Risk of ocular manifestations in patients with giant cell arteritis: a nationwide study in Sweden.

OBJECTIVE: No large-scale nationwide study has determined the risk of ocular manifestations in patients with giant cell arteritis (GCA). The aim was to study the incidence and risk factors of ocular manifestations in patients with GCA in Sweden. METHOD: A national cohort was created by linking Swedish nationwide registers. GCA patients were identified from the Swedish Hospital Inpatient and Outpatient Registers between 2002 and 2010, and were followed until the development of ocular manifestations. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for ocular manifestations in patients with GCA compared to those without GCA. RESULTS: We identified 3737 males and 8311 females with GCA. A total of 1618 individuals had subsequent ocular manifestations, representing 13.4% of the GCA patients. The overall SIR of ocular manifestations was 6.96 (95% CI 6.63-7.31). The risk for disorders of the optic nerve or visual tract was particularly high (SIR = 51.68, 95% CI 46.12-57.73). Men with GCA had a higher risk than women, and GCA patients without polymyalgia rheumatica (PMR) symptoms had a higher risk than those with PMR symptoms. Living outside big cities was negatively associated with ocular manifestations in GCA patients, whereas hypertension and diabetes were associated with an increased risk of ocular manifestations. CONCLUSION: The overall risk of ocular manifestations was higher in GCA patients than in the general population, especially for men and for those without PMR symptoms.

The association between apolipoprotein M and insulin resistance varies with country of birth.

BACKGROUND AND AIMS: Risk of type 2 diabetes mellitus (T2DM) differs according to ethnicity. Levels of apolipoprotein M (ApoM) have been shown to be decreased in T2DM. However, its role in different ethnicities is not known. We examined the differences in plasma ApoM levels in Swedish residents born in Iraq (Iraqis) and Sweden (Swedes) in relation to T2DM and insulin resistance (IR). METHODS AND RESULTS: Iraqis and Swedes, aged 45-65 years residing in Rosengård area of Malmö were randomly selected from census records and underwent an oral glucose tolerance test. Plasma levels of ApoM were quantified in 162 participants (Iraqis, n = 91; Swedes, n = 71) by a sandwich ELISA method. Age-, sex-, and body mass index (BMI) adjusted plasma ApoM levels differed by country of birth, with Swedes having 18% higher levels compared to Iraqis (p = 0.001). ApoM levels (mean ± SD) were significantly decreased in Swedes with T2DM (0.73 ± 0.18) compared to those with normal glucose tolerance (NGT) (0.89 ± 0.24; p = 0.03). By contrast, no significant difference in ApoM levels was found between Iraqis with T2DM (0.70 ± 0.17) and those with NGT (0.73 ± 0.13; p = 0.41). In multivariate linear regression analysis with an interaction term between IR and country of birth, low ApoM levels remained significantly associated with IR in Swedes (p = 0.008), independently of age, sex, BMI, family history of diabetes, HDL, LDL, and triglycerides, but not in Iraqis (p = 0.35). CONCLUSION: Our results show that ApoM levels differ according to country of birth and are associated with IR and T2DM only in Swedes.

Mothers, places and risk of hospitalization for childhood asthma: a nationwide study from Sweden: epidemiology of allergic disease.

OBJECTIVE: This study examines whether neighbourhood deprivation increases the risk of hospitalization for childhood asthma, after accounting for individual-level maternal socio-demographic characteristics. DESIGN: An open cohort of all singleton children aged 2-11 years was followed between January 1, 1995 and December 31, 2006. Childhood residential addresses were geocoded and classified according to the level of neighbourhood deprivation. Data were analysed by multilevel logistic regression, with individual-level characteristics (sex, age, maternal marital status, family income, maternal educational attainment, maternal immigration status, maternal urban/rural status, mobility, maternal asthma history and maternal smoking) at the first level and level of neighbourhood deprivation at the second level. RESULTS: During the study period, among a total of 866,860 children, 17,682 (2.0%) were hospitalized with childhood asthma. Age-adjusted hospital rates for childhood asthma increased with increasing level of neighbourhood deprivation. In the study population, 1.9% and 2.3% of children in the least and most deprived neighbourhoods, respectively, were affected by childhood asthma. Hospital rates of childhood asthma increased with increasing neighbourhood-level deprivation across all individual-level maternal socio-demographic categories, including marital status, educational attainment, urban/rural status, maternal history of asthma and smoking. The odds ratio (OR) for those living in high-deprivation neighbourhoods vs. those living in low-deprivation neighbourhoods was 1.23 (95% confidence interval, 1.16-1.30). High neighbourhood deprivation remained significantly associated with childhood asthma risk after adjustment for maternal socio-demographic characteristics (OR=1.08, p = 0.016). CONCLUSIONS: This study is the largest so far on neighbourhood influences on childhood asthma. Our results suggest that neighbourhood characteristics affect the risk of hospitalization for childhood asthma independent of maternal socio-demographic characteristics.

