Factor V (Arg 506-->Gln) mutation in young survivors of myocardial infarction

Many young patients with venous thromboembolic disease are partially resistant to the anticoagulant action of activated protein C as a result of factor V (Arg 506 --> Gln) mutation. The frequency of this mutation in young patients with arterial thrombotic diseases, such as myocardial infarction, is less well established. We studied 100 young patients with myocardial infarction and 100 age- and sex-matched controls. One patient (1%; 95% CL 0.05-6.2) and two controls (2%; 95% CL 0.3-7.7) were heterozygotes for the mutation; there was no homozygote in either group. Hence, premature myocardial infarction is not associated with heterozygosity for factor V (Arg 506 --> Gln) mutation.     

Oligonucleotide ligation assay for detection of the factor V mutation (Arg506-->Gln) causing protein C resistance

Two distinct stages in regulation of protein kinases are detectable upon cellular transformation of CEF induced by pp60v-src. Upon cellular transformation induced by ts v-src mutants, the kinase activities of Mek and p42Erk are rapidly induced at the early stage and significantly decreased at the late stage of cellular transformation. In contrast, a novel p63SAMK is partially activated at the early stage and is fully activated at the late stage of cellular transformation. However, p90RSK is activated through the entire course of cellular transformation. In this study, I detect a transient down-regulation of p90RSK activity that is inducible in cultures at the late stage of the src-induced cellular transformation by an increase of extracellular pH value from 7 to 8 and unidentified components in DMEM, but not in cultures which are at the early stage. Concomitant with down-regulation of p90RSK activity, the kinase activities of Mek, p42Erk, and p63SAMK are also down-regulated. Blockage of down-regulation of p90RSK activity by pretreatment of cells with different phosphatase inhibitors correlates with blockage of the down-regulation of either p42Erk or p63SAMK activity. Multiple pathways appear to involve in regulation of p90RSK activity. The discrepancy in regulation of protein kinase activity between the early and late stages of cellular transformation induced by pp60src may indicate a change in signaling cascades during the progress of cellular transformation. The induction of the down-regulation event in this study may provide a new approach to investigate the regulation not only of protein kinases but also phosphatases in transformed cells.     

The factor V Leiden mutation (R506Q) is not a major risk factor for migrainous cerebral infarction

The etiology of migrainous cerebral infarction is unknown, but may involve prothrombotic coagulation abnormalities. Therefore, we studied resistance to activated protein C and the presence of the Arg506Gln factor V Leiden mutation in 20 patients with migrainous cerebral infarction. Only one heterozygous carrier of the mutation was found, whereas other patients did not carry the mutation. This indicates that the factor V Leiden mutation is not a major risk factor for migrainous cerebral infarction.     

A case of hypereosinophilic syndrome associated with factor V Leiden mutation and thrombosis

The authors present a case of serotonin syndrome in a prisoner who was transferred to a psychiatric hospital because of increasing psychotic symptoms. They discuss some factors that appear to put some populations at higher risk for such syndromes, and recommend increased vigilance for such problems in those identified populations.     

The prevalence of factor V Leiden (1691 G-->A) mutation in Turkey

Resistance to activated protein C (APC), which is caused by a single point mutation in the gene for factor V, is a common risk factor for thrombosis. In this study, we screened factor V (FV) Leiden mutation in 81 subjects. The mutation in the heterozygous form was found in 7.1 percent of our normal population. This high frequency suggests that screening for the FV mutation should be considered in patients with a family history of thrombosis.     

A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506)

Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.     

Antenatal screening for factor V Leiden mutation: a critical appraisal

Because of its acid-labile nature, omeprazole is usually administered as encapsulated enteric-coated granules. The gelatin capsule and acid-resistant coating are essential for effective drug absorption and optimal bioavailability. OBJECTIVE: This study tested the effectiveness of nonencapsulated, intact omeprazole granules in suppressing intragastric acidity when administered through a gastrostomy. METHODS: Fourteen male patients with established gastrostomies underwent a baseline 24-h intragastric pH monitoring study while off any acid-suppressing medication. Via the gastrostomy, they then received 7 days of dosing with 20 mg omeprazole as intact granules in orange juice. Twenty-four-hour intragastric pH monitoring was repeated on the seventh day. RESULTS: Mean intragastric pH during the baseline study was 1.8 (+/- SD 0.7). This pH increased to 4.9 +/- 0.8 with omeprazole granules (p < 0.0001). Median intragastric pH rose from 1.3 to 5.3 (p < 0.0001). During the baseline study, intragastric pH was above 3 for 21.2 +/- 14.1%, above 4 for 14.9 +/- 11.0%, and above 5 for 9.5 +/- 8.4% of the 24-h recording period. Corresponding values after 7 days of omeprazole were 80 +/- 15.1%, 72.5 +/- 16.3%, and 59.1 +/- 16.6% (p < 0.0001 for each comparison with pretreatment values). CONCLUSION: Omeprazole effectively suppresses intragastric acidity when given through a gastrostomy tube as nonencapsulated, intact granules.     

