The effect of ß-receptor blockade on factor VIII levels and thrombin generation in patients with venous thromboembolism

2003 ◽  
Vol 89 (05) ◽  
pp. 837-841 ◽  
Author(s):  
Verena Schönauer ◽  
Sandra Giannini ◽  
Günter Christ ◽  
Peter Quehenberger ◽  
Christian Bieglmayer ◽  
...  

SummaryHigh factor VIII (FVIII) is a risk factor for venous thromboembolism (VTE). The pathomechanism by which high FVIII leads to an increased risk of VTE is unknown. Physical activity and infusion of adrenalin provoke a rise in FVIII, which can be blocked by a nonselective β-blockade. We tested the hypothesis that in patients with a VTE β-blockade decreases FVIII and inhibits coagulation activation.17 male patients with high FVIII (> 170 IU/dL, n = 7) or low FVIII (<150 IU/dL, n = 10) and a history of VTE received 40 mg of propranolol thrice daily for 14 days. FVIII and vasopressin levels were measured before and during propranolol intake and 28 days thereafter. At the same time points, haemostatic system activation was investigated by measuring prothrombin fragment f1.2 (f1.2) and thrombin antithrombin complexes (TAT) in venous blood and in blood emerging from a skin incision (shed blood).The mean FVIII level before propranolol was 192 IU/dL and 115 IU/dL in patients with high and low FVIII, respectively. During and 28 days after propranolol, no significant change in FVIII was seen in both groups. Changes in f1.2 and TAT were not detectable in either venous blood or in shed blood.β-receptor blockade did not lower FVIII or inhibit haemostatic system activation in patients with VTE and persistently high FVIII. Administration of propranolol cannot be recommended as secondary thromboprophylaxis in patients with high FVIII.

1997 ◽  
Vol 77 (04) ◽  
pp. 685-689 ◽  
Author(s):  
Paul A Kyrle ◽  
Johannes Brockmeier ◽  
Ansgar Weltermann ◽  
Sabine Eichinger ◽  
Wolfgang Speiser ◽  
...  

SummaryCoumarin-induced skin necrosis is believed to be due to a transient hypercoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X during initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a technique that investigates coagulation activation in the microcirculation.We determined in 10 healthy volunteers the concentrations of prothrombin fragment F1+2 (f1.2) and thrombin-antithrombin complex (TAT) in blood emerging from an injury of the microvasculature (bleeding time incision) before and after initiation of both high-inten- sity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F Vila) and the activities of FII, F VII, F X and protein C were measured in venous blood.A rapid decline of F VII and protein C was observed in venous blood with activities at 24 h of 7 ± 1% and 43 ± 2%, respectively, during the high-intensity regimen. A 20 to 30% reduction of f1.2 and TAT was seen in venous blood at 72 h with no major difference between the high- and the low-intensity regimen. F Vila levels were substantially affected by anticoagulation with a >90% reduction at 48 h during the high-intensity regimen. Following high-intensity coumarin, a >50% decrease in the fl.2 and TAT levels was found in shed blood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT levels was seen neither in shed blood nor in venous blood.Our data do not support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-induced skin nekrosis.


2004 ◽  
Vol 91 (01) ◽  
pp. 80-86 ◽  
Author(s):  
Brigitte Piccapietra ◽  
Johanna Boersma ◽  
Joerg Fehr ◽  
Thomas Bombeli

SummaryNo relevant deficiency of TFPI or genetic polymorphisms could thus far consistently be associated with venous thromboembolism. We hypothesized that the substrates of the TFPI protein, including FVII or FX (rather than the protein itself) could induce a hypercoagulable state. We created a novel TF-based clotting assay that evaluated the anticoagulant response to exogenously added recombinant TFPI. The response to TFPI was expressed as the ratio of the clotting time with and without TFPI. By using 118 healthy controls, we established a reference range between 1.31 and 1.93 (mean value ± 2 standard deviations (SD), 1.62 ± 0.31). We then evaluated samples from 120 patients with a history of venous thromboembolism but no evidence of hereditary and acquired thrombophilia. The range of the patients’ ratios was significantly (P < 0.001) lower, falling between 1.2 and 1.78 (mean value ± 2 SD, 1.49 ± 0.29). Of the 120 patients, 39 (32.5%) had a TFPI sensitivity ratio below the 10th percentile of the controls, compared with 11 (9.3%) of the healthy controls. The crude odds ratio for venous thrombosis for subjects with a TFPI sensitivity ratio below the 10th percentile was 13 (95% CI; range, 3.1 to 54.9) compared with those with a ratio above 1.8 (90th percentile). Patients with idiopathic thromboembolism did not have a decreased TFPI sensitivity ratio more often than patients with thrombosis with a circumstantial risk factor. Based on these results, a reduced response to TFPI may lead to an increased risk of venous thrombosis.


