Activated protein C resistance and the factor V Leiden mutation in children with thrombosis

To determine the prevalence of activated protein C resistance and the factor V Leiden mutation (position 1691, arginine 506 to glutamine substitution) in children with thrombosis, plasma samples from children with thrombosis were tested for activated protein C resistance. DNA was analyzed for the factor V Leiden mutation. Five of 34 children (15%) had activated protein C resistance; each was heterozygous for the factor V Leiden mutation. All 5 children heterozygous for the factor V Leiden mutation suffered non-CNS venous thromboses comprising 21% of the group of children (5/24) with non-CNS venous thrombotic events. Each of these 5 children had a family history of thrombosis. In conclusion, children with non-CNS venous thrombosis should be evaluated for the factor V Leiden mutation. Children most likely affected are those with a family history of thrombosis. Am. J. Hematol. 57:29–32, 1998. © 1998 Wiley-Liss, Inc.     

Factor V Q 506 mutation in children with thrombosis

The factor V Leiden mutation in 12 children with thrombosis and in 20 controls was investigated. Five heterozygous individuals and 1 homozygous individual among the cases with thrombosis and 1 heterozygous individual among controls were found. Central nervous system thromboses were increased in children with the factor V mutation, associated with protein S deficiency. © 1996 Wiley-Liss, Inc.     

Evidence for a single origin of factor V Leiden

Factor V Leiden is the most common hereditary blood clotting disorder so far identified, with an allele frequency of 4%. The low prevalence of the mutation outside of Europe suggests it occurred as a single event in the European founding population. In this study four polymorphisms have been identified defining different haplotypes in the exon 13 region of the factor V gene. One of these polymorphisms predicts a novel amino acid change, threonine to serine, in the B-domain of factor V. Statistical evidence for a single origin of factor V Leiden is provided through the association of the mutation with a single exon 13 haplotype.     

Evidence for a single origin of factor V Leiden

Factor V Leiden is the most common hereditary blood clotting disorder so far identified, with an allele frequency of 4%. The low prevalence of the mutation outside of Europe suggests it occurred as a single event in the European founding population. In this study four polymorphisms have been identified defining different haplotypes in the exon 13 region of the factor V gene. One of these polymorphisms predicts a novel amino acid change, threonine to serine, in the B-domain of factor V. Statistical evidence for a single origin of factor V Leiden is provided through the association of the mutation with a single exon 13 haplotype.     

False negative factor V Leiden assay following allogeneic stem cell transplant

We report a case where a phenotypic test (an activity assay for activated protein C resistance) correctly indicated that the patient had an abnormality, whereas the initial genetic test (a PCR-based DNA assay used to detect the mutation in the FV gene) incorrectly indicated that the patient did not. The apparent false negative result of the DNA-based test was due to the use of peripheral blood leucocytes for DNA analysis. The patient had undergone a stem cell transplant several months before, and the leucocytes in her blood were derived from the stem cell donor, which lacked the FV defect.     

Factor V Leiden: the venous thrombotic risk in thrombophilic families

Factor V Leiden (FVL) leads to a sevenfold increased risk of venous thrombosis and is present in 50% of individuals from families referred because of unexplained familial thrombophilia. We assessed the association of FVL with venous thromboembolism (VTE) in 12 thrombophilic families of symptomatic probands with FVL in a retrospective follow-up study. We screened 182 first- and second-degree relatives of the 12 unrelated propositi for the FVL mutation and the occurrence of VTE. The incidence rate of VTE in carriers of FVL (0.56%/year) was about six times the incidence for the Dutch population (0.1%/year). The incidence rate in non-carriers also appeared to be higher (0.15% per year). At the age of 50 years, the probability of not being affected by VTE was reduced to 75% for carriers and to 93% for non-carriers (P = 0.009). Identification of carriers of FV Leiden may be worthwhile in young symptomatic individuals and their relatives with a strong positive family history of venous thromboembolism or a history of recurrent venous thrombosis who may be at risk (e.g. pregnancy, use of oral contraceptives). After adjustment for prothrombin G20210A (present in two families), even higher thrombotic incidence rates were found in carriers and non-carriers of FVL. This makes the presence of other unknown prothrombotic risk factors more probable in these families.     

