Evaluation of D-dimer levels in patients with prosthetic valve thrombosis: Relationship with thrombus burden and cerebrovascular events

Evaluation of D-dimer levels in patients with prosthetic valve

thrombosis: relationship with thrombus burden and

cerebrovascular events

Sinan Cers¸it

, Sabahattin Gu¨ndu¨z

, Emrah Bayam

, Ahmet Gu¨ner

,

Semih Kalkan

, Macit Kalc¸ık

, Su¨leyman Karakoyun

, Mustafa Ozan Gu¨rsoy

,

Mahmut Yesin

, O

¨ zkan Candan

and Mehmet O

¨ zkan

Plasma D-dimer level is an indicator of thrombosis and endogenous fibrinolytic activity. We investigated the association between the D-dimer levels and thrombus burden and cerebrovascular events in patients with obstructive prosthetic valve thrombosis (PVT). This retrospective study included 47 patients with obstructive left-sided PVT and 32 controls in whom PVT was excluded with comprehensive transthoracic and transesophageal echocardiography (TEE). The patient group included 11 aortic, 27 mitral, and 9 aortic and mitral valve PVT patients and the control group included 2 aortic, 25 mitral, and 5 aortic and mitral valve patients. Laboratory analysis including plasma D-dimer levels was performed at the time of admission in all patients. The baseline

characteristics were similar between the two groups. The plasma D-dimer levels were significantly higher in patients with obstructive PVT compared with controls [680 (110 – 3590) vs. 310 (80 – 380)mg/l; P < 0.001]. By multivariate logistic regression analysis high D-dimer level, low-INR value on admission, high NYHA functional class and recent history of cerebrovascular accident (CVA), and transient ischemic attack (TIA) were the independent predictors of obstructive PVT. A plasma D-dimer level of greater than 365mg/l predicted the presence of PVT with a sensitivity of 81% and a specificity

of 69% (AUCU 0.781, P < 0.001). Plasma D-dimer levels were significantly higher in patients with a recent history of CVA/TIA [2140 (470 – 2980) vs. 590 (380 – 830)mg/l; P U 0.021]. In addition to the so-called indicators of PVT including subtherapeutic anticoagulation, increased D-Dimer levels may strengthen the suspicion of PVT. Moreover, higher plasma D-dimer levels were associated with higher thrombus burden and higher prevalence of recent CVA/TIA.Blood Coagul Fibrinolysis 29:294 – 299 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.

Blood Coagulation and Fibrinolysis2018, 29:294–299

Keywords: cerebrovascular accident, D-dimer, prosthetic heart valve, thrombosis, transesophageal echocardiography, transient ischemic attack

a

Department of Cardiology, Kos¸uyolu Kartal Heart Training and Research Hospital, I˙stanbul andbSchool of Health Sciences, University of Ardahan, Ardahan, Turkey

Correspondence to Sinan Cers¸it, MD, Atalar Mah., Seyrantepe Sok., No: 3 Kartal, I˙stanbul, Turkey

Tel: +90 5555202385; fax: +90 2164596321; e-mail: sinancersit@hotmail.com Received18 December 2017 Revised 12 February 2018

Accepted22 February 2018

Introduction

Prosthetic valve thrombosis (PVT) is a rare complica-tion associated with high morbidity and mortality [1]. Typically, PVT affects 0.5 – 0.8% of left-sided pros-thetic valves [2,3]. Inadequate anticoagulation, the early postoperative period, atrial fibrillation, presence of multiple prosthetic valves, ventricular dysfunction, and pregnancy are the major risk factors for the development of PVT [4]. Patients with PVT may present with dyspnea, decreased exercise capacity, palpitation, thromboembolism including cerebrovas-cular accident (CVA), and transient ischemic attack (TIA). Early detection and diagnosis may often be limited by a progressive or insidious course. There-fore, comprehensive transthoracic (TTE) and transe-sophageal echocardiography (TEE) are currently recognized as the most accurate diagnostic methods in patients with clinical signs and symptoms of PVT [4,5].

