modulus. This study shows a differential distribution of the two polymorphisms among the French territory. These polymorphisms confer a very mild hypercoagulable state as shown by the limited increased in basal D-dimers in mutated FV-G1691A populations and only a trend that does not reach statistical significance for FII-G20210A population.

D-dimer: a characteristic of the coagulation state of each patient with chronic atrial fibrillation

BACKGROUND AND OBJECTIVE It is accepted that patients with atrial fibrillation (AF) are characterised by increased levels of plasmatic D-dimers, with a wide inter-individual variability depending on the patients and therapeutic characteristics, but it has not been established if this level was predictive of the risk of arterial thromboembolic event. In order to answer such a question, it has to be established if the D-dimer level in a given patient is characteristic of such a patient (stable over time) if also fluctuating with time (and useless to characterise the patient). METHODS AND RESULTS One hundred thirty clinically stable patients with chronic AF were recruited (anticoagulant: group 1, antiaggregant aspirin: group 2, no antithrombotic: group 3). During the follow-up of patients without clinical events (n=63), it is notable that in patients with D-dimer levels <500 ng/ml, these remained <1000 ng/ml, in patients with levels between 500 and 1000 ng/ml, these did not reach 1590 ng/ml, and in those with D-dimers >1000 ng/ml, the levels remained relatively stable. Mean age and D-dimer levels were lower in group 1 (74.4 years and 509.1 ng/ml, respectively) than in group 2 (82.4 years, p=0.0003 and 1015.7 ng/ml, p<0.0001, respectively) and in group 3 (79.3 years and 1289.3 ng/ml, p<0.0001, respectively). The effect of the antithrombotic therapy was independent of the age of patients (p=0.017). CONCLUSION D-dimer levels in patients with chronic AF remain in the same range over time. They are lower on anticoagulant therapy than on antiaggregant or no antithrombotic therapy, irrespective of age. Thus, D-dimers appear to be a useful parameter for assessing the degree of hypercoagulability of patients whatever their age.

How does ticlopidine treatment lower plasma fibrinogen

Many clinical studies have evaluated the clinical efficiency of ticlopidine in vascular pathology and in few of these studies the plasma Fg level was determined as a biological parameter and not a primary end point. All these studies are heterogeneous because plasma Fg concentration have been measured using various methods, patients were included at various time after the acute event and were followed over a period of 1 to 24 months of treatment with ticlopidine, patients suffered from various pathology: peripheral arterial disease, cerebrovascular disease, diabetes or polycythemia vera. Despite the heterogeneity of these prospective studies, a general trend indicates a decrease in the plasma Fg levels by 10 to 25% with ticlopidine compared to placebo. This decrease in circulating Fg was associated with clinical improvement, and, when studied, hemorheological modifications (decreases in whole blood and plasma viscosities). The mechanism of ticlopidine action is discussed.

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations

BACKGROUND Peri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients. OBJECTIVES To test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL. METHODS Patients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure. RESULTS Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL. CONCLUSIONS A 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

Erythropoietin and granulocyte colony-stimulating factor increase plasminogen activator inhibitor-1 release in HUVEC culture

UNLABELLED Recombinant human erythropoietin (rHuEPO) is considered to be a mitogenic and chemotactic agent in cultured endothelial cells (ECs). The effect of recombinant granulocyte-macrophage (rGM-CSF) and granulocyte (rG-CSF) colony-stimulating factors on the proliferation of human umbilical vein endothelial cells (HUVECs) has been controversial. METHODS HUVEC proliferation and the release of endothelial markers in HUVEC culture stimulated by rHuEPO, rGM-CSF and G-CSF were measured. RESULTS We found the dose-dependent stimulating effect of rHuEPO and rGM-CSF on HUVEC proliferation, but we did not achieve this with rG-CSF. rHuEPO like rG-CSF was an effective agent in stimulating the plasminogen activator inhibitor (PAI)-1 release from HUVECs to a cultured medium, while rGM-CSF failed. CONCLUSION We suggest that rHuEPO showed prothrombotic changes in HUVEC culture. Our results support the idea of suspected rHuEPO direct prothrombotic role in haemodialysed patients treated with rHuEPO.