Factor V Leiden in central venous catheter-associated thrombosis

Subclavian vein thrombosis is a well-recognized complication following central venous catheter insertion and is associated with significant morbidity. The factor V Leiden mutation is an important risk factor for deep venous thrombosis and pulmonary embolism. Whether this mutation also predisposes patients fitted with a central venous catheter to subclavian vein thrombosis is not known. The occurrence of central venous catheter-associated thrombosis was investigated in 277 consecutive patients receiving an allogeneic bone marrow transplantation. All patients received a tunnelled double or triple catheter positioned in the subclavian vein. Catheter-associated thrombosis was diagnosed on the basis of clinical signs of thrombosis, i.e. swelling and/or redness of the limb or venous engorgement and was confirmed with a colour-flow Doppler ultrasound. Thirteen patients were heterozygous for the factor V Leiden mutation. Seven of these patients had a subclavian vein thrombosis (54%), while this occurred in only 9% of the factor V Leiden-negative patients, corresponding with a relative risk of 7.7 (95% CI 3.3-17.9). Factor V Leiden is attributable for 17.3% of all thrombosis in patients with central venous catheters. The majority of patients with the factor V Leiden mutation with a central venous catheter will develop thrombosis. Patients with a factor V Leiden mutation should receive adequate thrombosis prophylaxis upon catheter introduction and the catheter should be removed immediately after the treatment. Based on this very high risk, we advise testing for factor V Leiden in all bone marrow transplantation patients receiving a central venous catheter.     

Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C

We report a kindred in which two siblings suffered spontaneous venous thromboses in the second decade of life. Further investigation showed reduced coagulation factor V (FV) activity and activated protein C resistance (APCR) ratio but no other thrombophilic abnormalities. The reduction in APCR ratio persisted in a modified APCR assay in which FV activity was normalized between test and control plasmas. Analysis of the FV gene showed that the thrombotic individuals had a complex genotype that included two novel point mutations c.529G>T and c.1250T>C resulting in FV E119X and FV I359T substitutions inherited on different alleles. Individuals in the kindred with FV E119X or FV I359T substitutions alone were asymptomatic. We suggest that the FV I359T substitution confers pro-thrombotic risk and APCR, but that this is only clinically manifest when co-inherited with the FV E119X allele. The FV I359T substitution creates a new consensus sequence for N-linked glycosylation within the FV heavy chain and we speculate that this abnormal glycosylation may disrupt activated protein C-mediated proteolysis of the variant FV and FVa.     

Cerebral infarct associated with factor V Leiden mutation in a boy with hemophilia A

An 11-year-old boy with mild hemophilia A was admitted to our hospital because of focal convulsions. Magnetic resonance imaging showed an old occipital infarct. Protein C, S, antithrombin III, anticardiolipin antibodies and fibrinogen were normal. Heterozygosity for factor V Leiden mutation was detected. We suggest that factor V Leiden mutation should be studied in hemophiliacs with thrombosis. Am. J. Hematol. 56:189–190, 1997. © 1997 Wiley-Liss, Inc.     

