Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study.

BACKGROUND: Several studies have shown that the family history of venous thromboembolism (FHVTE) is a predictor of first venous thromboembolism (VTE). However its role in recurrent VTE is still controversial. OBJECTIVES: To investigate whether the presence of FHVTE is a risk factor for VTE recurrence in patients from a well-characterized Malmö thrombophilia study. METHODS: VTE patients from the Malmö Thrombophilia Study were followed from discontinuation of warfarin treatment until diagnosis of VTE recurrence or to the end of the study (maximum follow-up 9.8 years). RESULTS: There were 127 events of VTE recurrence (12.2%) registered during the follow-up. Multivariate Cox regression analysis in patients with unprovoked first VTE showed that FHVTE was associated with higher risk of VTE recurrence (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-2.9) compared with patients with no FHVTE. Stratification of data according to thrombophilia status of patients showed that compared with the reference group (no FHVTE or thrombophilia), thrombophilia together with FHVTE was associated with a higher risk of VTE recurrence (HR 3.2, 95% CI 1.8-5.9) than thrombophilia alone (HR 1.8, 95% CI 1.02-3.2) independent of DVT location and duration of warfarin treatment. FHVTE was mainly an important risk factor of VTE recurrence in women (HR 3.1, 95% CI 1.6-5.8) but not in men (HR 1.1, 95% CI 0.6-2.2). CONCLUSION: Our results show that FHVTE is a risk factor for VTE recurrence in patients who had unprovoked first VTE. Furthermore, presence of FHVTE may be an additional risk factor of VTE recurrence in thrombophilia-positive patients.

Invasive Fusobacterium necrophorum infections and Lemièrre's syndrome: the role of thrombophilia and EBV.

The purpose of this investigation was to describe the clinical spectrum of invasive Fusobacterium necrophorum infections and Lemièrre's syndrome, to examine the role of underlying thrombophilia and concomitant mononucleosis in Lemièrre's syndrome, and to describe thromboembolic complications. Patients with invasive F. necrophorum infections were identified either prospectively or retrospectively through the regional database of clinical microbiology from 2000 to 2015. Patient records were reviewed and blood samples from patients with Lemièrre's syndrome were collected for Epstein-Barr virus (EBV) serology and screening for thrombophilia. Of the 65 patients included, 33 had Lemièrre's syndrome. Of the remaining 32 patients, other infections of the respiratory tract and abdominal or urogenital infections were most common. Patients with Lemièrre's syndrome or other tonsillar infections were younger than patients from the other groups. For Lemièrre's syndrome, the 26 patients with severe sepsis on admittance had longer duration of symptoms. Three of five patients who developed distant manifestations had more than 14 days of symptoms. Jugular vein thrombosis was verified in 14 patients, two of whom developed serious complications. Three of 26 patients tested had factor V Leiden mutation, corresponding to the background prevalence. One of 22 patients tested had a concomitant EBV infection. This study confirms earlier studies of the clinical spectrum caused by F. necrophorum. For Lemièrre's syndrome, the study adds to the knowledge on thromboembolic outcome, demonstrating that jugular vein thrombosis may cause severe complications. The time to treatment seems to be important for the risk of severe disease. In this study, concomitant EBV infection or underlying thrombophilia was uncommon.

Performance of two relatively new quantitative D-dimer assays (Innovance D-dimer and AxSYM D-dimer) for the exclusion of deep vein thrombosis.

INTRODUCTION: D-dimer assays are now widely used as the first-line test in the diagnostic algorithm of suspected deep vein thrombosis (DVT). The aim of this study was to evaluate the performance of two relatively new quantitative D-Dimer assays (Innovance and AxSYM) by comparison with a clinical gold standard. PATIENTS AND METHODS: 311 samples from outpatients with clinical suspicion of DVT, included in a prospective management study, was analysed (prevalence of DVT 23%). The diagnostic workup included estimation of pre-test probability, D-dimer determination, objective imaging as well as 3 month clinical follow up of negative patients. RESULTS: No significant differences were seen in sensitivity and negative predictive values between Innovance, AxSYM and the reference assays. The area under the ROC curve was slightly lower for the AxSYM assay and the correlation to the reference assays was only moderate (r < 0.8) whereas the agreement with the Vidas assay was near excellent (kappa = 0.8). The Innovance assay reached the highest AUC, showed a strong correlation with the reference assays (r > or = 0.9) and a good agreement with the Vidas assay (kappa = 0.76). In combination with a low pre-test probability score the Innovance assay reached a NPV of 100% (95% CI, 92-100) and the AxSYM assay 98% (95% CI, 87-100). CONCLUSION: The Innovance and AxSYM assays show an overall good and comparable performance for the exclusion of DVT when compared to the established assays. Our results for the AxSYM assay indicate that the optimal cut-off value needs to be further evaluated.

Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study.

OBJECTIVES: To investigate the reliability of a combined strategy of clinical assessment score followed by a local D-dimer test to exclude deep vein thrombosis. For comparison D-dimer was analysed post hoc and batchwise at a coagulation laboratory. DESIGN: Prospective multicenter management study. SETTING: Seven hospitals in southern Sweden. SUBJECTS: 357 patients with a suspected first episode of deep vein thrombosis (DVT) were prospectively recruited and pre-test probability score (Wells score) was estimated by the emergency physician. If categorized as low pre-test probability, D-dimer was analysed and if negative, DVT was considered to be ruled out. The primary outcome was recurrent venous thromboembolism (VTE) during 3 months of follow up. RESULTS: Prevalence of DVT was 23.5% (84/357). A low pre-test probability and a negative D-dimer result at inclusion was found in 31% (110/357) of the patients of whom one (0.9%, [95% CI 0.02-4.96]) had a VTE at follow up. Sensitivity, specificity, negative predictive value and negative likelihood ratio for our local D-dimer test in the low probability group were 85.7%, 74.5%, 98.2%, and 0,19 respectively compared to 85.6%, 67,6%, 97.9% and 0,23 using batchwise analysis at a coagulation laboratory. CONCLUSION: Pre-test probability score and D-dimer safely rule out DVT in about 30% of outpatients with a suspected first episode of DVT. One out of 110 patients was diagnosed with DVT during follow up. No significant difference in diagnostic performance was seen between local D-dimer test and the post hoc batch analysis with the same reagent in the low probability group.

The complex between activated protein C and protein C inhibitor: A clinically useful indicator of aortic aneurysms?

The concentration of the complex between activated protein C and the protein C inhibitor reflects the degree of activation of blood coagulation. A sandwich method has been devised that measures the complex concentration in blood plasma. A key feature of the method is that the catching monoclonal antibody recognizes a complex-dependent neoepitope in PCI, which is a prerequisite, since the concentration of uncomplexed PCI is approximately 10(4)-fold higher than that of the complex. In patients with atherosclerotic disease, those with aortic aneurysms exhibit a three-fold increase in complex concentration compared to that of normal subjects.

On difficulties in diagnosing deep vein thrombosis in daily clinical work and research practice.

This article enlightens the diagnostic difficulties when performing and interpreting a phlebography or color Doppler ultrasonography (CDU), which may have serious consequences in the daily clinical and laboratory work. In laboratory research as well as in clinical trials the most fundamental principle is to obtain a correct diagnosis. Less than 50% of patients with deep venous thrombosis (DVT) manifest the classical symptoms and signs of DVT and consequently the diagnosis is based upon methods such as phlebography or CDU. Some veins are especially hard to display, i.e. the veins of the planta pedis, the deep muscle veins of the calf and thigh and the deep internal iliac vein. Thus, the ideal diagnostic method must display the whole venous system from the planta pedis to the caval vein. A false negative examination puts the patient at risk of pulmonary embolism, which may present with a sudden onset and fatal outcome. A venous dysfunction as well as recurrent DVT will also be a continuous risk factor. A false positive interpretation may result in unnecessary anticoagulation treatment and bleeding complications. The combination of phlebography and CDU together with the strict use of a scoring method will increase the possibility of a proper diagnosis focusing on the diagnostically difficult areas of the venous system.

Inflammatory bowel disease promotes venous thrombosis earlier in life.

BACKGROUND: Patients with inflammatory bowel disease (IBD) may be at increased risk of having venous thromboembolism. METHODS: Medical records from 1,253 IBD patients attending hospital care during the years 1987-97 were studied. These patients were recruited from a population of 340,000 inhabitants. Patients with verified venous thrombosis were characterized clinically, and blood samples were examined for coagulopathy including analyses of antithrombin, plasminogen, protein C, protein S, factor V, and prothrombin mutations. As control groups we used 99 patients with verified venous thrombosis and no history of IBD and 288 volunteers with no history of thrombosis. RESULTS: The incidence of venous thrombosis was 1.5/1,000 IBD patients per year, which is comparable to the background population. The mean age was significantly lower in IBD patients than in non-IBD patients (53 versus 64 years, P= 0.0225). We found one patient with antithrombin deficiency but none with protein C, protein S, or plasminogen deficiency. Factor V mutation was as prevalent in IBD patients with thrombosis as in thrombotic non-IBD patients (27% versus 28%) and 3.0 times (95% confidence interval, 0.8-11.9) more frequent in IBD patients with thrombosis than in healthy controls. Prothrombin mutation was not detected in IBD patients with venous thrombosis. CONCLUSION: We found no increased incidence of venous thrombosis in IBD patients compared with a background population. However, IBD patients had venous thrombosis earlier in life than non-IBD patients. Although factor V mutation may contribute to thrombosis, IBD acts as a trigger through mechanisms that still remain unexplained.