D-dimer, a degradation product of cross-linked fibrin, has been demonstrated to be a useful marker of endogenous coagulation activation and thrombosis [6,7]. High plasma D-dimer levels have been shown in patients with periph-eral vascular disease, venous thromboembolism, and acute ischemic stroke [8–11]. Increased D-dimer levels may reflect ongoing thrombus formation within cerebral vessels and may stimulate the inflammatory process. Activated inflammation and activated coagulation, in concert with each other, may contribute to the develop-ment of PVT-related CVA/ TIA [12]. In the current study, we sought to evaluate the relationship between D-dimer levels and obstructive mechanical prosthetic PVT and prevalence of recent CVA/TIA.

Methods

Study population and design

Between January 2013 and December 2016, 47 consecu-tive symptomatic patients with obstrucconsecu-tive PVT (27 with

mitral, 11 with aortic, and 9 with both mitral and aortic prostheses) and 32 (25 with mitral, 2 with aortic, and 5 with both mitral and aortic prostheses) age-matched and sex-matched patients with normally functioning prosthe-ses without thrombus who had undergone comprehen-sive TEE examinations for several indications including recent inadequate anticoagulation, suspected parapros-thetic regurgitation, pannus formation, or patient –pros-thesis mismatch (PPM) were included in this single-center retrospective study. Patients with nonobstructive asymptomatic PVT, left ventricular ejection fraction (LVEF) less than 0.30, left atrial and left atrial appendage thrombi, severe spontaneous echocontrast, unavailable plasma D-dimer test results and asymptomatic status on admission, presence of additional right-sided valve pros-thesis, coexisting paravalvular regurgitation, pannus, a PPM, infection, pregnancy, liver or renal diseases, malig-nancy, recent surgery, chronic inflammatory disease, and deep venous thrombosis were excluded. As presence of asymptomatic nonobstructive thrombi are mostly an inci-dental finding during TEE examination of the patients with mechanical valves, the timing of thrombus forma-tion can not be determined in most cases. The D-dimer levels assessed at a random time interval, may not confi-dentially reflect the true association with thrombus for-mation. Hence patients with asymptomatic and nonobstructive thrombi were excluded from the study. Written informed consent was obtained from the parti-cipants and the study was approved by the Local Ethics Board.

All patients were evaluated using TTE and TEE. Inef-fective anticoagulation with vitamin K antagonist was defined as suboptimal international normalized ratio (INR) levels (<2) which persisted for at least 3 months before the start of symptoms. The patient demographics, BMI, functional status, symptoms, elapsed time since valve surgery (ETSVS), prosthetic valve size and brands, anticoagulation status, heart rhythm, history of CVA/TIA, history of diabetes or hypertension, laboratory parameters including plasma D-dimer and INR, LVEF, left atrial diameter, transprosthetic gradients, valve and thrombus areas were entered into a database. Venous blood samples were drawn from each patient at the time of admission for analyzing laboratory parameters including plasma D-dimer and INR. Plasma D-D-dimer levels were determined by quantitative D-dimer, micro-latex immunoassay with AMAX Auto D-dimer (Trinity Biotech, Bray, Ireland) on an AMAX 200 coagulation analyser (Trinity Biotech). The reference range for D-dimer levels provided by the manufacturer were 0–540 mg/l.

Echocardiographic methods

Following TTE, two-dimensional (2D) and real-time three-dimensional TEE images were performed in all patients. A one-lead electrocardiogram was displayed on the monitor. TTE and TEE measurements including

LVEF, left atrial diameter, transmitral maximum and mean gradients, and effective orifice area were obtained according to current guidelines [1,13]. TEE was per-formed by using an X7-2t transducer on an iE33 ultra-sound machine (Philips Medical Systems, Andover, Massachusetts, USA).