2002 ◽  
Vol 88 (10) ◽  
pp. 587-591 ◽  
Author(s):  
Karine Lacut ◽  
Grégoire Le Gal ◽  
Patrick Van Dreden ◽  
Luc Bressollette ◽  
Pierre-Yves Scarabin ◽  
...  

SummaryActivated protein C (APC) resistance is the most common risk factor for venous thromboembolism (VTE). Previous studies mostly analysed patients under 70 years and reported a four-to sevenfold increased risk. This case-control study included consecutive patients referred for a clinical suspicion VTE to our medical unit: 621 patients with a well-documented diagnosis (cases) and 406 patients for which the diagnosis was ruled out and who had no personal history of VTE (controls). APC resistance related to factor V Leiden was defined by either a positive DNA analysis or a positive STA® Staclot APC-R assay. Under 70 years, APC resistance was associated with a threefold increased risk of VTE (odds ratio 3.2, 95% CI, 1.7 to 6.0), whereas in patients over 70 years, it appeared to be no longer a strong risk factor (odds ratio 0.8, 95% CI, 0.4 to 1.7). Age appeared as an effectmeasure modifier with a significant interaction (p = 0.005). Our data suggest that APC resistance is not a risk factor for VTE in elderly.


1999 ◽  
Vol 82 (10) ◽  
pp. 1232-1236 ◽  
Author(s):  
Ansgar Weltermann ◽  
Karl Philipp ◽  
Erich Hafner ◽  
Alexandra Kaider ◽  
Eva-Maria Kittl ◽  
...  

SummaryNormal pregnancy is associated with alterations of the hemostatic system towards a hypercoagulable state and an increased risk of venous thromboembolism. The risk of venous thrombosis is higher in pregnant women with factor V Leiden (FVL) than in those with wildtype factor V. Routine laboratory assays are not useful to detect hypercoagulable conditions. A prospective and systematic evaluation of hemostatic system activation in women with and without FVL during an uncomplicated pregnancy employing more sensitive markers of hypercoagulability, such as prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-Dimer, or the endogenous thrombin potential (ETP), an indicator of the plasma’s potential to generate thrombin, has not been performed. We prospectively followed 113 pregnant women with (n = 11) and without (n = 102) FVL and measured F1+2, TAT, D-Dimer and the ETP at the 12th, 22nd and 34th gestational week as well as 3 months after delivery (baseline) in each subject. None of the women developed clinical signs of venous thromboembolism during pregnancy or postpartum. Pregnant women with and without FVL exhibited substantial activation of the coagulation and fibrinolytic system as indicated by a gradual increase of F1+2, TAT and D-Dimer throughout uncomplicated pregnancy up to levels similar to those found in acute thromboembolic events (p < 0.0001 by analysis of variance for each parameters). Levels of F1+2 and TAT were comparable between women with and without FVL, but levels of D-Dimer were significantly higher in women with FVL than in those without the mutation (p = 0.0005). The ETP remained unchanged in both women with and without FVL at all timepoints. Our data demonstrate a substantial coagulation and fibrinolytic system activation in healthy women with and without FVL during uncomplicated pregnancy. An elevated F1+2, TAT or D-Dimer level during pregnancy is not necessarily indicative for an acute thromboembolic event. The normal ETP in both women with and without FVL suggests that the capacity of the plasma to generate thrombin after in vitro activation of the clotting system is not affected by pregnancy. Higher levels of D-Dimer in women with FVL than in women with wildtype factor V at baseline as well as during pregnancy indicate increased fibrinolytic system activation in carriers of the mutation.


