CC BY
2COMPARISON OF PLASMA COAGULABILITY AFTER SHORT-TERM TREATMENT WITH ROSUVASTATIN VERSUS ATORVASTATIN IN UNSTABLE ANGINA PATIENTS
Yuliya Tyravska, postgraduate student Internal Medicine #4 Department, Bogomolets National Medical University, Kyiv, Ukraine, ORCIDID: https://orcid.org/0000-0002-4403-5550,
Viktor Lizogub, D. Sc., Professor, Head of Internal medicine #4 Department, Bogomolets National Medical University, Kyiv, Ukraine, ORCID ID: https://orcid.org/0000-0003-3603-7342
Nataliia Raksha, PhD, assistant of Biochemistry Department, Taras Shevchenko National University, ORCID ID: https://orcid.org/0000-0001-6654-771X
Oleksii Savchuk, D. Sc., Professor, Head of Biochemistry Department, Taras Shevchenko National University, Kyiv, Ukraine, ORCID ID: https://orcid.org/0000-0003-3621-6981
DOI: https://doi.org/10.31435/rsglobal_ws/30092020/7202
ARTICLE INFO
Received: 23 July 2020 Accepted: 10 September 2020 Published: 30 September 2020
KEYWORDS
Unstable angina, atorvastatin, rosuvastatin, coagulation, prothrombin pool, soluble fibrin monomer complex.
ABSTRACT
Statins are the integral medications for the management of patients with acute coronary syndrome including unstable angina (UA) with multiple pleiotropic effects. However, the influence of statins on the coagulation system is controversial. Our study aimed to explore the effects of atorvastatin and rosuvastatin in high doses on some coagulation parameters (prothrombin pool (PP) and soluble fibrin-monomer complexes (SFMC) concentration) after a 7-days follow-up period in patients with UA. We recruited 50 patients aged 55 to 70 years with progressive UA. Standard therapy according to ESC guidelines 2020 was recommended for all patients. Before treatment onset, they were divided into 2 groups: group A - 26 patients were prescribed atorvastatin, group R - 24 patients with rosuvastatin treatment. The blood samples to analyze the concentration of PP and SFMC were collected twice - before the treatment onset and 7 days after. We revealed significant decrease in PP concentration (p=0,02) and increase in SFMC concentration (p=0,01) in group A patients while there were no significant changes of investigated parameters (p=0,94, p=0,57 respectively) in group R. Additionally, we have noted significant negative correlation between baseline PP concentration and direction of PP changes (r=-0,803, p<0,001) as well as PP changes direction and SFMC concentration after treatment (r=-0,655, p<0,001). Thus, we may consider that atorvastatin and rosuvastatin are characterized by different influences on coagulation in patients with progressive UA with standard basic treatment. The rebound coagulation system activation after anticoagulant discontinuation is more pronounced in UA patients against a background of atorvastatin treatment in comparison with rosuvastatin.
Citation: Yuliya Tyravska, Viktor Lizogub, Nataliia Raksha, Oleksii Savchuk. (2020) Comparison of Plasma Coagulability After Short-Term Treatment with Rosuvastatin Versus Atorvastatin in Unstable Angina Patients. World Science. 7(59). doi: 10.31435/rsglobal_ws/30092020/7202
Copyright: © 2020 Yuliya Tyravska, Viktor Lizogub, Nataliia Raksha, Oleksii Savchuk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Introduction. Statins (3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) are considered a cornerstone in prevention and treatment of atherosclerosis and its complications [1, 2], as it was shown that this group of medicines reduces the risk of major vascular events [3] as well as cardiovascular and all-cause mortality [4].
While the enormous targeted investigations were performed to analyze the data regarding the direct pharmacological hypolipidemic mechanism of statins [5], the plethora of statins' pleiotropic effects was revealed [6]. Most of them are explained by the anti-inflammatory properties of statins [7]. Thus, statins adjust two main pathogenetic mechanisms of coronary artery disease progression, particularly dyslipoproteinemia and inflammation. It was found that even short-term treatment with statins influence on coronary heart disease, which is of high importance regarding the management of patients with acute coronary syndrome [8].
