Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome?

Background Direct oral anticoagulants (DOACs) demonstrate a lower risk-benefit ratio than vitamin K antagonists (VKAs) for secondary thromboprophylaxis of thrombotic events. But there are no data on the efficacy of DOACs for the prevention of thrombotic recurrence in patients with antiphospholipid syndrome (APS). In this study, we evaluated the efficacy of DOACs to prevent recurrences of thrombotic events in patients with APS. Methods This was a single-center pilot, using a multi-step Fleming design. If seven or fewer patients presented treatment failure with rivaroxaban, the study could conclude efficacy. Results A total of 23 patients were included. APS involved the veins only ( n = 19), arteries only ( n = 2) or both ( n = 1) and 1 patient exhibited catastrophic antiphospholipid syndrome (CAPS). Overall, two patients were positive for lupus anticoagulant, anti-beta-2 glycoprotein I antibodies and anticardiolipid antibodies (triple positivity). The mean duration of follow up was 35.6 (range, 29-40) months. A total of six treatment failures were reported: one patient, with triple positivity, developed bilateral distal pulmonary embolism (PE) after 20 months of treatment with rivaroxaban, two patients refused to take rivaroxaban, the treatment was stopped in three other patients: two with adverse effects and one with chronic iron-deficiency anemia. Conclusions Rivaroxaban may represent an alternative for secondary thromboprophylaxis for thrombo-embolism in patients with APS, in particular, those with poor international normalized ratio (INR) control and those who are not at the highest risk of recurrent thrombosis, such as those with triple positivity.

[Diagnosis and treatment of iron overload]. / Diagnostic et traitement d'une surcharge en fer.

Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000µg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120µmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions.

Systematic screening for occult cancer in elderly patients with venous thromboembolism: a prospective study.

BACKGROUND: Cancer is an established risk factor for venous thromboembolism (VTE) and the incidence of cancer increases in the elderly. The benefit of screening for occult cancers in this population is still not clear. AIM: To evaluate a systematic screening programme for cancer in elderly patients with VTE. METHODS: This was a prospective study with a 12-month follow-up period. It was conducted in a single centre in consecutive patients over the age of 70 years who had a confirmed diagnosis of VTE. Predefined non-invasive screening techniques for cancer with clinical, laboratory (including tumour markers) and radiological investigations (abdominal ultrasound, chest X-ray and a thoraco-abdominopelvic computed tomography scan) were evaluated. RESULTS: Fifty patients with a median age of 80 years (range: 70 to 94 years) were included. One patient was diagnosed with chronic lymphocytic leukaemia at inclusion and cancers were found in three other patients during the follow-up period (rectosigmoid adenocarcinoma with hepatic metastases, hepatocellular carcinoma and gastric adenocarcinoma). Only one of the four cancers could have been treated at an earlier stage. The mortality rate of the entire cohort after 12 months was 28%. Two patients died as a direct consequence of cancer. DISCUSSION: In this study of elderly patients, a non-invasive screening strategy did not detect several cancers that were subsequently overt clinically. A full history, clinical examination and routine laboratory investigations might be the optimal first-line strategy to detect cancer after the diagnosis of VTE in elderly patients, but regular clinical examinations during follow up are warranted.

Rituximab-induced serum sickness in refractory immune thrombocytopenic purpura.

Serum sickness may occur in patients treated with chimeric monoclonal antibody. Rituximab, an anti-CD20 chimeric monoclonal antibody, is used with increasing frequency in chronic immune thrombocytopenic purpura (ITP). Rituximab is relatively safe; however, serum sickness is reported in 1-20% of patients, more commonly among those with autoimmune conditions. We describe a case of serum sickness in a patient with ITP and review the literature of rituximab-induced serum sickness.

[Genetic iron overloads and hepatic insulin-resistance iron overload syndrome: an update]. / Surcharges en fer d'origine génétique et hépatosidérose dysmétabolique.

Hepcidin inhibits intestinal absorption of iron through internalisation of ferroportin. Its discovery helps to better understand the genetic iron overloads. The insulin resistance-hepatic iron overload (IR-HIO)--also coined as the dysmetabolic iron overload syndrome--is a common cause or iron overload. This article is a review about genetic iron overloads and IR-HIO. Type 1 haemochromatosis C282Y +/+ accounts for 95% of the haemochromatosis. Hepatic fibrosis may develop if serum ferritin is higher than 1000 microg/l but can be partially reversible with phlebotomies. Juvenile haemochromatosis (type 2) and type 3 haemochromatosis (mutation of the transferrin receptor 2) are very uncommon. Several mutations of the ferroportin gene can cause usually mild iron overload of autosomal dominant inheritance. Aceruleoplasminemia is an uncommon disorder involving cerebral iron overload. The causes and consequences of the IR-HIO are unknown. Treatment of IR-HIO is focused on metabolic syndrome and phlebotomies are questionable because the overload is moderate and intestinal absorption of iron seems to be low. MRI (or other non invasive methods) is needed to truly assess iron overload because serum ferritin overestimates it in metabolic syndrome. Several points have to be elucidated: how HFE interferes with hepcidin in type 1 haemochromatosis; the causes of variability of iron overload; the benefits of populations screening; the advantage of phlebotomies in IR-HIO; the use of new oral iron chelators.

