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Introduction
The vitamin K antagonist (VKA) Warfarin is indicated for the prophylaxis and treatment of venous and arterial thromboembolic disorders1. However, the management of warfarin therapy is challenging due to its narrow therapeutic index and is associated with increased risk of haemorrhage2, 3. Warfarin’s extended half-life with an indirect way of thrombin inhibition causes adequate anticoagulation to take effect only after several days4. Moreover, due to the wide variation of response among patients, frequent monitoring of their prothrombin time-international normalized ratio (INR) is compulsory in order to optimize the therapeutic efficacy of warfarin5.
Numerous studies have associated ethnicity to warfarin sensitivity and it was reported that Asian population requires lower doses of warfarin compared to their Caucasian counterpart in order to achieve the target INR6-8.
In Malaysia, a recent study has identified the clinical relevance of pharmacogenetics with warfarin dose prediction which contributed to about 37% of warfarin dose variation9. The estimated prevalence of asymptomatic atrial fibrillation (AF) in the Malaysian primary care setting is 0.75%12. With the substantial number of patients at an elevated risk of developing thromboembolic events still living in a rural setting, anticoagulation considerations, particularly those involving on VKA such as Warfarin, remains a challenge.
The Sarawak General Hospital Heart Centre is the only cardiology anticoagulation clinic in the state of Sarawak run by a multidisciplinary team, involving pharmacists and doctors10. The quality measure of anticoagulation management is via assessment of how well the patient’s intensity of anticoagulation is maintained within the therapeutic index.
This analysis of time in therapeutic range (TTR) has been used to summarize the INR control over a period of time and has been proposed to be used as a surrogate marker to evaluate the clinical outcomes11, 12.
Recent large-scale clinical studies revealed that an increase in TTR (>60 to 65%) is sufficient to be associated with a reduction in haemorrhage, thromboembolism and risk for stroke events13, 14. However, the TTR status and the recommended therapeutic range for patients in a multiethnic Asian population may be different from Caucasian ancestry, and may vary across different centres. It was reported that the country mean TTR of the multicenter RELY and ROCKET-AF studies varied from 44 to 77%, and 43 to 71% respectively13, 15. It was likely that the most important baseline characteristic associated with variability in TTR in the individual patient was the mean TTR of the institution or country.
A recent study conducted at the Sarawak General Hospital Heart Centre reported a median time at target range at 61.6% (IQR 44.6-74.1%) based on the Rosendaal method10.
Various studies have been conducted to identify the potential predictors of the quality of anticoagulation based on TTR14, 16, but no studies have associated direct plasma clotting factor levels with TTR. It has been suggested that direct measurement of certain clotting factors could be useful for reflecting the extent of anticoagulation and antithrombotic effect of oral VKAs as these drugs are known to influence the functional concentrations of these clotting factors indirectly17.
Some findings indicate that Factor II and X could have some potential as oral anticoagulant response marker, due to their extended half-lives compared to FVII and FIX18-20.
Several studies have been carried out and a nonproportional relationship was found between INR and both response markers, indicating that a low INR results in a high FII and FX level18, 21.
One study also found a poor correlation between supratherapeutic INR levels with factor II and X22. As an extension of previous studies, this cross-sectional study was undertaken to investigate the factors influencing TTR in patients undergoing long term warfarin therapy in Malaysian populations, by investigating activated Factor II (thrombin) and Factor Xa (FXa) expression in the coagulation cascade.
AIM of study
The aim of this study is to investigate the association of plasma thrombin and FXa levels with the time in therapeutic range in patients on long term warfarin therapy. Hence, the specific aims of this study are:
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1.
To compare the plasma concentration level of thrombin and FXa in both poorly and well controlled TTR groups
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2.
To investigate the association of plasma thrombin and FXa with known risk factors of atrial fibrillation.
