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1.
Rev Med Interne ; 43(4): 206-211, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34953621

ABSTRACT

INTRODUCTION: Hypo- and hypercalcemia are common and some causes require urgent diagnosis and treatment. Measurement of ionized calcium is the reference test to diagnose calcium disorders but total calcium adjusted for protein or albumin concentration is more often used. METHODS: Patients hospitalised in a general internal medicine department from September 2013 to December 2015 who had a total plasma calcium concentration and a serum albumin or protein concentration measured within 24h of a ionized calcium blood measurement were included. Total calcium was adjusted for protein or albumin concentration using widely used formulas and compared to ionized calcium as the gold standard. RESULTS: Among 210 included patients, 46 (22%) had hypocalcemia, 124 (59%) normocalcemia and 40 (19%) hypercalcemia according to ionized calcium concentration. Total calcium had 50% sensitivity and 95% specificity to diagnose hypocalcemia and a 93% sensitivity and 89% specificity to diagnose hypercalcemia. Adjusting total calcium for protein or albumin concentrations did not increase and sometimes decreased diagnostic accuracy. CONCLUSION: Total calcium, with or without albumin/protein adjustment, is poorly sensitive to screen for hypocalcemia. Unadjusted total calcium is as sensitive as protein- or albumin-adjusted total calcium to screen for hypercalcemia. These data argue against the use of albumin- or protein-adjusted calcium. Ionized calcium measurement should be performed to confirm dyscalcemia in patients with abnormal total calcium concentration and to rule out hypocalcemia in patients with total calcium concentration in the lower range of normal values.


Subject(s)
Hypercalcemia , Hypocalcemia , Calcium , Calcium, Dietary , Humans , Hypercalcemia/diagnosis , Hypocalcemia/diagnosis , Internal Medicine , Serum Albumin
2.
Ann Dermatol Venereol ; 139(3): 199-203, 2012 Mar.
Article in French | MEDLINE | ID: mdl-22401685

ABSTRACT

BACKGROUND: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione. CASE REPORT: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued. DISCUSSION: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.


Subject(s)
Anticoagulants/adverse effects , Drug Eruptions/diagnosis , Phenindione/analogs & derivatives , Protein C Deficiency/diagnosis , Protein C Deficiency/genetics , Skin/pathology , Venous Thromboembolism/drug therapy , Abdominal Wall , Aged , Anticoagulants/therapeutic use , Biopsy , Capillaries/pathology , Drug Eruptions/pathology , Female , Genetic Carrier Screening , Humans , Long-Term Care , Necrosis , Phenindione/adverse effects , Phenindione/therapeutic use , Protein C Deficiency/chemically induced , Protein C Deficiency/pathology , Recurrence
3.
J Thromb Haemost ; 8(12): 2718-26, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20880255

ABSTRACT

BACKGROUND: Only a few mutations associated with qualitative protein S deficiency have already been described. Sensitivity and specificity for type II PROS1 mutations of commercially available reagents for measuring Protein S (PS) activity are not well established. Whether these mutations are significant risk factors for thrombosis remains an unresolved question. METHODS: In order to address the first point, we present and discuss the results of PROS1 analysis performed in the 30 probands with type II PS-inherited deficiency suspicion and 35 relatives, studied in our laboratory between 2000 and 2008. In order to investigate the influence of type II mutations on the coagulability level, thrombin generation tests were performed on plasma from 102 PROS1 type II, type I/III or PS Herleen mutation heterozygous carriers and controls. RESULTS: Mutations (12 novel, six already described) which probably explain the qualitative phenotype, were found in 27 (90%) out of the 30 probands studied. In relatives, 78% of heterozygotes presented with a type II phenotype. An APC resistance phenotype was documented in type II and type I/III defects heterozygous carriers; however, the effect of type II was milder than the effect of type I/III PS mutations. CONCLUSIONS: A PS functional assay (Staclot PS, Stago) was efficient in screening for PROS1 type II defects, particularly in probands. A significant positive influence of type II mutations on ex vivo thrombin generation was demonstrated. However, whether these mutations increase the risk of venous thromboembolism requires further investigation.