[Abdominal manifestations of Henoch-Schönlein purpura in adults. A retrospective study of 23 cases]. / Atteintes digestives du purpura rhumatoïde de l'adulte. Etude d'une série rétrospective de 23 patients.

INTRODUCTION: Gastrointestinal manifestations of Henoch-Schönlein purpura (HSP) in adults may be severe. Data about treatment are controversial and the outcome is seldom described. METHODS: Twenty-three patients with gastrointestinal manifestations of HSP (ACR criteria) were retrospectively studied. We proposed to use clinical and radiological (CT scan) severity scores to assess the usefulness and the efficacy of corticosteroid therapy. RESULTS: Age at onset ranged from 16 to 80 years (median 39). Gastrointestinal manifestations included abdominal pain (96%), vomiting (52%), gastrointestinal bleeding (39%), diarrhoea (13%) and intestinal obstruction (9%). Scores of disease clinical severity were calculated in 21 patients. Fourteen, three and four had severe, intermediate and mild disease, respectively. Ten patients in the group with severe clinical involvement underwent CT scan that showed severe radiological involvement (parietal thickening of several bowel loops of the same segment or several segments with ileal involvement). Eleven patients out of 14 with clinically severe disease were given corticosteroids. Two patients out of three with intermediate and three patients out of four with mild scores also received corticosteroids. The others received supportive care. In-patients with severe clinical scores, gastrointestinal symptoms improved within 2 days when they were given corticosteroids and within 12.3 days without corticosteroids (p<0.0002). No side effect was observed with steroid therapy. CONCLUSION: These results suggest that corticosteroids may reduce abdominal symptoms of HSP in adults with clinically severe disease. They are safe when CT scan is performed.

[Nodular thrombophlebitis and granulomatous systemic disease]. / Thrombophlébites nodulaires et maladies systémiques granulomateuses.

INTRODUCTION: Nodular thrombophlebitis is septal hypodermitis characterised by vasculitis with vein thrombosis. It may indicate serious underlying disorders. EXEGESIS: We present two cases of nodular superficial phlebitis, which revealed tuberculosis and sarcoidosis. CONCLUSION: Nodular thrombophlebitis are classic during evolution of Behçet disease or Buerger vasculitis. In sarcoidosis, erythema nodosum and granulomatous involvement are the most common cutaneous manifestation. Nodular thrombophlebitis has never been described. Panniculitis are classical in tuberculosis. But most cases are erythema nodosum and cases of erythema induratum of Bazin. Nodular thrombophlebitis could reveal thrombophilic abnormalities, and even more neoplasms especially when they are recurrent and migratory.

Effect of daily versus twice weekly long-term iron supplementation on iron absorption and status in iron-deficient women: a stable isotope study.

OBJECTIVES: This work aims at studying the effect of daily versus twice weekly long-term Fe supplementation on Fe absorption and status in Fe-deficient women. DESIGN AND METHODS: The study design is a randomized controlled open study carried out in the Internal Medicine Department, CHU de Clermont-Ferrand, France. Twenty-four young women participated in this study and were randomized into two groups: Group 1 received 50 mg Fe daily, and group 2 received 50 mg Fe twice weekly for 3 months. On day 10 (D10) and on day 90 (D90) of Fe supplementation, blood samples were obtained, and women received orally about 5 mg of 57Fe, and blood was sampled at different times over 24 h. The 57Fe absorption was evaluated by calculating the areas under the curves (AUC). Fe and oxidative stress status were also assessed. RESULTS: 57Fe absorption was similar in both groups on D10 but was greatly decreased in Group 1 and remained high in Group 2 on D90. Fe status was more improved in Group 1 than in Group 2. Oxidative stress status remained statistically unchanged. CONCLUSIONS: Our study shows that daily Fe supplementation is able to correct an Fe deficiency much more than twice weekly Fe supplementation in young women.

[Natural history of portal cavernoma without liver disease. A single centre retrospective study of 32 cases]. / Évolution naturelle des cavernomes portaux non liés à une hépatopathie. Étude rétrospective monocentrique de 32 observations.