Early prediction of the sensitivity of warfarin in elderly patients by the fall in factor VIIc and protein C at the induction of treatment.

Indications of oral anticoagulation (OA) therapy for venous thromboembolism and atrial fibrillation increase with age [1]. Elderly patients are more sensitive to OA [2] and their risk for bleeding complications is increased [3,4]. There is a strong relationship between the intensity of the anticoagulant effect and the risk of bleeding [5,6]. A recommendation for an international normalized ratio (INR) of 2.0 to 3.0 is made for most indications [1]. It is important to maintain INR below 3.0 especially in the elderly [7]. Many authors agree that there is a need to improve the safety of anticoagulants in the elderly by careful monitoring of anticoagulant therapy in order to maximize their time in the optimal therapeutic range [1,2,8]. The start of this treatment is a critical period, as the hemorrhagic risk lies mainly in the induction phase [4]. Warfarin is the most widely used oral anticoagulant. It is a drug with a small therapeutic window and its dose–response curve is complex [9,10]. There is a great interand intraindividual pharmacokinetic and pharmacodynamic variability [11]. For all these reasons, it is difficult to predict the correct induction dose [12]. INR is the

Prevalence of Hereditary Thrombophilia in Patients Older Than 75 Years With Venous Thromboembolism Referred for Thrombophilia Screening

BACKGROUND Few studies focused on genetic risk factors for venous thromboembolism (VTE) in the very elderly people. In patients aged 75 years and older with VTE referred for laboratory screening tests for thrombophilia, we aimed: (i) to estimate the F5G1691A and F2G20210A mutation prevalence; (ii) to compare prevalence rates with those of a control group; and (iii) to compare the prevalence rates between patient subgroups, defined as with one or multiple VTE episodes and with provoked/unprovoked VTE. METHODS Data were extracted from two prospective thrombophilia registries according to the following inclusion criteria: Caucasian patients aged 75 years and older presenting with at least one confirmed VTE episode. Associated VTE risk factors had been recorded using a standardized questionnaire. Laboratory tests included plasma antithrombin, protein C, and protein S activity measurements and F5G1691A and F2G20210A genotyping. RESULTS Of the 312 patients (mean age: 84 ± 6 years; 245 women and 67 men), 47.1% had two or more VTE episodes and 63.5% patients had unprovoked VTE. None had deficiencies in antithrombin, protein C, or protein S. The F5G1691A and F2G20210A mutations were found in 29 (9.3%, 95% confidence interval [CI]: 6.3-13.1) and 18 (5.8%, 95% CI: 3.5-9.0) patients, respectively, versus 3.4% (95% CI: 1.9-4.9) and 3.1% (95% CI: 2.6-3.5) in control subjects (p = .0002 and p = .0082, respectively). Overall, 45 (14.4%) patients carried at least one mutated allele. No associations were found between F5G1691A/F2G20210A, unprovoked VTE or recurrence (p > .05). CONCLUSIONS Our study provides new data on genetic risk factors for VTE in the very elderly people. Whether identification of hereditary thrombophilia in elderly patients may influence patients management in this age group remains unanswered.

Efficacy and safety of continuous infusion of factor VII concentrate in a factor VII-deficient patient at high risk for arterial thrombosis.

Factor VII (FVII) deficiency, a rare autosomal recessive coagulopathy, manifests mainly as bleeding in association with surgery [1] or trauma. Bleeding is usually treated or prevented by injection of FVII concentrate. Because FVII has a half-life of 4–6 h when given as bolus injections [2]; these injections must be repeated four times per day. With this regimen, plasma FVII clotting activity (FVII : C) usually goes through a succession of peaks and troughs, with a potential increased risk of thrombosis during the peaks [3–5]. Repeated intravenous bolus of FVII to prevent bleeding during tooth extraction in a patient with a plasma FVII (FVII : C) level below 4% was associated with severe aorto-iliac thrombosis [4]. Continuous FVII infusion has been suggested as a means of reducing the risk of bleeding and thrombosis [6,7]. In a patient undergoing hip replacement surgery, a pre-surgical FVII bolus followed by a continuous FVII infusion for 21 days proved effective and safe [6].