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Impaired fibrinolysis in degenerative mitral and aortic valve stenosis

Impaired fibrinolysis in degenerative mitral and aortic valve stenosis Valvular heart disease is associated with an increased thromboembolic risk. Impaired fibrinolysis was reported in severe aortic stenosis (AS). Little is known about fibrinolysis in mitral stenosis (MS). We sought to compare fibrinolysis impairment in AS and MS. We studied 121 individuals scheduled for elective aortic valve (AV) or mitral valve (MV) surgery for AS (n = 76) or MS (n = 45), in order to compare fibrinolysis impairment. Fibrinolytic capacity was assessed by determination of clot lysis time (t ) and fibrinolysis inhibitors, including plasma plasminogen activator inhibitor-1 (PAI-1) antigen (PAI-1:Ag) 50% and activity, thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity. Prolonged t (+ 29%), elevated TAFI 50% activity (+ 12%), TAFI:Ag (+ 21%), and PAI-1:Ag (+ 84%) were observed in patients with MS, compared with those with AS. t Correlated with mean and maximal MV gradients (r = 0.43, p < 0.0001 and r = 0.39, p < 0.0001, respectively), but 50% not with AV gradients. Mean and maximal MV gradients correlated with TAFI activity and PAI:Ag. Patients with perma- nent atrial fibrillation (AF; 35 with MS and 5 with AS) had longer t (by 22%, p = 0.0002) and higher PAI-1:Ag (by 74%, 50% p < 0.0001) than the remainder. In the whole group, postoperative drainage volumes correlated inversely with PAI-1:Ag (r = − 0.22, p = 0.02). MS is associated with more pronounced impairment of global fibrinolytic capacity than AS at the stage of surgical intervention, which is in part driven by AF. Our findings suggest that hypofibrinolysis might be implicated in the progression of MS and its thromboembolic complications. Keywords Fibrinolysis · Aortic stenosis · Mitral stenosis · TAFI · PAI-1 · Fibrin · Cardiac surgery Highlights Introduction Valvular heart disease (VHD) remains a key public health Valvular heart disease is associated with increased problem worldwide. Degenerative aortic stenosis (AS) is thromboembolic risk common in developed countries, and its prevalence increases Degenerative mitral stenosis is associated with more pro- with age [1]. The mechanisms involved in the development nounced impairment of global fibrinolytic capacity than of AS resemble the ones involved in the development of aortic stenosis at the stage of surgical intervention coronary artery atherosclerosis [2]. Mitral stenosis (MS), Atrial fibrillation contributes to fibrinolysis impairment on the other hand, is related to the structural abnormality of in mitral stenosis the mitral valve (MV) apparatus, and can be a distant sequel The role of fibrinolysis in pathology and progression of of rheumatic fever, or may result from severe non-rheumatic valvular disorders and their thromboembolic complica- degenerative mitral annular calcification [3 ]. Mitral annu- tions needs to be investigated lar calcification is present in up to 10% of elderly patients, and MS develops in 1–2% of this group [3, 4]. It has been shown that atherosclerotic risk factors are associated with * Piotr Mazur mitral annular calcification leading to MS [5 ]. Based on the [email protected] 2015 Society of Thoracic Surgeons Adult Cardiac Surgery Institute of Cardiology, Jagiellonian University Medical Database Report, isolated aortic valve replacement (AVR) College, 80 Pradnicka St., 31-202 Krakow, Poland was performed in 21,921 patients, while isolated mitral valve The John Paul II Hospital, Krakow, Poland replacement (MVR) in 5180 cases in United States alone [6]. KCRI, Krakow, Poland Vol.:(0123456789) 1 3 194 P. Mazur et al. Blood coagulation leads to thrombin-mediated conver- degenerative AS or MS. All patients were assessed preopera- sion of fibrinogen to fibrin. Fibrin clots composed of tightly tively by a local ‘heart team’, and the surgery was conducted packed thin fibers with small pores are relatively resistant according to the ‘heart team’ indication. to lysis [7] and such prothrombotic clot phenotype has been The exclusion criteria were: rheumatic etiology of VHD shown in multiple disease states, such as myocardial infarc- (to exclude the confounding effect of inflammation), ongo- tion (MI) [8] or ischemic stroke [9]. Although the research ing infective endocarditis, combined AV and MV replace- on AS is most frequently focused on calcification, in 2013 ment procedure, emergency surgery, root dilation requiring our group documented impaired fibrinolysis in 74 patients aortic surgery, prior cardiac surgery, MI or percutaneous with severe AS, evidenced by prolonged plasma fibrin clot coronary intervention (PCI) followed by dual antiplatelet lysis time (CLT) and increased plasma plasminogen activa- therapy within 1 month prior to enrolment, renal failure tor inhibitor-1 (PAI-1), as compared to controls [10]. CLT (serum creatinine > 177 µmol/L), prior bleeding diathesis, was positively correlated with the valve leaflet thickness, arterial or venous thromboembolic events within the previ- the degree of valve calcification, valvular fibrin and PAI-1 ous 6 months, known cancer, any chronic inflammatory dis - expression [10]. ease. Concomitant CABG, as well as current anticoagulant Impaired fibrinolysis is usually driven by increased levels therapy were not used as exclusion criteria. Necessity for and/or enhanced function of its inhibitors. PAI-1 is a key concomitant valve repair (due to secondary mitral regurgita- regulator of fibrinolysis that controls the plasmin-generating tion [MR] in AS, and tricuspid regurgitation [TR] in MS) activity of tissue-type plasminogen activator and urokinase- was not used as an exclusion criterion. In-hospital cardio- type plasminogen activator [11]. PAI-1 expression is found vascular death was defined as death due to cardiovascular in as many as in 69% of the human AS valves [12]. Another diseases, occurring during the same hospitalization. b fi rinolysis inhibitor, thrombin activatable b fi rinolysis inhib - Echocardiography was performed by an experienced car- itor (TAFI), which cleaves C-terminal lysine and arginine diologist on a Toshiba APLIO 80 (Toshiba, Tokyo, Japan) residues from partially degraded fibrin, thereby attenuating ultrasound machine. AS was defined as severe when mean efficient plasminogen activation, has also been shown to be transvalvular pressure gradient was ≥ 40 mmHg and/or AV elevated in AS patients [13]. Clinical relevance of varying area was ≤ 1 cm . All enrolled AS patients had to be symp- levels of circulating fibrinolysis inhibitors in VHD is unclear tomatic. MS was deemed a surgical indication in a symp- due to the paucity of data. It has been reported in a study on tomatic