Subject(s)
Blood Proteins/genetics , Mutation , Protein S Deficiency/genetics , Adolescent , Adult , Aged , Female , Genetic Carrier Screening , Humans , Male , Middle Aged , Phenotype , Protein S , Thrombin/biosynthesis , Thromboembolism/genetics , Young Adult
6.
Hum Genet ; 126(3): 449-56, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19466456

ABSTRACT

Hereditary protein S (PS) deficiency is an autosomal disorder caused by mutations in the PS gene (PROS1). Conventional PCR-based mutation detection identifies PROS1 point mutations in approximately 50% of the cases. To verify if gross copy number variations (CNVs) are often present in point mutation-negative hereditary PS deficiency we used multiplex ligation-dependent probe amplification (MLPA) as a detection tool in samples from individuals with a high probability of having true PS deficiency. To this end, DNA samples from nine PS deficient probands with family members (seven type I and two type III) and nine isolated probands (three type I and six type III), in whom PROS1 mutations were not found by DNA sequencing, were evaluated. An independent quantitative PCR (qPCR) was performed to confirm the findings of the MLPA assay. Family members were also tested when DNA was available. Gross abnormalities of PROS1 were found in six out of eighteen probands. In three probands complete deletion of the gene was detected. Two probands had a partial deletion involving different parts of the gene (one from exon 4 through 9 and another from exon 9 through 11). One family showed a duplication of part of PROS1. qPCR analysis was in accordance with these results. In conclusion, this study substantiates that gross gene abnormalities in PROS1 are relatively common in hereditary PS deficient patients and that MLPA is a useful tool for direct screening of CNVs in PROS1 point mutation-negative individuals.


Subject(s)
Blood Proteins/genetics , Gene Deletion , Gene Duplication , Point Mutation , Protein S Deficiency/genetics , DNA Mutational Analysis/methods , Exons , Family Health , Female , Humans , Male , Mutation , Pedigree , Polymerase Chain Reaction , Protein S/genetics
7.
Ann Biol Clin (Paris) ; 66(4): 437-40, 2008.
Article in French | MEDLINE | ID: mdl-18725346

ABSTRACT

The association of a thrombo-embolic venous disease and multiple osteonecroses occurring in the presence of biological risk factors for thrombosis is rarely described in the literature. We report here the case of a 35-year old patient with such clinical manifestations. This patient is heterozygous for a novel mutation of the protein C gene (N102S) and for FV Leiden polymorphism. The clinical history is characterized by numerous thrombo-embolic venous episodes associated with several episodes of epiphysis osteonecrosis requiring two hip total prostheses and two knee total prostheses. The particular clinical features here are the multiple osteonecroses and the unusual localisation of brain and genital thromboses. The absence of both venous thromboembolic and osteonecrosis events in the relatives presenting the same genetic pattern suggests broad phenotype variations in the clinical expression of these genetic abnormalities. In osteonecrosis associated with thrombophilia, some authors have proposed treatment with stanazolol, which increase circulating protein C concentration. The effectiveness of this drug among such patients should be evaluated by clinical studies.


Subject(s)
Factor V/genetics , Heterozygote , Mutation , Osteonecrosis/genetics , Protein C/genetics , Venous Thrombosis/genetics , Adult , Humans , Male , Osteonecrosis/complications , Pedigree , Venous Thrombosis/complications
9.
J Thromb Haemost ; 2(11): 1882-8, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15550015

ABSTRACT

Heparin-induced thrombocytopenia (HIT) occurs in nearly 3% of patients treated with heparin after cardiopulmonary bypass (CPB). HIT carries a risk of severe thrombotic complications, and must be diagnosed rapidly. To identify simple criteria for estimating the probability of HIT after CPB, we retrospectively analyzed the files of 84 patients with suspected HIT after CPB and we analyzed the usefulness of several variables collected at the time of HIT suspicion to estimate HIT probability. HIT was confirmed in 35 cases and ruled out in 49 cases, on the basis of a platelet increment after heparin withdrawal, detection of heparin-dependent antibodies, and absence of other clear cause of thrombocytopenia. A biphasic platelet count from CPB to the first day of suspected HIT, an interval of >/= 5 days from CPB to the first day of suspected HIT, and a CPB duration of

