|We found some differences in the hemostatic parameters between the patients with IHH and healthy controls. Increased platelet count, FV and FX activities and decreased AT III levels in patients with IHH represent a potential hypercoagulable state, which might augment the risk for atherosclerotic and atherothrombotic complications. Therefore, IHH may be associated with an increased risk of CVD. However, sex hormones may play a role at different levels of the complex hemostatic system in patients with IHH. PMID: 18591887
Glueck CJ, Goldenberg N, Budhani S, Lotner D, Abuchaibe C, Gowda M, Nayar T, Khan N, Wang P. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res. 2011 Oct;158(4):225-34.
Our specific aim was to describe thrombosis (osteonecrosis of the hips, pulmonary embolism, and amaurosis fugax) after exogenous testosterone was given to men with no antecedent thrombosis and previously undiagnosed familial thrombophilia. After starting testosterone patch or gel, 50 mg/day or intramuscular testosterone 400 mg IM/month (YIKES, that injection would produce levels many times normal for a male for 2 weeks, men should receive 100mg/week!-HHL) , 2 men developed bilateral hip osteonecrosis 5 and 6 months later, and 3 developed pulmonary embolism 3, 7, and 17 months later. One man developed amaurosis fugax 18 months after starting testosterone gel 50 mg/day. Of these 6 men, 5 were found to have previously undiagnosed factor V Leiden heterozygosity, 1 of whom had ancillary MTHFR C677T homozygosity, and 2 with ancillary MTHFR C677T-A1298C compound heterozygosity. One man had high factor VIII (195%), factor XI (179%), and homocysteine (29.3 umol/L). Thrombotic events after starting testosterone therapy are associated with familial thrombophilia. We speculate that when exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on familial thrombophilia, thrombosis occurs. Men sustaining thrombotic events on testosterone therapy should be screened for the factor V Leiden mutation and other familial and acquired thrombophilias. PMID: 21925119
Holmegard HN, Nordestgaard BG, Schnohr P, Tybjaerg-Hansen A, Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost. 2013 Dec 11. Epub
BACKGROUND: Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations also associate with risk of VTE is unknown. OBJECTIVE: We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population. METHODS: We studied 4,658 women, not receiving exogenous estrogen, and 4,673 men from the 1981-1983 examination of the Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis (DVT) and/or pulmonary embolism (PE)) during a follow-up of 21 years (range: 0.02-32years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time dependent covariates and corrected for regressio n dilution bias. RESULTS: Multifactorially adjusted hazard ratios of VTE for individuals with estradiol >75th versus ≤25th percentile were 0.84(95%CI: 0.25-2.85), 1.05(0.53-2.08), and 1.05(0.03-35.13) for pre-, and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64(0.03-12.32), 1.11(0.66-1.86), and 1.30(0.62-2.73). In addition, no associations were observed for extreme hormone percentiles (>95th versus ≤75th ) and risk of DVT and PE or recurrent VTE. CONCLUSION: This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE. PMID: 24329981
Jesse RL, Loesser K, Eich DM, Qian YZ, Hess ML, Nestler JE. Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann N Y Acad Sci. 1995 Dec 29;774:281-90.
The hypothesis has been advanced that the adrenal steroids dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) exert antiatherogenic and cardioprotective actions. Platelet activation has also been implicated in atherogenesis. To determine if DHEA and DHEAS affect platelet activation, the effects of these steroids on platelet aggregation were assessed both in vitro and in vivo. When DHEAS was added to pooled platelet-rich plasma before the addition of the agonist arachidonate, either the rate of platelet aggregation was slowed or aggregation was completely inhibited. Inhibition of platelet aggregation by DHEA was both dose- and time-dependent. Inhibition of platelet aggregation by DHEA was accompanied by reduced platelet thromboxane B2 (TxB2) production. Inhibition of platelet aggregation by DHEA was also demonstrated in vivo. In a randomized, double-blind trial, 10 normal men received either DHEA 300 mg (n = 5) or placebo capsule (n = 5) orally three times daily for 14 days. In one man in the DHEA group arachidonate-stimulated platelet aggregation was inhibited completely during DHEA administration, whereas in three other men in the DHEA group the rate of platelet aggregation was prolonged, and the sensitivity and responsiveness to agonist were reduced. None of the men in the placebo group manifested any change in platelet activity. These findings suggest that DHEA retards platelet aggregation in humans. Inhibition of platelet activity by DHEA may contribute to the putative antiatherogenic and cardioprotective effects of DHEA.
