The paradoxical association between inherited factor VII deficiency and venous thrombosis.

Inherited factor VII (FVII) deficiency is considered to be a haemorrhagic disease. Nonetheless, some patients paradoxically present with venous thrombosis. We assessed whether there was a link between phenotype and genotype in seven patients with inherited FVII deficiency and thrombosis (eleven venous thrombotic events). For each patient (FVII:C < 50%), clinical data were collected, aetiological assessment of risk factors for thrombosis was investigated, and direct sequencing of the nine exons and promoter of the FVII gene (F7) was performed. We present the second series ever published on FVII patients with thrombosis. In nine of the eleven thrombotic events, there was at least one classical triggering risk factor; clinical (n = 4), familial antecedent (n = 2), or biological, defined by phospholipid-binding antibodies or elevated FVIII:C levels (n = 7). In contrast to a previous series, only two events occurred after surgery, performed both with and without replacement therapy. The thrombotic event remained unexplained in one young patient, highlighting the lack of 'protection' against venous thrombosis by low FVII:C levels. Genetic mutations were found to be heterogeneous. Among the seven F7 sequence alterations identified in the present study, only two (p.Ala354Val and p.Arg364Gln) have previously been reported in FVII-deficient patients presenting with venous thrombosis. Our genetic analyses of the F7 mutations in these patients show the complexity of FVII deficiency associated with thrombosis. These data justify a holistic, clinical and biological approach for patients with these specific symptoms. This series also strongly suggest that mild FVII deficiency should not prevent physicians from using antithrombotic prophylaxis in FVII-deficient patients.

Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate.

The incidence of factor VIII inhibitor was studied in a cohort of 56 previously untreated patients with severe hemophilia A (factor VIII below 1 U/dl). They received only one brand of highly purified factor VIII concentrate (HPSD-VIII) prepared by conventional chromatography with a solvent-detergent step for viral inactivation. Follow-up since the first infusion of HPSD-VIII was from 1 to 76 months (mean = 29) and cumulative exposure days (CED) from 1 to over 100 (median = 26). Five patients (9%) developed an inhibitor after 6 to 19 CED, only one being a high responder (2%), showing a low incidence of inhibitor compared with previous studies using high purity plasma-derived or recombinant products.

CD5 negative B-cell chronic lymphocytic leukemia: clinical and biological features of 42 cases.

Chronic lymphocytic leukemia cell (CLL) usually (95%) express B-phenotype and the CD5 antigen which is usually present on the surface of normal T cells. However, among B CLL, 7 to 20% do not express CD5. The significance of the lack of CD5 expression remains unclear. We reviewed 42 consecutive CD5- B CLL seen in three French medical centers from 1985 to 1991 and compared them with 79 CD5+ B CLL. Immunophenotype studies were performed using indirect immunofluorescence under light microscopy as well as flow cytometry after 1988. B CLL was considered to be CD5 negative when less than 5% of mononuclear cells expressed CD5 after subtraction of the number of T-cells. Cases with CD5- B CLL had isolated splenomegaly more frequently (p = 2.10(-7)). They frequently expressed a higher level of surface immunoglobulin (S-Ig) or the switch mu/delta phenotype (p = 4.7 10(-2)). The median survival time was not reached but no significant difference between CD5 negative and positive B CLL was observed at the time of our data analysis (p = 0.97). Clinical presentation of CD5- B CLL seems to be different from other forms of B CLL. Although, no conclusion can be reached in terms of prognosis, CLL with low expression of CD5 should be regarded as a subtype of CLL with a different clinical presentation than CD5+ CLL.

Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V Leiden mutation and type I factor V deficiency. Variable expression when analyzed by different activated protein C resistance functional assays.

The laboratory diagnosis of activated protein C (APC) resistance is based on a weak anticoagulant response to APC using a chronometric procedure confirmed in almost all cases by molecular diagnosis of the FV Leiden mutation. A recently-developed Xa-based assay (Accelerimat, Biomerieux) was compared with two different activated partial thromboplastin time (APTT)-based procedures (Coatest APC resistance and Modified Coatest, Chromogenix) in 115 patients with a personal or familial history of thrombotic disease, or both, being studied for the FV Leiden mutation. Our results confirmed the improvement in specificity for the FV Leiden mutation when the APTT-based assay was performed after dilution of samples in FV-deficient plasma (Modified Coatest). However, five patients who were heterozygous for the FV Leiden mutation appeared to be homozygous when tested by both APTT-based assays. These patients, belonging to three different families, had a FV type I deficiency with FV plasma levels between 43 and 64%. In contrast, the Xa-based method was not influenced by the decrease in plasma FV levels. Thus, this procedure is more specific than APTT-based assays to predict the genotype status of the FV Leiden mutation.

[Exacerbation of an autoimmune thrombocytopenic purpura during treatment with interferon alpha in a woman with chronic viral hepatitis C]. / Exacerbation d'un purpura thrombopénique auto-immun au cours du traitement par l'interféron alpha chez une femme atteinte d'une hépatite chronique virale C.