Large-scale screening for factor V Leiden mutation in a north-eastern German population

A 37-year-old man was referred with thoracic pain after a deceleration trauma. He also had a cerebral contusion and a wrist fracture. There were no sings of hypovolemic shock. Computerized tomography (CT) of the chest and transoesophageal echocardiography (TEE) demonstrated a type B aortic dissection originating just distal to the left subclavian artery. There was a patent false lumen without rupture or distal ischaemia. Conservative treatment was given. A paralytic ileus developed and abdominal complaints persisted for several months. Angiography showed normal patency of mesenteric vessels. On follow-up, 3 years after the accident a slight aortic dilation was found on CT thorax without development of a post-dissection aneurysm. Blunt thoracic injury to the aorta usually gives rise to aortic rupture in the region of the isthmus, which can be complete or partial. In the latter case a false aneurysm may develop. An intimal tear after blunt trauma leading to type B aortic dissection rarely occurs. General principles regarding treatment of type B dissection also apply to this particular condition.     

Effect of anticoagulant therapy on the hypercoagulable state in patients carrying the factor V Arg506Gln mutation

The National Practitioner Data Bank (NPDB), created by the 1986 Health Care Quality Improvement Act, has been in operation since 1990. Hospitals and other credentialing bodies must query the NPDB when granting and renewing privileges. The NPDB receives about 25,000 reports of adverse actions against health practitioners each year. The NPDB was designed to be a flagging system providing information to licensing or credentialing authorities who would further examine practitioner records. Its purpose is to ensure that decision makers have information that might not otherwise be readily available, especially in the case of incompetent practitioners who move from hospital to hospital or state to state. Access to NPDB information is a concern for consumers and providers alike. Only 2% of matched reports to the NPDB made a difference in hospital privileging decisions. A limitation of NPDB information is that malpractice payments recorded in the NPDB do not necessarily constitute a comprehensive and definitive reflection of actual health care incompetence. All health care providers need to be aware of the NPDB, its mission, potential impact on their ability to be credentialed, and proposed additional uses of its information.     

Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients

BACKGROUND and PURPOSE: Different coagulation disorders have been associated with cerebral venous thrombosis (CVT). Until now, fewer than 50 patients have been reported with CVT and the factor V Leiden (FVL) mutation. Although the prevalence of FVL-positive patients with CVT ranged from 10% to 25%, it was as low as 0.5% to 3% in the control groups. Most other studies had not systematically searched for concomitant risk factors or previous thromboembolic events. To better define the relevance of the FVL mutation in conjunction with additional risk factors in CVT, we conducted the present case-control study. METHODS: Fifty-five patients with CVT were compared with 272 healthy controls. A standardized interview regarding established risk factors for venous thrombosis and the patients' and their families' histories for thromboembolic events was performed. The presence of the FVL mutation was determined by polymerase chain reaction on DNA obtained from peripheral blood leukocytes. RESULTS: Of 55 patients, 8 (14.5%) were heterozygous for the FVL mutation compared with 17 of 272 controls (6.25%). The relative risk for the presence of FVL was 2.55 (95% confidence interval, 1.04 to 6.26; P=0.04). Additional risk factors for CVT were frequently found in both the presence and absence of FVL. Recurrence of venous thromboembolic events was more frequent in patients with the FVL mutation (5 of 8 patients, 62.5%) than in those without this anomaly (8 of 47 patients, 17%; P<0.005). CONCLUSIONS: Our study confirms the FVL mutation as the most relevant hereditary risk factor for CVT. Coexisting risk factors are usually involved in the initiation of CVT. Patients with the FVL mutation are at an increased risk for recurrent venous thrombosis.     

"Pseudo homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds

We report a prospective, stratified study of 60 PCA-cups and 60 RM-polyethylene cups which have been followed for a median time of 90 months, with annual radiography. The radiological migration of cups was measured by the computer-assisted EBRA method. A number of threshold migration rates from 1 mm in the first year to 1 mm in five years have been assessed and related to clinically determined revision rates. A total of 28 cups showed a total migration of 1 mm or more within the first two years; 13 of these cups have required revision and been exchanged. The survival curves of cups which had previously shown early migration were considerably different from those without early migration. For cups with a migration of less than 1 mm within the first two years the mean survival at 96 months was 0.96 +/- 0.02; for migrating cups, it was 0.63 +/- 0.11 (log-rank test, p=0.0001; chi-square value=39.4). Early migration is a good predictor for late loosening of hip sockets.     