The presence of obstruction was defined on the basis of Doppler echocardiographic measurements (peak veloc-ity, mean gradient, effective orifice area, velocity ratio, and acceleration time as appropriate). The cutoff values for these Doppler parameters were defined based on the latest recommendations [1,13]. The largest thrombus area was measured by 2D TEE between 08 and 1808 angles where there was less interference with acoustic shadowing. In the presence of a single mass, the throm-bus was traced, otherwise each thromthrom-bus was traced separately and the thrombus areas were finally summed up.

Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 19.0. (IBM Corp., Armonk, New York, USA). The data distribution was tested with the Shapiro–Wilk test. Continuous variables with approximately normal distribution were reported as the conventional mean 2SD for Gaussian population distributions. Those without normal distribution were reported as medians with interquartile range. Categorical variables were expressed as frequency and percentages (%). Continuous variables were compared using Stu-dent’s t-test or the Mann–Whitney U test as appropriate. Categorical variables were compared using the chi-square test. A logistic regression analysis was performed as mean with 95% confidence interval in order to identify any independent associates of obstructive PVT. A receiver operating characteristic (ROC) curve analysis was per-formed to evaluate the sensitivity and specificity of plasma D-dimer for detecting obstructive PVT. Correla-tional analyses were performed using Pearson and Spear-men’s correlation tests as appropriate. P value less than 0.05 was considered as statistically significant.

Results

The comparison of baseline characteristics between the groups is indicated in Table 1. Age, sex, BMI, prevalence of hypertension, diabetes mellitus and atrial fibrillation, ETSVS and prosthetic valve localizations were similar between the groups. Poorer functional capacity (49 vs. 10%, P < 0.001) and increased prevalence of recent his-tory of CVA/TIA (23 vs. 3%, P¼ 0.014) were observed in obstructive PVT group as compared with controls. INR levels on admission were lower and the prevalence of inadequate anticoagulation status (70 vs. 16%, P < 0.001) were significantly higher in patients with PVT than controls (Tables 1 and 2).

LVEF and left atrial diameters were similar between PVT group and controls. The patients with obstructive PVT had lower mitral valve area [1.2 (1–1.5) vs. 2.2 (2.1– 2.5) cm2, P < 0.001] and higher transmitral mean gradi-ents [13 (10–21) vs. 6 (5–7) mmHg, P < 0.001] when compared with controls. The mean transaortic gradients were also higher in PVT group as compared with controls [54 (40–58) vs. 22 (20–25) mmHg, P < 0.001] whereas the mean aortic valve area was significantly lower in PVT group [0.7 (0.5–0.8) vs. 1.3 (1.3–1.4) cm2, P < 0.001] (Table 2).

Almost all laboratory parameters were similar between PVT group and controls except for D-dimer levels and INR value on admission. The median plasma D-dimer level [680 (110–3590) vs. 310 (80–380) mg/l, P < 0.001] was significantly higher in patients with obstructive PVT when compared with controls (Table 3 and Fig. 1a). The parameters, which were significantly different between PVT patients and controls in univariate analyses were taken into multiple logistic regression analysis. High NYHA functional class, recent history of CVA/ TIA, high plasma D-dimer level, and low INR value on admission were identified as independent predictors

of PVT [OR 2.481; 95% CI 0.053 0.482; P¼ 0.015; OR 2.414; 95% CI 0.055–0.578; P¼ 0.018; OR 2.121; 95% CI 0.008–0.257; P¼ 0.037 and OR (2.080); 95% CI 0.248 to 0.005; P ¼ 0.041, respectively] (Table 4). By ROC curve analysis, a plasma D-dimer level of at least 365 mg/l predicted the presence of PVT with a sensitivity of 81%, a specificity of 69%, a positive predictive value (PPV) of 79.2%, and a negative predictive value (NPV) of 71% (AUC¼ 0.781, P < 0.001, 95% CI 0.678–0.884; Fig. 2). Baseline characteristics and D-dimer levels were com-pared between the patients with and without a recent history of CVA/TIA. Plasma D-dimer levels were signifi-cantly higher in patients with a recent history of CVA/ TIA [2140 (470–2980) vs. 590 (380–830) mg/l; P¼ 0.021] (Fig. 1b). The patients with a recent history of CVA/TIA had significantly higher thrombus area as compared with patients without CVA/TIA [2.2 (1.4–2.4) vs. 1.2 (1.0–1.6) cm2; P¼ 0.006] (Fig. 3a).