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

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Location and extent of deep vein thrombosis in patients with and without FV:R 506Q mutation.

Resistance to activated protein C due to FV:R 506Q mutation is the most common known genetic risk factor for deep leg vein thrombosis (DVT). The aim of this prospective study was to describe and compare the location and extent of DVT, reflected by a scoring system, in a group of patients with and without FV:R 506Q mutation. Of 247 consecutively included patients undergoing phlebography 105 had a DVT, 36 (35%) in the FV:R 506Q mutation group and 69 (65%) in the non-FV:R 506Q mutation group. Compared to the non-FV:R 506Q mutation group there was a significant increase in the incidence of DVT in the FV:R 506Q mutation group (p = 0.041, OR = 1.79 [1.02-3.15]), a significantly lower mean DVT score of the iliofemoral vein segments (p = 0.0081) and a significantly lower incidence of DVT in the iliofemoral vein segments (p = 0.007, OR = 10.6 [1.3-83.3]), 1/36 (2.8%) compared to 16/69 (23.2%). As controls 288 blood donors were included, with and without FV:R 506Q mutation and with no history of DVT in order to evaluate risk factors of DVT. The odds ratio of an iliofemoral DVT was 0.5 ([0.06-3.90), p = 0.50]) when FV:R 506Q mutation was present, compared to the control group, and at locations below the iliofemoral segments 5.28 ([3.01-9.28], p = less than 0.0001). Our findings provide the basis of a detailed phlebographic description and for the first time, to our best knowledge, shows a specific phlebographic pattern that may be linked to an inherited hypercoagulable state.

Increased prevalence of apolipoprotein E3/E4 genotype among Swedish renal transplant recipients.

There is increasing evidence that lipoproteins are involved in the progression of kidney diseases and in the deterioration of kidney transplant function, although the exact mechanism is still not known. Common polymorphisms of apolipoprotein E genotype associate with the variability of lipoprotein levels and composition. We have, therefore, determined the apolipoprotein E genotype in a group of 112 renal transplant patients, of whom 27 had had an episode of acute vascular rejection, while 85 had not. We found no difference in apolipoprotein E genotype distribution or in relative allele frequency in the vascular rejection group as compared with the group without vascular rejection. The apolipoprotein E genotype distribution in the transplant group was also compared with that in a group of 407 healthy Swedish individuals. The E3/E4 genotype occurred with a significantly increased frequency in the transplant group: 38.3 versus 16% in the control group (p < 0.001). The prevalence of individuals carrying the epsilon4 allele among the transplant group was also significantly higher (44%) as compared with the control group (30%; p < 0.01). This increase was entirely due to the predominant increase of E3/E4, as the E4/E4 genotype was less frequent in transplant recipients than in normal controls (3.5 vs. 10.6%; p < 0.05). The relative frequencies of epsilon2 (0.044), epsilon3 (0.716), and epsilon4 (0.238) alleles in the renal transplant group were not different from those of normal controls (0. 078, 0.718, and 0.202, respectively). With regard to the prevalence of E4/E4 in the two groups, the lack of difference in the relative frequency of the epsilon4 allele must be interpreted with caution. The results thus suggest that the E3/E4 genotype may be associated with the progression of kidney disease leading to renal insufficiency. However, the apolipoprotein E genotype does not seem to influence the risk of vascular rejection among transplant recipients.

Mesenteric vein thrombosis due to factor V Leiden gene mutation.

BACKGROUND: Mesenteric venous thrombosis is a rare cause of acute abdominal pain that may be the result of coagulation abnormalities. METHODS: Four consecutive patients with mesenteric venous thrombosis underwent haematological evaluation. RESULTS: All four had activated protein C resistance resulting from a single mutation in the gene coding for coagulation factor V. Three had surgery; in one patient the diagnosis was made by ultrasonography. One of the patients who had surgery died but the other three survived and were treated with long-term anticoagulation. CONCLUSION: Activated protein C resistance may be an important pathogenetic factor in primary mesen-teric vein thrombosis.

[New system for testing mechanical heart valves. Self-monitoring at home of anti-vitamin K therapy means greater freedom for the patient]. / Nytt system testar den mekaniska hjärtklaffen. Egenkontroll i hemmet av antivitamin K-terapin ger patienten större frihet.

Self-monitoring of anti-vitamin K treatment by patients with heart valve prostheses is a good alternative to hospital control. Self-monitoring at home allows patients more freedom and opportunity to take greater responsibility for their treatment. Experience from over a years' complication-free treatment of 12 patients is reported in the article.

A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease.

