Arthropathy and surgery in congenital factor VII deficiency

A 35-year-old woman with severe (less than 1 percent) factor VII deficiency had recurrent hemarthroses involving the left knee, leading to deformity, pain, and virtually complete loss of function. It was elected to perform a total knee replacement. In preparation for surgery, the patient received heat-treated prothrombin complex concentrate containing 870 units of factor VII per vial. A dose of 50 U/kg raised the factor VII level to 115 percent. At surgery, dense adhesions were found within the joint, the articular cartilage was overgrown with pannus extending out to the lateral patella, and there was extensive deformity of the femoral condyle and tibial plateau. The joint was excised and replaced by a cemented Microloc prosthesis. Postoperatively, factor VII levels were maintained above 10 percent by six-hourly infusions of concentrate. Beginning on Day 4, single daily infusions of 25 U/kg were given prior to physical therapy. No bleeding occurred, and the patient was ambulating at the time of discharge 20 days postoperatively. This experience indicates that despite its short half-life (less than four hours), factor VII levels sufficient to prevent bleeding can be maintained in factor VII-deficient patients undergoing major operative procedures.     

Molecular biology and clinical manifestation of hereditary factor VII deficiency

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.     

Long-term successful percutaneous coronary intervention in factor VII deficiency

Factor VII deficiency (FVIId) is a congenital coagulation disorder with a wide spectrum of bleeding phenotypes. Percutaneous coronary intervention requires full anticoagulation during stent implantation to avoid acute coronary thrombosis and long-term dual antiplatelet therapy. Feasibility of percutaneous coronary intervention in FVIId is not described in literature. We present a successful case of percutaneous coronary intervention in a 55-year-old male with FVIId, discussing briefly the periprocedural handicaps (anticoagulation regimen and hemostasis at arterial puncture site) as the safety of long-term antiplatelet therapy, and future implications for recombinant FVIId administration in a patient with a previous coronary stent.     

Mitral valve surgery in severe congenital factor VII deficiency

The estimated incidence of congenital factor VII deficiency is 1:500 000. Severe FVII deficiency is associated with spontaneous bleeding such as intraarticular or intracranial haemorrhage. The risk of perioperative bleeding is high during cardiac surgery as a result of the exposure to extracorporeal circulation, systemic anticoagulation, loss of coagulation factors, and postoperative platelet malfunction. Effective treatment of pre-existing coagulopathy is crucial, as increased morbidity and mortality are associated with allogenic blood transfusions. We report a 67-year-old Caucasian male patient with severe congenital FVII deficiency, undergoing successful and uneventful elective mitral valve repair surgery, radiofrequency epicardial atrial fibrillation ablation, and exclusion of the left atrial appendage. He presented with severe symptomatic mitral valve regurgitation, moderate pulmonary artery hypertension, and paroxysmal atrial fibrillation; his left ventricular ejection fraction was 67%. Three years before surgery, during a routine assessment of a grade I renal failure, a spontaneous International Normalised Ratio of 4.1 was observed. He had no history of previous spontaneous bleeding. The diagnosis of a severe FVII deficiency, with an FVII activity below 2% (normal references values in City Hospital Triemli Zurich: 55–170%) was made.     

Hip surgery in a patient with severe factor VII deficiency

We describe the clinical history of a 35-year-old woman with severe cross-reacting-material-negative factor VII deficiency. Because of a severe hemophilic arthropathy of the hips, reconstructive surgery was indicated. After advice was obtained from 11 clinical hemostasis experts it was decided to use plasma for factor VII replacement during and after surgery and to use pneumatic boots to prevent thrombosis. Volume overload was treated with plasmapheresis and diuretics. The operation was carried out without abnormal blood loss and the patient recovered without thromboembolic complications. We conclude that continuous infusion of plasma is a suitable way to replace factor VII provided adequate venous access is available for plasmapheresis.     