Materials and methods
Study Design
This was a single-centre cross-sectional study jointly conducted by doctors, clinical pharmacists and other members of a multidisciplinary team in a hospital setting.
Patients and eligibility criteria
A total of 289 patients with atrial fibrillation on long term warfarin therapy were screened between September 2012 and July 2013. Patients undergoing long term warfarin therapy with at least 10 INR determinations (Coagucheck, Roche Diagnostics, Mannheim, Germany), an age of greater than 18 years, and warfarin therapy continuing throughout a 6 month observation period were recruited with prior written inform consent.
The Ninth American College of Chest Physicians (ACCP) guidelines are followed for target ranges, dose initiation and dose titration12. Due to the erratic INR readings within the first 3 weeks of anticoagulation initiation, these readings were excluded for analyses16.
Patients who reported active smoking history, alcohol excess, stroke or myocardial infarction within the preceding 3 months, a creatinine clearance <15mL/min, liver disease and those non-adherent to medication, were excluded from this study. Patients who were unable or unwilling to give written informed consent were also excluded from this study.
A total of 188 eligible patients participated in the study. A TTR cut-off point of 66% was used in this study as a TTR close to 66% was indicated as a benchmark for high-quality anticoagulation16, 23, 24.
Group 1 or poorly controlled patients of TTR < 66% consisted of 102 patients, while Group 2 or well controlled patients of TTR≥ 66% consisted of 86 patients.
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Malaysian Ministry of Health Medical Research and Ethics Committee.
Prothrombin Time Monitor
Baseline INR was obtained via a portable PT monitor (Coagucheck, Roche Diagnostics, Mannheim, Germany) requiring only a finger prick test. The monitor is internally calibrated so that the mean normal PT is 12.6 seconds.
Each lot of strips inserted into the monitor is coded with calibration information specific to the thromboplastin time. The ISI for the thromboplastin reagent was set at 1.8 per manufacturer’s instruction. This method is fast, accurate and comparable to routine laboratory methods25.
Measurement of plasma levels of activated Factor II (thrombin) and Factor Xa
Whole blood was obtained via standard venepuncture at an antecubital vein using a 23G needle. Baseline plasma samples were obtained from 5ml of whole blood collected in Ethylenediaminetetraacetic Acid (EDTA) tubes, centrifuged at 1000g for 10 min at room temperature, divided into aliquots and stored at -80°C until batch analysis.
Samples were analysed by commercial kits of ELISA for activated Factor II (thrombin) and Factor Xa (Cusabio, Wuhan, Hubei, China). The upper and lower limit of detection by ELISA for thrombin was 500ng/ml and 7.8ng/ml respectively whereas the upper and lower limit of detection by ELISA for FXa was 20ng/ml and 0.312ng/ml respectively. Intra-assay and interassay coefficient variations were less than 8% and 10%, respectively. The final results were presented as ug/ml for thrombin and ng/ml for FXa.
Statistical Analysis
Categorical variables were presented as frequencies with percentages and numerical variables as mean with standard deviation or median with interquartile range.
The overall percentage time in therapeutic range (TTR) was calculated based on the method established by Rosendaal et al., which uses linear interpolation to estimate the time spent at each INR value26.
TTR was also calculated using the traditional method as described in the ACCP guidelines: number of INR measurements within target range divided by the total number of INR measurements 12. For univariate analyses, the independent sample t-test and Pearson’s Chi-square test (or Fisher exact test as appropriate) were used to determine the differences of variables between two subgroups, i.e. normal vs. poor TTR patients. Normally distributed continuous variables are expressed as mean (SD) and were compared using the t test.
The non-normal variables are expressed as median (interquartile range; IQR) and were compared using the Mann-Whitney U test. Variables with a p<0.05 level of significance were entered into multivariate logistic regression using the forward stepwise model analysis to identify independent predictors. All analyses were performed using the SPSS 16.0 for Windows (SPSS Inc.). All statistical analysis were two-sided with analyses being significant if α≤0.05
Results
Using the TTR value of 66% as the cut-off point, the baseline characteristics of the 102 patients in Group 1 and the 86 patients in Group 2 were well matched. (Table 1). Among the 188 patients, 18.6% had paroxysmal AF, 8.5% had persistent AF, 47.3% had permanent AF and 25.5% had other forms of AF.