patient when MV area was ≤ 1.5 cm [16]. Valve 28 individuals with severe MS that blood coagulation activa- regurgitation was graded with color Doppler flow analysis tion and fibrinolytic activity assessed using plasma D-dimer using the following scale: none (0), trivial (1), mild (2), levels were increased in MS, compared with controls [14]. moderate (3) and severe (4). If a patient was on oral vita- Marin et al. showed impaired fibrinolysis in 24 MS patients, min K antagonist (VKA) therapy prior to operation, it was compared with 18 controls, as reflected by elevated PAI-1 stopped 5 days before admission, and perioperative bridging (both in patients with atrial fibrillation [AF] and in sinus with low molecular weight heparin (LMWH) was initiated. rhythm), without assessment of the overall fibrinolytic A regimen of 1 mg/kg enoxaparin twice daily was applied plasma capacity [15]. in all cases. To the best of our knowledge, there are no studies The study was performed in accordance with the Declara- comparing the functional status of the fibrinolytic system tion of Helsinki, and received approval of the Jagiellonian between different degenerative valvular disorders. We University Ethical Committee. All patients provided their sought to compare the fibrinolytic system activity in patients written informed consent. with late-stage degenerative AS (a degenerative valvular disease with high-velocity flow) with patients with degen- Operative management erative MS (a group with a stenotic valvular condition with lower flow velocity). A multimodal approach was employed, All patients underwent standardized anaesthesia and which included assessment of global fibrinolytic capacity received median sternotomy. Cardio-pulmonary bypass and fibrinolysis inhibitors. (CPB) was performed at moderate hypothermia (esopha- geal temperature, 32 °C) using a non-pulsatile roller pump (Jostra Medizintechnik AG, Hirrlingen, Germany) and a Methods 40 µm arterial blood filter (Jostra Medizintechnik AG, Hir - rlingen, Germany), with blood flow at 2.0–2.4 l/min/m , Patients and mean arterial pressure at 40–60 mmHg. Aortic valve anatomy was confirmed intraoperatively by a surgeon in AS. From February 2013 to April 2014 we recruited 121 indi- Tranexamic acid was administered in two doses (20 mg/kg viduals scheduled for elective valvular surgery due to i.v. after sternotomy, and 20 mg/kg i.v. after the end of CPB) 1 3 Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 195 in all cases. All patients were transferred to the intensive and percentages. The Shapiro–Wilk test was used to test care unit (ICU) for postoperative ventilation, and extubated the normality of continuous variables. To examine the dif- following standard criteria. ferences between two independent groups Student’s t-test or Mann–Whitney U test were used, as appropriate. The χ Laboratory investigations test or Fischer’s exact test was used for categorical variables. To assess linear correlation between variables, the Pearson Fasting blood samples were collected from an antecubital correlation coefficient (Pearson’s r) for normally distributed vein with minimal stasis at 6–8 a.m. on the day of surgery, variables or Spearman’s rank correlation coefficient (Spear - prior to the onset of any surgery-related procedures. Plasma man’s rho) for non-normally distributed variables were cal- samples were centrifuged within 30 min of collection, fro- culated. Linear regression was used to test the influence of zen, and stored in aliquots at − 80 °C until assayed. Rou- MS, AF and VKA use on t . These variables were tested 50% tine methods were used for standard laboratory parameters. in simple regression, and then put together into a multiple Commercially available enzyme-linked immunoabsorbent model. Statistical analysis was performed with STATIS- assays were used to determine plasma PAI-1 antigen (PAI- TICA 12.0 (StatSoft, Tulsa, OK). Two sided p-values < 0.05 1:Ag; Hyphen, Neuville, France), PAI-1 activity (PAI-1:Act; were considered statistically significant. American Diagnostica, Stamford, CT, USA) and TAFI anti- gen (Stachrom TAFI, Diagnostica Stago, Asnieres, France). Plasma TAFI activity was measured by a chromogenic Results assay using the ACTICHROME® Plasma TAFI Activity Kit (American Diagnostica, Stamford, CT, USA). We also Patient characteristics measured activated and inactivated TAFI antigen in plasma (TAFIa/TAFIai; Diagnostica Stago, Asnieres, France), A total of 97 patients (46% men) with preserved left ven- plasmin-α-2-antiplasmin complexes (PAP; DRG Instru- tricular function were included in the study. Seventy-six ments, Marburg, Germany) and platelet factor 4 (PF4; R&D patients (63%) underwent surgery for AS (26 had a bicuspid Systems, Minneapolis, MN, USA). valve), and 45 (37%) for MS, and the clinical and echocar- diographic characteristics of both groups are presented in Clot lysis assay Table 1. MS patients had lower BMI, were more often diag- nosed with AF, had a history of stroke and were treated Plasmin-mediated fibrinolysis in the presence of recom- with VKA, while AS patients more often had hypertension, binant tissue plasminogen activator (rtPA) (Boehringer hypercholesterolemia and CAD, and received aspirin, ACEI Ingelheim, Ingelheim, Germany) was evaluated as previ- and statins. MS patients were in higher New York Heart ously described [17, 18]. Briefly, 100 µL of citrated plasma Association class, had mildly decreased left ventricular sys- was diluted with 100 µL of a buffer (0.05 mol/L Tris–HCl, tolic function, and demonstrated higher values of INR and 0.15 mol/L NaCl, pH 7.4), containing 20 mmol/L calcium APTT (Table 1.). chloride, 1 U/mL human thrombin (Sigma-Aldrich), and Operative and postoperative characteristics are presented 14 µmol/L rtPA. The assembly kinetics was monitored by in Table  2. MS patients required a shorter aortic cross- spectrophotometry at 405 nm, in duplicate. Lysis time was clamping, and more frequently received a mechanical valve, defined as the time required for a 50% decrease in fibrin clot but did not differ from AS patients in terms of re-exploration absorbance (t ) and was chosen as a marker of the clot for bleeding, transfusions or early mortality. 50% susceptibility to fibrinolysis. The interassay and intraassay coefficients of variation were below 6%. Fibrinolysis Statistical analysis In MS, t was prolonged (+ 29%), TAFI activity (+ 12%), 50% TAFI:Ag (+ 21%), and PAI-1:Ag (+ 69%) were elevated, The study was powered to have an 80% chance of detecting when compared with AS subjects (Fig. 1; Table 2.). No dif- a 25% intergroup difference in t using a p-value of 0.05, ferences in fibrinogen, d-dimer or PAP levels were noted. 