Occupational and socio-economic risk factors for giant cell arteritis: a nationwide study based on hospitalizations in Sweden.

OBJECTIVES: Socio-economic and occupational factors may contribute to risk of immune-mediated disorders. The importance of these factors in giant cell arteritis (GCA) is unknown. This is the first nationwide study with the aim of investigating possible associations between socio-economic status (SES)/occupation and hospitalization for GCA. METHOD: A nationwide database was constructed by linking Swedish census data to the Hospital Discharge Register to obtain data on all first hospitalizations with a main diagnosis of GCA in Swedish adults between 1970 and 2008. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated for different occupations. Three cohorts were defined based on 53 occupational titles recorded in Swedish census data in 1970, 1980, and 1990. RESULTS: In individuals aged over 50 years, 3293 males and 4726 females were hospitalized with GCA. Only minor or inconsistent associations were observed for education and SES and GCA. Some occupations were associated with increased risk of GCA. However, the risks were modest or not consistent between the three cohorts investigated. Only male fishermen, whalers, and sealers had an SIR of > 2 (2.14). However, the risk of GCA was only increased in one cohort. Both women (0.83) and men (0.83) born outside Sweden had a lower risk of GCA. The adjustment variables hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and coronary heart disease (CHD) were associated with higher risk of GCA. CONCLUSIONS: Occupation and SES are not strong risk factors for GCA. However, GCA was associated with co-morbidities and country of birth, calling for further studies.

Venous thromboembolism does not share strong familial susceptibility with pre-eclampsia/eclampsia: a nationwide family study in Sweden.

OBJECTIVE: Genetic variants associated with venous thromboembolism (VTE) have been suggested to be involved in the pathogenesis of pre-eclampsia/eclampsia (PEC/EC). This nationwide study aimed to determine whether VTE shares familial susceptibility with PEC/EC. DESIGN: Population-based cohort study. SETTING: Sweden. SAMPLE: A total of 941 841 Swedish women delivering their first child between 1987 and 2008. METHODS: Data from the Swedish Multigeneration Register were linked to the Swedish Hospital Discharge Register. The risk of PEC/EC was determined in primiparous women with a family history of VTE (in parents and/or siblings), compared with primiparous women without a family history of VTE. Odds ratios (ORs) were calculated by logistic regression. MAIN OUTCOME MEASURE: PEC/EC in first pregnancy. RESULTS: In total, 43 621 women had PEC/EC in association with their first pregnancy. The OR for PEC/EC in women with a family history of VTE was 1.06 (95% CI 1.01-1.11); however, a family history of VTE was associated with higher odds of PEC/EC among women with previous hypertension (OR 1.38, 95% CI 1.25-1.52). CONCLUSION: A family history of VTE is weakly associated with PEC/EC risk, and is not clinically useful for the prediction of PEC/EC. The results of the present study suggest that it is unlikely that strong disease-causing mutations shared by VTE and PEC/EC are common in the Swedish population. The novel association between family history and PEC/EC among the subgroup with previous hypertension needs further confirmation in future studies.

Tissue tropism of Toxoplasma gondii in turkeys (Meleagris gallopavo) after parenteral infection.