The median years (IQR) that the patients were treated on warfarin was 5(3,9). The mean TTR using the Rosendaal method in this cohort was 61.85 (21.67)%. Group 1 had a significantly lower mean TTR value compared to Group 2 (45.95% vs 80.71%; p<001). The average weekly warfarin dose in this cohort was 19.66(7.22)mg. Of the out of range readings, 29% were subtherapeutic and 15% were supratherapeutic.
Plasma levels of thrombin and FXa with TTR
Plasma levels of thrombin and FXa in both groups are presented in table 2. Thrombin levels were significantly higher in Group 1 compared to Group 2 (513.65 vs 374.01 ug/ml; p=0.002). Univariate analysis showed that there was a signifi cant but poor correlation between thrombin concentration with TTR (r=-0.166, p=0.023). There was however no correlation between FXa concentrations with TTR (0.84 vs 0.78 ng/ml; p=0.504). Both thrombin and FXa showed no correlation with the INR at point of recruitment (r=-0.047, p=0.52 and r=-0.038, p=0.61), respectively.
Impact of risk factors of atrial fi brillation on thrombin and FXa levels
Despite the TTR status and warfarin dose, the elevated thrombin levels could be influenced by other confounding factors. We therefore perform additional analyses to ascertain whether an elevation in the plasma level of thrombin were associated with known risk factors of atrial fi brillation (Table 3). The plasma level of thrombin was signifi cantly higher in females (761.95 vs 513.49 ug/ml; p<0.001). However, significantly lower levels of thrombin concentration was found in those with hypertension, diabetes mellitus and coronary artery disease (all p>0.05). There was a significant increase in thrombin levels in patients with BMI of less than 25 compared to those with a BMI of 25 or more (p>0.001). Thrombin levels were significantly associated with BMI (r=0.280, p>0.001). There was no correlation between plasma thrombin levels with chronic heart failure, prior bleeding risk and prior stroke events. There was no significant difference in plasma FXa levels in those with hypertension, diabetes mellitus, coronary artery disease, chronic heart failure, BMI, prior bleeding risk and prior stroke events. After adjustment for other variables significant in bivariate analysis (Table 4) we found that gender, TTR, BMI and hypertension risk factor were found to have signifi cant correlations with plasma thrombin levels. With the 4 signifi cant variables, the model explains 15.4% of variation of the plasma thrombin level in this study sample (R2=0.154).
R2= 0.154 meaning that with the 4 significant variables, the model explains 15.4% of variation of plasma thrombin levels in the study sample
Discussion
Atrial fibrillation (AF) bestow a significant risk of stroke and systemic thromboembolism rendering oral anticoagulation therapy playing a pivotal role for stroke prevention27. Thrombosis is the main player in the development of atherosclerosis and its acute vascular complications28. Referring to Virchow’s triad, there are three determinants for thrombus formation: (1) circulatory stasis; (2) endothelial injury; and (3) hypercoagulable state29. Of these, the clotting cascade is particularly important and is often targeted by new drug therapies to interfere with arterial thrombogenesis30. Thrombin is located downstream of both the extrinsic and intrinsic amplification pathways of the anticoagulation cascade31. Each pathway consists of tissue factors (TF) and a number of coagulation factors (Factors II, VII, IX and X) which eventually contribute to thrombin amplifi cation32. Following endothelial injury, the blood coagulation cascade is activated via extrinsic pathway where the exposed tissue factors will bind to coagulation factor VII which further activate factor IX then X. The activation of factor X to Xa further drives the pathway for thrombin activation by the conversion of prothrombin to thrombin (Factor IIa). Therefore, thrombin is the key protein that promotes the conversion of fibrinogen to fi brin which ultimately, forms the thrombus33. To date, no study has investigated the association of the activated Factor II and X with the TTR, in a multiethnic Asian population.