50% based on the values of these parameters in the published arti- In the whole cohort (n = 121), t , TAFI activity and PAI- 50% cle [19]. In order to demonstrate such a difference or greater 1:Ag positively correlated with MV (but not AV) gradients in this variable, 20 patients were required in each group. The (Fig.  2.). t correlated also with MR degree (r = 0.29, 50% patient enrollment continued until a suc ffi ient number of MS p = 0.001). patients was met. Continuous variables were presented as In all patients (n = 121), there was a positive association mean ± standard deviation (SD) or median and quartiles, as between t and PAI-1:Ag (r = 0.21, p = 0.02), and negative 50% appropriate. Categorical variables were presented as counts 1 3 196 P. Mazur et al. Table 1 Baseline patient characteristics Variable Normal reference values All patients (n = 121) Valve stenosis p Value (where applicable) Aortic (n = 76) Mitral (n = 45) Age, years 65 (61–74) 66 (61–74) 64 (59–69) 0.06 Male sex, n (%) 57 (47) 40 (53) 17 (38) 0.11 BMI, kg/m 27.4 ± 4.8 28.2 ± 4.6 26.3 ± 4.8 0.03 Diabetes mellitus, n (%) 39 (32) 26 (34) 13 (29) 0.55 Arterial hypertension, n (%) 94 (78) 67 (88) 27 (60) 0.0003 Persistent atrial fibrillation, n (%) 40 (33) 5 (7) 35 (78) < 0.0001 Paroxysmal atrial fibrillation, n (%) 5 (4) 5 (7) 0 (0) 0.51 LVEF ≤ 40%, n (%) 16 (13) 9 (12) 7 (16) 0.37 Hypercholesterolemia, n (%) 85 (70) 59 (78) 26 (58) 0.02 Current smoking, n (%) 9 (7) 5 (7) 4 (9) 0.47 History of smoking, n (%) 28 (23) 16 (21) 12 (27) 0.48 Coronary artery disease, n (%) 49 (41) 39 (51) 10 (22) 0.002 Previous MI, n (%) 19 (16) 15 (20) 4 (9) 0.09 Previous stroke, n (%) 7 (6) 1 (1) 6 (13) 0.01 NYHA functional class 2 (2–3) 2 (2–3) 3 (2–3) 0.006 Medication  Aspirin, n (%) 61 (50) 50 (66) 11 (24) < 0.0001  VKAs, n (%) 46 (38) 10 (13) 36 (80) < 0.0001  ACEI, n (%) 76 (63) 53 (70) 23 (51) 0.04  β-Blocker, n (%) 97 (80) 65 (86) 32 (71) 0.05  Statin, n (%) 84 (69) 59 (78) 25 (56) 0.01 Laboratory variables  INR 0.90–1.20 1.04 (0.99–1.10) 1.02 (0.98–1.07) 1.08 (1.03–1.18) < 0.0001  APTT, s 25.9–36.6 26.5 (24.8–28.9) 26.0 (24.5–28.2) 27.9 (25.6–30.2) 0.009  Fibrinogen, g/L 1.5–4.0 3.3 (2.8–4.0) 3.2 (2.8–3.9) 3.4 (2.6–4.2) 0.95  D-dimer, ng/mL < 500 450 (311–591) 439 (305–556) 488 (341–617) 0.24  Creatinine, µmol/L 62–106 86 (76–102) 84 (77–96) 90 (75–105) 0.45 Echocardiography  Aortic valve pressure gradient   Maximal (mmHg) 67 (14–87) 79 (65–97) 7 (5–11) < 0.0001   Mean (mmHg) 42 (14–53) 47 (38–56) 4 (3–8) < 0.0001  Aortic valve regurgitation (degree) 1 (0–2) 1 (1–2) 1 (0–1) 0.01  Mitral valve pressure gradient   Maximal (mmHg) 7 (4–17) 4 (3–7) 17 (13–22) < 0.0001   Mean (mmHg) 3 (1–6) 2 (1–3) 7 (6–11) < 0.0001  Mitral valve regurgitation (degree) 2 (1–3) 1 (1–2) 3 (1–4) < 0.0001  Tricuspid valve regurgitation (degree) 1 (0–2) 1 (0–1) 2 (1–3) < 0.0001  Left ventricular ejection fraction (%) 55 (46–60) 60 (49–65) 52 (46–60) 0.04 Bold values used to visually identify significant p-values (<0.05) Data shown as mean ± SD or as median (IQR), or number (percentage) ACEI angiotensin-converting enzyme inhibitors, Ag antigen, APTT activated partial thromboplastin time, BMI body mass index, LVEF left ven- tricular ejection fraction, INR international normalized ratio, NYHA New York Heart Association. The p-values refers to the comparison between patients with aortic stenosis and mitral stenosis between t and PAP (r = − 0.45, p < 0.0001). PAI-1:Ag Preoperative APTT correlated inversely with PAI- 50% and PAP correlated with BMI (r = 0.28, p = 0.002 and 1:Ag (r = − 0.20, p = 0.03) and TAFIa/TAFIai (r = − 0.19, r = 0.22, p = 0.01, respectively). p = 0.04). 1 3 Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 197 Table 2 Operative and postoperative characteristics and fibrinolytic parameters Variable Normal reference val- All patients (n = 121) Valve stenosis p Value ues (where applicable) Aortic (n = 76) Mitral (n = 45) Aortic cross-clamp time, min 72 (60–89) 74 (64–90) 62 (49–81) 0.004 CPB time, min 116 (95–143) 115 (98–144) 116 (84–142) 0.36 Biprosthesis, n (%) 52 (43) 48 (63) 4 (9) < 0.0001 Mechanical prosthesis, n (%) 69 (57) 28 (37) 41 (91) < 0.0001 Concomitant CABG, n (%) 18 (15) 13 (17) 5 (11) 0.27 Mitral valve repair 1 (1) 1 (1) 0 (0) 0.63 Tricuspid valve repair 6 (5) 0 (0) 6 (13) 0.002 Bicuspid aortic valve 26 (–) 26 (34) – – Postoperative drainage after 12 h, mL 440 (333–628) 440 (350–620) 440 (300–640) 0.51 Rethoracotomy for bleeding, n (%) 7 (6) 6 (8) 1 (2) 0.21 ICU length of stay, days 1 (1–3) 1 (1–2) 1 (1–4) 0.22 In-hospital death, n (%) 7 (6) 3 (4) 4 (9) 0.23 Fibrinolytic parameters  t min 6.2–9.3* 14.1 (11.3–18.3) 12.6 (9.8–16.3) 16.2 (14.1–21.9) < 0.0001 50%,  TAFI: Ag, IU/dL 56.0–105.0 100.6 (81.3–121.8) 92.8 (69.9–120.7) 112.4 (97.1–122.1) 0.005  TAFI activity, µg/mL 19.9–29.1* 43.0 (37.0–48.8) 39.8 (32.3–47.5) 44.7 (41.1–50.3) 0.007  TAFIa/TAFIai, ng/mL 3.0–10.0 14.9 (11.5–19.4) 15.7 (11.4–20.8) 14.2 (12.4–17.5) 0.29  PAI-1:Ag, ng/mL 1.0–25.0 16.1 (10.5–25.1) 13.4 (9.8–19.5) 22.6 (16.1–29.7) 0.0001  PAI-1 activity, IU/dL 7.0–26.7 10.9 (6.3–18.7) 10.3 (5.9–18.1) 12.7 (6.8–19.5) 0.37  PAP, µg/mL 0.12–0.70 0.55 (0.47–0.64) 0.54 (0.44–0.67) 0.55 (0.47–0.64) 0.84 Platelet activation  Platelet factor 4, ng/mL 94.7–100.0* 147.4 (135.0–159.5) 142.9 (132.9–155.4) 152.3 (139.1–165.7) 0.006 Bold values used to visually identify significant p-values (<0.05) Data shown as mean ± SD or as median (IQR), or number (percentage) ACEI angiotensin-converting enzyme inhibitors, BMI Body Mass Index, ICU intensive care unit, PAI-1 plasminogen activator inhibitor-1, PAI- 1:Ag plasminogen activator inhibitor-1 antigen, PAP plasmin-α-2-antiplasmin complexes, TAFI thrombin-activatable fibrinolysis inhibitor, t 50% time required for a 50% decrease in fibrin clot absorbance. Asterisk denotes that the values are based on a assessment of healthy controls evalu- ated in our laboratory. The p-values refers to the comparison between patients with aortic stenosis and mitral stenosis Fig. 1 Intergroup differences between patients with aortic and mitral stenosis  in t , PAI-1 antigen and activity (panel a), and TAFI antigen, 50% activity, and TAFIa/TAFIai (panel b) 1 3 198 P. Mazur et al. 1 3 Fig. 2 Correlations between t , TAFI activity and PAI-1 antigen and mean (panels a, b and c, respectively) and maximal transvalvular mitral pressure gradients (panels d, e and f, respectively) 50% Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 199 Preoperative fibrinogen was correlated with TAFI:Ag Discussion (r = 0.18, p = 0.047) and TAFIa/TAFIai (r = 0.25, p = 0.008). TAFIa/TAFIai was also associated with creatinine (r = 0.27, The novel finding of this study is that individuals suffering p < 0.004) and age (r = 0.45, p < 0.0001). In AV patients, from MS (at the stage requiring surgical intervention) have patients with bicuspid aortic valve, compared with those with more impaired global efficiency of fibrinolysis, compared normal anatomy, apart from being younger (63 [60–67] vs. with subjects with AS, as reflected by longer t , higher 50% 72 [64–76] years, respectively, p = 0.002), and having lower activity of TAFI, and higher levels of PAI-1. body mass index (26.0 [23.8–29.4] vs. 28.9 [26.4–32.0] We report a positive association of t with both maxi- 50% kg/m , respectively, p = 0.006), had lower TAFI activity mal and mean transvalvular MV gradients, as well as with (36.6 ± 11.0 vs. 43.3 ± 14.4%, respectively, p = 0.046), but the degree of MR. We also observed the association of TAFI did not differ regarding t and other parameters. activity and PAI-1:Ag with transvalvular MV gradients. 