Høibraaten E, Abdelnoor M, Sandset PM. Hormone replacement therapy with estradiol and risk of venous thromboembolism--a population-based case-control study.Thromb Haemost. 1999 Oct;82(4):1218-21.
Recent epidemiological studies on hormone replacement therapy (HRT) containing mainly conjugated equine estrogens indicate increased risk for venous thromboembolism (VTE). The purpose of the present epidemiological study was to evaluate the effect of HRT containing natural estrogens, i.e., estradiol, on the risk of VTE. HRT formulations containing estradiol are commonly used in Scandinavia. The study was a population-based case-control study. Cases were consecutive females, aged 44-70 years, discharged from Ullevål University Hospital with the diagnosis of deep venous thrombosis or pulmonary embolism during 1990-1996. Fifty-one women with cancer-associated thrombosis were excluded from the study. Controls were randomly collected from the same source population and matched by age. The material comprised 176 cases and 352 controls, i.e., 2 controls for each case. Only formulations containing estradiol were used. The frequency of HRT use was 28% (50/176) in cases and 26% (93/352) in controls. The estimated matched crude odds ratio with 95% confidence interval was 1.13 (0.71-1.78), which indicates no significant association of overall use of HRT and VTE. The estimated adjusted odds ratio was 1.22 (0.76-1.94) performing multi-confounder adjustment using the conditional logistic model and adjusting for hypertension, coronary heart disease, diabetes mellitus, smoking habit, BMI, and the presence of previous VTE. Stratification for time of exposure indicated an increased risk of VTE during the first year of use with a crude odds ratio of 3.54 (1.54-8.2). This effect was reduced by extended use to a crude odds ratio of 0.66 (0.39-1.10) after the first year of use. We conclude that use of HRT containing estradiol was associated with a threefold increased risk of VTE, but this increased risk was restricted to the first year of use. PMID: 10544901
Holmegard HN, Nordestgaard BG, Schnohr P, Tybjaerg-Hansen A, Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost. 2013 Dec 11.
BACKGROUND: Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations also associate with risk of VTE is unknown. OBJECTIVE: We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population. METHODS: We studied 4,658 women, not receiving exogenous estrogen, and 4,673 men from the 1981-1983 examination of the Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis (DVT) and/or pulmonary embolism (PE)) during a follow-up of 21 years (range: 0.02-32years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time dependent covariates and corrected for regression dilution bias. RESULTS: Multifactorially adjusted hazard ratios of VTE for individuals with estradiol >75th versus ≤25th percentile were 0.84(95%CI: 0.25-2.85), 1.05(0.53-2.08), and 1.05(0.03-35.13) for pre-, and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64(0.03-12.32), 1.11(0.66-1.86), and 1.30(0.62-2.73). In addition, no associations were observed for extreme hormone percentiles (>95th versus ≤75th ) and risk of DVT and PE or recurrent VTE. CONCLUSION: This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE. PMID: 24329981
Jin H, Wang DY, Mei YF, Qiu WB, Zhou Y, Wang DM, Tan XR, Li YG. Mitogen-activated protein kinases pathway is involved in physiological testosterone-induced tissue factor pathway inhibitor expression in endothelial cells. Blood Coagul Fibrinolysis. 2010 Jul;21(5):420-4.
The mechanism of testosterone inducing the tissue factor pathway inhibitor (TFPI) in protecting against thrombosis is unknown. We aimed to elucidate the mechanisms involved in the induction by observing, in human umbilical vein endothelial cells (HUVECs), the phosphorylation of mitogen-activated protein kinases (MAPKs), a major cell signaling system. The level of testosterone regulating several signaling pathways, including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun-N-terminal kinase (JNK), and p38 MAPK, was measured by western blot in HUVECs. ELISA and quantitative real-time reverse transcriptase-PCR were used to analyze TFPI expression after blocking ERK1/2 (with PD98059) or JNK (with SP600125) pathway in HUVECs. Testosterone-induced a rapid phosphorylation of ERK1/2, JNK and p38 MAPK in HUVECs, which could not be inhibited by androgen receptor antagonist flutamide. Blocking ERK1/2 or JNK pathway could significantly impair testosterone-induced TFPI at both translational and transcriptional levels in HUVECs. Testosterone at a physiological concentration may help to prevent thrombosis development by stimulating TFPI expression in HUVECs, partly through the ERK1/2 and JNK MAPK pathway. PMID: 20442653
Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011 Oct;18(10):1052-9.