There was a moderate positive correlation between plasma D-dimer levels and the thrombus area in patients with PVT (r¼ 0.427; P ¼ 0.003; Fig. 4). Patients were

Table 1 Baseline clinical characteristics in patients with and without obstructive prosthetic valve thrombosis

PVT (n¼ 47) Controls (n¼ 32) P value Age (years) 49 13 54 12 0.072 Sex (male/female), n (%) 13 (28)/34 (72) 15 (47)/17 (53) 0.080 BMI, (kg/m2_{) 27.8 3.3 27.4 3.6 0.556} Hypertension, n (%) 19 (40) 15 (47) 0.570 Diabetes mellitus, n (%) 4 (9) 5 (15) 0.329 Atrial fibrillation, n (%) 15 (32) 14 (43) 0.284 Subtherapeutic INR status, n (%) 33 (70) 5 (16) <0.001 NYHA functional class I and II/III and IV, n (%) 24/23 (51/49) 29/3 (90/10) <0.001 Recent history of CVA/TIA, n (%) 11 (23) 1 (3) 0.014

ETSVS (months) 57 (4–276) 55 (10–360) 0.873

Prosthetic valve locations

Mitral, n (%) 27 (58) 25 (78)

Aortic, n (%) 11 (23) 2 (7) 0.092

Aortic and mitral, n (%) 9 (19) 5(15)

Values are presented as means SDs and medians with interquartile range in parentheses. PVT, prosthetic valve thrombosis; CVA, cerebrovascular accident; ETSVS, elapsed time since valve surgery; INR, international normalized ratio; NYHA; New York Heart Association; TIA, transient ischemic attack.

Table 2 Baseline echocardiographic characteristics in patients with and without obstructive prosthetic valve thrombosis

PVT (n¼ 47) Controls (n¼ 32) P value LA diameter (cm) 43 (39–47) 41 (39–49) 0.865 LV EF, (%) 53 (45–57) 51 (45–53) 0.450 PHT-derived prosthetic valve area (cm2₎

Aortic 0.7 (0.5–0.8) 1.3 (1.3–1.4) <0.001 Mitral 1.2 (0.9–1.5) 2.2 (2.0–2.5) <0.001 Transprosthetic mean gradient (mmHg)

Aortic 54 (40–58) 22(20–24.5) <0.001 Mitral 13 (10–21.2) 6 (5–7) <0.001 Thrombus area (cm2) 1.4 (1.2–1.8) – –

Values are presented as medians with interquartile range in parentheses. PVT, prosthetic valve thrombosis; LA, left atrium; LV EF, left ventricular ejection fraction; PHT, pressure half-time.

Table 3 The baseline laboratory characteristics of study population

PVT (n¼ 47) Controls (n¼ 32) P value WBC (103_{/ml) 8.6 (7.0–9.2) 6.6 (6.8–11.9) 0.667} Hemoglobin (g/dl) 12.1 1.7 11.6 1.8 0.263 Platelet (103 /ml) 233 (194–284) 246 (182–253) 0.273 Glucose (mg/dl) 101 (89–113) 100 (89–129) 0.671 Urea (mg/dl) 33 (26 -39) 33 (26–45) 0.689 Creatinine (mg/dl) 0.7 (0.5–0.8) 0.7 (0.6–1.2) 0.236 AST (U/l) 35 (23–52) 28 (24–38) 0.250 ALT (U/l) 21 (16–30) 23 (18–31) 0.671 Sodium (mEq/l) 135.9 4.4 136.2 3.3 0.742 Potassium (mEq/l) 4.2 (4.0–4.5) 4.1 (3.9–4.2) 0.244 ESR (mm/h) 24 (19–32) 28 (19–51) 0.151 CRP (mg/dl) 0.6 (0.6–2.3) 1.6 (0.5–6.8) 0.124 INR on admission 1.9 0.8 2.5 0.6 0.001 D-dimer (mg/l) 680 (110- 3590) 310 (80- 380) <0.001 Values are presented as means SDs and medians with interquartile range in parentheses. PVT, prosthetic valve thrombosis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; INR, international normalized ratio; WBC, white blood cell.