PURPOSE: Portal cavernoma follows a chronic occlusion of the portal vein. The long-term consequences of portal cavernoma are not well known. The objective of this study was to report the aetiology of the portal cavernoma and its natural course after excluding liver diseases causes. METHODOLOGY: A single centre retrospective study based on the data collected from the radiology department of the Clermont-Ferrand hospital was conducted from 2000 to 2011. All the patients for whom an imagery found a portal cavernoma have been looked for excluding the patients having a liver disease whatever the aetiology and the Budd-Chiari syndrome. RESULTS: Thirty-two cases (18 women and 14 men) were selected. The mean age at diagnosis was 54.2 years and the mean follow-up period was 5.4 years. The discovery of a portal cavernoma was incidental for 8 cases. An aetiology was found for 24 cases: it was an haematological aetiology in 15 cases (10 myeloproliferative syndromes, 2 antiphospholid syndromes, 1 thalassemia major, 1 hyperhomocysteinemia, 1 prothrombin gene mutation), a general aetiology in 2 cases (1 coeliac disease, 1 pancreatic neoplasia), and a local inflammation in 7 cases. A dysmorphic aspect of the liver was noticed on medical imaging for 11 out of the 32 cases. A liver biopsy was performed in 4 patients and was normal for all of them. Sixteen patients developed oesophageal varices, 4 patients developed ascites, 3 developed asymptomatic biliary compression by the portal cavernoma, and the patient who had been followed for the longest time (15 years) developed an encephalopathy. CONCLUSION: In addition to its underlying etiology, the prognosis of portal is mainly related to the occurrence of oesophageal varices that may develop during the follow-up of the patients.

[Non infectious endocarditis: retrospective study (6 cases)]. / Endocardites non infectieuses: étude rétrospective (6 cas).

PURPOSE: If there is cardiac valve vegetation and the blood cultures are negatives we need to look for slow growing bacteria, fungi, Legionella pneumophilia, Bartonella henselae and quintana, Brucella melitensis and abortus, Coxiella burneti, Chlamydiae pneumoniae by serologic tests. The diagnosis of non- infectious endocarditis could be considered only if these results were negative. The main purpose of this study was to describe the clinical and echocardiographic signs of non-infectious endocarditis cases observed in two different wards. METHODS: This study was done retrospectively during a five-year period in a cardiology and an internal medicine wards. The selection criteria are: the proof of at least one cardiac valve vegetation, observed on echocardiography, negative blood cultures and negative serologic tests as described above. RESULTS: Six non-bacterial endocarditis were described. Four Libman-Sacks endocarditis, two associated with a primary antiphospholipid syndrome revealed by an acute ischemia of leg for one patient and by an eclampsia for another and the other two associated with a systemic lupus erythematous revealed by fever for one patient and by neurologic symptoms for the other. One fibroblastic endocarditis associated to an essential hypereosinophilia and one marastic endocarditis associated to a metastatic mucin-producing cancer. CONCLUSIONS: For these six cases, a complete physical examination, a CBC for hypereosinophylia, a dosage of antiphospholipid antibodies and a thoraco-abdominal CT-scan allowed the etiologic diagnosis of non infectious endocarditis. Libman Sacks endocarditis associated with an antiphospholipid syndrome is the main etiology for which a long-term anticoagulation treatment was not followed.

[Therapeutic intensification and autologous stem cell transplantation in autoimmune diseases]. / Intensification thérapeutique et autogreffe de cellules souches hématopoïétiques pour le traitement des maladies auto-immunes.

THE PATHOPHYSIOLOGY of most autoimmune diseases is often poorly understood. EXPERIMENTAL CONSIDERATIONS and clinical experience suggest that high doses immunoablation followed by stem cell transplantation is a therapeutic option to consider for certain severe autoimmune disorders. THE CONCEPT OF RESTORING NORMAL IMMUNE REACTIVITY must in part br true since current results of 466 transplants (445 autologous, 21 allogeneic) patients suffering from various autoimmune diseases show a beneficial outcome in approximately 2/3 of the patients. TO IMPROVE THE EFFICACY AND SAFETY OF SUCH AN AGGRESSIVE PROCEDURE in patients with potentially affected vital organs by the underlying autoimmune disease, it is especially important to follow international consensus guidelines and to centrally collect clinical data for in depth analysis in the EBMT International Stem Cell Project for Autoimmune Disease in Basel, Switzerland. PHASE III STUDIES ARE RUNNING FOR SYSTEMIC SCLEROSIS (Astis, Autologous Stem cell Transplantation International Rheumatoid Arthritis Trial) started in 2003. A STUDY PROJECT IS PLANNED FOR MULTIPLE SCLEROSIS (Astims, Autologous Stem cell Transplantation International Multiple Sclerosis).