Hirschsprung's disease, affecting one in 5000 live newborns, is the most common cause of neonatal intestinal obstruction. The obstruction or, later in life, constipation arises from the lack of enteric ganglia in the hindgut, thus resulting in poor coordination of peristalsis. Mutations in Hirschsprung patients have so far been reported in five genes associated in two different receptor-ligand systems, RET-GDNF/NTN and EDNRB-EDN-3, and an additional gene with yet unknown precise function, SOX10. We report the results of single-stranded conformation polymorphism screening of the endothelin-3 gene in a Swedish population-based material of 66 sporadic and nine familial Hirschsprung's disease cases. We have found a novel heterozygous mutation in exon 2, c.262insG, in a patient with sporadic short segment Hirschsprung's disease without any Waardenburg features. This frameshift results in a premature stop two codons further on. Because this stop is introduced 5' of the biologically active protein, this mutation can hence be predicted to result in haplo-insufficiency.

Activated protein C resistance (FV:Q506) and pregnancy.

Activated protein C (APC) resistance, due to a point mutation in the factor V gene (FV:Q506), is a major risk factor for venous thromboembolism. To determine the prevalence of APC resistance in a large series of pregnant women, and to elucidate its obstetric consequences, we performed a prospective study in Malmo, Sweden, comprising 2,480 women enrolled in early pregnancy. The presence of APC resistance (the FV:Q506 allele) was determined. The women were interviewed about their medical histories including venous thromboembolic events (VTE) in relatives. The outcome variables were the VTE rate, intrapartum blood loss, and the prevalence of selected pregnancy complications such as fetal loss, pre-eclampsia. and intrauterine growth retardation. The overall prevalence of APC resistance was 11% (270/2480). The APC-resistant subgroup did not differ significantly from the non-APC-resistant subgroup in terms of pregnancy complications, but was characterized by an 8-fold higher risk of VTE (3/270 vs. 3/2210), a lower rate of profuse intrapartum haemorrhage (3.7% vs. 7.9%) (p = 0.02), and less intrapartum blood loss (340 ml vs. 361 ml) (p = 0.04). Despite the high prevalence of APC resistance in this series of gravidae (11%), its presence was unrelated to adverse pregnancy outcome apart from an 8-fold increased risk of VTE.

A new scoring system for the detailed description of the distribution and thrombotic burden in deep leg vein thrombosis.

The scoring system most commonly used to date to describe the thrombotic burden of deep vein thrombosis (DVT) excludes several deep vein segments and is thereby of limited use in research. The aim of this prospective, comparative study was to develop a new scoring and distribution system that would include all major deep veins of the leg and pelvis. In total, 247 consecutive patients were included, of whom 105 had a positive phlebography. The positive phlebographies were registered in the new system and the result was compared with that obtained by the Marder system. In 72% (76/105) of the patients the DVT distribution was not completely described and the thrombotic burden was significantly underestimated by the Marder system. Of these, 12% (13/105) were not scored at all, thus representing false-negative investigations. It was possible to score all DVTs and important vein segments of these patients with the new system. The scoring system previously used excludes several deep vein segments. A description of the important vein segments, where DVT is shown to originate and propagate, is mandatory in a scoring system designed for the purpose of research of DVT and later detected deep vein insufficiency. The new system meets this demand.

Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B).

Hirschsprung disease is a congenital malformation affecting 1 in 5000 live births. The absence of parasympathetic neuronal ganglia (Meissner, Auerbach) in the hindgut results in poor coordination of peristaltic movement, and a varying degree of constipation. Four different genes have been implicated in the pathogenesis of Hirschsprung disease: the RET tyrosine kinase receptor gene; one of its ligands, the glial cell line-derived neurotrophic factor (GDNF) gene; the endothelin receptor B (EDNRB) gene; and its ligand, endothelin-3 (EDN3). Recently, combinations of mutations in two of these genes (RET and GDNF) have been reported in Hirschsprung patients. We report a family with missense mutations in both the RET gene (R982C) and the EDNRB gene (G57S). In this family, three out of five members have the two mutations, but only one, a boy, has the Hirschsprung disease phenotype. This illustrates the complexity of the molecular background of Hirschsprung disease.

Low frequency of RET mutations in Hirschsprung disease in Sweden.

Hirschsprung disease is a congenital malformation, where absence of intramural ganglia in the hindgut results in a defect in the coordination of peristaltic movement. This leads to ileus in the newborn or, more often, constipation in children and adults. The disease affects one in 5000 live births. Siblings of affected cases are at an increased risk (4%) of developing the disease. Among cases. males are affected more often than females. The first major susceptibility gene for Hirschsprung disease is the RET proto-oncogene on 10q11.2. Germline RET mutations in Hirschsprung disease are mainly inactivating, and have been reported to account for up to 20 and 50% of sporadic and familial cases, respectively. We have screened Swedish population-based samples from 62 sporadic cases and seven familial cases of Hirschsprung disease with single strand conformation polymorphism (SSCP), and found five mutations.