OBJECTIVE: The aim of this study was to quantify the magnitude of risk reduction for venous thromboembolism events associated with an estradiol transdermal system relative to oral estrogen-only hormone therapy agents. METHODS: A claims analysis was conducted using the Thomson Reuters MarketScan database from January 2002 to October 2009. Participants 35 years or older who were newly using an estradiol transdermal system or an oral estrogen-only hormone therapy with two or more dispensings were analyzed. Venous thromboembolism was defined as one or more diagnosis codes for deep vein thrombosis or pulmonary embolism. Cohorts of estradiol transdermal system and oral estrogen-only hormone therapy were matched 1:1 based on both exact factor and propensity score matching, and an incidence rate ratio was used to compare the rates of venous thromboembolism between the matched cohorts. Remaining baseline imbalances from matching were included as covariates in multivariate adjustments.RESULTS:Among the matched estradiol transdermal system and oral estrogen-only hormone therapy users (27,018 women in each group), the mean age of the cohorts was 48.9 years; in each cohort, 6,044 (22.4%) and 1,788 (6.6%) participants had a hysterectomy and an oophorectomy at baseline, respectively. A total of 115 estradiol transdermal system users developed venous thromboembolism, compared with 164 women in the estrogen-only hormone therapy cohort (unadjusted incidence rate ratio, 0.72; 95% CI, 0.57-0.91; P = 0.006). After adjustment for confounding factors, the incidence of venous thromboembolism remained significantly lower for estradiol transdermal system users than for estrogen-only hormone therapy users. CONCLUSIONS: This large population-based study suggests that participants receiving an estradiol transdermal system have a significantly lower incidence of venous thromboembolism than do participants receiving oral estrogen-only hormone therapy. PMID: 21775912
Lapecorella M, Orecchioni A, Dell'Orso L, Mariani G. Upper extremity deep vein thrombosis after suspension of progesterone-only oral treatment. Blood Coagul Fibrinolysis. 2007 Jul;18(5):513-7.
The intake of steroid hormone contraceptives is a strong and independent risk factor for venous thromboembolism. Several studies have assessed an increased risk of venous thromboembolism in women using oral contraceptives who are carriers of the G20210A mutation in the prothrombin gene. Most trials evaluating the thrombotic risk of oral contraceptives are based on combined oral preparations, but only a few focus on progestogen-only oral preparations. Results from such studies are conflicting and globally assess the thrombotic risk, ranging from modest to slightly increased. Furthermore, little is known about the relationship between the C677T mutation in the methylenetetrahydrofolate reductase gene and the progestogen-based preparations. Herewith we report the case of a 49-year-old woman with a complex genetic thrombosis risk factor who had taken oral progesterone for 15 months without any complication, but then experienced severe left upper extremity deep vein thrombosis 2 months after the drug suspension. PMID: 17581329
Lowe GD, Upton MN, Rumley A, McConnachie A, O'Reilly DS, Watt GC. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein--a cross-sectional population survey. Thromb Haemost. 2001 Aug;86(2):550-6.
The effects of hormone replacement therapy (HRT) on thrombosis risk, thrombotic variables, and the inflammatory marker C-reactive protein (CRP) may vary by route of administration (oral versus transdermal). We studied the relationships of 14 thrombotic variables (previously related to cardiovascular risk) and CRP to menopausal status and to use of HRT subtypes in a cross-sectional study of 975 women aged 40-59 years. Our study confirmed previously-reported associations between thrombotic variables and menopausal status. Oral HRT use was associated with increased plasma levels of Factor IX, activated protein C (APC) resistance, and CRP; and with decreased levels of tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity. Factor VII levels were higher in women taking unopposed oral oestrogen HRT. The foregoing associations were not observed in users of transdermal HRT; hence they may be consequences of the "first-pass" effect of oral oestrogens on hepatic protein synthesis. We conclude that different effects of oral and transdermal HRT on thrombotic and inflammatory variables may be relevant to their relative thrombotic risk; and suggest that this hypothesis should be tested in prospective, randomised studies. PMID: 11522002
Markel A, Manzo RA, Strandness DE Jr The potential role of thrombolytic therapy in venous thrombosis. Arch Intern Med 1992 Jun;152(6):1265-7.