2021 ◽  
Vol 8 ◽  
Author(s):  
Yong-Jian Zhu ◽  
Yu-Ping Zhou ◽  
Yun-Peng Wei ◽  
Xi-Qi Xu ◽  
Xin-Xin Yan ◽  
...  

Background: The association between anticoagulation outcomes and prior history of venous thromboembolism (VTE) in chronic thromboembolic pulmonary hypertension (CTEPH) has not been established. This study aimed to compare the efficacy and safety of anticoagulation treatment in CTEPH patients with and without prior history of VTE.Methods: A total of 333 CTEPH patients prescribed anticoagulants were retrospectively included from May 2013 to April 2019. The clinical characteristics were collected at their first admission. Incidental recurrent VTE and clinically relevant bleeding were recorded during follow-up. The Cox proportional regression models were used to identify potential factors associated with recurrent VTE and clinically relevant bleeding.Results: Seventy patients (21%) without a prior history of VTE did not experience recurrent VTE during anticoagulation. Compared to CTEPH patients without a prior history of VTE, those with a prior history of VTE had an increased risk of recurrent VTE [2.27/100 person-year vs. 0/100 person-year; hazard ratio (HR), 8.92; 95% confidence interval (CI), 1.18–1142.00; P = 0.029] but a similar risk of clinically relevant bleeding (3.90/100 person-year vs. 4.59/100 person-year; HR, 0.83; 95% CI, 0.38–1.78; P = 0.623). Multivariate Cox analyses suggested that a prior history of VTE and interruption of anticoagulation treatments were significantly associated with an increased risk of recurrent VTE, while anemia and glucocorticoid use were significantly associated with a higher risk of clinically relevant bleeding.Conclusions: This study is the first to reveal that a prior history of VTE significantly increases the risk of recurrent VTE in CTEPH patients during anticoagulation treatment. This finding should be further evaluated in prospective studies.


2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Aida Lydia ◽  
Yassir Yassir ◽  
Rudy Hidayat ◽  
Suhendro Suwarto

Background: Uric acid (UA) levels are associated with increased risk of cardiovascular events and mortality in hemodialysis patients. However, there are still conflicting data on the mechanism of increased risks related to uric acid levels. Objectives: This study assessed the association between uric acid levels and symmetric dimethylarginine (SDMA), as a marker of cardiovascular disease, in the subjects undergoing hemodialysis twice weekly. Methods: This was a cross-sectional study conducted in a tertiary hospital in Jakarta, Indonesia. We included all the adults who underwent hemodialysis twice weekly for at least three months in our hospital. Subjects already on uric acid lowering therapy, pregnant or lactating women and those with a history of malignancy were excluded. Uric acid and SDMA levels were measured at the same time in pre-dialysis venous blood samples. Bivariate analysis was performed using the Mann-Whitney U test or one-way ANOVA. Results: A total of 126 subjects were included. The median level of UA was 8.4 mg/dL (IQR: 2.6, min: 4.1, max: 13.6), and 72 subjects (57.14%) had UA levels of 8 mg/dL or higher. The median SDMA level was 535.5 (312.7) mmol/dL (min: 119.7, max: 1895.5). Subjects with UA levels > 8 mg/dL had significantly higher SDMA levels compared to subjects with UA levels < 8 mg/dL (550.1 (IQR: 357.25) vs 491.35 (IQR: 181.1), P: 0.0475). Conclusions: In twice-weekly hemodialysis patients, UA levels above 8 mg/dL were associated with increased SDMA levels.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A826-A827
Author(s):  
Siroj Dejhansathit ◽  
Ana Marcella Rivas Mejia ◽  
Kenneth Nugent