Characterization of a Cys329Gly mutation causing hereditary factor VII deficiency

We have previously reported a homozygous Cys329Gly mutation in a Chinese patient with factor VII (FVII) deficiency. Others have found a heterozygous Cys329Gly mutation in the F7 gene from patients of three different pedigrees. However, none of the reports included the expression and characterization of the mutant FVII in vitro. To investigate the effect of Cys329Gly on FVII function, we carried out transient transfections of baby hamster kidney cells (BHK-21) with a mutant FVII construct and compared the results to those obtained using a wild-type FVII construct and vector control. The results demonstrate that the level of FVII:Ag secreted into the medium by transfected BHK-21 cells with mutant construct was not affected, but the coagulation activity of the mutant FVII was undetectable. We conclude that Cys329 is critical to FVII coagulation, and the replacement of cysteine 329 by glycine leads to the loss of coagulation activity in the patients, possibly the molecular basis for FVII deficiency in the patients.     

Congenital factor VII deficiency

Summary Four new cases with congenital homozygous factor VII deficiency are described. Factor VII levels were reduced to <1%,3%,8% and 10%, respectively. The incidence and severity of bleeding symptoms were well correlated with the measured factor VII activity. In the severe case of factor VII deficiency (<1%) a home treatment program was started because of severe recurrent hemarthroses. This entailed transfusions of 20 U/kg body weight prothrombin complex or factor VII concentrate in case of acute bleeding approximately every three weeks. These transfusions have been carried out successfully without any problems. In contradiction, two brothers with hypoproconvertinemia (factor VII 8% and 10%, respectively) reached an age of more than 70 years. Despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on our experience we suggest that in patients with factor VII deficiency of less than 10%, when undergoing surgery, should be maintained a minimal factor VII activity of 10–15% during the first three postoperative days.     

Atherosclerosis is associated with delirium after coronary artery bypass graft surgery

OBJECTIVES: To investigate whether atherosclerosis of the ascending aorta, internal carotid arteries, and coronary arteries is predictive of postoperative delirium in subjects undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective cohort study. SETTING: Boston Veterans Affairs Healthcare System. PARTICIPANTS: Thirty-six male veterans undergoing primary CABG surgery. MEASUREMENTS: Subjects underwent Duplex ultrasound to assess stenosis in the internal carotid arteries. Information on the ascending aortic plaque, as assessed by transesophageal echocardiogram, and the number of coronary vessels bypassed was collected. To create an atherosclerosis score, the number of atherosclerotic areas was added. A validated delirium battery was administered to the subjects preoperatively and on postoperative Days 2 and 5. RESULTS: Fifteen subjects (41.7%) developed delirium postoperatively. In bivariate analysis, carotid stenosis of 50% or more (relative risk (RR)=3.5, 95% confidence interval (CI)=1.5-8.1) and moderate-severe ascending aortic plaque (RR=2.9, 95% CI=1.0-8.5) were significantly associated with the development of delirium. There was a trend toward a significant association for three or more vessels bypassed (RR=9.6, 95% CI=0.6-145.3). After controlling for age, baseline cognition, and medical comorbidity, the atherosclerosis score was significantly associated with postoperative delirium (adjusted RR=2.7, 95% CI=1.1-6.8). CONCLUSION: In this preliminary report, atherosclerosis in the carotid arteries, aorta, and coronary circulation is associated with the development of delirium after CABG surgery. Further investigation into atherosclerosis as a risk factor for delirium is warranted.     

重型遗传性凝血因子Ⅶ缺陷症家系分子遗传学分析

目的 探讨遗传性凝血因子Ⅶ(FⅦ)缺陷症家系基因突变的类型。方法 检测凝血和止血指标以明确诊断;用DNA直接测序法对先证者及其家庭成员FⅦ基因的全部外显子及其侧翼、5’和3’非翻译区进行分析;将含杂合缺失突变外显子克隆入pMD18-TTA克隆载体中,对来自父母的两条染色体的相应序列分别测序。应用限制性内切酶StuI、MspI进行酶切分析。结果 先证者FⅦ的6号、8号外显子分别发现了1个错义杂合突变：9482位G→T,导致Arg(CG-A)152被Leu(CU-G)替代;11348位C→T突变,导致Arg(C-GG)304Trp(U-GG)突变;克隆的pMD18-TTA克隆载体测序结果显示一个杂合缺失：在11487～9位(CCC)缺失一个C,引起框移突变(已证实,后两种杂合突变均来自母亲),使351位His变为Thr,在其后编码与正常氨基酸序列完全不同的6个氨基酸后出现了翻译终止密码。其中,先证者Arg152 Leu杂合突变来自父亲,其祖父具有相同的杂合突变,父亲还含有Arg353Gln杂合多态性;其祖母为Arg304Trp杂合突变且含有Arg353Gln杂合多态性;姑姑和大伯分别为Arg353Gln杂合多态性和Arg304Trp杂合突变。PCR辅助限制性酶切证实了先证者及其家系成员的两种错义突变。结论 在该例家系中发现了Arg304Trp、Arg152Leu、11487～9位(CCC)缺失一个C三种杂合性突变,其中后两种突变为国际首次报道。     

