Prevalence Of Activated Protein C Resistance Research Articles

Prevalence of the Factor V E666D Mutation and Its Correlation With Activated Protein C Resistance in the Chinese Population

Factor V (FV) Leiden mutation-related activated protein C resistance (APCR) is one of the common inherited risk factors for venous thromboembolism (VTE) in caucasian population. Although APCR could be identified in some of the Chinese healthy people and patients with VTE, it was not related to FV Leiden mutation. In 2008, we have identified a novel FV mutation (FV E666D) in exon 13 in a hereditary APCR family. And we presumed that the novel mutation might be a genetic defect of APCR in the Chinese population. The aim of our study was to evaluate the prevalence of FV E666D mutation and its correlation with APCR in the Chinese population in a larger series. From June 2009 to January 2011, 163 consecutive patients who underwent thrombophilia tests in our hospital were recruited. The clinical data were retrospectively reviewed. Thrombophilia tests included APCR, anticoagulant proteins, and antiphospholipid antibodies. Factor V E666D mutation was detected. Of the 163 patients, 6 (3.7%) were identified as APCR positive, 2.9% for patients without thrombosis and 5.1% for patients with thrombosis or thrombosis history. Factor V E666D mutation was not detectable in all the 163 patients including 6 APCR-positive patients. The prevalence of APCR either in the nonthrombotic patients or in the patients with thrombosis was lower than that reported in other Chinese studies. Our study couldn't provide illustration whether FV E666D mutation is correlated with APCR in the Chinese population.

High Prevalence of Activated Protein C Resistance and Factor V Leiden Mutation in an Arab Population and Patients With Venous Thrombosis in Kuwait

Activated protein C resistance (APC-R) because of clotting factor V Leiden mutation (FVL; Arg506Gln; G1691A) is a risk factor for the development of venous thromboembolic disorders (VTE). APC-R/FVL was reported to be very high in White patients with VTE (15% to 65%) and healthy populations (1% to 15%), and to be very low or absent in non-White patients. Studies on Arab patients and populations were very inconsistent. This study reports APC-R and FVL in Arabs living in Kuwait. Whole venous blood samples were collected from 400 patients with VTE and 200 healthy controls, all of whom were of Arab ethnicity living in Kuwait. The samples were used to separate plasma for an APC-R test, and DNA extraction for polymerase chain reaction and restricted fragment length polymorphism were performed. APC-R was on an automated hemostasis analyzer, and values less than 2.0 were reported as APC-R. Polymerase chain reaction and restricted fragment length polymorphism tests were performed using standard methods, and the results were reported as normal wild-type homozygous GG, FVL homozygous AA, or FVL heterozygous GA. Sixty-three out of 400 patients (15.75%) and 4 out of 200 healthy controls (2%) had APC-R and at least one copy of FVL. Fifty-one patients and 4 controls were heterozygous whereas only 12 patients were homozygous. The prevalence of APC-R and FVL is quite high in Arabs living in Kuwait, being comparable with the prevalence reported in Whites, although being toward the lowest values reported there.

The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62-3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.

The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion

The role of thrombophilia and thyroid autoimmunity in unexplained infertility (UI), implantation failure (IF) and recurrent spontaneous abortion (RSA) is controversial and poorly understood. From March, 2004 to January, 2007, 119 women were prospectively included: 32 oocyte donors, 31 patients with UI, 26 with IF and 30 with RSA. The IF and RSA groups presented normal preimplantation genetic screening. Protein C, protein S, antithrombin III, lupus anticoagulant, activated protein C resistance (APCR), immunoglobulin M and G anticardiolipin antibodies, homocystine, Factor V Leiden, prothrombin G20210A mutation, methylentetrahydrofolate reductase C677T mutation, thyroid-stimulating hormone (TSH), free thyroxine, anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies were assessed. The prevalence of thrombophilia was high and similar among groups. In the IF group, the prevalence of APCR (15.4%), lupus anticoagulant (11.5%) and combined thrombophilia (19.2%) was higher, but not significantly different, than the other three groups. The prevalence of thyroid autoimmunity in women with IF (anti-TPO antibodies, P = 0.009; anti-TPO plus anti-TG antibodies,P = 0.04) and UI (anti-TPO, P = 0.002; anti-TG, P = 0.019; anti-TPO plus anti-TG antibodies, P = 0.005) was significantly increased in comparison to those with RSA. There was also a trend towards a higher prevalence of thyroid autoimmunity in the UI and IF groups than in the control group. TSH and free thyroxine levels all remained within a normal range. When embryo aneuploidy is ruled out, thrombophilia could constitute an etiologic factor in IF. Furthermore, thyroid autoimmunity is strongly related to UI and IF.

Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage.

Activated protein C (APC) resistance, both in its congenital form, due to the factor V Leiden mutation, and in its acquired form, are important risk factors for systemic venous thrombosis. In view of the suspected thrombotic aetiology of some cases of recurrent miscarriage, the prevalence of APC resistance was determined among 1111 consecutive Caucasian women with a history of either recurrent early miscarriage (three or more consecutive pregnancy losses at <12 weeks gestation; n = 904) or a history of at least one late miscarriage (>12 weeks gestation; n = 207). A control group of 150 parous Caucasian women with no previous history of adverse pregnancy outcome was also studied. Acquired APC resistance was significantly more common among both women with recurrent early miscarriage (8.8%: 80/904; P = 0.02) and those with late miscarriage (8.7%: 18/207; P = 0.04) compared with controls (3.3%: 5/150). In contrast, the frequency of the factor V Leiden allele was similar among (i) women with recurrent early miscarriage (3.3%:60/1808; 58 heterozygotes and one homozygote), (ii) those with late miscarriage (3.9%:16/414; 14 heterozygotes and one homozygote) and (iii) the control group (4.0%:12/300; 12 heterozygotes). Acquired but not congenital APC resistance (due to the factor V Leiden mutation) is associated with both early and late miscarriage.

Are women with polycystic ovary syndrome resistant to activated protein C?

Objective: This study was performed to test the hypothesis that an increased prevalence of activated protein C (APC) resistance in women with polycystic ovary syndrome (PCOS) puts them at increased risk of miscarriage and thrombosis. Design: Case control study. Setting: A district general hospital in the United Kingdom. Patient(s): Forty-one women with PCOS and 25 controls. Intervention(s): Clinical histories, ultrasound scans, and venepunctures. Main Outcome Measure(s): Diagnosis of PCOS or control, clinical histories, APC resistance according to an activated partial thromboplastin time–based assay. Result(s): There was no significant difference in the proportion of women with APC resistance in both groups (three women in the PCOS group [7%] vs. one woman in the control group [4%]). The prevalence of APC resistance in the entire study population was 6.5%. In the PCOS group, 29% (12/41) gave a positive family history of thrombosis compared with 8% (2/25) in the control group. None of the women with a positive family history of thrombosis had abnormal antithrombin 111, protein C, or protein S levels. Conclusion(s): This study suggests that women with PCOS may have the same prevalence of APC resistance as the background population and that APC resistance may not put them at a higher risk of thrombosis or miscarriage compared with the case of the general population.

Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection.

The factor V R506Q mutation (FV R506Q, FV:Q506, or FV Leiden) resulting in activated protein C (APC) resistance is the most common inherited risk factor for venous thrombosis, including in renal transplant recipients. We investigated a possible association between the FV mutation and early renal graft loss, and the prevalence of macro- and microvascular thrombosis, endothelialitis, and fibrinoid vascular necrosis by FV genotype. One hundred and nine renal allograft recipients were genotyped for FV mutation. A vascular rejection subgroup of patients (n=29) had experienced at least one episode of vascular rejection, or graft thrombosis. A second group of patients (n=80) had experienced no acute rejection and retained a well-functioning graft. The prevalence of APC resistance was numerically but not statistically significantly higher in the vascular rejection group (17.2%) compared with the group without rejection episodes (7.5%) (P=0.16). There was a significant association between the presence or absence of FV mutation and graft survival, with a 55.6% 1-year graft survival rate versus a 76.4% rate, respectively (P=0.02). The prevalence of vascular rejection, as evidenced by endothelialitis or fibrinoid vascular necrosis, was significantly associated with APC resistance but macro- or microvascular thrombosis were not. Renal transplant recipients who are carriers of the FV:Q506 allele have an increased risk of early graft loss. Vascular rejection changes including endothelialitis and fibrinoid vascular necrosis were more common in this group, and therefore an association between the hypercoagulable state, which entails an up-regulation of the mitogenic and proinflammatory enzyme thrombin, and the immunological challenge to the endothelium may be the cause of inferior prognosis in these patients.