Turkeys are known to be natural hosts for the zoonotic protozoan parasite Toxoplasma gondii. The objective of the present study was to gain further knowledge of possible predilection sites of T. gondii infection in this species after parenteral application of tachyzoites. A total of 38 turkeys were infected with different doses of T. gondii tachyzoites. Birds were killed either 6 to 8 or 10 to 12 weeks after the experimental infection. Fourteen different tissues per bird were investigated by a nested polymerase chain reaction (PCR) for the presence of the parasites' DNA. T. gondii DNA was found in any type of tissue analysed; in 86.1 % of all infected birds, at least one sample was tested positive. Over all intravenously infected birds, 15.4 % of all analysed samples contained T. gondii DNA. Most frequently affected tissues were liver (43.3 % positive samples), breast muscle (26.7 % positive samples) and heart (20.0 % positive samples), while the brain was less frequently positive (6.7 %). The number of positive tissues varied from zero to seven tissues per animal with at least one T. gondii-positive edible tissue sample in 80 % of all intravenously infected birds. Still, the results did not indicate defined target tissues or a cyst distribution pattern. Nonetheless, edible organs were most frequently parasitised. The number of positive findings did not differ between the early and the late examination time points. Therefore, a persistence of the tissue stages until the end of the study (12 weeks after infection) is concluded.

Family history and risk of hospital treatment for varicose veins in Sweden.

BACKGROUND: Family history has been suggested as a risk factor for varicose veins, but recall bias may inflate the familial risks. The aim of this nationwide study was to determine familial risks for hospital treatment for varicose veins. METHODS: Data from the Swedish Multi-Generation Register of people aged 0-76 years were linked to Hospital Discharge Register data for 1964-2008. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were treated in hospital for varicose veins and compared with those whose relatives were not. Only main diagnoses of varicose veins were considered. RESULTS: A total of 39 396 people had hospital treatment for varicose veins. The familial SIR among offspring with one affected parent was 2·39 (95 per cent confidence interval 2·32 to 2·46). The SIR for those with one affected sibling was 2·86 (2·76 to 2·97). SIRs were increased in both men and women. The SIR for individuals with two or more affected siblings or with two affected parents was 5·88 (5·28 to 6·53) and 5·52 (4·77 to 6·36) respectively. The SIR for the wives of men treated for varicose veins was 1·69 (1·59 to 1·80); that for the husbands of women treated for varicose veins was 1·68 (1·58 to 1·79). CONCLUSION: Using the Swedish Hospital Discharge Register, and thereby eliminating recall bias, family history of hospital treatment for varicose veins was associated with an increased risk of similar treatment among relatives. The increased spousal risk suggests a contribution from non-genetic factors.

Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden.

OBJECTIVE: This is the first nationwide study to determine familial risks of unusual forms of venous thrombosis amongst offspring of affected parents and amongst siblings. DESIGN AND SETTINGS: The Swedish Multigeneration Register of 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the period 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for venous thromboembolism (VTE), as determined by the International Classification of Diseases, compared to those whose relatives were not affected by VTE. RESULTS: The total number of hospitalized patients with VTE was 45 362, of which 1824 (4.0%) were affected by a rare thrombotic condition. The familial SIRs in cases with a history of VTE in parents or siblings were significantly increased for migrating thrombophlebitis (1.81; 95% confidence interval (CI) 1.40-2.31), portal vein thrombosis (2.35; 95% CI 1.77-3.06), vena cava thrombosis (1.96; 95% CI 1.42-2.64) and cerebral venous thrombosis (1.74; 95% CI 1.30-2.28). Budd-Chiari syndrome (SIR, 0.92; 95% CI 0.24-2.38) and renal vein thrombosis (SIR, 1.72; 95% CI 0.62-3.77) were not significantly associated with parental or sibling history of VTE; however, these two conditions were very rare, and therefore, we cannot draw any definite conclusions from this finding. CONCLUSIONS: Family history is an important risk factor for most unusual forms of VTE. Moreover, even the paraneoplastic phenomenon, migrating thrombophlebitis (Trousseau's syndrome), is associated with a family history of VTE. Thus, our data suggest that most rare forms of VTE have a familial background.

Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.