Subject(s)
Cardiopulmonary Bypass/adverse effects , Heparin/adverse effects , Predictive Value of Tests , Probability , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Aged , Antibodies/blood , Diagnosis, Differential , Female , Heparin/immunology , Humans , Male , Middle Aged , Platelet Count , Retrospective Studies , Risk Factors
10.
J Thromb Haemost ; 2(9): 1594-600, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15333036

ABSTRACT

Oral contraceptive (OC) use is associated with an increased risk of venous thromboembolism. Previous data reported higher thrombotic risk in women using third-generation combined OC than in those using second generation OC. The difference could be explained by differential effects of progestagens on plasma sensitivity to activated protein C (APC). The main purpose of this cross-sectional study was to assess the influence of a progestagen-only OC (chlormadinone acetate) as well as the effect of several combined OC with different progestagen components on APC resistance. The effect of APC on endogenous thrombin potential (ETP) was investigated in the plasma of healthy women using either combined OC (n=82) or progestagen-only OC (n=28), and in non-users (n=64). Carriers of factor V Leiden were excluded. Compared with non-users, there was no significant change in APC resistance in women using progestagen-only OC. Women who used combined OC were less sensitive to APC than non-users (P < 0.001) and the difference was significantly more pronounced in women using third-generation OC (n=41) than in those who used second-generation OC containing levonorgestrel (n=22) (P < 0.05). Compared with OC containing levonorgestrel, use of norethisterone-containing OC (n = 9) was associated with an increased resistance to APC (P < 0.05). Women who used cyproterone-containing OC (n = 10) were less sensitive to APC than those using third-generation OC (P < 0.05) or second-generation OC containing levonorgestrel (P < 0.05). Protein S, factor II and FVIII levels explained in part the OC-related changes in APC sensitivity variations. ETP-based APC resistance may contribute to explain why different brands of OC can be associated with different levels of thrombogenicity.


Subject(s)
Activated Protein C Resistance/chemically induced , Contraceptives, Oral/adverse effects , Progesterone Congeners/adverse effects , Activated Protein C Resistance/blood , Adult , Chlormadinone Acetate/adverse effects , Contraceptives, Oral, Combined/adverse effects , Contraceptives, Oral, Synthetic/adverse effects , Cross-Sectional Studies , Estrogen Replacement Therapy/adverse effects , Female , Humans , Middle Aged , Thromboembolism/chemically induced , Venous Thrombosis/chemically induced
11.
J Thromb Haemost ; 2(8): 1334-40, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15304039

ABSTRACT

BACKGROUND: The FIIG20210A polymorphism has been associated with arterial wall thickness and atherothrombotic diseases in selected subgroups. The FVArg506Gln polymorphism does not seem to be associated with arterial diseases. Few data are available on these polymorphisms and the risk of peripheral arterial disease (PAD). OBJECTIVES: To study the association between the FIIG20210A and FVArg506Gln polymorphisms and PAD and its clinical severity. To examine the potential interactions with traditional vascular risk factors. PATIENTS AND METHODS: We studied 184 consecutive male patients under 70 years of age with symptomatic PAD and 330 age-matched male controls free of symptomatic PAD and with no cardiovascular history. We evaluated the FIIG20210A and FVArg506Gln polymorphisms in all subjects. RESULTS: Mean age was 57.1 +/- 7.2 years (cases) and 56.7 +/- 7.6 years (controls). The FII20210A allele was more frequent in PAD patients with odds ratios (OR) of 3.77 (1.39-10.2) in univariate analysis and 4.30 (1.3-14.7) after adjustment for diabetes, smoking, hypertension and hypercholesterolemia. In smokers or past smokers the magnitude of the association was markedly increased but there was no evidence of an interaction between tobacco exposure and FIIG20210A. In case subjects, the FII20210A allele was also associated with critical ischemia [OR = 4.1 (1.1-15.7), P = 0.039 in multivariate analysis]. FVArg506Gln was not associated with PAD [OR = 0.65 (0.27-1.54) and 0.77 (0.28-2.1) in univariate and multivariate analyses, respectively]. CONCLUSIONS: The FIIG20210A gene polymorphism may be a risk factor for PAD and its severity. In contrast, the FVArg506Gln polymorphism is not associated with PAD.