Abstract Background: Venous thromboembolism (VTE) that have significant morbidity and mortality for patients in the community and hospital. A recent meta-analysis found a significantly increased risk of incidence VTE among patients with hyperthyroidism compared to patients without hyperthyroidism. To our knowledge, no study has attempted to explore whether screening for TSH levels in VTE patients leads to a diagnosis of undiagnosed thyroid dysfunction as VTE could be the first presenting symptom. Method: We conducted a retrospective cohort study and analyzed data of all patients treated at University Medical Center, Lubbock, Texas in 18-85 years of age with a diagnosis of DVT and/or PE in 2019. Qualitative chart review to identify cases of clinically significant TSH screening in VTE patients that leads to thyroid dysfunction diagnosis. Associations between variables tested using Student’s t-test, chi-square, and Fisher’s exact test. Results: Of total of 533 participants with diagnosis of VTE in 2019, 85 participants were included in the study. Seven participants (8.24%) were found to have high TSH level (&gt;4.2 mIU/mL). None of them was found to have low level of TSH. Participants in high TSH group were more likely to be female (71.43%) and Caucasian (71.43%). In high TSH group patients tended to have both PE and DVT diagnosis at the same admission (71.43%). Weight and BMI were significance higher than those with normal TSH level. Segna et al conducted a prospective multicenter cohort study on association between thyroid dysfunction and venous thromboembolism. The study measure thyroid hormones and thrombophilic biomarkers at 1 year after the acute VTE and follow for the recurrent VTE (rVTE). They found that after 20.8 months of follow-up, 9% developed rVTE. However, none of them was found in subclinical hyperthyroidism group. Furthermore, in their multi-variate analyses, the hazard ratio for rVTE was 0.80 (95%CI 0.23-2.81) subclinical hyperthyroidism compared with euthyroid participants. They concluded that subclinical hyperthyroidism may be associated with lower rVTE risks. Similarly, with Liviu study found hyperthyroidism was not associated with an increased risk of VTE. Qualitative chart review in our patients with high TSH resulted that none of them had history of tobacco use. One participant was on birth control pills with the history of cervical carcinoma. Conclusion:The association of thyroid dysfunction and the development of VTE is debated on the literature review. In our study we found multiple patients with high TSH level (8.24%) in VTE patients with no prior history of thyroid dysfunction. TSH could play an important role in hypercoagulable state. Subclinical hypothyroidism and/or hypothyroidism may induce a prothrombotic event. However, larger cohort studies with higher prevalence of high TSH participants are needed to prove a relationship between TSH level and VTE events.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3298-3298
Author(s):  
Radhika Gangaraju ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Jessica Wu ◽  
Wendy Landier ◽  
...  

