Anxiety and depression in patients three months after myocardial infarction: Association with markers of coagulation and the relevance of age.

OBJECTIVE: Anxiety and depression are associated with an activation of coagulation and an impairment of fibrinolysis, which may contribute to the increased cardiovascular risk associated with the two disorders. However, very few studies have examined the impact of psychological distress on coagulation factors in coronary artery disease patients. The aim of this study was to assess the correlation between anxiety/depression and factors of coagulation and fibrinolysis in patients who had suffered an acute MI three months prior. METHODS: In 148 patients, anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS) shortly after MI and three months later. At the second time of assessment, plasma levels of fibrinogen, factor VII, factor VIII, von Willebrand factor, prothrombin-fragment 1 and 2, tissue-plasminogen-activator, plasminogen activator inhibitor-1, D-dimer, and homocysteine were measured. RESULTS: In 32% of the patients, elevated levels of anxiety and depression were found three months after a MI. Multiple regression analyses showed that coagulation and fibrinolysis markers were not significantly associated with HADS anxiety and depression scores. We found that age, gender, BMI, and smoking status were significant predictors for haemostasis factors. A higher age was associated with a higher coagulability but lower anxiety levels. CONCLUSION: We measured parameters of coagulation and fibrinolysis in patients three months after MI and found no predictive value of HADS anxiety and depression scores shortly after MI or at the time of blood sampling. The effects of age on the relationship between anxiety and haemostasis should be further investigated.

A common F13A1 intron 1 variant IVS1+12(A) is associated with mild FXIII deficiency in Caucasian population.

Mild factor XIII deficiency is an underdiagnosed coagulation disorder. Considering the large number of coding and non-coding polymorphisms identified in the F13A1 gene, there is a possibility that some of these might result in alterations of plasma FXIII levels and cause mild FXIII deficiency. Recently, a homozygous F13A1 gene intron 1 variant (IVS1+12C>A) was found in a patient with FXIII deficiency. In vitro expression studies for this variant demonstrated its lowering effect on FXIII levels. In order to determine the impact of this variant on a population level, we analysed the prevalence of this variant in three clinically and genetically defined population cohorts: an apparently healthy control cohort C1 (n = 102), a mild FXIII deficiency cohort C2 with no detectable F13A1 or F13B gene mutations (n = 183) and a mild FXIII-A deficiency cohort C3 exhibiting heterozygous F13A1 mutations (n = 37). FXIII activity was determined using photometric assay on plasma samples. The F13A1 gene intron 1 variant was analysed by direct sequencing. The C1 cohort showed a normal distribution of FXIII activity (mean 114.1 ± 20.86%). Mean FXIII activity levels for the C2 and C3 cohorts were 54.45 ± 11.12% and 44.21 ± 10.16%, respectively. The frequencies of minor allele (A) were 0.07 in C1 cohort, 0.19 in C2 cohort and 0.11 in C3 cohort. The difference in minor allele frequencies for the C1 and C2 cohorts were highly significant (p < 0.001). The greater frequency of the IVS1+12(A) variant among C2 cohort patients suggests that this polymorphism is associated with mild FXIII deficiency.

Can activation of coagulation and impairment of fibrinolysis in patients with anxiety and depression be reversed after improvement of psychiatric symptoms? Results of a pilot study.

Anxiety and depression are associated with an activation of coagulation and impairment of fibrinolysis. This study addresses the question whether these findings are reversed after psychotherapy and improvement of psychiatric symptoms. Three factors of coagulation and fibrinolysis as well as level of anxiety and depression were reassessed in 12 patients 1 to 3 years after intensive inpatient psychotherapy. The patients showed a substantial improvement of their severe anxiety disorder and comorbid depressive disorder. Simultaneously, we found a significant decrease in factor VII and plasminogen activator inhibitor. We conclude that reduction of severe anxiety and depression may be associated with a reversal of the procoagulant effect (activation of coagulation and impairment of fibrinolysis) of these psychological states. Because of the small sample size of this pilot study, further research is needed.

Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort.

Deficiencies of natural anticoagulant proteins including antithrombin (AT), protein C (PC) and protein S (PS) are important causes of inherited thrombophilia. This study aimed to report on the practical experience gained in performing genetic analyses of a large cohort of patients with AT, PC and PS deficiencies and to relate this knowledge to clinical application. We genotyped a large cohort of 709 unrelated patients with AT (231), PC (234) and PS (244) deficiencies referred to us by physicians throughout Germany. Mutations were detected by direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The highest mutation detection rate (MDR) was found for the SERPINC1 gene (83.5%), followed by the PROC (69%) and PROS1 (43%) genes. Even at AT activities close to the normal range (75%), the MDR was 70%. Contrastingly, for PC and PS deficiencies, the MDR dropped significantly and mildly lowered to subnormal values. At PS activities >55% for PS no mutations were detected. Mutation profiles of all three genes were similar with the highest prevalence for missense mutations (63-78%), followed by nonsense (7-11%), splice-site mutations (7-13%), small deletions (1-8%), small insertions/duplications (1-4%) and large deletions (3-6%). In conclusion, genetic testing is a useful diagnostic tool for diagnosing thrombophilia. Based on our data, genetic analysis for patients with AT deficiency is indicated for all subnormal activities. In contrast, genotyping is not advisable for PC activities >70% and for PS activities >55%.

