Free protein S deficiency is a risk factor for venous thrombosis

A recent study suggests that protein S deficiency is not a risk factor for venous thrombosis. Since this unexpected finding would have important clinical implications if confirmed, we performed a case-control study with the aim to determine the prevalence of protein S deficiency in patients with thrombosis and in healthy individuals taken from the general population and the relative risk of thrombosis in protein S-deficient patients. Free protein S concentration was measured in 327 consecutive patients with at least one venous thrombotic episode and in 317 age- and sex-matched control individuals. Different normal reference ranges were obtained and adopted for men and women. Protein S deficiency was found in 3.1% (95% CI: 1.5-5.2) of patients and in 1.3% of controls (95% CI: 0.3-2.8). Ten patients and 4 control subjects had protein S deficiency, which determined a relative risk of thrombosis (sex- and age-adjusted odds ratio) of 2.4 (95% CI: 0.8-7.9). When men and women were analyzed separately, the risk was 5.0 (95% CI: 0.6-43.6) and 1.6 (95% CI: 0.4-6.7) respectively. PS-deficient men had more thrombotic episodes than women and later in life. Multivariate analysis established that sex was an independent determinant of the number of episodes, as was age, while PS deficiency was not. However sex and PS deficiency status were both determinants of age at first thrombotic episode.     

Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients

BACKGROUND and PURPOSE: Different coagulation disorders have been associated with cerebral venous thrombosis (CVT). Until now, fewer than 50 patients have been reported with CVT and the factor V Leiden (FVL) mutation. Although the prevalence of FVL-positive patients with CVT ranged from 10% to 25%, it was as low as 0.5% to 3% in the control groups. Most other studies had not systematically searched for concomitant risk factors or previous thromboembolic events. To better define the relevance of the FVL mutation in conjunction with additional risk factors in CVT, we conducted the present case-control study. METHODS: Fifty-five patients with CVT were compared with 272 healthy controls. A standardized interview regarding established risk factors for venous thrombosis and the patients' and their families' histories for thromboembolic events was performed. The presence of the FVL mutation was determined by polymerase chain reaction on DNA obtained from peripheral blood leukocytes. RESULTS: Of 55 patients, 8 (14.5%) were heterozygous for the FVL mutation compared with 17 of 272 controls (6.25%). The relative risk for the presence of FVL was 2.55 (95% confidence interval, 1.04 to 6.26; P=0.04). Additional risk factors for CVT were frequently found in both the presence and absence of FVL. Recurrence of venous thromboembolic events was more frequent in patients with the FVL mutation (5 of 8 patients, 62.5%) than in those without this anomaly (8 of 47 patients, 17%; P<0.005). CONCLUSIONS: Our study confirms the FVL mutation as the most relevant hereditary risk factor for CVT. Coexisting risk factors are usually involved in the initiation of CVT. Patients with the FVL mutation are at an increased risk for recurrent venous thrombosis.     

Frequent factor II G20210A mutation in idiopathic portal vein thrombosis

OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) in post-Billroth II (BII) gastrectomy is more difficult due to anatomical changes. The difficulties include entrance to the afferent loop and selective cannulation. Our aim here is to report the success rate and special manipulations and techniques of this procedure. METHODS: A retrospective review of 56 ERCP procedures in post-BII gastrectomy patients was performed. There were 43 male and 13 female patients with a mean age of 63 yr (range, 32-78 yr). All cases were tried with forward-viewing endoscope first. Of the failed cases, 10 were retried by side-view duodenoscope. The entrance to the afferent loop was attempted by starting from the upper opening at the anastomosis site and, if this failed, then using the lower opening; presence of bile; and air-contrasted afferent loop under fluoroscopy. If failure of afferent loop entrance resulted, hand compression over the mid-abdomen, or polypectomy snare in the working channel of the endoscope, was tried. For failure of common bile duct cannulation with straight catheters, techniques of pushing the catheter against the duodenal wall and bending the tip of the endoscope or guidewire were used. RESULTS: The success rate of afferent loop entrance was 76.7% (43 of 56 cases). The afferent loop was identified in the upper orifice of the anastomosis in 93% (40 of 43) of the cases. Eight cases of afferent loop entrance could be facilitated by hand compression, and three by polypectomy snare in the working channel of the endoscope. The success rate of ERCP cannulation in those successful afferent loop intubation cases was 81.3% (35/43 cases). Most of the selective common bile duct (CBD) cannulation was achieved by straight (new) catheter and an additional six cases were successful using the techniques mentioned. No serious complications were encountered, except three cases of submucosal hemorrhage. CONCLUSION: The overall success rate of BII ERCP was 62.5% (35 of 56 cases). The special manipulations mentioned in BII ERCP can be helpful in certain cases.     