50% These associations point to the connection between MS and Comorbidities impairment of fibrinolysis. While several tests to assess global plasma fibrinolytic Patients with permanent AF (35 with MS and 5 with AS) activity are available, we used a plasma-based test, in which had longer t than individuals without documented AF a thrombin-induced fibrin clot is lysed by exogenously added 50% (16.0 [13.1–22.6] vs. 13.1 [10.1–16.3] min, p = 0.0002) and rt-PA at relatively high concentrations. This approach was higher PAI-1:Ag (23.4 [15.9–31.4] vs. 13.4 [9.7–19.4] ng/ successfully applied in previous papers [17, 18, 20, 21]. In mL, p < 0.0001). Patients with paroxysmal AF (n = 5) had contrast to the assay previously used by our group in AS higher PAI-1:Ag than individuals without documented AF patients [10], the current method does not use tissue factor, (24.6 [19.0–25.2] vs. 13.4 [9.7–19.4] ng/mL, p = 0.03). and the rtPA concentrations are higher. Based on previous To verify the influence of MS on t in the presence reports, t may be more sensitive to detect the impact of 50% 50% of persistent AF and VKA use, linear regression was uti- PAI-1 on fibrin clot properties [20]. Our findings supported lized. In univariate analysis, all variables were significant this observation by showing that PAI-1:Ag is positively cor- (MS: b = 4.91, adjusted R = 0.17, p < 0.0001; AF: b = 2.54, related with t values. 50% adjusted R = 0.06, p = 0.005; VKA: b = 4.50, adjusted In patients with VHD, we found that inhibition of fibrinol- R = 0.14, p < 0.0001). In multivariate analysis (final model, ysis was modulated most notably by the presence of AF, a adjusted R = 0.18, p < 0.0001), only MS was the predictor prothrombotic condition, involving increased thrombin gen- of t (b = 3.42, p = 0.01). eration and fibrinogen concentrations [22, 23]. Marin et al. 50% reported higher levels of PAI-1 in patients with MS who Surgical outcomes also had AF, as compared with MS patients in normal sinus rhythm [15]. We observed higher PAI-1 levels, along with There were no intergroup differences in the early mortality prolonged t , in subjects with AF (TAFI activity was unaf- 50% rate, re-exploration for bleeding and the length of ICU stay. fected by AF, and modulated only by MS incidence). Our The fatal cases (n = 7) did not differ from survivors with findings are in line with the recent paper by Drabik et al., regard to TAFI and t , but had lower PAI-1 activity (5.3 who reported prolonged CLT and increased PAI-1 levels in 50% [4.1–12.6] vs. 11.5 [6.5–19.3] IU/dL, respectively, p = 0.04). subjects with non-valvular AF [24]. Impaired fibrinolysis, A median postoperative chest tube drainage volume was improved by oral anticoagulants, was also reported by other 440 ml with no AS–MS intergroup difference (Table  2.). investigators exploring fibrinoysis in AF [25, 26]. Only few In patients who required re-exploration for bleeding the patients with progressed MS will present without AF, and median chest-tube output was more than twofold higher than AF contributes to blood stasis in the left atrium in the set- in remaining patients (1120 [650–2000] vs. 420 [320–590] ting of MV stenosis—another component in Virchow’s triad mL, respectively; p = 0.0002). In the whole group (n = 121) equation. The observation that even in MS patients AF is a the postoperative drainage volumes correlated inversely potent enough factor to significantly alter fibrinolysis pro- with platelet count (r = − 0.29, p = 0.002), BMI (r = − 0.25, vides additional evidence for the necessity of anticoagula- p = 0.007), fibrinogen (r = − 0.26, p = 0.006) and PAI-1:Ag tion in this disorder. Nevertheless, MS was a predictor of (r = − 0.22, p = 0.02). Patients with high drainage volumes t independently of AF in this study. 50% (≥ 1000 mL; n = 8, 7%), compared with those with lower The preoperative history of VKA therapy in both groups volumes (n = 113) had lower PAI-1:Ag (by 40%, p = 0.02), warrants a comment. While the groups differed regarding but there were no differences in any other parameters. VKA use, it is unlikely that VKAs influenced the results of t test, markedly elevated in MS patients. Previously, 50% the permeability of the fibrin network was shown to rise in 1 3 200 P. Mazur et al. parallel to elevations of INR and shortening of CLT in AF latter: form of TAFI following the completion of its biologi- patients [25], thus, it could be expected that in the setting cal function of C-terminal arginine and lysine cleavage from of VKA use, t would be shorter. Also LMWHs prolong partially degraded fibrin). A novel observation in the current 50% clot formation and increase the clot susceptibility to lysis study is that the MS is associated with higher TAFI activity [27], and as all anticoagulated patients in this study received than AS, and this finding is independent of AF presence. LMWH bridging prior to operation, t shortening could The similar TAFIa/TAFIai values might be explained by 50% be expected. That notwithstanding, patients with MS, who “compensatory” changes in inactivated TAFI levels in both in this study were most often subjected to anticoagulation, groups, leading to similar ratios. A role of TAFI in hypofi- also had the most “prothrombotic” fibrin clot phenotype (and brinolysis in valvular disorders warrants further studies. longest t ). One might speculate that the effects of VKAs 50% and LMWHs on clot susceptibility to lysis are, arguably, Limitations abolished by MS and AF. On the other hand, our findings point to the importance of anticoagulation in MS, especially The MS and AS groups are representative to patients in eve- with concomitant AF. The prothrombotic state, as presented ryday practice, however they were not matched, and differed by us, is associated with MS, to some extent irrespectively of in some aspects. MS subjects are underrepresented, although AF. Further studies are needed to verify the hypothesis that this reflects the trends in open heart