We report the case of a 40-year-old woman with chronic viral hepatitis C and latent idiopathic thrombocytopenic purpura who developed severe thrombocytopenia during alpha interferon therapy. Platelet-associated IgG titers were elevated, and platelet antibodies were detected in the serum. Intravenous administration of high-dose polyvalent immunoglobulins was ineffective, but a normal platelet count was obtained after corticosteroid therapy. A history of idiopathic thrombocytopenic purpura could be considered a contraindication for alpha-interferon therapy in patients with chronic viral hepatitis.

[Preliminary study of the use of low-molecular weight heparin to prevent thrombotic risk]. / Etude préliminaire à l'utilisation des héparines de bas poids moléculaire en prévention du risque thrombotique.

This study involved two stages: In vitro study. Three LMWHs, CY 216-CY 222 (Choay) and PK 10169 (Pharmuka), were compared to standard heparin, SH (Choay), and to a high-molecular-weight heparin, HAF (Choay), which particularly revealed a dissociation of anti-Xa (++) and anti-IIa (+) activities for the LMWHs: (table: see text) In vivo study. Healthy volunteers. Subcutaneously injections of PK 10169 or CY 222 according to various protocols (rythm of injections, dosage). For both LMWHs, the dissociation of anti-Xa and anti-IIa activities reoccurs in vivo. A peak of anti-Xa effect was observed 3 to 4 hours after the injections. The duration period of this activity is about 12 hours. The importance of the global platelet tests HT and TEG (modified for the highest doses) should be noted. Study of haemorrhagic tendencies in patients with slight thrombotic risk. From this preliminary study, protocols with CY 216, CY 222 and PK 10169 are proposed for the prevention of thrombotic risk in orthopaedic surgery (injections at 12-hour intervals).

Acquired inhibitor to factor VIII in a patient with Hodgkin's disease following treatment with interferon-alpha.

We describe a young woman who developed acquired haemophilia after 18 months of interferon (IFN-)-alpha therapy. This patient had been monitored since 1992 for Hodgkin's disease initially treated by chemotherapy. After two relapses, she received intensive chemotherapy followed by an autologous peripheral progenitor cell graft. IFN-alpha was then administered for 18 months. Bleeding of the limbs and tongue occurred 1 month after withdrawal of IFN-alpha and high titres (123 Bethesda units) of autoantibody to factor VIII (FVIII):C were measured. Prednisone (1 mg kg(-1) day(-1)) achieved rapid cessation of the bleeding and FVIII autoantibodies were undetectable 5 months later. This case report suggests that the activated partial thromboplastin time should be regularly checked in every patient treated with IFN-alpha in cases of unexplained bleeding, together testing for antibodies to FVIII if the bleeding is prolonged.

[HIV infection among type A and B hemophiliacs]. / Infection VIH chez les hémophiles A et B.

Evolution of HIV infection was studied in 480 hemophiliacs A and 78 hemophiliacs B treated in the "Centre-West" Region. 23.3% hemophiliacs A and 46.1% hemophiliacs B were contaminated by HIV. In this region, HIV seroprevalence in hemophiliacs A was lower than the prevalence noted at the national level (51.2%); this is certainly due to the use of frozen cryoprecipitates in the treatment of a high number of hemophiliacs A. A higher number of hemophiliacs B developed the disease: 12.5% hemophiliacs A versus 22% hemophiliacs B. Moreover hemophilic B patients had a more rapid evolution towards the disease since 6 out of 14 hemophiliacs A and 7 out of 8 hemophiliacs B with AIDS died. The fact that hemophiliacs B were significantly older than hemophiliacs A might be one of the reasons, but it must be noted that the contamination often occurred earlier in hemophiliacs B and was perhaps more important. The more severe evolution in the hemophiliac B group noted in our region is not found in American studies, which may be due to the different ways of preparing Factor IX concentrates in France and the United States.

The kinetics of antibodies against hepatitis C virus may predict viral clearance in exposed hemophiliacs.

Several studies have reported the spontaneous loss of hepatitis C virus (HCV) antibodies in HCV-exposed persons. However, the relationship between seroreversion and spontaneous virus clearance has yet to be precisely determined in a single homogeneous population of untreated immunocompetent patients. In this study, 32 human immunodeficiency virus-seronegative hemophiliacs who had been exposed to HCV were followed for a mean duration of 141 months; 22 remained chronic carriers (68.8%). All but 1 of the nonviremic patients (90.0%) showed partial (8 cases) or complete (2 cases) seroreversion. In contrast, all but 1 of the viremic patients (95.1%) had a stable serologic profile when analyzed by a recombinant immunoblot assay. The results indicate that any HCV antibody-positive immunocompetent patient with no detectable serum HCV RNA and normal alanine aminotransferase values and whose serial samples show a progressive decrease in the level of HCV antibodies present may be considered as having a resolved infection.