divided into two groups according to median D-dimer levels in PVT group [Group I (n¼ 25): D-dimer level <680 mg/l and Group II (n¼ 22): D-dimer level 680 mg/ l]. The thrombus area was significantly higher in Group II than Group I [1.55 (1.15–2.22) vs. 1.20 (1.20–1.55); P¼ 0.046] (Fig. 3b).

Discussion

There are two main findings of this study. First, plasma D-dimer levels are significantly elevated in patients with left-sided obstructive PVT compared with those having normally functioning prostheses. However, despite being statistically significant, a cut-off D-dimer of less than 365 mg/l is not a suitable indicator for excluding those without PVT because of relatively moderate NPV as it is quite below the upper limit of the reference range. Secondly, a plasma D-dimer level above the upper nor-mal limit, low INR value on admission, high NYHA functional class and recent history of CVA/TIA were also shown to be predictors of obstructive PVT in multiple variable analysis. Moreover, we for the first time, dem-onstrated that plasma D-dimer levels above the upper limit of reference are associated with increased thrombus burden and prevalence of recent CVA/TIA in patients with obstructive PVT.

PVT is a life-threatening condition. Comprehensive TEE is currently recognized as the most accurate method

of detecting both obstructive and nonobstructive PVT [14–17]. However, TEE may not be available in certain centers or may not be rapidly performed in all symptom-atic patients whenever such patients are admitted in outpatient clinic settings. In addition, TEE may not be tolerated by all patients with obstructive symptoms, and TTE may sometimes be insufficient in differentiat-ing thrombus, particularly from pannus, vegetations, or other causes of prosthetic valve dysfunction [18]. There-fore, clinicians still need rapid, relatively noninvasive, and easily applicable methods for identifying PVT. Fibrinogen levels, anticardiolipin antibodies, antitissue plasminogen activator antibodies, and AB0 blood groups may play a role in the pathogenesis of PVT [19–22]. Elevated plasma D-dimer levels suggest the presence of hypercoagulability or pro-thrombotic state. Thus D-dimer has been taken as a potential noninvasive marker

Fig. 1

(a) The median plasma D-dimer level in patients with obstructive prosthetic valve thrombosis compared with controls. (b) Plasma D-dimer levels in patients with and without a recent history of cerebrovascular accident/transient ischemic atttack.

Table 4 Multivariate regression analysis showing independent predictors of obstructive PVT

OR 95% CI P value D-dimer level 2.121 0.008–0.257 0.037 INR level 2.080 0.248 to 0.005 0.041 High NYHA functional class 2.481 0.053–0.482 0.015 History of CVA/TIA 2.414 0.055–0.578 0.018 CI, confidence interval; CVA, cerebrovascular accident; INR, international normal-ized ratio; NYHA, New York Heart Association; OR, odds ratio; PVT, prosthetic valve thrombosis; TIA, transient ischemic attack.