surgery, with a high patients with advanced MS, but with no documented AF, prevalence of AS in patients requiring surgical intervention would benefit from anticoagulant therapy, and to indicate [6]. Still, small sample size of MS patients might be a reason which treatment modality would be most beneficial. for underpowering. Long term follow-up to seek for throm- Furthermore, plasma PAI-1 was associated with enhanced botic complications was beyond the scope of the current bleeding after cardiac surgery in a study by Ozolina et al. on study. Despite sharing many risk factors [2, 5], degenerative 79 cardiosurgical patients (as few as 29 underwent valvular AS and MS likely differ in the underlying pathology. Most surgery) [28]. We demonstrated that plasma PAI-1:Ag is MS patients had AF. inversely correlated with chest-tube output. Yet, even with significant differences in PAI-1:Ag between AS and MS patients, we failed to show any differences in drainage vol- Conclusions umes. Our results confirm that fibrinolysis is a contributor to post-operative blood loss after cardiac surgery, but not We demonstrated that degenerative MS is associated with potent enough to reveal clinical effects after elective valvular more pronounced impairment of global fibrinolytic capac- surgery. It should be mentioned that the bleeding tendency ity than AS at the stage of surgical intervention. AF likely in AS [29] is largely driven by the imbalance in von Wille- contributes to fibrinolysis impairment in MS, but the role brand factor high molecular weight multimers [30]. In our of fibrinolysis in valvular disorders in terms of progression study, the postoperative blood loss was also associated with of the disease and thromboembolic complications requires preoperative fibrinogen level, PLT and BMI. Among the further studies. The relationship between the preoperative factors like fibrinogen or PLT, the cardiosurgical bleeding fibrinolysis activation, antifibrinolytic treatment, and postop- and transfusion risk scores consequently list low BMI/body erative outcomes in cardiac surgery needs to be investigated. weight as a risk factor [31]. Interestingly, PAI-1:Ag and BMI were positively associated in our study, and this association Acknowledgements This work was supported by a grant from the is in line with previous reports [32]. Inhibition of b fi rinolysis Polish Ministry of Science (N N402 383338 to Anetta Undas) and has long been a target of strategies aimed at bleeding reduc- a Grant from the National Science Centre (2012/05/N/NZ5/00846 to tion in cardiac surgery, but there is no obvious consensus on Piotr Mazur). the antifibrinolytic therapy in cardiac surgery. Our results suggest that different groups of patients might require a dif- Compliance with ethical standards ferent antifibrinolytic regimen for optimal outcomes, with Conflict of interest The authors declare that they have no conflicts of adjustment according to the diagnosis-dependent activity of interest. fibrinolysis. In the current report, along with t we studied TAFI, 50%, Ethical approval All procedures were in accordance with the ethical another important fibrinolysis inhibitor, using three assays standards of the institutional ethical committee and with the 1964 Hel- sinki declaration and its later amendments. [33]. This aspect of fibrinolyis was not studied yet in the context of VHD. TAFI:Ag measures all forms of TAFI in Informed consent Informed consent was obtained from all individual plasma: pro-TAFI, active and inactivated TAFI. 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Impaired fibrinolysis in degenerative mitral and aortic valve stenosis

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Medicine & Public Health; Cardiology; Hematology
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Abstract

Valvular heart disease is associated with an increased thromboembolic risk. Impaired fibrinolysis was reported in severe aortic stenosis (AS). Little is known about fibrinolysis in mitral stenosis (MS). We sought to compare fibrinolysis impairment in AS and MS. We studied 121 individuals scheduled for elective aortic valve (AV) or mitral valve (MV) surgery for AS (n = 76) or MS (n = 45), in order to compare fibrinolysis impairment. Fibrinolytic capacity was assessed by determination of clot lysis time (t ) and fibrinolysis inhibitors, including plasma plasminogen activator inhibitor-1 (PAI-1) antigen (PAI-1:Ag) 50% and activity, thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity. Prolonged t (+ 29%), elevated TAFI 50% activity (+ 12%), TAFI:Ag (+ 21%), and PAI-1:Ag (+ 84%) were observed in patients with MS, compared with those with AS. t Correlated with mean and maximal MV gradients (r = 0.43, p < 0.0001 and r = 0.39, p < 0.0001, respectively), but 50% not with AV gradients. Mean and maximal MV gradients correlated with TAFI activity and PAI:Ag. Patients with perma- nent atrial fibrillation (AF; 35 with MS and 5 with AS) had longer t (by 22%, p = 0.0002) and higher PAI-1:Ag (by 74%, 50% p < 0.0001) than the remainder. In the whole group, postoperative drainage volumes correlated inversely with PAI-1:Ag (r = − 0.22, p = 0.02). MS is associated with more pronounced impairment of global fibrinolytic capacity than AS at the stage of surgical intervention, which is in part driven by AF. Our findings suggest that hypofibrinolysis might be implicated in the progression of MS and its thromboembolic complications. Keywords Fibrinolysis · Aortic stenosis · Mitral stenosis · TAFI · PAI-1 · Fibrin · Cardiac surgery Highlights Introduction Valvular heart disease (VHD) remains a key public health Valvular heart disease is associated with increased problem worldwide. Degenerative aortic stenosis (AS) is thromboembolic risk common in developed countries, and its prevalence increases Degenerative mitral stenosis is associated with more pro- with age [1]. The mechanisms involved in the development nounced impairment of global fibrinolytic capacity than of AS resemble the ones involved in the development of aortic stenosis at the stage of surgical intervention coronary artery atherosclerosis [2]. Mitral stenosis (MS), Atrial fibrillation contributes to fibrinolysis impairment on the other hand, is related to the structural abnormality of in mitral stenosis the mitral valve (MV) apparatus, and can be a distant sequel The role of fibrinolysis in pathology and progression of of rheumatic fever, or may result from severe non-rheumatic valvular disorders and their thromboembolic complica- degenerative mitral annular calcification [3 ]. Mitral annu- tions needs to be investigated lar calcification is present in up to 10% of elderly patients, and MS develops in 1–2% of this group [3, 4]. It has been shown that atherosclerotic risk factors are