Resistance to activated protein C caused by the factor VR506Q mutation is a common risk factor for venous thrombosis

In 1993, inherited resistance to activated protein C (APC) was described as a novel risk factor for venous thrombosis. APC-resistance is present in 20-60% of venous thrombosis cases. It is caused by a single point mutation in the factor V gene which substitutes arginine (R) at position 506 with a glutamine (Q). The mutation is common in Caucasians with up to 15% prevalence in the population, whereas it is not found among other human races. Mutated factor V (FVR506Q, FV:Q506 or FV Leiden) is partially resistant to APC which results in a hypercoagulable state conferring a life-long increased risk of thrombosis. Individuals having FV:Q506 combined with other anticoagulant defects have a high risk of thrombosis, and it is now generally accepted that severe thrombophilia is a multigenetic disease. Easy functional and genetic tests for inherited APC-resistance will profoundly influence the development of prophylactic regimens and hopefully result in a decreased incidence of thrombosis.     

Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene

The odds ratio for the FII 20210G/A mutation in 504 patients with venous thromboembolism compared to controls was 2.0 (95% CI 1.0-4.0) and, for factor V Leiden, 5.8 (95% CI 3.3-10.3). 3/504 patients were heterozygous for both mutations. None of the patients had combined natural anticoagulant deficiency and the FII 20210G/A mutation. We conclude that the FII 20210G/A mutation is present in 2.6% of the population and the relative risk of venous thromboembolism in carriers is 2.0.     

An improved method for the detection of the G20210A transition in the prothrombin gene

A lectin histochemistry study was performed in the supraglottic and subglottic regions of 10 hamsters. The submucosal glands were observed by light microscopy. The supraglottic submucosal glands presented numerous mucous tubules but on the other hand, the subglottic submucosal glands had serous tubules which finished at the distal portion in serous acini. The results suggest that the distribution of fucosylated-mucin and serum-type glycoproteins between the supra- and subglottic submucosal glands suggest a different viscosity and function of the mucus.     

The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease

A genetic variation in the 3'-untranslated region of the prothrombin mRNA (20210 G/A) has recently been reported to be associated with elevated plasma prothrombin levels and with an increased incidence of venous thrombosis. We determined the frequency of this mutation, the detection of which was improved by allele-specific amplification of exon 14 and by denaturing gradients (denaturing gradient gel electrophoresis), in cohorts of patients affected by venous thrombosis (n = 132) or by coronary or cerebrovascular diseases (n = 195) and in normal subjects from various populations. An overlapping frequency of the heterozygous genotype (4%) was found in normal subjects from Italy and Cyprus, and no carrier was detected in 40 subjects of Indian or Somali origin. The 20210 GA heterozygous genotype was not increased in frequency in patients with arterial disease. In contrast, the GA genotype was associated (P = .007) with venous thrombosis both in simple heterozygotes (16%) with a family history of thrombosis as well as in double heterozygotes (14%) for other known thrombophilic defects. A synergic interaction between the prothrombin 20210 GA genotype and the factor V Leiden mutation, both potentially affecting the prothrombinase complex, was suggested by the early onset of thrombosis (median age 22 years) in doubly heterozygous patients. The association of the 20210 A allele with higher prothrombin levels was confirmed in the Italian population. However, the prothrombin assay does not allow an efficient preselection of patients for the DNA analysis.     