Fig. 2

Receiver operator characteristic curve for D-dimer level to predict obstructive prosthetic valve thrombosis.

of thrombogenesis and thromboembolism [23]. Plasma D-dimer levels have been found to be predictive of left atrial thrombi in patients with mitral stenosis who are undergoing mitral valve surgery [24,25]. Giansante et al. [26] have demonstrated a negative correlation between plasma D-dimer levels and intensity of oral anticoagula-tion in patients with prosthetic heart valves. Nazli et al. [27] suggested increased plasma D-dimer levels can be clinically helpful in predicting the presence of PVT. Likewise, in current study, the mean D-dimer levels were higher in the obstructive PVT group than controls. However, in the study authored by Nazli et al., the diagnostic performance of the calculated cut-off of 445 mg/l was higher above the upper normal limit

(195 mg/l) of the D-dimer test used in that study. In contrast, in the current study, the calculated cut-off of 365 mg/l was below the upper reference limit (540 mg/l). This may explain the differences between the diagnostic performance of D-dimer tests in the two studies. The plasma D-dimer level above the upper normal limit, low INR value on admission, high NYHA functional class and recent history of CVA/TIA were associated with increased risk of obstructive PVT. D-dimer levels were also increased with thrombus size on mechanical pros-thetic valve. However, a relatively moderate PPV may limit its use to predict PVT. Moreover, in clinical set-tings, such as deep venous thrombosis, pulmonary embo-lism, and acute aortic dissection, D-dimer has an excellent NPV [28–30]. In our study, although a cut-off D-dimer of <365 mg/l is found to be as a significant indicator for excluding PVT, it does not necessarily exclude PVT as it has a relatively moderate NPV. As the D-dimer levels were significantly elevated in obstruc-tive PVT patients, its measurement in patients with suspected PVT may serve as a beneficial laboratory marker. However, one should take into account its lim-ited sensitivity and specificity. Furthermore, increased plasma D-dimer levels are not by themselves diagnostic of PVT but may alert the clinician to refer the patient for more detailed examination, such as TEE.

Several studies showed that patients with stroke had acutely increased plasma dimer levels. Plasma D-dimer levels, however, are neither sensitive nor specific enough to be utilized in stroke diagnostics and cannot replace either clinical or radiological evaluation [31–33]. Park et al. [31] demonstrated positive correlation between levels of D-dimer and infarction volume in patients with stroke. Increased D-dimer is an indicator of systemic hypercoagulability and may reflect the presence of coa-gulopathy or may activate inflammation and ongoing thrombus formation systemically or within cerebral

Fig. 3

(a) Thrombus area in patients with and without cerebrovascular accident/transient ischemic atttack. (b) Thrombus area at prosthetic valve thrombosis with plasma D-dimer level less than 680 mg/l and at least 680 mg/l.

Fig. 4

The correlation between the plasma D-dimer levels and the thrombus area in patients with prosthetic valve thrombosis.

vessels [32,33]. On the basis of previous literature, no study has addressed the association between plasma D-dimer levels and thrombus size and prevalence of recent CVA/TIA in patients with obstructive PVT. Increased plasma D-dimer levels may be a sign of high thrombus burden and may pose high risk for CVA/TIA in PVT patients.

This study had several limitations. The main limitation of the study was that PVT is a multifactorial disease, and that the genetic factors, which predisposed to thrombosis were not investigated. Secondly, it was a single-center study with a limited number of patients. Thirdly, our study includes a selected patient population with left-sided mechanical prostheses. Our results may not be extra-polated to those with bioprosthetic valves or right-sided valve prostheses. Moreover, patients with asymptomatic nonobstructive PVT were not included in this study. In conclusion, in addition to the so-called indicators of PVT including inadequate anticoagulation and other factors, an elevation in plasma D-dimer level may strengthen the suspicion of PVT and may be also sign of PVT-related CVA/TIA. A low plasma D-dimer level has a moderate predictive ability in excluding PVT and can be used as a complementary marker rather than replacing a TEE and cranial examination.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

1 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP3rd, Fleisher LA, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017; 135:e1159–e1195. 2 O¨ zkan M, Gu¨ndu¨z S, Gu¨rsoy OM, Karakoyun S, Astarcıog˘lu MA, Kalc¸ık M,

et al. Ultraslow thrombolytic therapy: a novel strategy in the management of PROsthetic MEchanical valve Thrombosis and the prEdictors of outcomE: the Ultra-slow PROMETEE trial. Am Heart J 2015; 170:409–418. 3 Ozkan M, Cakal B, Karakoyun S, Gu¨rsoy OM, Cevik C, Kalc¸ik M, et al.

Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis in pregnancy with low-dose, slow infusion of tissue-type plasminogen activator. Circulation 2013; 128:532–540.

4 Gu¨rsoy MO, Kalc¸ık M, Yesin M, Karakoyun S, Bayam E, Gu¨ndu¨z S, et al. A global perspective on mechanical prosthetic heart valve thrombosis: diagnostic and therapeutic challenges. Anatol J Cardiol 2016; 16:980–989. 5 O¨ zkan M, Gu¨rsoy OM, Atasoy B, Uslu Z. Management of acute ischemic stroke occurred during thrombolytic treatment of a patient with prosthetic mitral valve thrombosis: continuing thrombolysis on top of thrombolysis. Anatol J Cardiol 2012; 12:689 –690.

6 Linkins LA, Takach Lapner S. Review of D-dimer testing: good, bad, and ugly. Int J Lab Hematol 2017; 39 (Suppl 1):98–103.

7 Riley RS, Gilbert AR, Dalton JB, Pai S, McPherson RA. Widely used types and clinical applications of D-dimer assay. Lab Med 2016; 47:90–102. 8 Gardiner C, Pennaneac’h C, Walford C, Machin SJ, Mackie IJ. An

evaluation of rapid D-dimer assays for the exclusion of deep vein thrombosis. Br J Haematol 2005; 128:842–848.

9 Hsu PJ, Chen CH, Yeh SJ, Tsai LK, Tang SC, Jeng JS. High plasma D-dimer indicates unfavorable outcome of acute ischemic stroke patients receiving intravenous thrombolysis. Cerebrovasc Dis 2016; 42:117–121. 10 Kleinegris MC, ten Cate H, ten Cate-Hoek AJ. D-dimer as a marker for

cardiovascular and arterialthrombotic eventsinpatientswith peripheralarterial disease. A systematic review. Thromb Haemost 2013; 110:233–243.

11 Van Es N, Van der Hulle T, Bu¨ller HR, Klok FA, Huisman MV, Galipienzo J, et al. Is stand-alone D-dimer testing safe to rule out acute pulmonary embolism? J Thromb Haemost 2017; 15:323–328.

12 Ageno W, Finazzi S, Steidl L, Biotti MG, Mera V, Melzi D’Eril G, Venco A. Plasma measurement of D -dimer levels for the early diagnosis of ischemic stroke subtypes. Arch Intern Med 2002; 162:2589–2593.

13 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L‘. Recommendations for cardiac chamber quantification by

echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 28:1.e14–39.e14. 14 Ozkan M, Gu¨ndu¨z S, Biteker M, Astarcioglu MA, C¸ evik C, Kaynak E, et al.

Comparison of different TEE-guided thrombolytic regimens for prosthetIc valve thrombosis: the TROIA trial. JACC Cardiovasc Imaging 2013; 6:206–216. 15 Ozkan M, Gu¨rsoy OM, Astarcıog˘lu MA, Gu¨ndu¨z S, Cakal B, Karakoyun S,

et al. Real-time three-dimensional transesophageal echocardiography in the assessment of mechanical prosthetic mitral valve ring thrombosis. Am J Cardiol 2013; 112:977–983.

16 Ozkan M, Kaymaz C, Kirma C, So¨nmez K, Ozdemir N, Balkanay M, et al. Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: a study using serial transesophageal echocardiography. J Am Coll Cardiol 2000; 35:1881–1889.

17 Gu¨rsoy OM, Karakoyun S, Kalc¸ik M, Go¨kdeniz T, Yesin M, Gu¨ndu¨z S, et al. Usefulness of novel hematologic inflammatory parameters to predict prosthetic mitral valve thrombosis. Am J Cardiol 2014; 113:860–864. 18 Kalc¸ık M, Gu¨rsoy MO, Karakoyun S, Yesin M, Astarcıog˘lu MA, O¨ zkan M.