Activated protein C resistance shows an association with pregnancy-induced hypertension.

A common mutation in the factor V gene, the Leiden mutation, is the most frequent genetic cause of resistance to activated protein C (APC). Recent studies have shown that the prevalence of APC resistance is associated with severe pregnancy-induced hypertension (PIH). Our objective was to determine whether the factor V Leiden mutation is more prevalent in patients who developed severe PIH than in normotensive pregnant women. In 70 women with a history of severe PIH, of whom 15 had pre-eclampsia, we investigated common coagulation factors as well as APC resistance (factor V related). We found that seven of these 70 women showed low values for APC. Out of these, five were heterozygous and none was homozygous for factor V Leiden mutation. In a control group of normotensive pregnant women we found a 3.0% rate of APC resistance and a 3.0% rate of carriers of the Leiden mutation. These results indicate a significantly higher prevalence of both APC resistance and factor V Leiden mutation in women with severe PIH. Placental infarctions and micro-embolisms are considered to be one of the principle pathophysiological changes in severe PIH. Our results suggest that APC resistance is a risk factor for severe PIH, in addition to its well-known role in macrothrombo-embolism.

Hereditary disorders of the protein C system in central artery and branch arteriolar occlusions

Resistance to activated protein C (APC) is the most common hereditary defect in patients with venous thrombosis. There are conflicting reports on the prevalence of APC resistance in patients with arterial thrombosis, e.g. coronary arteries, compared to the APC resistance prevalence among the normal population. The prevalence of APC resistance in branch retinal artery occlusion (BRAO) and central retinal artery occlusion (CRAO) is unknown. 29 consecutive patients with arterial retinal occlusions (BRAO, n = 12; CRAO, n = 17) were included in this prospective study over a 23-months-period. We searched for APC resistance, protein C or S deficiencies, as well as for acquired vascular risk factors. Factor-V-deficient plasma and genetic analysis with a PCR method were employed for APC resistance determination. Protein C and protein S activity were determined with functional tests. APC resistance was found in 3 of 29 patients (10.3%). Two of these patients had BRAO and one patient CRAO. Comparing this prevalence to the APC resistance prevalence within the normal population (9%), the difference was not statistically significant. 27 patients (93.1%) had one or more vascular risk factors (arterial hypertension = 19 [65.5%], hyperlipidaemia = 14 [48.2%], smoking = 7 [24.1%], diabetes mellitus = 5 [17.2%], carotid artery stenosis = 5 [17.2%]). We could not find an increased prevalence of APC resistance in patients with CRAO or BRAO when compared to the normal population.

Multicenter Evaluation of PCR Methods for the Detection of Factor V Leiden (R506Q) Genotypes

Activated protein C (APC) resistance is reported to be present in 20–60% of individuals with a history of venous thrombosis (1). Thus, the prevalence of APC resistance in Caucasian patients with a history of venous thromboembolism is much greater than the prevalence of protein C deficiency, protein S deficiency, or antithrombin deficiency (1). The APC resistance phenotype is associated with a guanine-to-adenine substitution at nucleotide 1691 of the factor V gene (1). This mutation produces a glutamine-for-arginine (R506Q) substitution at factor V residue 506 (factor V Leiden). The risk of thrombosis is increased five- to eightfold in individuals heterozygous for factor V Leiden and 30- to 140-fold in homozygous individuals (1). Coagulation-based assays for the detection of APC resistance have been described and are commercially available. The APC resistance ratios from some of these assay systems, however, have demonstrated overlap between unaffected individuals and individuals heterozygous for factor V Leiden (1). Newer coagulation-based assays have been reported, but it is not clear that they can be used in all clinical settings. Unlike coagulation-based assays for APC resistance, DNA-based assays are not affected by pregnancy, the therapeutic use of anticoagulants, the use of oral contraceptives, or the presence of inhibitors such as lupus anticoagulants. Therefore, a rapid and accurate nucleic-acid-based assay to detect the factor V Leiden mutation is highly desirable. Bertina et al. (2) reported the first assay for the detection of factor V Leiden, a PCR-based assay that detects the guanine-to-adenine substitution at nucleotide 1691 by taking advantage of the loss of an Mnl I restriction site in the PCR product if the mutation is present. This assay has been used in several published reports on APC resistance. Other DNA-based assays have also been reported, including …

Activated protein C resistance in pediatric inflammatory bowel disease.