Far less attention is paid to the influence of statins onto the hemostasis, though the latter imbalance occupies a fitting first place especially in case of coronary artery disease destabilization, when atherothrombosis occurs [2].
Traditionally, acute cardiovascular events are reckoned to be connected tightly with the formation of platelet-rich thrombi. But the insufficient effect of even double antiplatelet therapy and finally results of autopsy findings with fibrin-rich thrombi that cause myocardial infarction suggest the underestimated role of the coagulation with thrombin as the central enzyme [9] and its precursor prothrombin. Consequently, it stands to reason that anticoagulants are mandatory medicines for the management of patients with acute coronary syndrome [2]. Soluble fibrin monomer complex (SFMC) which is famous for its diagnostic potential in patients with myocardial infarction and unstable angina (UA) [10] is one of the coagulation cascade intermediate products with further fibrin polymer formation as the direct way to thrombosis occurrence [11].
Ancillary effects of statins on the coagulation system were described in several reviews but with a note about rather controversial results of studies. There is some data about the influence of statins on thrombin and fibrin [12, 13].
Thus, the main target of our study was to investigate whether the difference between statins regarding changes in blood plasma coagulability exists. Among all types of statin, it was chosen atorvastatin and rosuvastatin as the most widely used representatives of this group which vary in their lipophilicity, elimination half-life, potency, and the mevalonic acid pathway influence [14]. For this purpose, we have analyzed 2 parameters: SFMC and prothrombin pool (PP) which reflects the concentration of all molecules with epitopes of prothrombin origin [15]. A 7-days follow-up period (36 hours after anticoagulant withdrawal) was of high interest for us as just at this time the risk of thrombotic events increases.
Materials and Methods. In our prospective observational study, we recruited 50 patients aged between 55 and 70 years old (19 females (38%)) which were hospitalized to the cardiology department with an established diagnosis of progressive unstable angina. Also, we included only those patients who had not been taking statins for at least 3 months (mainly, because of low compliance with treatment).
The protocol of the study was approved by the Research Ethics Committee of the Bogomolets National Medical University. The patients gave written consent to participate after the explanation of the survey design.
All patients received conservative standardized treatment according to the current ESC Clinical Practice Guidelines [2], particularly anticoagulant (enoxaparin 1 mg/kg twice daily 3 days, 0,5 mg/kg twice daily 2 days subcutaneously), acetylsalicylic acid (ASA) 75 mg once daily, clopidogrel 75 mg once daily, bisoprolol in dosage depending on heart rate (HR) and blood pressure (BP) once daily, angiotensin-converting enzyme inhibitor (ACEi) (enalapril/ramipril/perindopril in individual dosage), nitrates in infusion once daily and 20 mg in tablets twice daily, pantoprazole 20 mg once daily. But depending on statin therapy which was prescribed the patients we formed 2 groups. The patients of group A have been treated with atorvastatin 60 mg per day, while the patients of group R were recommended rosuvastatin 20 mg per day. Such a dosage is believed to be equivalent to these medicines [16]. The follow-up period was 7 days.
The exclusion criteria were conditions with a possible thrombophilic state such as heart defects, persistent atrial fibrillation / atrial flutter, cardiomyopathies, non-ischemic myocardial injuries, heart failure IIB-III stage, endocrinological disorders, active infection, chronic diseases in the period of exacerbation, blood diseases including coagulopathies, anemia of II-III stage, glomerular filtration rate less than 60 ml/min./1,73 m2, hepatic dysfunction, malignancy, traumas, and bleedings within 6 months before this study, myocardial infarction or stroke within 1 year before this survey.
Immediately after admission the patients passed the general clinical examination with anamnesis gathering, ECG at rest registration, qualitative troponin I test.
If according to the preliminary information the patient met inclusion criteria we collected blood samples for hemostatic parameters under investigation (PP, SFMC) before initiation of treatment. We controlled above mentioned hemostatic parameter after 7 days of treatment (36 hours after enoxaparin discontinuation). Blood samples were taken by phlebotomy in sodium citrate, centrifugated, aliquoted, and frozen until use. We determined SFMCs concentration by colorimetric orthophenanthroline method. We used ELISA immune assays with primary and secondary antibodies following the manufacturer's instructions (Santa Crus Biotechnology, CA, USA) to evaluate PP concentration.