[Infections associated to severe thrombotic events and antiphospholipid antibodies]. / Infections associées à des évènements thrombotiques sévères avec présence d'anticorps antiphospholipides.

The authors present 2 cases of infections in which the presence of antiphospholipid antibodies (APL), anticardiolipin and anti-beta2-GP1, was associated to the occurrence of significant thrombotic events: 1) a 55-year-old male patient whose serology (indirect immunofluorescence) revealed Coxiella burnetii infection (phase 2 antigens) with IgG at 1,600 and IgM at 50 (significant titer: IgG>or=200 and IgM>or=50); 2) and a 20-year-old male patient with a CMV infection confirmed by serology (IgG: 44 U/ml, significant threshold 6, IgM: 2.1 U/ml, significant threshold 0.9).

[Anticoagulation and peripartum management]. / Influence des anticoagulants sur la prise en charge péri-partum.

OBJECTIVE: To compare peripartum management of anticoagulated patients concerning locoregional analgesia, post-partum hemorrhage and thrombotic events according to planified interruption or not of antithrombotic therapy. PATIENTS AND METHODS: We conducted a single tertiary care center retrospective study of all deliveries associated with antithrombotic therapy from January 2005 to September 2011. RESULTS: We identified 120 cases with prophylactic (71%) or curative (29%) anticoagulation. Two thrombotic events occurred. In case of curative therapy, the use of locoregional analgesia was lower (P<0.0001) and post-partum hemorrhage occurred more frequently (P=0.07) compared to prophylactic therapy. According to planified interruption or not of antithrombotic therapy, we observed a more prolonged duration of therapeutic interruption before delivery (55.6h±63.3 vs 26.4 h±11.6, P<0.0001), higher use of locoregional analgesia (83% vs 71%, P=0.02) but no difference concerning cesarean rate (35% vs 39%, P=0.8) or post-partum hemorrhage (13% vs 14%, P=0.9). CONCLUSION: In case of curative anticoagulation, plannified interruption favours the use of perimedullar analgesia after 24hour delay. In case of preventive anticoagulation, plannified interruption appears unnecessary as the 12hour delay is easier to reach.

Combined idiopathic retroperitoneal and mediastinal fibrosis with pericardial involvement.

We report the case of a 54-year-old woman with renal failure related to bilateral hydronephrosis. Clinical and radiologic findings were consistent with retroperitoneal fibrosis associated with pleuro-pericardial involvement. These features matched criteria for combined idiopathic retroperitoneal fibrosis and idiopathic mediastinal fibrosis. There are few reported cases of pericardial involvement in this combined disorder. In our observation, nuclear-magnetic resonance was the radiologic procedure of choice for aortic exploration. The responsibility of therapeutic agents (beta-adrenoreceptor-blocking drugs and ergotamine) and therapeutic options for the sclerosing disease are also discussed. Bilateral ureteral stents and corticosteroids produced favorable outcome without recurrence one year after treatment was stopped.

[Cerebral-vein thrombosis: retrospective study of twenty seven cases]. / Thrombophlébite cérébrale: étude rétrospective de vingt-sept cas.

PURPOSE: Among the locations of venous thrombosis, even if rare, cerebral-vein thrombosis is a severe event with a high mortality rate. No aetiology is found in 20 to 30% of the cases. In recent years, inherited coagulation disorders have been described, as risk factors for venous thrombosis. We report the results of a retrospective study of 27 patients who suffered cerebral-vein thrombosis, in which coagulation abnormalities have been searched for. METHOD: The patients were referred to the haemostasis laboratory of the Henri Mondor hospital between august 1982 and June 1988, after a cerebral-vein thrombosis. The predisposing factors, personal and family history of thromboembolism, clinical presentation, thrombosis location, evolution under treatment and long-term outcome, have been noted. Deficiencies in antithrombine, protein C, protein S, the Factor V Leiden and the G20210A prothrombin-gene mutation, the presence of lupus anticoagulant, of anticardiolipin antibodies as well as a hyperhomocysteinaemia have been searched, either at the initial presentation, or a posteriori. RESULTS: Fourty-one percent of patients had a coagulation abnormality. The prevalence of the different abnormalities was: inherited deficiency in AT 7.4%, in PC 8%, in PS 12.5%, factor V Leiden mutation 12%, G20210A prothrombin-gene mutation 12%. Two patients had combined defects: AT and PC deficiency in one, F V Leiden and F II G20210A mutations in one. e of the patient had lupus anticoagulant. Three patients had a significant rate of anticardiolipin antibodies. Five patients out of eight displayed a moderate hyperhomocysteinaemia. Nothing (past history, age, predisposing factors) distinguished those patients bearing a coagulation disorder from the others. The venous thromboembolic relapse rate of 15 % (4/27 patients). Three of them had an inherited thrombophilic abnormality. CONCLUSION: We recommend an investigation of the haemostasis after every cerebral venous thrombosis.