There is evidence for a hypercoagulable state in inflammatory bowel disease (IBD), and small vessel thrombosis has been identified in the bowel of patients with Crohn's disease, suggesting thrombosis as a possible etiologic factor. Activated protein C (APC) resistance is the most common inherited disorder leading to thrombosis and accounts for 30% to 40% of episodes of idiopathic venous thrombosis. The prevalence of APC resistance was studied in 23 patients with IBD (17 with Crohn's disease, 6 with ulcerative colitis) and in 11 control subjects with recurrent abdominal pain or celiac disease, using an APC resistance screening method. One patient with Crohn's disease had a positive screen result, two patients (one with Crohn's, one with ulcerative colitis) had borderline results, and results in all of the control subjects were normal. One patient with Crohn's disease had a history of a thromboembolic event but had a normal screen result. Activated protein C resistance does not seem to play a major role in the etiology of the hypercoagulable state in inflammatory bowel disease.

Relationship Between Activated Protein C Resistance and Central Venous Device-Related Complications

We studied the relationship between activated protein C (APC) resistance and the central venous devices (CVD)-related complications in 61 cancer patients (44 females `and 17 males, median age 50 years, 71 CVD) from November 1994 to November 1995. Two patients (3.3%) had APC resistance, i.e., APC ratio &lt; 2. Twelve episodes of bactercmia, 8 site infections, 31 cases of CVD dysfunction requiring urokinase (UK), and 3 CVD-retated thromboses were noted. With Cox's proportional hazard models, low APC ratios and high d-dimer levels were significantly associated with CVD-related bacteremia (p = 0.0207 and 0.0210). Such an association was not observed with site infection and CVD dysfunction. The incidence of thrombosis was too low to be analyzed. However, one patient with APC resistance developed subclavian vein thrombosis, leading to eventual removal of the catheter. The prevalence of APC resistance in cancer patients and its association with bacteremia are discussed. Key Words : Activated protein C resistance—Central venous catheters—Bacteremia— Catheter site infection—Thrombosis.

Activated Protein C Resistance in Ischemic Stroke Not Due to Factor V Arginine 506 →Glutamine Mutation

Resistance to activated protein C (APC), a natural plasma anticoagulant, is the most common identifiable risk factor for venous thromboembolic disease. One point mutation in coagulation factor V that renders it APC-resistant is found in >90% of APC-resistant venous thrombosis patients. To determine the prevalence of APC resistance and of this factor V mutation in stroke, we screened a group of ischemic stroke patients. Hispanic ischemic stroke patients were screened using two different activated partial thromboplastin time-based assays. One assay using neat patient plasma determined APC resistance, and the other assay using patient plasma diluted into factor V-deficient plasma determined APC-resistant factor V, including the Arg506-->Gln mutation. Results were compared with those in 31 Hispanic control subjects of similar ages. Six of 63 (9.5%) stroke patients had APC resistance compared with none of 31 (0%) control subjects. No patient or control subject had APC-resistant factor V, ie, the factor V Arg506-->Gln mutation. In Hispanic patients with ischemic stroke, the incidence (approximately 10%) of APC resistance is not caused by the factor V Arg506-->Gln mutation. APC resistance not caused by this factor V mutation may be a risk factor for ischemic stroke in this population.

Second-trimester pregnancy loss is associated with activated C resistance.

We have investigated whether activated protein C resistance (APCR) is associated with second-trimester miscarriage. The prevalence of APCR was significantly higher amongst women with a history of second-trimester miscarriage (10/50; 20%) compared with either women with a history of first-trimester miscarriages only (4/70; 5.7%) or a control group of parous women with no previous history of pregnancy losses (3/70; 4.3%) (P < 0.02). These results suggest that APCR may be an important mechanism of second-trimester pregnancy loss, possibly related to the increase in intravascular coagulation that occurs during pregnancy.