Also, we performed echocardiography as well as a basic routine blood analysis set (hepatic and renal panel, complete blood count, lipidogram) and hs-Troponin I test.
We used SPSS (version 22, IBM Corp, USA) for data analysis. Test for normality was provided with the Shapiro Wilk test. We presented numerical data as the median with interquartile range (Me(IQR)), while nominal variables were reported in absolute values (percentage) and compared by using the chi-squared test (x2). We used the Mann-Whitney (U) test for unpaired samples and the Wilcoxon test (W) for paired samples to weigh the differences between numerical variables. The correlation between variables was examined with the use of Pearson or Spearman correlation depending on the type of variables. P-value <0,05 was considered statistically significant.
Results. In our survey we included 50 patients (age 66,0 (60,0-67,0) years, 19 females (38,0%)) with progressive UA. In general, both groups are comparable, and some peculiarities of the investigated population are reported in further tables.
Baseline characteristics of patients are presented in table 1. There was no significant difference between groups including preliminary treatment. The latter is rather important while taking into account multiple indirect influences of medicines onto coagulation. Relatively low compliance with the treatment should be mentioned in recruited patients.
Table 1. Baseline characteristics of patients
Parameter Group A Group R p
Age, years 63,0(60,0-67,3) 66,0 (64,0-67,0) 0,39
Females, n (%) 8 (42,1) 11 (57,9) 0,27
BMI, kg/m2, 30,6 (27,2-32,7) 28,3 (26,7-30,0) 0,06
Preliminary treatment
RAASi, n (%) 18 (69,2) 19 (79,2) 0,07
Diuretic, n (%) 6 (23,1) 7 (29,2) 0,75
CCB, n (%) 2 (7,7) 2 (8,3) 0,89
p-blocker, n (%) 13 (50,0) 14 (58,3) 0,14
ASA, n (%) 8 (30,8) 11 (45,8) 0,38
Nitrate, n (%) 2 (7,7) 5 (20,8) 0,23
BMI - body mass index; RAASi - inhibitor of renin angiotensin aldosterone system; CCB - calcium channel blocker, ASA - acetylsalicylic acid
Table 2 represents 3 main groups of criteria according to which the diagnosis was established, particularly clinical features, biochemical marker (hs-cTn) and ECG changes while admission. Though in general two groups are consistent, hs-cTn concentration tends to be higher in group R.
Table 2. Diagnostic criteria of unstable angina among the groups
Parameter Group A Group R p
Complaints while admission
Typical pain, n (%) 16 (61,5) 17 (70,8) 0,12
Atypical pain, n (%) 6 (23,0) 6 (25,0) 0,72
Dyspnoe (equivalent), n (%) 2 (7,7) 1 (4,2) 0,24
hs-cTn, pg/ml 21,95 (17,72-28,62) 27,00 (22,25-30,95) 0,08
HR, beats/min. 76,0 (70,0-83,0) 72,0 (70,0-78,0) 0,17
ST-segment depression, n (%) 16 (61,5) 20 (83,3) 0,09
T wave variability, n (%) 15 (57,7) 17 (70,8) 0,38
New-onset LBBB, n (%) 2 (7,7) 0 0,49
hs-cTn - high sensitive cardiac troponin; HR - heart rate; LBBB - eft bundle branch block
Chest pain was the prevailing complaint in observed patients (90,0%). 33 patients (66%) suffered from typical retrosternal pain which was provoked by minimal physical exertion or even at rest, others described the discomfort in cardiac region (6, (12,0%)), in scapular region (6, (12,0%)), dyspnoe as the only possible equivalent of pain (3 (6%)) or just general fatigue which occurs suddenly (2 (4%)). Other additional complaints included dyspnoe (70,4%), palpitation (59,8%), headache (40,5%), dizziness (40,8%). In general, regarding complaints the groups were comparable.
The results of basic biochemical tests, echocardiography and BP while admission are demonstrated in table 3. Lipidogram parameters of both groups patients were above recommended targeted levels for high-risk patients while other biochemical characteristics were within normal ranges.