BACKGROUND--Anticoagulant therapy for lower extremity deep-vein thrombosis (DVT) has been shown to reduce mortality from pulmonary embolism, but subsequent morbidity from the postthrombotic syndrome remains high. Thrombolytic therapy produces higher lysis rates of venous thrombi than heparin alone. Some studies suggest a lower incidence of postthrombotic sequelae after early use of streptokinase. These potential benefits are limited to those patients without contraindications for this therapy. METHODS--For the past 3 years we have prospectively studied patients with DVT documented by duplex scanning. The records of these patients were reviewed to determine what proportion of this population would have been candidates for thrombolytic therapy. For this analysis, contraindications to the use of thrombolytic agents included: (1) recent surgery (less than 1 month); (2) recent major trauma; (3) active or recent bleeding; (4) brain disease (cerebrovascular accident, brain tumor, arteriovenous malformation); (5) pregnancy; and (6) bleeding diathesis. Also, patients with prior ipsilateral DVT and those with acute symptoms present for 7 or more days were not considered to be candidates for thrombolytic therapy. RESULTS--A contraindication to thrombolytic therapy was present in 194 (93%) of 209 patients with a diagnosis of DVT, including four patients with a relative contraindication. Two or more contraindications were present in 65 cases (31%). Recent surgery was the most frequent factor precluding therapy, being present in 71 patients. A history of DVT in the affected leg was present in 45 patients. CONCLUSIONS--Only 15 (7%) of 209 patients with DVT exhibited no contraindications for thrombolytic treatment. Only a small fraction of patients with venous thrombosis will be potential candidates for this therapy.
McIntyre JA. The appearance and disappearance of antiphospholipid autoantibodies subsequent to oxidation--reduction reactions. Thromb Res. 2004;114(5-6):579-87.
The mechanisms that cause the appearance of autoantibodies are not understood. Compared to normal antibody production, factors responsible for autoantibody synthesis are more complex; they are thought to disrupt the normal mechanisms proposed to eliminate or down-regulate self-antibodies or to interfere with anti-self-receptor editing. Data presented show that autoantibodies exist in the blood of all normal individuals. The autoantibodies appear after simple oxidation-reduction (redox) reactions and react by ELISA, immunofluorescence, flow cytometry, Western blots, and in lupus anticoagulant (LA) assays. Antiphospholipid antibody (aPL) specificities detected after redox are cardiolipin (aCL), antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE), antiphosphatidylcholine (aPC), and LA. These antibody activities were confirmed in several outside laboratories. The aPL isotypes detected in ELISA are plasma protein-dependent and include IgG, IgA, and IgM. Oxidizing agents tested to date include hemin, KMnO4, and NaIO4. Furthermore, aPL appear after exposure to direct current (DC)-mediated electromotive force. Alternating current (AC) is ineffective. Commercial IvIg preparations, also a source of IgG autoantibodies, provide a less complex milieu than plasma or serum for studying the biology of aPL redox-mediated mechanisms. Inhibition of hemin-mediated IvIg aPL conversion can be achieved by the addition of antioxidants, e.g., ascorbic acid, hemopexin, apotransferrin, and by addition of normal plasma or serum. Remarkably, the aPL specificities in the blood of autoimmunity patients disappear subsequent to application of redox reactions. These data document the hitherto unknown existence of redox-reactive autoantibodies in all normal individuals. The evolutionary persistence of these redox-sensitive antibodies raises interesting possibilities about their potentially beneficial role in immunological homeostasis.
Miller GJ, Bauer KA, Barzegar S, Cooper JA, Rosenberg RD. Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease. Thromb Haemost. 1996 May;75(5):767-71.