Factor V Gene Mutation Is a Risk Factor for Cerebral Venous Thrombosis

To evaluate the association between coagulation defects and cerebral venous thrombosis, a case-control study was conducted in 25 patients who had no autoimmune, neoplastic or infections disease and 75 healthy individuals. There were no patients with deficiency of protein C or protein S. Four had resistance to activated protein C (APC) and one had APC resistance associated with antithrombin deficiency. APC resistance was investigated by DNA analysis, and diagnosed by the presence of a point mutation in the factor V gene, which predicts replacement of Arg506 with Gln at one of the two APC cleavage sites in activated factor V. The prevalence of APC resistance was 20% in patients and 2.7% in controls. This difference was statistically significant (p = 0.01) and the odds ratio was 9.1. A circumstantial factor predisposing to cerebral venous thrombosis (such as oral contraceptive intake, pregnancy, puerperium, trauma or prolonged immobilization) was reported in 72% of cases. In conclusion, APC resistance is the most frequent coagulation abnormality associated with cerebral venous thrombosis.

The incidence of activated protein C resistance among patients with deep vein thrombosis and healthy subjects in Osaka

Recently, activated protein C resistance (APCR) has been described as a new familial thrombophilia in which anticoagulant activity of activated protein C (APC) is impaired likely due to a single point mutation of factor V (1,2). According to several recent reports (3,4,5), the prevalence of APCR is very high in normal population as well as in patients with deep vein thrombosis (DVT). However, all the data related to APCR have derived from Westerners and no information is available on APCR in other countries and races. Therefore, attempts were made to investigate the incidence of APCR in patients with DVT and healthy subjects in Osaka. Also, the influence of warfarin administration on the screening was investigated.

Resistance to Activated Protein C as an Additional Genetic Risk Factor in Hereditary Deficiency of Protein S

Inherited 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, the prevalence of APC resistance in 18 unrelated thrombosis-prone families with inherited protein S deficiency was investigated to determine its role as additional genetic risk factor for thrombosis. In addition, a detailed evaluation of the clinical manifestations in these families was performed. Venous thrombotic events had occurred in 47% of the protein S-deficient patients (64/136) and in 7% of relatives without protein S deficiency (14/191). As estimated from Kaplan-Meier analysis, 50% of protein S-deficient family members and 12% of those without protein S deficiency had had manifestation of venous thromboembolism at the age of 45 years. The age at the first thrombotic event ranged from 10 to 81 years (mean, 32.5 years) and a large intrafamilial and interfamilial variability in expression of thrombotic symptoms was seen. The factor V gene mutation related to APC resistance was present in 6 (38%) of 16 probands available for testing; in total, the mutation was found in 7 (39%) of the 18 families. In family members with combined defects, 72% (13/18) had had thrombosis as compared with 19% (4/21) of those with only protein S deficiency and 19% (4/21) of those with only the factor V mutation. In conclusion, APC resistance was found to be highly prevalent in thrombosis-prone families with protein S deficiency and was an additional genetic risk factor for thrombosis in these families. The results suggest thrombosis-prone families with protein S deficiency often to be affected by yet another genetic defect.

The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects.

A poor anticoagulant response to activated protein C (APC) in an activated partial thromboplastin time (aPTT) assay (APC resistance) was recently reported to be a cause of familial thrombophilia. The response to APC was measured in 30 patients suffering from juvenile or recurrent stroke, in 40 patients suffering from venous thromboembolism and in 50 healthy subjects. The prevalence of APC resistance was found to be significantly higher among patients with stroke (20%, P < 0.003) and venous thrombosis (17.5%, P < 0.02) compared with the prevalence of APC resistance among normal controls (2%). In one case of venous thrombosis, the proposita's family (A) could be investigated and in five out of nine investigated members (56%) a poor or borderline response to APC was detected. The family (B) of another APC-resistant patient revealed six subjects with poor coagulation response to APC out of eight family members studied (75%). Measuring protein S activity with an automated calcium-thromboplastin-based protein S activity assay, a significant correlation (P < 0.0001) between the results of this functional protein S assay and APC resistance (represented by the ratio (Rs value) of clotting time with and without addition of activated protein C) was observed. Nine out of 14 patients (64%) with poor APC response showed protein S activities below the normal range. Assessment of protein S activity with a second protein S clotting assay using factor Va as substrate confirmed only 47% of the decreased levels of the thromboplastin-based protein S clotting assay.(ABSTRACT TRUNCATED AT 250 WORDS)