Table 3. General baseline laboratory and instrumental characteristics
Parameter Group A Group R p
TC, mM/L 6,03 (4,85-6,82) 4,99 (4,57-6,61) 0,16
LDL-C, mM/L 3,45 (2,19-4,66) 3,02 (2,62-3,35) 0,11
HDL-C, mM/L 1,20 (1,07-1,67) 1,42 (0,97-1,84) 0,64
TGs, mM/L 2,27 (1,60-2,83) 1,97 (1,26-2,27) 0,08
ALT, IU/L 0,75 (0,65-0,92) 0,75 (0,65-0,83) 0,19
AST, IU/L 0,60 (0,50-0,70) 0,55 (0,50-0,64) 0,45
GFR, mL/min/1,73 m2 60,0 (47,0-81,0) 59,5 (45,0-71,0) 0,55
Glucose, mM/L 4,8 (3,9-5,8) 5,0 (4,3-5,6) 0,38
WBC, x109/L 7,8 (6,8-8,2) 7,8 (5,8-9,6) 0,53
RBC, x1012/L 5,0 (4,5-5,3) 4,8 (4,3-5,1) 0,13
Hb, g/L 145,0 (132,0-148,0) 138,0 (133,0-146,0) 0,17
Platelets, x109/L 256,0 (201,0-292,0) 243,5 (170,0-384,0) 0,94
EDV, mL 118,0 (109,0-129,0) 113,0 (100,0-121,0) 0,34
ESV, mL 43,2 (33,7-68,0) 42,0 (39,0-63,0) 0,54
IVS, mm 1,21 (1,11-1,40) 1,21 (1,10-1,24) 0,32
EF, % 55,5 (50,0-61,0) 61,0 (55,2-63,0) 0,14
sBP, mmHg 150,0 (140,0-160,0) 147,5 (120,0-160,0) 0,91
dBP, mmHg 90,0 (82,0-92,5) 86,0 (80,0-93,0) 0,52
TC - total cholesterol; LDL-C - low-density lipoprotein cholestero ; HDL-C - high-density
lipoprotein cholesterol; TGs - triglycerides; ALT - alanine transaminase; AST - aspartate transaminase; GFR - glomerular filtration rate; WBC - white blood cells; RBC - red blood cells; Hb - hemoglobin; EDV - end-diastolic volume; ESV - end-systolic volume; IVS - interventricular septum; EF- ejection fraction; sBP - systolic blood pressure; dBP - diastolic blood pressure_
The investigated patients were characterized by hypertensive left ventricular hypertrophy with preserved ejection fraction. Also, while admission the normal blood pressure was registered only in 6 patients (12%).
To sum up all above-mentioned the groups were comparable by main characteristics. The dynamic changes of investigated hemostatic parameters are shown in table 4.
Table 4. The concentration of prothrombin pool (PP) and soluble fibrin-monomer complexes SFMC) before the treatment and after 7 days follow-up period_ _
Variable Group A n=26 Group R n=24 p§ p#
Before After p* Before After p*
PP, rel.units/mL 0,163 (0,158-0,175) 0,158 (0,151-0,164) 0,02 0,166 (0,158-0,178) 0,168 (0,157-0,174) 0,94 0,62 0,001
SFMC, ^g/mL 15,5 (10,0-17,0) 18,0 (15,8-21,0) 0,01 19,0 (15,0-22,5) 18,5 (16,0-22,7) 0,57 0,01 0,31
PP - prothrombin pool; SFMC - soluble fibrin monomer complexes; before - at baseline; after -after 7-days follow-up period; * - paired-test (W) in each group as compared to baseline; § - p of intergroup comparison at baseline (unpaired U-test); # - p of intergroup comparison after follow-up period (unpaired U-test)
Before treatment PP concentration did not significantly differ between groups in contrast to SFMC concentration which was higher in group R. The same baseline trend was regarding hs-cTn concentration. However, after treatment, we registered the opposite relationship between the investigated parameters of groups. Thus, while the SFMC's concentration between groups was compatible, the PP concentration in group R was significantly higher than in group A. At the same time there were no significant changes of PP (-0,59 (-2,46-2,90)%) and SFMCs (-0,36 (-19,6-8,6)%) concentration in group R unlike group A in which we noted significant decrease in PP concentration by 4,9% (-4,9( -10,8-1,84)%) and increase in SFMC concentration by 10,8 (2,7-21,3)%.