The mean TTR(SD) of 61.9(21.67)% found in this study is comparable with previously reported studies10 and other international publications13, 34, 35. In the present work, we obtained a relationship between TTR and activated Factor II or thrombin, which seems to be the result of a non-linear behavior. However, the relevance of this correlation need to be evaluated carefully as the current study only relied on a single baseline sample. The exact correlation of plasma thrombin concentration to each INR result is yet to be evaluated in this study.
In addition, plasma thrombin levels were found to be significantly higher in Group 1 with a majority (39.6%) of the out-of-range readings being subtherapeutic. Group 1 also have significantly lower weekly warfarin dose compared to Group 2 (Table 1) indicating that plasma thrombin might play a role in underwarfarinised patients on low weekly warfarin dose. This could be due to clinicians in our settings are less aggressive when it comes to warfarin dose increment especially in warfarin sensitive patients6. Alternate dosing did not play signifi cant role in TTR status.
The negative correlation found between plasma thrombin levels and the weekly warfarin dosing suggests that warfarin dosing reduces plasma thrombin levels in a non-linear behavior. There was however no association found between both biomarkers and baseline INR as opposed to previous similar studies18. Factor Xa was not associated with either TTR or weekly warfarin dose which further suggests that plasma levels of factor Xa does not fall proportionally with plasma thrombin levels, although both biomarkers are interconnected in the blood coagulation cascade. These findings were consistent with previous similar studies reporting that a relatively lower activity level in factor X was found in comparison with the levels of factor II, VII and IX at the same INR value19, 21.
Although we found that male patients have higher mean TTR, a finding which is reported elsewhere 16, 36-38, this difference were found to be not significant in this study. In addition, we found that females are associated with higher plasma thrombin levels regardless of their TTR status. We also found that plasma thrombin levels was associated with BMI in a non-linear pattern where patients with a BMI of 25 or more have significantly lower plasma thrombin levels compared to those of normal BMI. The reasons for this remain unclear.
Plasma thrombin levels in this study were significantly lower in patients with hypertension, diabetes mellitus and coronary artery disease although one study demonstrated a correlation of thrombin levels with low levels of glucose28. One possibility for this is that patients identified with these vascular risk factors were being treated aggressively for these, and could have led to a reduction in thrombin levels. Thrombin levels were significantly elevated in females, but not males, regardless of these cardiovascular risk factors. Again, reasons for this is unclear.
Due to limited studies conducted, we are currently not able to draw a cut off value in the plasma thrombin concentration to indicate the efficacy of warfarin therapy. In the case of bleeding, a similar study has reported a poor correlation of supratherapeutic INR with an elevated risk of bleeding to factor II and X. A minimal decreasing trend in those factor levels from an INR of 5.0 to >15.0 with high interindividual variation was found22. However, Factor Xa in this study showed no correlation with BMI, hypertension, diabetes mellitus, coronary artery disease, prior bleeding and stroke risk factors which suggests that it might be a less valuable predictive marker compared to thrombin. Previous studies conducted only evaluated the plasma levels of coagulation factors in patients receiving long term warfarin therapy without taking into account the patients cardiovascular risk factors17, 18, 21, 39.
In terms of concurrent medications, neither plasma thrombin nor factor Xa level was associated with the total number of medications that the patients are taking. However, this finding is debatable as we did not compare specific groups of medications such as anti-arrhythmics, diuretics and beta-blockers with both biomarker levels in this cohort.