Potential inherited causes of recurrent prosthetic mitral valve thrombosis in a pregnant patient suffering from recurrent miscarriage. Korean Circ J 2014; 44:268–270.

19 Aykan AC, Go¨kdeniz T, Gu¨ndu¨z S, Astarcıog˘lu MA, Gu¨rsoy OM, Ertu¨rk E, et al. Value of serum fibrinogen levels in the assessment of mechanical prosthetic valve thrombosis. J Heart Valve Dis 2014; 23:222–227. 20 Aykan AC¸ , Go¨kdeniz T, Kalc¸ık M, Astarcıog˘lu MA, Gu¨ndu¨z S, Karakoyun S,

et al. Role of anticardiolipin antibodies in the pathogenesis of prosthetic valve thrombosis: an observational study. Herz 2015; 40:528–533. 21 O¨ zkan M, Kalc¸ık M, Gu¨rsoy MO, O¨cal L, Griffini S, Karakoyun S, et al.

Assessment of anti-tissue type plasminogen activator antibodies in patients with prosthetic heart valve thrombosis: the ATA Trial. J Cardiovasc Pharmacol Ther 2016; 21:372–380.

22 Astarcıog˘lu MA, Kalc¸ık M, Yesin M, Gu¨rsoy MO, S¸en T, Karakoyun S, et al. AB0 blood types: impact on development of prosthetic mechanical valve thrombosis. Anatol J Cardiol 2016; 16:820–823.

23 Geersing GJ, Erkens PM, Lucassen WA, Buller HR, Cate HT, Hoes AW, et al. Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. BMJ 2012; 345:e6564.

24 Wan H, Wu S, Yang Y, Zhu J, Zhang A, Liang Y. Plasma fibrin D-dimer and the risk of left atrial thrombus: a systematic review and meta-analysis. PLoS One 2017; 12:e0172272.

25 Kurakula N, Durgaprasad R, Velam V, Akula VS, Kasala L, Muvva KV. Predictive value of D-dimer levels and tissue Doppler mitral annular systolic velocity for detection of left atrial appendage thrombus in patients with mitral stenosis in sinus rhythm. Echocardiography 2016; 33:264–275. 26 Giansante C, Fiotti N, Calabrese S, La Verde R, Pandullo C, Scardi S, et al.

D-dimer and anticoagulation in patients with mechanical prosthetic heart valves. A 2-year follow-up. Arterioscler Thromb Vasc Biol 1997; 17:1320–1324. 27 Nazli C, Kinay O, Tunc B, Ergene O, Gedikli O, Ayata A, et al. Diagnostic

value of D-dimer and antithrombin-III levels in predicting prosthetic heart valve thrombosis. Tex Heart Inst J 2003; 30:268–279.

28 Huang B, Yang Y, Lu H, Zhao Z, Zhang S, Hui R, et al. Impact of d-dimer levels on admission on inhospital and long-termoutcome in patients with type A acute aortic dissection. Am J Cardiol 2015; 115:1595–1600. 29 Eggebrecht H, Naber CK, Bruch C, Kroger K, von Birgelen C, Schmermund

A, et al. Value of plasma fibrin D-dimers for detection of acute aortic dissection. J Am Coll Cardiol 2014; 44:804 –809.

30 Bates SM, Takach Lapner S, Douketis JD, Kearon C, Julian J, Parpia S, et al. Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study. J Thromb Haemost 2016; 14:504–509.

31 Park YW, Koh EJ, Choi HY. Correlation between serum D-dimer level and volume in acute ischemic stroke. J Korean Neurosurg Soc 2011; 50:89–94. 32 Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ. Hemostatic function

and progressing ischemic stroke: D-dimer predicts early clinical progression. Stroke 2004; 35:1421–1425.

33 Haapaniemi E, Tatlisumak T. Is D-dimer helpful in evaluating stroke patients? A systematic review. Acta Neurol Scand 2009; 119:141–150.