[Homocystinuria in adulthood]. / L'homocystinurie à l'âge adulte.

Homocystinuria is a genetically determined inborn error of the methionine amino acid pathway characterized by increased plasma homocysteine. In its major form, homocystinuria, is due to cystathionine beta synthase deficiency. Treatment of these adulthood patients lead physicians to call up on the skilled advices of pediatricians. But prevention and treatment of age related vascular and osteoporotic complications are still to be evaluated.

[Diagnosis of iron deficiency: evaluation of the "soluble transferrin receptor/transferrin" ratio]. / Diagnostic de la carence en fer: évaluation du rapport "récepteur soluble de la transferrine/ferritine".

OBJECTIVE: This study was aimed at determining the diagnostic value of conventional laboratory tests regarding the iron status and serum transferrin receptor in hospitalized patients. METHODS: Patients who had to undergo bone marrow aspirate examination were included in this 8-month prospective study. Iron deficiency was defined as the absence of stainable iron on bone marrow examination. Patients with stainable iron were included in the control group. The higher value of diagnostic efficacy determined the cut-off value for each parameter of the iron status. RESULTS: Twenty-one patients (17 females, four males) (mean age: 52 years) with iron deficiency and 33 control subjects (20 females, 13 males) (mean age: 60 years) were included in the study. The ratio serum transferrin receptor/serum ferritin had the best diagnostic efficiency (78%) with a sensitivity of 81% and a specificity of 97%. Serum ferritin alone with a cut-off value of 60 micrograms/L had the same specificity (97%) but a lower sensitivity (76%). The diagnostic value of all other analyzed tests was below 66% (transferrin alone, mean corpuscular volume, transferrin saturation, iron, serum transferrin receptor alone, red cell distribution width). CONCLUSION: Among in-patients, ferritin remains the first intention test to diagnose iron deficiency, but the cut-off value should be increased (60 micrograms/L in this study). The ratio "serum transferrin receptor to serum ferritin" provides the highest specificity with a higher cost and should be used only in doubtful cases.

[Gastroparesis on a gastric ulcer]. / Gastroparésie sur ulcère gastrique.

INTRODUCTION: Gastroparesis is the failure of the stomach to empty because of decreased gastric motility. It's a fairly frequent medical problem. Diabetes is the most common known cause. OBSERVATION: The first case report is that of an 82 year-old woman, in whom acute gastric distension occurred, evoking a gastric volvulus on the scan. Upper endoscopy revealed gastric ulcers. All symptoms disappeared with medical treatment. The second case report concerns a 37 year-old man who was admitted with signs of occlusion. CT scans revealed acute gastric distension. Emergency surgery revealed no gastric volvulus. Upper endoscopy revealed gastritis and numerous ulcers. The signs regressed with medical treatment. DISCUSSION: Our observations are original in their -pseudo-surgical discovery. Acute gastric distension is rare, but must be recognised because of the risk of perforation and rupture of the stomach walls. These case reports are also original in their aetiology. Gastric ulcers are rarely described in this situation. CONCLUSION; Gastroparesis is a frequent situation but potentially severe. A review of the principle signs, aetiology and treatment is made.

[Cold agglutinins and cryoglobulinemia in a patient with hepatitis C]. / Agglutinines froides et cryoglobulinémie chez un patient avec une hépatite C.

OBJECTIVES: Cold agglutinins and cryoglobulins are uncommon in the same patient as observed in our case. CASE REPORT: A 74-year-old patient suffered repeated episodes of hemolytic anemia for one year and had hepatitis C anti-virus antibodies. Mixed cryoglobulinemia was found at levels which increased during episodes of acute hemolysis in addition to anti-I cold agglutinins. Two-dimensional electrophoresis revealed identical oligoclonal cold agglutinins and cryoglobulins. DISCUSSION: Unlike mixed cryoglobulinemia, cold agglutinins are not known to occur subsequent to hepatitis C infection. The identical immunoglobulins observed in our patient suggest a common origin. Chronic anti-I cold oligoclonal agglutinins are rarely observed and could be an intermediary step towards monoclonal lymphopathy as has been described in prolonged hepatitis C infection.