Resistance to activated protein C (APC) is the most prevalent inherited cause of venous thrombosis. The APC resistance phenotype is associated with a single point mutation in the factor V gene, changing Arg506 in the APC cleavage site to a Gln. We have investigated 50 Swedish families with inherited APC resistance for this mutation and found it to be present in 47 of them. Perfect cosegregation between a low APC ratio and the presence of mutation was seen in 40 families. In seven families, the co-segregation was not perfect as 12 out of 57 APC-resistant family members were found to lack the mutation. Moreover, in three families with APC resistance, the factor V gene mutation was not found, suggesting another still unidentified cause of inherited APC resistance. Of 308 investigated families members, 146 were normal, 144 heterozygotes, and 18 homozygotes for the factor V gene mutation and there were significant differences in thrombosis-free survival curves between these groups. By age 33 yr, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestation of venous thrombosis.

Resistance to activated protein C due to a factor V gene mutation The most common inherited risk factor of thrombosis.

The protein C anticoagulant pathway is of major importance in maintaining vascular patency. Resistance to the key enzyme of this system, activated protein C (APC), is a recently discovered congenital defect of the protein C system. This genetic defect is present in 20% to 60% of venous thrombosis patients, making it by far the most common known pathogenetic risk factor of thrombosis. APC resistance is due to a single point mutation in the factor V gene (G to A at nucleotide position 1691) that predicts the replacement of arginine(506) by glutamine. This is associated with the loss of one of three APC cleavage sites in factor Va, one of the substrates for APC, and hypercoagulability. The identification of APC resistance as an additional genetic risk factor in a large proportion of symptomatic protein C- and protein S-deficient families has provided evidence that thrombosis is a polygenetic disease. Thus, several genetic defects act in concert with environmental factors in the pathogenesis of venous thromboembolism.

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.

Rapid plasma virus and CD4+ T-cell turnover in HIV-1 infection: evidence for an only transient interruption by treatment.

OBJECTIVES: To analyse the short-term kinetics of viral plasma RNA and CD4+ T cells numbers in patients with different initial CD4+ T-cell counts treated with different antiretroviral regimens. METHODS: In 10 HIV-1 positive patients, in vivo kinetics of plasma HIV RNA and CD4+ T cells were studied during antiretroviral treatment. Lymphocyte subpopulation analysis, quantitative polymerase chain reaction (PCR), p24 antigen enzyme immunoassay (EIA) and beta 2-microglobulin EIA were performed at days 0, 3, 7, 10, 14, 21 and 28 of treatment. One additional patient served as a control. The resulting curves were fitted. Half-lives were calculated using the time constant T of decrease or increase [T1/2 = In(2) x T]. Calculations of virus and CD4+ T-cell turnover were multiplied by the total blood volume. RESULTS: Viral plasma RNA half-life ranged from 1.1 to 5.1 days, independent of prior or actual treatment and initial CD4+ T-cell count. The calculated peripheral blood viral plasma RNA turnover varied between 0.02 and 55.8 x 10(8) copies/ml/day and showed some negative correlation with initial CD4+ T-cell counts. CD4+ T-cell turnover estimates ranged from 0.01 to 7.5 x 10(8) cells/day. Most patients showed an immediate reincrease of virus load after the nadir. Changes in HIV p24 antigen paralleled HIV plasma RNA in p24 antigen-positive patients. beta 2-microglobulin decreased until day 7-15 in all but one case and rapidly reincreased to pretreatment values. CONCLUSIONS: The kinetics of virus and CD4+ T-cell turnover are uniformly rapid throughout a wide range of initial CD4+ T-cell counts. The magnitude of virus turnover varies considerably among individuals and appears to be inversely related to the initial CD4+ T-cell count. These data also argue for a rapid resumption of virus production and lymphocyte turnover during treatment.

Activated protein C resistance: from phenotype to genotype and clinical practice.