We have noticed intragroup differences in direction of changes that are presented in Table 5. A percentage of SFMC changes with the upward direction was significantly higher in group A. Meanwhile, no significant difference was noted in group R, though the downward trend of PP concentration in group A was in 65,4% of patients.
Table 5. Peculiarities of coagulation parameters changes among
Variable Group A Group R p
Decrease, n (% of group) Increase, n (% of group) Decrease, n (% of group) Increase, n (% of group)
PP, rel.units/mL 17 (65,4) 9 (34,6) 13 (54,2) 11 (45,8) 0,42
SFMC, ^g/mL 5 (19,2) 21 (80,8) 12 (50,0) 12 (50,0) 0,02
Finally, we have checked correlations between investigated parameters in observed groups. In terms of group A it was found strong negative correlation between PP concentration before treatment and direction of PP changes (r=-0,803, p<0,001), direct correlation of mild strength between PP and SFMC concentrations before treatment (r=0,626, p=0,001) as well as concentrations of PP before treatment and SFMC after (r=0,447, p=0,02). Also, negative relations of mild strength were noticed between PP changes direction and SFMC before treatment (r=-0,530, p=0,005) as well as after (r=-0,655, p<0,001).
In the group R we have noticed direct correlation between PP concentration before and after treatment (r=0,912, p<0,001) as well as SFMC concentration before and after (r=0,746, p<0,001). Though there were no significant relations between PP and SFMC concentrations before and after treatment, we have noted indirect relations between directions of PP and SFMC concentration changes (r=-0,585, p=0,003).
Discussion. The results of our study confirm several statements regarding statins' influence on organism and drug-drug relations, however, with some practical supplement.
Currently, there is no doubt in the short-term positive effects of high-dose statin therapy on the course of ACS. Zhi-Jian Liu et al. reported a significant decrease in high sensitive C reactive protein and malonaldehyde as markers of inflammation and oxidative stress respectively in patients with acute myocardial infarction and successful primary percutaneous coronary intervention received high-dose atorvastatin therapy in comparison with moderate after only 7 days follow-up period [17].
However, as far as we know almost no data is regarding the effects of statins on blood plasma coagulability after a short follow-up period as most investigators have described the data regarding a more prolonged period of statins' treatment. In general, it was mentioned that a decrease in thrombin generation is highly suggestive [18], especially in patients with hypercholesterolemia [19]. Tonu S. et al. registered a significant increase in prothrombin time after 8 weeks of treatment with atorvastatin and rosuvastatin in low doses [20]. Fenton et al. found out that simvastatin downregulated thrombin generation as prothrombin fragments F1+F2 in the blood plasma of type 2 diabetes patients were lowering after the treatment period [21]. On the other hand, it was reported no influence of statin on thrombin generation in patients with ACS [22].
The data regarding statins' influence on fibrinogen concentration as the source of SFMC are not less controversial. However, predominantly it was shown the impaired fibrinogen cleavage, decrease the amount of fibrinopertides after statin treatment, changes of fibrin clot characteristics [12].
In our study, we have registered a significant decrease in PP concentration and an increase in SFMC concentration in patients with progressive unstable angina after 7 days atorvastatin course unlike in patients after the rosuvastatin course no significant changes of both parameters were noted.
At first glance, a decrease in PP concentration is considered to be a good prognostic sign. However, an increase in SFMC concentration is supposed to be a marker of increased risk of thrombotic complications. We presume such condition may be connected with the "exhaustion" of PP after intensified coagulation with the active formation of SFMC. Such a decrease in coagulation potency may be in consequence of rebound thrombin generation after anticoagulant discontinuation [23].
The negative correlation between PP concentration before treatment and direction of PP changes as well as the positive relation between the concentration of PP before and SFMC after treatment come in support of our assumption.
In terms of rosuvastatin, a few peculiarities should be defined. Some pleiotropic effects of statins are supposed to be connected with the nonsterol isoprenoid pathway. It was shown the reduced expression of ubiquinone, dolichol synthesis, and protein prenylation pathway in recombinant yeast strain with human HMGR by atorvastatin whereas rosuvastatin caused diverse effects (expression of BTS1, COQ3, RER2 and downregulation of COQ2, CAT5, SEC59) [14]. Such finding direct to the possibility of intragroup distinctions between accessory effects of statins.