Subject(s)
Arteries/pathology , Factor V/genetics , Peripheral Vascular Diseases/genetics , Polymorphism, Genetic , Prothrombin/genetics , Aged , Alleles , Case-Control Studies , Diabetes Mellitus/pathology , Genotype , Humans , Hypercholesterolemia/genetics , Hypertension/genetics , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Risk Factors , Smoking
12.
Arch Mal Coeur Vaiss ; 96(11): 1111-5, 2003 Nov.
Article in French | MEDLINE | ID: mdl-14694788

ABSTRACT

Venous thrombo-embolic disease is a multifactorial disease which arises in situations of thrombosis risk with poorly understood genetic and/or acquired risk factors. Constitutional anomalies concerning five coagulation proteins (antithrombin, protein C, protein S, factor V and prothrombin) are established risk factors for which the harmful role has been demonstrated in thrombophilic families and/or in case-control studies. New studies (twin studies, GAIT study) which use joint subjects and appropriate statistical methods are aimed at a better understanding of the genetic component and the environmental component of thrombotic risk. They have allowed demonstration of the importance of the contribution of heredity to the variability of the coagulation parameter concentration and the variability of susceptibility to thrombosis, and have implied the influence of genes with pleiotrophic effect. The identification of these new loci will allow a better evaluation of the components of thrombotic risk and perhaps lead to individualised preventive therapeutic management.


Subject(s)
Genetic Predisposition to Disease , Thromboembolism/genetics , Venous Thrombosis/genetics , Estrogens/pharmacology , Humans , Phenotype , Risk Factors , Thromboembolism/physiopathology , Venous Thrombosis/physiopathology
14.
Blood Coagul Fibrinolysis ; 14(2): 191-6, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12632031

ABSTRACT

Population-based case-control studies and cases previously published suggest that the prothrombin G20210A mutation is a weak risk factor for thrombosis, leading to clinical expression mainly in the presence of other risk factors. We report the results of plasma and genetic analyses performed in a 13-year-old symptomatic boy homozygous for the 20210A allele and in his family, which are in accordance with this suggestion. These analyses demonstrated the presence of several PROC (R-5W, R87H) and PROS (R60C, T103N) gene mutations in this family. These additional mutations have modulating effects on clinical expression of the G20210A mutation. The present family study illustrates the concept of 'mild' mutation and the hypothesis that familial thrombophilia is a multifactorial disease.


Subject(s)
Protein C/genetics , Protein S/genetics , Prothrombin/genetics , Thrombophilia/genetics , Adolescent , Adult , Aged , Family Health , Female , Genetic Carrier Screening , Homozygote , Humans , Immunoblotting , Male , Middle Aged , Mutation , Pedigree , Protein C/metabolism , Protein C Deficiency/blood , Protein C Deficiency/genetics , Protein S/metabolism , Protein S Deficiency/blood , Protein S Deficiency/genetics , Thrombophilia/blood , Thrombosis/epidemiology , Thrombosis/genetics
15.
Gynecol Obstet Fertil ; 30(7-8): 611-5, 2002.
Article in French | MEDLINE | ID: mdl-12199045

ABSTRACT

The knowledge of genetic and occurred risk factors allows us to propose laboratory investigations in patients with thromboembolism (TE) to evaluate the risk for recurrence. Beside coagulation inhibitor deficiencies accounting for less than 10% of cases, factor V Leiden and prothrombin G20210A mutations are found in around 30% and 10% respectively. Increased factor VIII and hyperhomocysteinemia resulting from interaction of genetic factors and environmental factor are also risk factors for TE. Finally, antiphospholipid antibodies, a complex family of antibodies recognizing various phospholipid or phospholipid binding proteins, are also associated with TE.


Subject(s)
Thrombosis/diagnosis , Clinical Laboratory Techniques , Factor V/genetics , Factor VIII/metabolism , Humans , Hyperhomocysteinemia/complications , Mutation , Prothrombin/genetics , Recurrence , Risk Factors , Thrombosis/etiology , Thrombosis/genetics
16.
J Pediatr ; 139(5): 741-3, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11713457

ABSTRACT

Fatal cerebral hemorrhage involving the left thalamus in a neonate was attributed to deep cerebral vein thrombosis. Although antithrombin levels were at the lower end of the normal range, family and genetic studies showed constitutional type I antithrombin deficiency related to a novel missense mutation in the antithrombin gene.