The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis

Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677-->Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2l93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogenemia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease and also for venous thrombosis.     

Coagulation factor V gene mutation increases the risk of venous thrombosis in beh?et's disease

We investigated the prevalence of the coagulation factor V gene G1691A mutation in 64 patients with Beh?et's disease (BD) and in 107 apparently healthy individuals. The mutation was present in the heterozygous state in 37.5% of the patients with a history of deep vein thrombosis (12/32) and in 9.4% of the patients without any thrombotic event (3/32). Eleven healthy individuals were also heterozygous for the mutation (10.3%). The prevalence of the mutation in BD patients with and without thrombosis was significantly different (P = 0.0079). We conclude that the factor V gene mutation may play a major role in the development of venous thrombosis in BD.     

Dural puncture and activated protein C resistance: risk factors for cerebral venous sinus thrombosis

BACKGROUND: The biologic aggressiveness of squamous cell carcinoma of the oral cavity is reflected in its ability to metastasize to regional cervical lymph nodes. Patients with clinically negative cervical lymph nodes are believed to have a good prognosis; however, the prognosis of patients with lymph node metastasis occurring after excision or radiotherapy of the primary tumor is poor. METHODS: Univariate and multivariate analyses for occult lymph node metastasis (ONM) in 172 patients with clinically negative cervical lymph nodes were performed by the authors to elucidate the clinical and histologic tumor risk factors to enhance their ability to predict ONM. A multivariate Cox proportional hazards model and Hayashi's quantification theory type II were used to analyze prognostic factors and to determine the probability of ONM. RESULTS: Using Cox's proportional regression model, the factors linked to cancer specific survival were selected: tumor differentiation (P = 0.0330), mode of carcinoma invasion (P = 0.0175), and ONM (P = 0.0433). Pathologically identified metastatic lymph nodes were found in 21.5% of the cases studied (37 of 172 cases). The 5-year cancer specific survival was 94.0% for patients without lymph node metastasis, and 51.0% for patients with ONM (P < 0.0001, log rank test). The most significant predictors for ONM of each of the clinical and histologic factors, in descending order, were: mode of carcinoma invasion, intensity of lymphocytic infiltration, degree of differentiation, number of mitotic figures, and type of growth by means of Hayashi's quantification theory type II. The presence or absence of ONM in 147 of 172 patients (85.5%) was correctly predicted by the score at the point of intersection of the two curves, which was -0.03. Further investigation revealed that 28 of 32 new cases were differentiated accurately by means of this diagnostic system. CONCLUSIONS: The results of the current study suggest that this method of analysis can establish a reliable predictor of ONM, thereby facilitating correct choices for surgical procedures to enhance the survival rates of patients with clinically negative cervical lymph nodes.     

Increased p-homocysteine--a risk factor for thrombosis

In the healthy population P-homocysteine increases with age and the level is higher in men aged 30-60 years as compared to women of the same age group. Most often, elevated P-homocysteine is caused by genetic defects, vitamin deficiency (folic acid, B6- and B12-vitamin) or renal failure. Based on retrospective as well as prospective studies, it can be concluded that elevated P-homocysteine is a risk factor for arterial as well as venous thrombosis. Severely elevated P-homocysteine is capable of causing premature arteriosclerosis, whereas slightly elevated levels may also be involved. A slightly positive correlation has been found between P-homocysteine on one hand, and smoking, blood pressure and cholesterol on the other, whereas physical activity is slightly negatively correlated to P-homocysteine. Altered function of endothelial cells and coagulation has been demonstrated in relation to elevated P-homocysteine, but the pathogenetic mechanisms have not been fully elucidated. Usually, an elevated P-homocysteine is normalised by folic acid supplementation, although additional treatment with vitamin B6 may be required. Presumably, the risk of thrombosis is thereby reduced, but future controlled studies may reveal whether this holds true.