associated with * Piotr Mazur mitral annular calcification leading to MS [5 ]. Based on the [email protected] 2015 Society of Thoracic Surgeons Adult Cardiac Surgery Institute of Cardiology, Jagiellonian University Medical Database Report, isolated aortic valve replacement (AVR) College, 80 Pradnicka St., 31-202 Krakow, Poland was performed in 21,921 patients, while isolated mitral valve The John Paul II Hospital, Krakow, Poland replacement (MVR) in 5180 cases in United States alone [6]. KCRI, Krakow, Poland Vol.:(0123456789) 1 3 194 P. Mazur et al. Blood coagulation leads to thrombin-mediated conver- degenerative AS or MS. All patients were assessed preopera- sion of fibrinogen to fibrin. Fibrin clots composed of tightly tively by a local ‘heart team’, and the surgery was conducted packed thin fibers with small pores are relatively resistant according to the ‘heart team’ indication. to lysis [7] and such prothrombotic clot phenotype has been The exclusion criteria were: rheumatic etiology of VHD shown in multiple disease states, such as myocardial infarc- (to exclude the confounding effect of inflammation), ongo- tion (MI) [8] or ischemic stroke [9]. Although the research ing infective endocarditis, combined AV and MV replace- on AS is most frequently focused on calcification, in 2013 ment procedure, emergency surgery, root dilation requiring our group documented impaired fibrinolysis in 74 patients aortic surgery, prior cardiac surgery, MI or percutaneous with severe AS, evidenced by prolonged plasma fibrin clot coronary intervention (PCI) followed by dual antiplatelet lysis time (CLT) and increased plasma plasminogen activa- therapy within 1 month prior to enrolment, renal failure tor inhibitor-1 (PAI-1), as compared to controls [10]. CLT (serum creatinine > 177 µmol/L), prior bleeding diathesis, was positively correlated with the valve leaflet thickness, arterial or venous thromboembolic events within the previ- the degree of valve calcification, valvular fibrin and PAI-1 ous 6 months, known cancer, any chronic inflammatory dis - expression [10]. ease. Concomitant CABG, as well as current anticoagulant Impaired fibrinolysis is usually driven by increased levels therapy were not used as exclusion criteria. Necessity for and/or enhanced function of its inhibitors. PAI-1 is a key concomitant valve repair (due to secondary mitral regurgita- regulator of fibrinolysis that controls the plasmin-generating tion [MR] in AS, and tricuspid regurgitation [TR] in MS) activity of tissue-type plasminogen activator and urokinase- was not used as an exclusion criterion. In-hospital cardio- type plasminogen activator [11]. PAI-1 expression is found vascular death was defined as death due to cardiovascular in as many as in 69% of the human AS valves [12]. Another diseases, occurring during the same hospitalization. b fi rinolysis inhibitor, thrombin activatable b fi rinolysis inhib - Echocardiography was performed by an experienced car- itor (TAFI), which cleaves C-terminal lysine and arginine diologist on a Toshiba APLIO 80 (Toshiba, Tokyo, Japan) residues from partially degraded fibrin, thereby attenuating ultrasound machine. AS was defined as severe when mean efficient plasminogen activation, has also been shown to be transvalvular pressure gradient was ≥ 40 mmHg and/or AV elevated in AS patients [13]. Clinical relevance of varying area was ≤ 1 cm . All enrolled AS patients had to be symp- levels of circulating fibrinolysis inhibitors in VHD is unclear tomatic. MS was deemed a surgical indication in a symp- due to the paucity of data. It has been reported in a study on tomatic patient when MV area was ≤ 1.5 cm [16]. Valve 28 individuals with severe MS that blood coagulation activa- regurgitation was graded with color Doppler flow analysis tion and fibrinolytic activity assessed using plasma D-dimer using the following scale: none (0), trivial (1), mild (2), levels were increased in MS, compared with controls [14]. moderate (3) and severe (4). If a patient was on oral vita- Marin et al. showed impaired fibrinolysis in 24 MS patients, min K antagonist (VKA) therapy prior to operation, it was compared with 18 controls, as reflected by elevated PAI-1 stopped 5 days before admission, and perioperative bridging (both in patients with atrial fibrillation [AF] and in sinus with low molecular weight heparin (LMWH) was initiated. rhythm), without assessment of the overall fibrinolytic A regimen of 1 mg/kg enoxaparin twice daily was applied plasma capacity [15]. in all cases. To the best of our knowledge, there are no studies The study was performed in accordance with the Declara- comparing the functional status of the fibrinolytic system tion of Helsinki, and received approval of the Jagiellonian between different degenerative valvular disorders. We University Ethical Committee. All patients provided their sought to compare the fibrinolytic system activity in patients written informed consent. with late-stage degenerative AS (a degenerative valvular disease with high-velocity flow) with patients with degen- Operative management erative MS (a group with a stenotic valvular condition with lower flow velocity). A multimodal approach was employed, All patients underwent standardized anaesthesia and which included assessment of global fibrinolytic capacity received median sternotomy. Cardio-pulmonary bypass and fibrinolysis inhibitors. (CPB) was performed at moderate hypothermia (esopha- geal temperature, 32 °C) using a non-pulsatile roller pump (Jostra Medizintechnik AG, Hirrlingen, Germany) and a Methods 40 µm arterial blood filter (Jostra Medizintechnik AG, Hir - rlingen, Germany), with blood flow at 2.0–2.4 l/min/m , Patients and mean arterial pressure at 40–60 mmHg. Aortic valve anatomy was confirmed intraoperatively by a surgeon in AS. From February 2013 to April 2014 we recruited 121 indi- Tranexamic acid was administered in two doses (20 mg/kg viduals scheduled for elective valvular surgery due to i.v. after sternotomy, and 20 mg/kg i.v. after the end of CPB) 1 3 Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 195 in all cases. All patients were transferred to the intensive and percentages. The Shapiro–Wilk test was used to test care unit (ICU) for postoperative ventilation, and extubated the normality of continuous variables. To examine the dif- following standard criteria. ferences between two independent groups Student’s t-test or Mann–Whitney U test were used, as appropriate. The χ Laboratory investigations test or Fischer’s exact test was used for categorical variables. To assess linear correlation between variables, the Pearson Fasting blood samples were collected from an antecubital correlation coefficient (Pearson’s r) for normally distributed vein with minimal stasis at 6–8 a.m. on