Subject(s)
Antithrombins/deficiency , Cerebral Hemorrhage/genetics , Point Mutation , Antithrombins/genetics , Fatal Outcome , Humans , Infant, Newborn , Male , Venous Thrombosis/complications
19.
Thromb Res ; 101(2): 35-43, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11342204

ABSTRACT

The incidence of coronary heart disease is lower in premenopausal than in postmenopausal women, and estrogen use may be cardioprotective among postmenopausal women. Cellular adhesion molecules (CAM) are involved in the early stage of atherosclerosis, and short-term administration of oral estrogen decreased plasma concentrations of their soluble forms in postmenopausal women. However, data evaluating transdermal estrogen are sparse and long-term effect of hormone replacement therapy (HRT) on CAM is unknown. Therefore, we have investigated the association of circulating CAM (cCAM) with menopausal status and long-term HRT. Plasma levels of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), P-selectin, E-selectin, C-reactive protein (CRP), and fibrinogen were measured in 74 premenopausal women, 60 postmenopausal women not using HRT, 30 postmenopausal women using opposed oral estrogen therapy, and 30 postmenopausal women using opposed transdermal estrogen therapy. All women were apparently healthy and aged between 45 and 54 years. Duration of HRT ranged from 3 to 96 months. Postmenopausal women not receiving HRT had 24% higher mean levels of cICAM-1 than premenopausal women (318 vs. 255 ng/ml, P < .001). In postmenopausal women, users of oral estrogen had 16% lower, and users of transdermal estrogen had 17% lower mean levels of cICAM-1 than non-users (268 and 264 vs. 318 ng/ml, P = .001 for both comparisons). Furthermore, in users of transdermal route, the lowering effect of estrogen on cICAM-1 was dependent on treatment duration, while no time-dependent effect was seen in oral estrogen users. Users of transdermal estrogen had lower cVCAM-1 and P-selectin levels than postmenopausal non-users (327 vs. 364 ng/ml (P = .05) and 18 vs. 23 ng/ml (P = .05). There was no difference in CRP and E-selectin levels between the groups. Adjustment for age and body mass index (BMI) made no substantial change in the results. These data suggest that oral and transdermal estrogen may play a long-term cardioprotective role through favourable changes in endothelial function.


Subject(s)
Cell Adhesion Molecules/blood , Estrogens/administration & dosage , Menopause/blood , Administration, Cutaneous , Administration, Oral , Analysis of Variance , Case-Control Studies , E-Selectin/blood , Estrogens/pharmacology , Female , Hormone Replacement Therapy/methods , Humans , Intercellular Adhesion Molecule-1/blood , Middle Aged , P-Selectin/blood , Time Factors , Vascular Cell Adhesion Molecule-1/blood
20.
Arterioscler Thromb Vasc Biol ; 21(3): 445-51, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11231927

ABSTRACT

We analyzed the distal promoter region of the thrombomodulin (TM) gene (nucleotides -300 to -2052) in subjects from the Paris Thrombosis Study (PATHROS), a French case-control study of venous thrombosis, to identify polymorphisms that might modify TM gene expression. Eight novel mutations were found in the 40 DNA samples initially screened. Two of these mutations (-1748G/C and -1208/-1209 del TT) were frequent. One rare transition (-1166G/A) might have functional consequences owing to its position. These 3 mutations were screened for in the entire study population of 327 patients and 398 controls. None of the 3 was significantly associated with thrombosis. Interestingly, the -1208/-1209 TT deletion was associated with varicose veins in the patients. This mutation was in tight linkage disequilibrium with the +1418 C/T change in the coding sequence, a known polymorphism that predicts an Ala 455 Val substitution in the sixth epidermal growth factor-like TM module, a domain previously implicated in the proliferative functions of TM. This linkage suggests that the Ala 455 Val mutation may promote changes in these functions and thus be involved in varicose vein formation.


Subject(s)
Promoter Regions, Genetic/genetics , Thrombomodulin/genetics , Varicose Veins/genetics , Venous Thrombosis/genetics , Adult , Alleles , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Mutation , Prothrombin/metabolism , Thrombomodulin/metabolism
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