The anticoagulant protein C system is an important regulator of the blood coagulation process. Its targets are the procoagulant cofactors factor Va and factor VIIIa, which are cleaved and inactivated by activated protein C, protein S and intact factor V working as cofactors. Genetic defects of protein C or protein S were, together with antithrombin III deficiency, the previously established major causes of familial venous thromboembolism. However, these abnormalities are found in less than 5-10% of patients with thrombosis. Inherited resistance to activated protein C was recently identified as a major risk factor for venous thromboembolism. The activated protein C-resistance phenotype is found in 20-60% of the patients with venous thrombosis, depending on selection criteria and on the prevalence of activated protein C-resistance in the population. The frequency of activated protein C-resistance is 2-10% in the normal populations studied so far. In more than 90% of cases, the molecular background for the activated protein C-resistance is a single point mutation in the factor V gene, which predicts substitution of an arginine at position 506 by a glutamine. Mutated factor V is activated by thrombin or factor Xa in the normal way, but impaired inactivation of mutated factor Va by activated protein C results in a life-long hypercoagulability. Owing to the high prevalence of activated protein C-resistance in the population, it occasionally occurs in patients with deficiency of protein S, protein C or antithrombin III. Individuals with combined defects suffer more severely from thrombosis, and often at a younger age, than those with single defects, suggesting thrombophilia to be a multigenetic disease.

The genomic structure of the chicken ICSBP gene and its transcriptional regulation by chicken interferon.

The chicken interferon consensus sequence binding protein (ChICSBP) gene spans over 9 kb of DNA and consists, as its murine homolog, of nine exons. The first untranslated exon was identified by 5'-RACE technology. The second exon contains the translation initiation codon. Canonical consensus splice sites are found on every exon/intron junction. The introns are generally smaller than their mammalian counterparts. The ChICSBP and ChIRF-1 genes have been mapped by fluorescence in situ hybridization to different microchromosomes. The transcription start site has been mapped by primer extension. Inspection of the DNA sequence of a genomic clone containing the first exon and the region 1700-bp upstream revealed several potential cisregulatory elements of transcription. The ChICSBP mRNA is induced by recombinant ChIFN type I and ChIFN-gamma. A palindromic IFN regulatory element (pIRE) with high sequence homology to gamma activation site (GAS) sequences was functionally required in transient transfection assays for the induction of transcription by ChIFN-gamma.

Cloning of chicken interferon regulatory factor-2 (IRF-2) cDNA: expression and mapping of the IRF-2 gene.

A cDNA clone encoding a member of the avian interferon regulatory factor (IRF) family homologous to mammalian IRF-2 was isolated from cDNA library from poly[rI:rC]-induced chicken embryo fibroblasts (CEF). The deduced amino acid sequence shows a characteristic DNA binding domain of 124 amino acids at the amino-terminal end with 96.8% identity to human and 96% to mouse IRF-2. Identities in the C-terminal part are 77.5% and 77%, respectively. Identity to all other known members of the chicken IRF (Ch-IRF) family is distinctly lower. In C32 cells, an IRF-2 mRNA of 2.4 kb is constitutively expressed in very low amounts but is inducible by Ch-IFN in the absence or presence of cycloheximide. The Ch-IRF-2 gene is a single copy gene and was mapped by fluorescence in situ hybridization to the long arm of chromosome 4.

Sequence comparison of avian interferon regulatory factors and identification of the avian CEC-32 cell as a quail cell line.

Interferon (IFN) regulatory factor-1 (IRF-1) is a well-characterized member of the IRF family. Previously, we have cloned cDNA of several members of the chicken IRF (ChIRF) family and studied the function of ChIRF-1 in the avian cell line CEC-32. The IRF-1 proteins from primary chicken embryo fibroblasts (CEF) and CEC-32 cells differed in their electrophoretic mobility. To characterize the different forms of IRF-1 in avian cells, we compared the sequences of IRF-1 cDNA from CEC-32 cells, primary CEF, and quail fibroblasts (QEF). The deduced amino acid sequences of IRF-1 cDNA from chicken and quail show high similarity. Comparison of genomic sequences of IRF-1 and IFN consensus sequence binding protein (ICSBP) also confirm the relatedness of the members of the IRF family in quail and chicken. Based on these data, it is concluded that the avian fibroblast cell line CEC-32 is derived from quail. This conclusion is further supported by deoxynucleotide sequence comparison of a DNA fragment in an avian MHC class II gene and by fluorescence in situ hybridization (FISH) using the vertebrate telomeric (TTAGGG) repeat. Chromosome morphology and the lack of interstitial hybridization signals in macrochromosomes suggest that the CEC-32 cell line has probably been derived from Japanese quail.

Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1.

Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.

Homozygous APC-resistance combined with inherited type I protein S deficiency in a young boy with severe thrombotic disease.

Inherited resistance to activated protein C (APC) is a frequent cause of familial thrombosis. It is associated with a factor V gene point mutation replacing arginine506 in the APC-cleavage site with a glutamine. Thrombotic events are rare during childhood even in patients with homozygous APC-resistance. We now wish to report on a case of severe venous thrombosis, in a 10-year-old boy. He was found to have pronounced APC-resistance due to homozygous factor V gene mutation in combination with inherited type I protein S deficiency. The two traits were independently inherited in the family. The APC-resistance was partially corrected by adding factor V, whereas added protein S was without effect. This is the first reported case of homozygous APC-resistance combined with another inherited prothrombotic disorder. It illustrates how multiple genetic defects may provoke thrombosis at young age and emphasizes the need of complete evaluation of thrombotic patients in order to determine whether multiple risk factors exist.

A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis.

Thrombomodulin is an endothelial cell membrane glycoprotein that promotes protein C activation. It has been clearly demonstrated that the anticoagulant functions of the protein C system are important in the prevention of thromboembolic disease. Patients with protein C or protein S deficiency and/or resistance to activated protein C (APC resistance) are at higher risk for developing thromboembolic disease. The first mutation in the thrombomodulin gene was discovered in an American patient suffering from pulmonary embolism at the age of 45 (Ohlin and Marlar 1995). Here we report a case of sagittal sinus thrombosis in a 42-year-old Swedish woman. She was found to carry a heterozygous point mutation changing G127 to A, predicting an Ala25 to a Thr change in the mature thrombomodulin protein. This mutation was also found in her 16-year-old daughter, who so far has not suffered from any thrombotic events. The patient had no other detectable prothrombotic genetic defects associated with the coagulation system. This case supports the hypothesis of an association between mutations in the thrombomodulin gene and venous thrombosis.

Evaluation of original and modified APC-resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls.

APC-resistance is the most common hereditary condition associated with venous thrombosis. It is in a majority of cases due to a single point mutation in the factor V gene (FVR506Q). Currently used functional APC-resistance tests have 85-90% sensitivity and specificity for the FVR506Q mutation. A modified test which includes predilution of patient plasma in factor V depleted plasma has increased the sensitivity and specificity for the factor V mutation. However, neither the original nor the modified APC-resistance test have been evaluated in patients with acute thrombotic events. We have therefore used the original and the modified APC-resistance tests in 220 patients with clinically suspected acute deep venous thrombosis and in 278 healthy controls. The FVR506Q mutation was determined in all patients. The patients were classified as either DVT (deep venous thrombosis)-negative or DVT-positive depending on the outcome of contrast phlebography. In individuals with normal factor V genotype, the original APC-resistance test gave significantly lower APC-ratio values both in DVT-positive and DVT-negative patients than in healthy controls. The specificity of the original APC-resistance test for the FVR506Q mutation in controls and in DVT-negative and DVT-positive patients were 85%, 54% and 28%, respectively, when a cut off APC-ratio of 3.2 which insured 100% sensitivity was used. Using the modified APC-resistance test, essentially no difference in APC-ratios between patients with normal factor V genotype and healthy controls with normal factor V genotype was observed. The modified APC-resistance test had a specificity for the FVR506Q mutation of 98.8% at an APC-ratio cut off of 2.1 which ensured 100% sensitivity. The original APC-resistance test gave lower APC-ratios in women than in men and in patients with acute thrombosis as compared to controls. In conclusion, the modified APC-resistance test is highly sensitive and specific for the FVR506Q mutation. This test can be used in clinical practice as an easy to perform screening test for the FVR506Q allele. Moreover, the test performs equally well in patients with acute suspected venous thrombosis as in healthy controls.