the day of surgery, variables or Spearman’s rank correlation coefficient (Spear - prior to the onset of any surgery-related procedures. Plasma man’s rho) for non-normally distributed variables were cal- samples were centrifuged within 30 min of collection, fro- culated. Linear regression was used to test the influence of zen, and stored in aliquots at − 80 °C until assayed. Rou- MS, AF and VKA use on t . These variables were tested 50% tine methods were used for standard laboratory parameters. in simple regression, and then put together into a multiple Commercially available enzyme-linked immunoabsorbent model. Statistical analysis was performed with STATIS- assays were used to determine plasma PAI-1 antigen (PAI- TICA 12.0 (StatSoft, Tulsa, OK). Two sided p-values < 0.05 1:Ag; Hyphen, Neuville, France), PAI-1 activity (PAI-1:Act; were considered statistically significant. American Diagnostica, Stamford, CT, USA) and TAFI anti- gen (Stachrom TAFI, Diagnostica Stago, Asnieres, France). Plasma TAFI activity was measured by a chromogenic Results assay using the ACTICHROME® Plasma TAFI Activity Kit (American Diagnostica, Stamford, CT, USA). We also Patient characteristics measured activated and inactivated TAFI antigen in plasma (TAFIa/TAFIai; Diagnostica Stago, Asnieres, France), A total of 97 patients (46% men) with preserved left ven- plasmin-α-2-antiplasmin complexes (PAP; DRG Instru- tricular function were included in the study. Seventy-six ments, Marburg, Germany) and platelet factor 4 (PF4; R&D patients (63%) underwent surgery for AS (26 had a bicuspid Systems, Minneapolis, MN, USA). valve), and 45 (37%) for MS, and the clinical and echocar- diographic characteristics of both groups are presented in Clot lysis assay Table 1. MS patients had lower BMI, were more often diag- nosed with AF, had a history of stroke and were treated Plasmin-mediated fibrinolysis in the presence of recom- with VKA, while AS patients more often had hypertension, binant tissue plasminogen activator (rtPA) (Boehringer hypercholesterolemia and CAD, and received aspirin, ACEI Ingelheim, Ingelheim, Germany) was evaluated as previ- and statins. MS patients were in higher New York Heart ously described [17, 18]. Briefly, 100 µL of citrated plasma Association class, had mildly decreased left ventricular sys- was diluted with 100 µL of a buffer (0.05 mol/L Tris–HCl, tolic function, and demonstrated higher values of INR and 0.15 mol/L NaCl, pH 7.4), containing 20 mmol/L calcium APTT (Table 1.). chloride, 1 U/mL human thrombin (Sigma-Aldrich), and Operative and postoperative characteristics are presented 14 µmol/L rtPA. The assembly kinetics was monitored by in Table  2. MS patients required a shorter aortic cross- spectrophotometry at 405 nm, in duplicate. Lysis time was clamping, and more frequently received a mechanical valve, defined as the time required for a 50% decrease in fibrin clot but did not differ from AS patients in terms of re-exploration absorbance (t ) and was chosen as a marker of the clot for bleeding, transfusions or early mortality. 50% susceptibility to fibrinolysis. The interassay and intraassay coefficients of variation were below 6%. Fibrinolysis Statistical analysis In MS, t was prolonged (+ 29%), TAFI activity (+ 12%), 50% TAFI:Ag (+ 21%), and PAI-1:Ag (+ 69%) were elevated, The study was powered to have an 80% chance of detecting when compared with AS subjects (Fig. 1; Table 2.). No dif- a 25% intergroup difference in t using a p-value of 0.05, ferences in fibrinogen, d-dimer or PAP levels were noted. 50% based on the values of these parameters in the published arti- In the whole cohort (n = 121), t , TAFI activity and PAI- 50% cle [19]. In order to demonstrate such a difference or greater 1:Ag positively correlated with MV (but not AV) gradients in this variable, 20 patients were required in each group. The (Fig.  2.). t correlated also with MR degree (r = 0.29, 50% patient enrollment continued until a suc ffi ient number of MS p = 0.001). patients was met. Continuous variables were presented as In all patients (n = 121), there was a positive association mean ± standard deviation (SD) or median and quartiles, as between t and PAI-1:Ag (r = 0.21, p = 0.02), and negative 50% appropriate. Categorical variables were presented as counts 1 3 196 P. Mazur et al. Table 1 Baseline patient characteristics Variable Normal reference values All patients (n = 121) Valve stenosis p Value (where applicable) Aortic (n = 76) Mitral (n = 45) Age, years 65 (61–74) 66 (61–74) 64 (59–69) 0.06 Male sex, n (%) 57 (47) 40 (53) 17 (38) 0.11 BMI, kg/m 27.4 ± 4.8 28.2 ± 4.6 26.3 ± 4.8 0.03 Diabetes mellitus, n (%) 39 (32) 26 (34) 13 (29) 0.55 Arterial hypertension, n (%) 94 (78) 67 (88) 27 (60) 0.0003 Persistent atrial fibrillation, n (%) 40 (33) 5 (7) 35 (78) < 0.0001 Paroxysmal atrial fibrillation, n (%) 5 (4) 5 (7) 0 (0) 0.51 LVEF ≤ 40%, n (%) 16 (13) 9 (12) 7 (16) 0.37 Hypercholesterolemia, n (%) 85 (70) 59 (78) 26 (58) 0.02 Current smoking, n (%) 9 (7) 5 (7) 4 (9) 0.47 History of smoking, n (%) 28 (23) 16 (21) 12 (27) 0.48 Coronary artery disease, n (%) 49 (41) 39 (51) 10 (22) 0.002 Previous MI, n (%) 19 (16) 15 (20) 4 (9) 0.09 Previous stroke, n (%) 7 (6) 1 (1) 6 (13) 0.01 NYHA functional class 2 (2–3) 2 (2–3) 3 (2–3) 0.006 Medication  Aspirin, n (%) 61 (50) 50 (66) 11 (24) < 0.0001  VKAs, n (%) 46 (38) 10 (13) 36 (80) < 0.0001  ACEI, n (%) 76 (63) 53 (70) 23 (51) 0.04  β-Blocker, n (%) 97 (80) 65 (86) 32 (71) 0.05  Statin, n (%) 84 (69) 59 (78) 25 (56) 0.01 Laboratory variables  INR 0.90–1.20 1.04 (0.99–1.10) 1.02 (0.98–1.07) 1.08 (1.03–1.18) < 0.0001  APTT, s 25.9–36.6 26.5 (24.8–28.9) 26.0 (24.5–28.2) 27.9 (25.6–30.2) 0.009  Fibrinogen, g/L 1.5–4.0 3.3 (2.8–4.0) 3.2 (2.8–3.9) 3.4 (2.6–4.2) 0.95  D-dimer, ng/mL < 500 450 (311–591) 439 (305–556) 488 (341–617) 0.24  Creatinine, µmol/L 62–106 86 (76–102) 84 (77–96) 90 (75–105) 0.45 Echocardiography  Aortic valve pressure gradient   Maximal (mmHg) 67 (14–87) 79 (65–97) 7 (5–11) < 0.0001   Mean (mmHg) 42 (14–53) 47 (38–56) 4 (3–8) < 0.0001  Aortic valve regurgitation (degree) 1 (0–2) 1 (1–2) 1 (0–1) 0.01  Mitral valve pressure gradient   Maximal (mmHg) 7 (4–17) 4 (3–7) 17 (13–22) < 0.0001   Mean (mmHg) 3 (1–6) 2 (1–3) 7 (6–11) < 0.0001  Mitral valve regurgitation (degree) 2 (1–3) 1 (1–2) 3 (1–4) < 0.0001  Tricuspid valve regurgitation (degree) 1 (0–2) 1 (0–1) 2 (1–3) < 0.0001  Left ventricular ejection fraction (%) 55 (46–60) 60 (49–65) 52 (46–60) 0.04 Bold values used to visually identify significant p-values (<0.05) Data shown as mean ± SD or as median (IQR), or number (percentage) ACEI angiotensin-converting enzyme inhibitors, Ag antigen, APTT activated partial thromboplastin time, BMI body mass index, LVEF left ven- tricular ejection fraction, INR international normalized ratio, NYHA New York Heart Association. The p-values refers to the comparison between patients with aortic stenosis and mitral stenosis between t and PAP (r = − 0.45, p < 0.0001). PAI-1:Ag Preoperative APTT correlated inversely with PAI- 50% and PAP correlated with BMI (r = 0.28, p = 0.002 and 1:Ag (r = − 0.20, p = 0.03) and TAFIa/TAFIai (r = − 0.19, r = 0.22, p = 0.01, respectively). p = 0.04). 