New oral anticoagulation (NOAC) treatments targeting the inhibition of activated Factor II (thrombin) and Factor X (FXa) have emerged in recent years. Dabigatran is a direct thrombin inhibitor while Rivaroxaban and Apixaban are direct FXa inhibitors were all reported to be noninferior to warfarin in terms of stroke and thromboembolic prevention for patients with nonvalvular atrial fibrillation (AF)5, 15, 27, 40.
Furthermore, Dabigatran at a higher dose of 150mg twice daily did demonstrate superiority for prevention of thromboembolic events5, 41. Recently published data also concluded that haemorrhagic stroke rates, a potentially fatal condition were lower on Dabigatran compared to warfarin in Asian populations41.
These new oral anticoagulants (NOAC) display a predictable pharmacodynamics and pharmacokinetic profile with short half-lives, low incidence for food and drug interactions, requiring no regular dose adjustments and monitoring42, 43. However, their usage is restricted by their relatively higher costs and limited indications, scenarios typically found in developing countries10, 44. Moreover, Dabigatran was found in a study to be associated with a greater risk of non-hemorrhagic side effects 5. In addition, the use of Rivaroxaban and Apixaban were also limited by the lack of data for its long term safety and efficacy45.
A growing suggestion indicates that warfarin remains as the anticoagulant of choice if patients were within therapeutic range. To a large degree, cost of therapies of NOACs limit their immediate global adoption, as an immediate replacement for patients with non-valvular AF, a condition associated with serious clinical events such as stroke. The morbidity associated with non-fatal stroke and other such clinical events is substantial, and leads to arguably greater negative impact in developing countries, whereby healthcare systems have not yet matured sufficiently to fully support and manage both the patients and their caregivers. Objective measures of variables associated with poor INR control, and TTR being only a retrospective measurement, could better delineate those who may benefi t most from switching to the new NOACs.
In this cross-sectional study, it is anticipated that patients with poor TTR value of less than 66% and an arbitrary plasma thrombin level of above 513.65 ug/ml may be considered for switching to new NOACs treatment. However, these assumptions may only be applied to those that are already started on VKAs and not for anticoagulation-naïve patients. Hence, future studies looking specifically at both clinical and safety endpoints should be addressed to further support the standpoint of this study.
Study limitations
This is a single centre study involving a relatively small number of patients. Nevertheless, this is the first study reporting the relationship of thrombin and factor Xa markers in long-term warfarin treated patients in a Malaysian population, suggesting the potential use of these markers as diagnostic tools. This current study did not encompass the clinical outcomes on follow-up of patients, and therefore further studies in this fi eld are warranted.
Conclusion
This study suggests that plasma thrombin levels, but not Factor Xa, correlates well with TTR status, with higher levels found in patients with suboptimal INR control. Hence, thrombin levels may be a useful marker in refl ecting the quality of anticoagulation and in identifying poorly controlled warfarin patients. Consequently, this marker may also serve to target patients who may benefit from new oral anticoagulation therapies which aim to reduce thrombin and factor Xa levels. Larger studies, which addresses pharmacogenetics to validate the true relationship between thrombin and FXa with warfarin efficacy, are warranted.
Funding: The clinical research was supported by a grant from the NIH Ministry of Health Malaysia
Acknowledgement: Our appreciation and thanks to the Director-General of Health Malaysia, for permission to share and publish these findings.
Conflicts of Interest: The authors have no conflicts of interests to declare.
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Open Access: This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Correspondence to Dr Alan Fong, Consultant Cardiologist, Department of Cardiology, Sarawak General Hospital Heart Centre, 94300, Kota Samarahan, Sarawak, Malaysia. Telephone: (+60)82281111 E-mail: alanfong@crc.gov.my
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Lim, M., Anchah, L., Tiong, W. et al. Thrombin and FXa plasma concentration levels in patients with atrial fibrillation on long term warfarin therapy. Asean Heart J 22, 5 (2014). https://doi.org/10.7603/s40602-014-0005-1
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DOI: https://doi.org/10.7603/s40602-014-0005-1