Thrombin inhibition profiles in healthy individuals and thrombophilic patients.

Inhibition of thrombin by endogenous inhibitors plays a central role in the spatiotemporal control of clot formation. A failure to adequately inactivate thrombin such as in antithrombin deficiency generates a strong prothrombotic phenotype. To study if and to what extent delayed thrombin inactivation rates beyond antithrombin deficiency contribute to the prothrombotic phenotype we measured thrombin inhibition profiles in plasma samples obtained from 16 healthy individuals and 39 thrombophilic patients, including 17 patients diagnosed positive for anti-prothrombin/phospholipid antibodies. To test thrombin inhibition, thrombin was added to plasma, and endogenous thrombin inhibition stopped by addition of the reversible thrombin inhibitor argatroban. Subsequently, the amount of argatroban-complexed thrombin was measured using an oligonucleotide-based enzyme capture assay. In normal human plasma thrombin at concentrations up to 4 ng/ml (109 pM) became inactivated with an average half-life time of 56.4 ± 4.7 seconds (s). In antithrombin-deficient plasma the thrombin half-life was prolonged to 168.2 ± 14.9 s. Among the thrombophilic patients, only one with mild antithrombin deficiency showed impaired thrombin inactivation rates, whereas all other patients including the antiphospholipid positive patients showed thrombin inhibiting capacities within the normal range. We conclude that thrombin added to normal human plasma at subthreshold levels of ~100 pM or below becomes inactivated with a half-life time below 1 minute. Antiphospholipid antibodies do not prolong thrombin half-life times, making it unlikely that delayed thrombin inactivation contributes to the thrombotic phenotype of the antiphospholipid syndrome. In contrast, plasma levels of antithrombin falling below 80% of normal markedly prolong the thrombin half-life.

Coagulation activation and fibrinolysis impairment are reduced in patients with anxiety and depression when medicated with serotonergic antidepressants.

AIMS: Anxiety disorders have been shown to be correlated with an activation of coagulation and impairment of fibrinolysis. The aim of the study was to assess whether medication with a serotonergic antidepressant, which has been associated with abnormal bleeding, may modify this effect. METHODS: Thirty-one anxiety patients, mostly with comorbid depression, and 31 healthy controls were included in the study. Group differences between anxiety patients medicated with a serotonergic antidepressant, patients without serotonergic antidepressant and controls were assessed for activated partial thromboplastin time, fibrinogen, factor VII, factor VIII, von Willebrand factor, von Willebrand ristocetin cofactor activity, prothrombin fragment 1 + 2, thrombin-antithrombin complex, d-dimer, α2-antiplasmin, plasmin-α2-antiplasmin complex (PAP), tissue plasminogen activator and plasminogen activator inhibitor. Intervening variables, such as age, sex, body mass index and smoking, were accounted for. RESULTS: We found lower coagulation measures for fibrinogen (P = 0.03) and plasminogen activator inhibitor (P = 0.01), and higher levels of PAP (P = 0.046) in patients with serotonergic antidepressant than in patients without serotonergic antidepressant. When controlling for smoking and body mass index, differences between the two groups were significant for PAP (P = 0.02), von Willebrand ristocetin cofactor activity (P = 0.02) and activated partial thromboplastin time (P = 0.046). Coagulation scores were similar in patients with serotonergic antidepressant to those of healthy controls. CONCLUSIONS: Serotonergic antidepressants may counteract a procoagulant effect of anxiety and/or depression in anxiety patients.

Relative hyperhomocysteinemia in patients with panic disorder: a case-control study.

BACKGROUND: The aim of this work was to examine a possible association between a clinically relevant panic disorder and plasma total homocysteine concentration. METHODS: 23 patients with panic disorder with or without agoraphobia confirmed by a standardized clinical interview (Structural Clinical Interview for DSM-IV-German version) and 23 healthy controls matched for gender and age completed questionnaires (SCL-K9, STAI, ADS, STAXI) and had blood drawn after a 15 min rest. Plasma total homocysteine concentrations were measured by competitive enzyme immunoassay. Interfering variables such as age, gender, smoking status, comorbid depression and medication were controlled for. RESULTS: Patients with panic disorder had higher plasma homocysteine concentrations in comparison to the control group (mean value 11.00 vs. 9.14 mumol/l, p = 0.04 with age, gender, smoking status, comorbid depression and antidepressant medication being controlled for). Furthermore, homocysteine plasma concentration was positively correlated with Global Severity of Symptoms (SCL-K9, r(Pearson) = 0.41, p < 0.01). CONCLUSION: The findings of this study suggest a link between elevated plasma homocysteine levels and panic disorder. This raises a new hypothesis of another pathway to an increased risk of cardiovascular events in anxious individuals.

Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function.

BACKGROUND: Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. DESIGN AND METHODS: We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. RESULTS: All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. CONCLUSIONS: The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.

Common genetic coagulation variants are not associated with ischemic stroke in a case-control study.

OBJECTIVE: Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke. METHODS: Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G-->A and factor XIII Val34Leu. RESULTS: The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G-->A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (<40, 40-49, 50-59, > or =60 years). DISCUSSION: This study suggests that the analysis of prothrombin 20210G-->A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.

Association between anxiety and factors of coagulation and fibrinolysis.

BACKGROUND: Psychological stress and anxiety have been shown to produce an activation of coagulation and fibrinolysis. Resulting hypercoagulability is a risk factor for cardiovascular diseases, and could therefore contribute to an increased prevalence of coronary artery disease in anxiety patients. However, hemostasis function has not yet been studied in patients with clinically relevant anxiety disorders. METHODS: A group of anxiety patients (panic disorder with agoraphobia or social phobia) and a healthy control group (each n = 29) completed some questionnaires [SCL-K9 (a short form of the SCL-90-R), State Trait Anxiety Inventory, ADS (general depression scale)], and had blood drawn after a 15-min rest period. To assess the reaction of the hemostatic system by global entities, sum scores were computed from parameters of coagulation and fibrinolysis (fibrinogen, FVII, FVIII, vWF, F1 + 2, TAT, D-dimer, alpha(2)-AP, PAP, tPA, PAI-1). Interfering variables, such as age, gender, alcohol consumption and smoking status, were controlled. RESULTS: Anxiety patients scored higher in a composite hemostatic score and a sum score of fibrinolysis in comparison to the control group, with a predominant activation of inhibitors in fibrinolysis. However, the psychological variable with the closest association to hemostasis was not trait anxiety, but self-perceived worry about blood drawing before blood sampling was performed. CONCLUSIONS: The coagulation and fibrinolysis system is activated in the direction of a hypercoagulable state in patients with severe phobic anxiety, triggered by fear of blood drawing. This could be one mediating factor for the increased risk of cardiovascular diseases in this population. Acute situational phobic anxiety should be monitored closely when studying the association between anxiety and hemostasis.

Homocysteine and carotid intima-media thickness in a german population: lack of clinical relevance.

BACKGROUND AND PURPOSE: Common carotid artery intima-media thickness (CCA IMT) is a predictor of stroke. This study aimed to analyze whether homocysteine (Hcys) metabolism influences CCA IMT. METHODS: We analyzed the association of personal, clinical, and biochemical data (multivariate analysis) and of 9 polymorphisms involved in Hcys metabolism (ANOVA) with CCA IMT in 714 individuals of 187 families. RESULTS: CCA IMT was significantly predicted by age, sex, creatinine levels, lipoprotein(a) levels, pack-years of smoking, the presence of hypertension, and the presence of diabetes mellitus but not by Hcys levels. Homozygosity for the T allele of the polymorphism methylenetetrahydrofolate reductase c.677C>T was significantly associated with higher Hcys levels but not with a higher CCA IMT. CONCLUSIONS: These data do not support the thesis that elevated Hcys levels are causally involved in cerebrovascular disease.

Molecular analysis of thrombophilic risk factors in patients with dural arteriovenous fistulas.

Dural arteriovenous fistulas (DAVFs) are direct artery-to-cerebral venous sinus shunts. Our recent finding of a significantly increased prevalence of factor V (FV) Leiden in patients with DAVFs prompted us to evaluate prothrombinG20210A, MTHFRC677T, beta-fibrinogenG455A, PAI-14G/5G and FXIIIVal34Leu as additional risk factors for thrombophilia in 26 patients with DAVFs and a group of age- and gender-matched controls. There was no significantly increased prevalence of these risk factors in DAVF patients. We conclude that FV Leiden is of pathogenetic significance in the aetiology of a subgroup of DAVFs whereas the other thrombophilic risk factors are not likely to be involved.

Circulating adhesion molecules in patients with internal carotid artery stenosis.

To study the association of plasma concentrations of soluble adhesion molecules (sICAM-1, sVCAM-1 and sE-selectin) with atheroslerotic lesions at the origin of the internal carotid artery (ICA). 179 subjects were investigated by color Doppler ultrasound of whom 133 had and 46 had no plaques at the ICA origin. Stepwise logistic regression analysis revealed that hypertension (p < 0.001), sICAM-1 concentrations (p < 0.01) and smoking (p < 0.05) were independently associated with the presence of ICA plaques. Multivariate regression analysis revealed that sICAM-1 concentrations in subjects with plaque were negatively associated with the degree of ICA stenosis (p < 0.01) and positively associated with previous cerebral ischemia (p < 0.01), coronary heart disease (p < 0.05) and peripheral artery disease (p < 0.05). In conclusion, elevated sICAM-1 concentrations are independently associated with atherosclerosis of the ICA origin and are predominantly increased in patients with low-grade lesions and with clinical manifestations of vascular disorders.