Another point that should be mentioned is drug interactions between clopidogrel as medicine for double antiplatelet therapy and statins. While rosuvastatin is transformed by CYP2C9, clopidogrel and atorvastatin are metabolized by CYP3A4 isoenzyme of cytochrome P450 (CYP) [24]. The latter peculiarity of atorvastatin may cause an increase in major adverse thrombotic events [25]. The observed trend in the rosuvastatin group may be connected with either the above-mentioned facts.
We are inclined to qualify the absence of dynamic in group R after enoxaparin withdrawal as a better trend than a decrease in PP along with an increase in SFMC concentration.
Conclusions.
1. Statins are characterized by different influences on coagulation in patients with UA.
2. The rebound thrombin generation after enoxaparin discontinuation is less marked in UA patients against a background of rosuvastatin treatment in comparison with atorvastatin.
3. Rosuvastatin should be preferable to atorvastatin for patients with unstable angina if there was no previous statin treatment.
Acknowledgments.
We are thankful to the cardiologists and nurses of Kyiv City Clinical Hospital #12.
Declaration of Interest Statement. None
REFERENCES
1. Gupta, K. K., Ali, S., & Sanghera, R. S. (2019). Pharmacological Options in Atherosclerosis: A Review of the Existing Evidence. Cardiology and therapy, 8(1), 5-20. https://doi.org/10.1007/s40119-018-0123-0
2. Collet, A. J., Thiele, H., Barbato, E., Barthélémy, O., Bauersachs, J., Bhatt, D. L., Dendale, P., Dorobantu, M., Edvardsen, T., Folliguet, T., Gale, C. P., Gilard, M., Jobs, A., Siontis, G. C. M. (2020). ESC Scientific Document Group, 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal, 00, 1-79. https://doi.org/10.1093/eurheartj/ehaa575
3. Cholesterol Trearment Trialists' (CTT) Collaboration (2010). Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. The Lancet, 376(9753), 1670-1681. https://doi.org/10.1016/S0140-6736(10)61350-5
4. Gotto, A. M., & Moon, J. E. (2012). Management of cardiovascular risk: the importance of meeting lipid targets. The American journal of cardiology, 110(1 Suppl), 3A-14A. https://doi.org/10.1016/j.amjcard.2012.04.002
5. Toth, P. P., & Banach, M. (2019). Statins: Then and Now. Methodist DeBakey cardiovascular journal, 15(1), 23-31. https://doi.org/10.14797/mdcj-15-1-23
6. Oesterle, A., Laufs, U., & James, K. (2017). Pleiotropic Effects of Statins on the Cardiovascular System. Circulation Research, 120(1), 229-243. https://doi.org/10.1161/CIRCRESAHA.116.308537
7. Diamantis, E., Kyriakos, G., Quiles-Sanchez, L. V., Farmaki, P., & Troupis, T. (2017). The Anti-Inflammatory Effects of Statins on Coronary Artery Disease: An Updated Review of the Literature. Current cardiology reviews, 13(3), 209-216. https://doi.org/10.2174/1573403X13666170426104611
8. Liu, Z. J., Hu, G. P., Fei, M. Y., Yin, Z., Shi, Q. X., & Sun, F. (2018). Effects of Short-term High Dose Atorvastatin on Left Ventricular Remodeling in Patients with First Time Attack of Anterior Acute Myocardial Infarction. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih, 33(2), 84-90. https://doi.org/10.24920/11810
9. Asada, Y., Sato, Y., & Hatakeyama, K. (2020). Pathophysiology of atherothrombosis: Mechanisms of thrombus formation on disrupted atherosclerotic plaques. Pathology International, 70(6), 309-322. https://doi.org/10.1111/pin. 12921
10. Arthamin, M. Z., Parmadi, L., Djatmiko, D. P., & Lawanto, E. R. (2019). Analysis of soluble fibrin monomer as diagnostic marker for acute myocardial infarction and its correlation with cardiac troponin I. Clinical Pathology and Medical Laboratory, 25(3), 279-282. http://dx.doi.org/10.24293/ijcpml.v25i3.1505