Recombinant, activated factor VII for surgery in factor VII deficiency: a prospective evaluation - the surgical STER

Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 μg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.     

Experience with recombinant-activated factor VII in 30 patients with congenital factor VII deficiency

Recombinant-activated factor VII (rFVIIa) represents a therapeutic advance for the treatment and prevention of haemorrhage in patients with the rare bleeding disorder, congenital FVII deficiency. Thirty-nine cases of the use of rFVIIa in 30 patients with congenital FVII deficiency were identified from the international, internet-based registry haemostasis.com, which is a repository of case reports on the investigational use of rFVIIa that have been voluntarily submitted by physicians worldwide. These registry data have limitations compared with clinical-trial data but give valuable insights into a treatment for a rare disease that is virtually impossible to assess in conventional clinical trials. rFVIIa was used in: elective surgery (13 cases); haematoma (9 cases); emergency surgery (6 cases); epistaxis (4 cases); menorrhagia (2 cases); cover during childbirth (2 cases); disseminated intravascular coagulation (1 case; premature infant); removal of intradermal stitches (1 case); and haematuria (1 case). In 22/39 cases, rFVIIa was used prophylactically. Total dose and dosing schedules varied; median individual dose was 13.3 mug/kg body weight (bw) (range 1.2-223.8 mug/kg bw), median total dose was 38 microg/kg bw (range 1.2-758 microg/kg bw) and median number of doses was 3 (range 1-55). rFVIIa was generally associated with bleeding cessation or markedly reduced bleeding. Two adverse events were reported, but neither was regarded as being related to rFVIIa. These 39 cases support data confirming the safety and efficacy of rFVIIa in its EU-licensed indications, including that for preventing and/or controlling haemorrhage in patients with congenital FVII deficiency.     

Carrier detection in factor VII congenital deficiency

Thirty obligate and 28 possible carriers of factor VII congenital deficiency, belonging to 16 families, were studied in relation to the immunological variants to which the kindreds belonged, namely, VII+, VIIR and VII-. Factor VII activity and antigen determinations in these subjects formed two phenotypical patterns: a discrepant pattern characterized by a low ratio activity/antigen present in VII+ heterozygotes, and a non-discrepant pattern (normal ratio activity/antigen) which is present in the VII- and VIIR variants. In the first genetic variant the detection of carriers can be performed using the ratio VII:C/VII:Ag. In the other variant, which accounts for the vast majority of heterozygotes, the distribution of the carriers' factor VII is so widespread that a large overlap results between these subjects and the normals. The application of a probabilistic calculation performed by combining the actual values of factor VII:C and the genetic probability of carriership using Fisher's linear discriminant analysis, makes discrimination between carriers and normals easier.     

Atherosclerosis after coronary artery bypass surgery: results of recent studies and recommendations regarding prevention

Atherosclerosis is the most frequent cause of occlusion of aortocoronary saphenous vein grafts between 5 and 10 years after coronary artery bypass surgery. The typical atherosclerotic plaque appears between 1 and 3 years after operation and, at a mean of 5 years, histologic changes of atherosclerosis are present in 21% of grafts and in 27% of patients. Only approximately 60% of saphenous vein grafts remain patent at repeat angiography between 10 and 12 years after bypass surgery; 45% of patent grafts show atherosclerotic changes at angiography and 43% of patients show evidence of atherosclerosis in one or more saphenous vein grafts. We do not know whether the development or the progression of these atherosclerotic changes can be modified; however, the data currently available suggest that the administration of platelet inhibitors and/or of lipid lowering agents offer two promising avenues of investigation in patients undergoing aortocoronary saphenous vein bypass surgery. Until this has been carefully studied, the internal mammary artery should remain the preferred conduit for aortocoronary bypass grafting, whenever possible.