急性心肌梗死患者血清胎盘生长因子的动态变化

目的:观察急性心肌梗死(AMI)患者血清胎盘生长因子(PIGF)及超敏C-反应蛋白的动态变化及意义.方法:测定60例AMI患者(AMI组)发病第12小时、第3天、第7天血清中PIGF及超敏C-反应蛋白水平,并于第14天行超声心动图检测.另选40例健康体检者为正常对照组.PIGF采用酶联免疫吸附双抗体夹心法原理定量测定.结果:AMI组发病第12小时、第3天PIGF均显著高于正常对照组,差异有统计学意义(P＜0.05),第7天与正常对照组相比差异无统计学意义(P＞0.05);第12小时、第3天、第7天超敏C-反应蛋白均显著高于正常对照组,差异有统计学意义(P＜0.05);血清PIGF与左心室射血分数呈显著负相关(r=-0.654;P＜0.01),与左心室舒张末期容积和左心室舒张末期内径均呈显著正相关(r=0.845,0.684;P＜0.01).结论:AMI时患者血清PIGF水平显著增高,AMI后第3天达到相对高值,第7天降至正常人群水平.P1GF水平可能影响左心室重构.     

The factor V Leiden mutation in children with cancer and thrombosis

Thromboembolic phenomena, frequently observed in children with cancer who are undergoing chemotherapy, can cause significant morbidity and, less frequently, mortality. Many contributory factors have been identified. Whether the recently identified and most common coagulation defect predisposing to thrombosis, factor V Leiden, is associated with thrombosis in this setting, has not been explored. The current study was undertaken to determine the prevalence of the factor V Leiden mutation in children with cancer who developed thromboembolic phenomena as compared to those with cancer who did not. Genomic DNA was amplified using the polymerase chain reaction (PCR), followed by digestion of the amplification product with the restriction enzyme Mnl I. The digested PCR products were then size-fractionated to classify samples as heterozygous, homozygous or normal for the factor V Leiden mutation. 67 children with cancer were evaluated for the factor V Leiden mutation. One of 32 children with cancer and thrombosis, and none of 35 who had not experienced thrombotic problems, was found heterozygous for this mutation. We conclude that the factor V Leiden mutation does not play a significant role in the overall incidence of thromboses that occur in children with cancer.     

急性心肌梗塞患者的高胰岛素血症

检测１３例合并糖尿病的急性心肌梗塞（ＡＭＩ），２３例无糖尿病ＡＭＩ患者的空腹血胰岛素和Ｃ肽水平，并与２０例正常人作比较，发现两组均存在高胰岛素血症，合并糖尿病的ＡＭＩ组更为明显。１０例ＡＭＩ患者４周后复查，血胰岛素水平有显著下降。提示胰岛素在ＡＭＩ发病中有意义。     

Acute Myocardial Infarction in Diabetic Patients

ABSTRACT. All patients hospitalized during a 3-year period with an acute myocardial infarction were followed for the occurrence of reinfarction or death. The patients with diabetes mellitus (n=95) were compared with the non-diabetic population (n=545). The diabetics had a higher mortality rate (relative death rate of 1.44 vs. 0.93, p<0.01) and a higher frequency of reinfarctions (18.9 vs. 10.8%, p=0.04) than the non-diabetic population. A larger proportion of the diabetics had suffered a previous infarction, but the excess mortality was also present in those without a previous infarction. Established risk factors for death after myocardial infarction, such as age, infarct size, infarct localization and heart size, could not account for the difference in mortality. It is suggested that the increased mortality among the diabetics may be due to an increase in the rate of progression of the atherosclerotic heart disease.     

Factor V Leiden and the common haemochromatosis mutation HFE C282Y: is there an association in familial venous thromboembolic disease?

The involvement in venous thrombosis of the two most common mutations of the hereditary haemochromatosis gene (HFE C282Y and HFE H63D) was investigated in 239 patients with objectively proven venous thrombosis. Neither mutation showed an increased prevalence in the cohort (HFE C282Y: 13.0% (95% CI 9.3-17.8) patients, 16.2% (95% CI 14.3-18.2) controls; HFE H63D: 28.3% (95% CI 22.9-34.3) patients, 28.1% (95% CI 25.8-30.6) controls. Neither mutation was increased in patients with factor V Leiden (FVL) compared to those without. However, HFE C282Y was increased among patients who had both FVL and a family history of thrombosis (7/20), compared with those with FVL and no family history (1/22) (relative risk 7.97, 95% CI 1.5-43.1, P = 0.016).     

Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy

Activated protein C (APC) resistance phenotype/genotype discrepancy is a very rare event. The objective of this study was to characterize the molecular mechanisms in two cases of APC phenotype/genotype discrepancy. An approach using direct sequencing of each exon and splicing junctions of the factor V gene showed that two novel factor V null mutations combined with heterozygous factor V Leiden mutation were responsible for this discrepancy. Our results suggest the necessity to use both phenotypic and genotypic analyses in some cases to determine an accurate diagnosis.     

Spontaneous Coronary Artery Dissection in a Young Man with a Factor V Leiden Gene Mutation: A Case Report and Review of the Literature

Spontaneous coronary artery dissection is a rare but increasingly recognized cause of acute myocardial ischemia in young adults, especially in women. We report a case of spontaneous coronary dissection in a young healthy man who was also a carrier of the factor V Leiden gene mutation.     

Factor V Leiden, prothrombin 20210A and the risk of venous thrombosis among cancer patients

Cancer patients have an increased risk of venous thrombosis (VT). The association of factor V Leiden (FVL) and the prothrombin 20210A variant with VT in cancer patients is not established. We genotyped 101 cancer patients with VT and 101 cancer patients without VT for these polymorphisms. Five cases and three controls were heterozygous for FVL, yielding an odds ratio of 1.7 (95% confidence interval (CI) 0.3-10.7). Five cases and no controls were heterozygous for prothrombin 20210A, for an odds ratio of 6.7 (95% CI 0.9-infinity). Prothrombin 20210A may be associated with VT risk among cancer patients.     

基因重组细胞生长因子对AMI患者心脏功能的影响

目的:了解基因重组细胞生长因子(bFGF)对急性心肌梗塞(AMI)患者心脏收缩和舒张功能的影响.方法:将同期住院的70例AMI患者分为治疗组和对照组两组,两组在年龄、性别、梗塞部位及面积方面无明显差异,治疗组给予bFGF 1600U肌肉注射,每日一次,连用4周,于4周时用门控平衡法心血池心室显像复查心脏收缩和舒张功能并与对照组比较.结果:治疗组(bFGF组)心脏左室射血分数较对照组提高约20%(0.477±0.138:0.274±0.09,P=0.0003),左室峰充盈率也较对照组明显提高(2.362±0.918:1.318±0.398,P<0.005),治疗组患者的梗塞后心绞痛及室壁瘤发生率也较对照组明显下降.结论:bFGF可以促进AMI患者梗塞区血管的形成,有利于侧枝循环的建立,可以明显的改善AMI患者的心脏收缩及舒张功能,减少梗塞后心绞痛和室壁瘤的发生,可能成为一种新的有希望的AMI基因治疗方法.     

The Prognosis for Patients Referred with Suspected Acute Myocardial Infarction

ABSTRACT. Engby B, Strunge P, Olsen J. (Department of Internal Medicine, Horsens Hospital, Horsens, Denmark.) The prognosis for patients referred with suspected acute myocardial infarction. A follow-up investigation of the prognosis of 381 patients admitted with suspected acute myocardial infarction (AMI) has been carried out in respect of later AMI or death. During hospitalization the patients were divided into groups with particular attention to patients with no demonstrable myocardial infarction but with ischaemic heart disease (non-AMI) and patients with confirmed AMI. All patients were subjected to follow-up for 43 months (range 37–54). The mortality from cardiovascular causes after four years was 26.2% of 130 non-AMI patients and 25.8% of AMI patients. The majority of new infarctions were found in the AMI patients, but with even increase in both groups, 50% occurring within the first 12 months. The groups were studied with regard to earlier manifestations of ischaemic heart disease and heart failure during hospitalization, without any difference being observed. Due to the poor prognosis the question is raised whether non-AMI patients as a group should be offered prophylactic therapy.