11. Weisel, J. W., & Litvinov, R. I. (2013). Mechanisms of fibrin polymerization and clinical implications. Blood, 121(10), 1712-1719. https://doi.org/10.1182/blood-2012-09-306639
12. Undas, A., Brummel-Ziedins, K. E., Mann, K. G. (2014). Anticoagulant effects of statins and their clinical implications. Thrombosis andHaemostasis, 111, 1-9. http://doi.org/10.1160/TH13-08-0720
13. Gue, Y. X., & Gorog, D. A. (2017). Importance of Endogenous Fibrinolysis in Platelet Thrombus Formation. International journal of molecular sciences, 18(9), 1850. https://doi.org/10.3390/ijms18091850
14. Maciejak, A., Leszczynska, A., & Warchol, I. (2013). The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase. BMC Biotechnol 13, 68. https://doi.org/10.1186/1472-6750-13-68
15. Raksha, N., Burlova-Vasylieva, M., Torgalo, E., & Savchuk, O. (2014). The appearance of molecules of Prothrombin origin in blood upon development of atherothrombotic and cardioembolic ischemic stroke. Bulletin of Taras Shevchenko National University of Kyiv Series Biology, 68(3), 57-60. 10.17721/1728_2748.2014.68.57-60 '
16. Karlson, B. W., Palmer, M. K., Nicholls, S. J., Lundman, P., & Barter, P. J. (2016). Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis. European journal of preventive cardiology, 23(7), 744-747. https://doi.org/10.1177/2047487315598710
17. Liu, Z. J., Hu, G. P., Fei, M. Y., Yin, Z., Shi, Q. X., & Sun, F. (2018). Effects of Short-term High Dose Atorvastatin on Left Ventricular Remodeling in Patients with First Time Attack of Anterior Acute Myocardial Infarction. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih, 33(2), 84-90. https://doi.org/10.24920/11810
18. Undas, A., Brummel-Ziedins, K. E., & Mann, K. (2005). Statins and Blood Coagulation. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(2), 287-294. https://doi.org/10.1161/01.ATV.0000151647.14923.ec
19. Undas, A., Brummel, K. E., Musial, J., Mann, K. G., & Szczeklik, A. (2001). Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation, 103(18), 2248-2253. https://doi.org/10.1161/01.cir.103.18.2248
20. G.Tonu, S., Dewan, J., Hasnat, F., & Jahan, B. (2018). Comparison Between Atorvastatin and Rosuvastatin on Anti- Thrombogenic Effect in Patients with Hyperlipidemia. Journal of Enam Medical College, 8(3), 153-158. https://doi.org/10.3329/jemc.v8i3.38365
21. Fenton II, J. W., Brezniak, F. A., Ofosu, F. A., Shen, G. X., Jacobson, J. R., & Garcia, J. G. N. (2005). Statins and Thrombin. Current Drug Targets - Cardiovascular & Hematological Disorders, 5(2), 115-120. https://doi.org/10.2174/1568006043586189
22. Olivotti, L., Ghigliotti, G., Spallarossa, P., Leslie, S., Rossettin, P., Barsotti, A., & Brunelli, C. (2002). High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes. Blood Coagul Fibrinolysis, 13(4), 315-322.
23. Bijsterveld, Nick. R., Moons, A. H., Meijers, J. C. M., Tijssen, J. G. P., Buller, H. R., Levi, M., & Peters, R. J. (2002). Rebound thrombin generation after heparin therapy in unstable angina: A randomized comparison between unfractionated and low-molecular-weight heparin. Journal of the American College of Cardiology, 39(5), 811-817. https://doi.org/10.1016/S0735-1097(01)01825-3
24. Bates, E.R., Lau, W.C., & Angiolillo, D.J. (2011). Clopidogrel-drug interactions. Journal of American College of Cardiology, 57(11), 1251-1263. https://doi.org/10.1016/jjacc.2010.11.024 '
25. Brophy, J.M., Babapulle, M.N., Costa, V., & Rinfret, S. (2006). A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. American Heart Journal, 152(2), 263-269. https://doi.org/10.1016/j.ahj.2005.08.023.