BACKGROUND: BMT recipients are vulnerable to accelerated atherosclerosis due to prior exposure to radiation with or without chemotherapy, and consequent long-term cardiovascular morbidity, such as stroke. A comprehensive evaluation of the risk of late-occurring stroke in adult BMT survivors and the associated risk factors has not been performed. We addressed this gap using the resources offered by the BMTSS. METHODS: BMTSS includes patients transplanted between 1974 and 2014 at 3 US sites who survived ≥2y after BMT, were alive and ≥18y at BMTSS survey completion. The survey asked participants to report if a healthcare provider had diagnosed specific chronic health conditions (including stroke), or relapse of primary cancer or development of new cancer, along with age at diagnosis. The participants provided information on sociodemographics, health behaviors and medication use. Medical record abstraction was used for information regarding primary cancer diagnosis, therapeutic exposures (pre-BMT chemotherapy/radiation, transplant preparative regimens), stem cell source (autologous, allogeneic), graft type (bone marrow, cord blood or peripheral blood stem cells), and history of chronic graft vs. host disease (GvHD). A cohort of 908 siblings also completed the BMTSS survey and served as a comparison group. Informed consent was obtained from all participants. RESULTS: The study included 3,479 BMT survivors; 50.3% had received an allogeneic BMT, 54.8% were males; 71.4% were non-Hispanic whites. Median age at study participation was 59y (range: 18-89y) for BMT survivors and 57y (range: 18-90y) for siblings. Patient characteristics are shown in Table 1. BMT survivors were followed for a median of 9y (range: 2-41 y) from BMT. Stroke was reported by 136 BMT survivors (67 allogeneic, 69 autologous); of these, 75 (55%) patients developed stroke ≥2y after BMT. Conditional on surviving ≥2y after BMT, the 10y cumulative incidence of stroke was 3.8% (Fig 1), and was comparable for allogeneic (3.4±0.5%) and autologous (4.2±0.6%) BMT recipients, p=0.3. Stroke in BMT recipients compared with siblings: Using logistic regression, and after adjusting for sociodemographics, physical activity and relevant comorbidities, we found that allogeneic BMT survivors were at a 2.1-fold higher odds of reporting stroke as compared to siblings (95%CI: 1.2-3.7, p=0.01), and autologous BMT recipients were at a 1.7-fold higher odds of reporting stroke compared to siblings (95%CI: 0.9-3.0, p=0.09). Stroke after Allogeneic BMT: History of hypertension (HR=2.2, 95%CI: 1.2-3.9, p=0.007), venous thromboembolism (HR=3.4, 95%CI: 1.6-7.1, p=0.002), diagnosis of acute lymphoblastic leukemia (HR=4.9, 95%CI: 1.6-15.0, p=0.006), acute myeloid leukemia/ myelodysplastic syndrome (HR=5.2, 95%CI: 1.4-19.0, p=0.013) (ref: non Hodgkin lymphoma), pre-BMT exposure to alkylating agents (HR=3.3, 95%CI: 1.3-8.5, p=0.01) and pre-BMT neck radiation (HR=5.4, 95%CI: 1.2-23.8, p=0.03) were associated with increased stroke risk. Exercise was associated with lower stroke risk (HR: 0.5, 95%CI: 0.3-0.9, p=0.01). Stroke after Autologous BMT: The risk factors for stroke in autologous BMT survivors included: increasing age at BMT (HR=1.02/y, 95%CI: 1.0-1.1, p=0.05), history of hypertension (HR=1.8, 95%CI: 1.1-3.2, p=0.03), coronary heart disease (HR=2.8, 95%CI: 1.3-6.4, p=0.01) and venous thromboembolism (HR=2.3, 95%CI: 1.1-4.7, p=0.02). Relapse of primary disease or development of new cancer were not associated with increased stroke risk in either autologous or allogeneic BMT recipients. CONCLUSION: In this large study, we found that the incidence of stroke was 4% among BMT survivors, and that they are at an increased risk of developing stroke when compared to an unaffected comparison group. The study also identified subgroups among BMT survivors at increased risk of stroke such as those who received neck radiation and those with cardiovascular comorbidity. These findings suggest a need for increased awareness of stroke as a late complication of BMT, such that aggressive management of cardiovascular risk factors can be instituted among those at highest risk. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.


Haematologica ◽  
2020 ◽  
Vol 105 (10) ◽  
pp. 2368-2379
Author(s):  
Arun S. Shet ◽  
Maria A. Lizarralde-Iragorri ◽  
Rakhi P. Naik

The genetic and molecular basis of sickle cell disease (SCD) has long since been characterized but the pathophysiological basis is not entirely defined. How a red cell hemolytic disorder initiates inflammation, endothelial dysfunction, coagulation activation and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a history of VTE. Here, we thoroughly review the molecular basis for the prothrombotic state in SCD, specifically highlighting emerging evidence for activation of overlapping inflammation and coagulation pathways, that predispose to venous thromboembolism. We share perspectives in managing venous thrombosis in SCD, highlighting innovative therapies with the potential to influence the clinical course of disease and reduce thrombotic risk, while maintaining an acceptable safety profile.


Author(s):  
Douaa Al Rez ◽  
Hasan Naser Eldine ◽  
Marwan Alhalabi

Background: Recurrent pregnancy loss (RPL) is a serious problem on the women, it defined as two or more consecutive pregnancy losses before the fetus has reached birth. The aim of this study is to evaluate the association between the elevation in the factor VIII and RPL. Because women who have thrombophilia have increased risk of fetal loss in most studies.Methods: A total 72 women were recruited in this case control study. They divided into two groups: the RPL group included 41 women with a history of recurrent pregnancy loss and the control group included 31 healthy women, who had at least one successful pregnancy and none of them had a history of fetal loss or complicated pregnancy.Results: A majority of the patients of this study didn't have a high level of factor VIII, 9 of 41 (22%) patients of RPL group in comparison with 21 of 32 (65,6%) of control group, that suffer from the increase rate of FVIII, this means that factor VIII doesn't effect on RPL.Conclusions: The present study showed that the serum elevation in the factor VIII is not significantly associated with RPL.


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