The factor V Leiden mutation increases the risk of venous thrombosis in patients with inflammatory bowel disease

BACKGROUND & AIMS: Thromboembolic disease is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). The aim of this study was to determine the incidence and possible association of the factor V Leiden mutation with the development of thrombosis in patients with IBD. METHODS: This retrospective study included 11 patients with IBD and arterial or venous thrombosis and 51 patients with IBD and no history of thrombosis who were matched for age, sex, ethnic/racial origin, and type of IBD (controls). The presence of the factor V Leiden mutation was determined by coagulation assay and confirmed by a polymerase chain reaction method. RESULTS: Four of 11 IBD patients (36%) with thrombosis and 2 of 51 IBD controls (4%) were heterozygotes for the factor V Leiden mutation (relative risk, 14.00; 95% confidence interval, 1.55-169.25; P = 0.009, Fisher exact test). All thrombotic events in the patients with activated protein C resistance were venous with a calculated prevalence of 50% (4 of 8 patients) and a relative risk of venous thrombosis in IBD patients with factor V Leiden of 23 (95% confidence interval, 2-294; P = 0.005). CONCLUSIONS: In patients with IBD, inheritance of the factor V Leiden mutation results in a significant increased risk of venous thrombosis.     

The effect of Arg306-->Ala and Arg506-->Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S

Factor Va (fVa) is inactivated by activated protein C (APC) by cleavage of the heavy chain at Arg306, Arg506, and Arg679. Site-directed mutagenesis of human factor V cDNA was used to substitute Arg306-->Ala (rfVa306A) and Arg506-->Gln (rfVa506Q). Both the single and double mutants (rfVa306A/506Q) were constructed. The activation of these procofactors by alpha-thrombin and their inactivation by APC were assessed in coagulation assays using factor V-deficient plasma. All recombinant and wild-type proteins had similar initial cofactor activity and identical activation products (a factor Va molecule composed of light and heavy chains). Inactivation of factor Va purified from human plasma (fVaPLASMA) in HBS Ca2+ +0.5% BSA or in conditioned media by APC in the presence of phospholipid vesicles resulted in identical inactivation profiles and displayed identical cleavage patterns. Recombinant wild-type factor Va (rfVaWT) was inactivated by APC in the presence of phospholipid vesicles at an overall rate slower than fVaPLASMA. The rfVa306A and rfVa506Q mutants were each inactivated at rates slower than rfVaWT and fVaPLASMA. Following a 90-min incubation with APC, rfVa306A and rfVa506Q retain approximately 30-40% of the initial cofactor activity. The double mutant, rfVa306A/506Q, was completely resistant to cleavage and inactivation by APC retaining 100% of the initial cofactor activity following a 90-min incubation in the presence of APC. Recombinant fVaWT, rfVa306A, rfVa506Q, and rfVa306A/506Q were also used to evaluate the effect of protein S on the individual cleavage sites of the cofactor by APC. The initial rates of rfVaWT and rfVa306A inactivation in the presence of protein S were unchanged, indicating cleavage at Arg506 is not affected by protein S. The initial rate of rfVa506Q inactivation was increased, suggesting protein S slightly accelerates the cleavage at Arg306. Overall, the data demonstrate high specificity with respect to cleavage sites for APC on factor Va and demonstrate that cleavages of the cofactor at both Arg306 and Arg506 are required for efficient factor Va inactivation.     

Factor V Arg306-->Thr (factor V Cambridge) and factor V Arg306-->Gly mutations in venous thrombotic disease

We investigated the prevalence of two reported mutations of the factor V gene (factor V Arg306-->Thr, or factor V Cambridge, and factor V Arg306-->Gly) in 104 relatively young patients with verified venous thrombosis and in 208 age-, sex- and race-matched controls, in order to establish whether the two mutations are associated with increased predisposition for venous thrombosis. PCR amplification followed by BstNI and MspI digestion was employed to determine the genotypes, and each mutation was confirmed by DNA sequencing. Among the controls, one individual was found to be heterozygous for the factor V Arg306-->Thr mutation and one heterozygous for the factor VArg306-->Gly mutation; none of the patients carried either mutation. Our findings do not support factor V Cambridge and factor V Arg306-->Gly as risk factors for venous thrombosis.     

Is hormone replacement a risk factor for ischemic stroke in women with factor V Leiden mutation?

OBJECTIVE: To describe a patient with multifocal cerebral ischemia whose only identified potential risk factors were use of postmenopausal hormone replacement and heterozygosity to factor V Leiden mutation. DESIGN: A case report. SETTING: A tertiary care center. PATIENT: A 51-year-old woman taking hormone replacement (0.625 mg/d of estrogen alternating with 10 mg/d of medroxyprogesterone) presented with a generalized tonic-clonic seizure. She had persistent multifocal non-enhancing lesions on magnetic resonance imaging of the brain. A stereotactic biopsy of the brain performed to exclude gliomatosis cerebri was consistent with cerebral ischemia. An extensive evaluation to uncover the cause of stroke revealed only heterozygosity to factor V Leiden mutation. MAIN OUTCOME AND RESULTS: Hormonal replacement was discontinued and the patient had no recurrent ischemic strokes. CONCLUSIONS: Postmenopausal hormonal replacement may be a risk factor for ischemic stroke in women with the factor V Leiden mutation. Ongoing trials of hormonal replacement provide an opportunity to test this hypothesis.