The haemostatic system was examined in 2951 men aged 50 to 61 years, clinically free of cardiovascular disease, who were ranked according to a risk score for fatal coronary heart disease (CHD). Risk was judged from their serum cholesterol concentration, systolic blood pressure, body mass index and smoking habit. The status of the factor VII-tissue factor pathway was estimated from the plasma levels of factor VII coagulant activity, factor VII antigen and activated factor VII. Activation of factor IX was assessed from the plasma concentration of factor IX activation peptide. Activity within the common pathway was measured as the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A. All 6 markers of haemostatic status were positively and statistically significantly associated with risk, providing further evidence for a hypercoagulable state in men at high risk for fatal CHD. Plasma fibrinogen and serum triglyceride concentrations were also graded positively with risk. PMID: 8725721
Olié V, Canonico M, Scarabin PY. Postmenopausal hormone therapy and venous thromboembolism. Thromb Res. 2011 Feb;127 Suppl 3:S26-9.
INTRODUCTION: Hormone therapy (HT) is the most effective treatment to counteract menopauserelated symptoms. Because venous thromboembolism (VTE) is the main harmful effect of HT among young postmenopausal women, reducing VTE risk appears to be a relevant strategy to improve the benefit/risk profile of HT among postmenopausal women. METHODS: This article is a review of recent findings regarding the VTE risk among women using HT. RESULTS: Recent data confirmed the safety of the transdermal route of estrogens administration in postmenopausal women requiring treatment. In addition, epidemiological data showed that use of concomitant progestins could increase VTE risk compared with progesterone use. Finally, results of a meta-analysis showed that the VTE risk increased with doses of oral estrogens. CONCLUSION: The route of estrogen administration, the type of concomitant progestogens and the dose of estrogens are three important determinants of the thrombotic risk among postmenopausal women using HT. PMID: 21262434
Pais E, Alexy T, Holsworth RE Jr, Meiselman HJ. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc. 2006;35(1-2):139-42.
The vegetable cheese-like food, natto, is extremely popular in Japan with a history extending back over 1000 years. A fibrinolytic enzyme, termed nattokinase, can be extracted from natto; the enzyme is a subtilisin-like serine protease composed of 275 amino acid residues and has a molecular weight of 27.7 kDa. In vitro and in vivo studies have consistently demonstrated the potent pro-fibrinolytic effect of the enzyme. However, no studies to date have evaluated the effects of nattokinase on various hemorheological parameters and thus we have begun to assess the effects of the enzyme on RBC aggregation and blood viscosity. Blood samples were incubated with nattokinase (final activities of 0, 15.6, 31.3, 62.5 and 125 units/ml) for 30 minutes at 37 degrees C. RBC aggregation was measured using a Myrenne MA-1 aggregometer and blood viscosity assessed over 1-1000 s(-1) with a computer controlled scanning capillary rheometer (Rheolog). Our in vitro results showed a significant, dose-dependent decrease of RBC aggregation and low-shear viscosity, with these beneficial effects evident at concentrations similar to those achieved in previous in vivo animal trials. Our preliminary data thus indicate positive in vitro hemorheological effects of nattokinase, and suggest its potential value as a therapeutic agent and the need for additional studies and clinical trials.
Palareti G; Legnani C; Cosmi B; Guazzaloca G; Pancani C; Coccheri S Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002 Jan;87(1):7-12.
In some patients with previous venous thromboembolism (VTE) D-dimer levels (D-Dimer) tend to increase after oral anticoagulant therapy (OAT) is stopped. The aim of our study was to evaluate the predictive value of D-Dimer for the risk of VTE recurrence after OAT withdrawal. After a first episode of deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE), 396 patients (median age 67 years, 198 males) were followed from the day of OAT discontinuation for 21 months. D-dimer was measured on the day of OAT withdrawal (T1), 3-4 weeks (T2) and 3 months (+/- 10 days, T3) thereafter. The main outcome events of the study were: objectively documented recurrent DVT and/or PE. D-dimer was found to be increased in 15.5%, 40.3% and 46.2% of the patients at T1, T2 and T3, respectively. In 199 (50.2%) patients, D-dimer levels were elevated in at least one measurement. During a follow-up of 628.4 years, 40 recurrences were recorded (10.1% of patients; 6.4% patient-years of follow-up). D-dimer was increased in at least one measurement in 28 of these cases, but remained normal in 11 subjects (three of whom had recurrent events triggered by circumstantial factors, three with malignancy-associated factors) (in one subject D-dimer was not measured). The negative predictive value (NPV) of D-dimer was 95.6% (95% CI 91.6-98.1) at T3 and was even higher (96.7%; 95% CI 92.9-98.8) after exclusion of the six recurrences due to circumstantial factors.