1 3 Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 197 Table 2 Operative and postoperative characteristics and fibrinolytic parameters Variable Normal reference val- All patients (n = 121) Valve stenosis p Value ues (where applicable) Aortic (n = 76) Mitral (n = 45) Aortic cross-clamp time, min 72 (60–89) 74 (64–90) 62 (49–81) 0.004 CPB time, min 116 (95–143) 115 (98–144) 116 (84–142) 0.36 Biprosthesis, n (%) 52 (43) 48 (63) 4 (9) < 0.0001 Mechanical prosthesis, n (%) 69 (57) 28 (37) 41 (91) < 0.0001 Concomitant CABG, n (%) 18 (15) 13 (17) 5 (11) 0.27 Mitral valve repair 1 (1) 1 (1) 0 (0) 0.63 Tricuspid valve repair 6 (5) 0 (0) 6 (13) 0.002 Bicuspid aortic valve 26 (–) 26 (34) – – Postoperative drainage after 12 h, mL 440 (333–628) 440 (350–620) 440 (300–640) 0.51 Rethoracotomy for bleeding, n (%) 7 (6) 6 (8) 1 (2) 0.21 ICU length of stay, days 1 (1–3) 1 (1–2) 1 (1–4) 0.22 In-hospital death, n (%) 7 (6) 3 (4) 4 (9) 0.23 Fibrinolytic parameters  t min 6.2–9.3* 14.1 (11.3–18.3) 12.6 (9.8–16.3) 16.2 (14.1–21.9) < 0.0001 50%,  TAFI: Ag, IU/dL 56.0–105.0 100.6 (81.3–121.8) 92.8 (69.9–120.7) 112.4 (97.1–122.1) 0.005  TAFI activity, µg/mL 19.9–29.1* 43.0 (37.0–48.8) 39.8 (32.3–47.5) 44.7 (41.1–50.3) 0.007  TAFIa/TAFIai, ng/mL 3.0–10.0 14.9 (11.5–19.4) 15.7 (11.4–20.8) 14.2 (12.4–17.5) 0.29  PAI-1:Ag, ng/mL 1.0–25.0 16.1 (10.5–25.1) 13.4 (9.8–19.5) 22.6 (16.1–29.7) 0.0001  PAI-1 activity, IU/dL 7.0–26.7 10.9 (6.3–18.7) 10.3 (5.9–18.1) 12.7 (6.8–19.5) 0.37  PAP, µg/mL 0.12–0.70 0.55 (0.47–0.64) 0.54 (0.44–0.67) 0.55 (0.47–0.64) 0.84 Platelet activation  Platelet factor 4, ng/mL 94.7–100.0* 147.4 (135.0–159.5) 142.9 (132.9–155.4) 152.3 (139.1–165.7) 0.006 Bold values used to visually identify significant p-values (<0.05) Data shown as mean ± SD or as median (IQR), or number (percentage) ACEI angiotensin-converting enzyme inhibitors, BMI Body Mass Index, ICU intensive care unit, PAI-1 plasminogen activator inhibitor-1, PAI- 1:Ag plasminogen activator inhibitor-1 antigen, PAP plasmin-α-2-antiplasmin complexes, TAFI thrombin-activatable fibrinolysis inhibitor, t 50% time required for a 50% decrease in fibrin clot absorbance. Asterisk denotes that the values are based on a assessment of healthy controls evalu- ated in our laboratory. The p-values refers to the comparison between patients with aortic stenosis and mitral stenosis Fig. 1 Intergroup differences between patients with aortic and mitral stenosis  in t , PAI-1 antigen and activity (panel a), and TAFI antigen, 50% activity, and TAFIa/TAFIai (panel b) 1 3 198 P. Mazur et al. 1 3 Fig. 2 Correlations between t , TAFI activity and PAI-1 antigen and mean (panels a, b and c, respectively) and maximal transvalvular mitral pressure gradients (panels d, e and f, respectively) 50% Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 199 Preoperative fibrinogen was correlated with TAFI:Ag Discussion (r = 0.18, p = 0.047) and TAFIa/TAFIai (r = 0.25, p = 0.008). TAFIa/TAFIai was also associated with creatinine (r = 0.27, The novel finding of this study is that individuals suffering p < 0.004) and age (r = 0.45, p < 0.0001). In AV patients, from MS (at the stage requiring surgical intervention) have patients with bicuspid aortic valve, compared with those with more impaired global efficiency of fibrinolysis, compared normal anatomy, apart from being younger (63 [60–67] vs. with subjects with AS, as reflected by longer t , higher 50% 72 [64–76] years, respectively, p = 0.002), and having lower activity of TAFI, and higher levels of PAI-1. body mass index (26.0 [23.8–29.4] vs. 28.9 [26.4–32.0] We report a positive association of t with both maxi- 50% kg/m , respectively, p = 0.006), had lower TAFI activity mal and mean transvalvular MV gradients, as well as with (36.6 ± 11.0 vs. 43.3 ± 14.4%, respectively, p = 0.046), but the degree of MR. We also observed the association of TAFI did not differ regarding t and other parameters. activity and PAI-1:Ag with transvalvular MV gradients. 50% These associations point to the connection between MS and Comorbidities impairment of fibrinolysis. While several tests to assess global plasma fibrinolytic Patients with permanent AF (35 with MS and 5 with AS) activity are available, we used a plasma-based test, in which had longer t than individuals without documented AF a thrombin-induced fibrin clot is lysed by exogenously added 50% (16.0 [13.1–22.6] vs. 13.1 [10.1–16.3] min, p = 0.0002) and rt-PA at relatively high concentrations. This approach was higher PAI-1:Ag (23.4 [15.9–31.4] vs. 13.4 [9.7–19.4] ng/ successfully applied in previous papers [17, 18, 20, 21]. In mL, p < 0.0001). Patients with paroxysmal AF (n = 5) had contrast to the assay previously used by our group in AS higher PAI-1:Ag than individuals without documented AF patients [10], the current method does not use tissue factor, (24.6 [19.0–25.2] vs. 13.4 [9.7–19.4] ng/mL, p = 0.03). and the rtPA concentrations are higher. Based on previous To verify the influence of MS on t in the presence reports, t may be more sensitive to detect the impact of 50% 50% of persistent AF and VKA use, linear regression was uti- PAI-1 on fibrin clot properties [20]. Our findings supported lized. In univariate analysis, all variables were significant this observation by showing that PAI-1:Ag is positively cor- (MS: b = 4.91, adjusted R = 0.17, p < 0.0001; AF: b = 2.54, related with t values. 50% adjusted R = 0.06, p = 0.005; VKA: b = 4.50, adjusted In patients with VHD, we found that inhibition of fibrinol- R = 0.14, p < 0.0001). In multivariate analysis (final model, ysis was modulated most notably by the presence of AF, a adjusted R = 0.18, p < 0.0001), only MS was the predictor prothrombotic condition, involving increased thrombin gen- of t (b = 3.42, p = 0.01). eration and fibrinogen concentrations [22, 23]. Marin et al. 50% reported higher levels of PAI-1 in patients with MS who Surgical outcomes also had AF, as compared with MS patients in normal sinus rhythm [15]. We observed higher PAI-1 levels, along with There were no intergroup differences in the early mortality prolonged t , in subjects with AF (TAFI activity was unaf- 50% rate, re-exploration for bleeding and the length of ICU stay. fected by AF, and modulated only by MS incidence). Our The fatal cases (n = 7) did not differ from survivors with findings are in line with the recent paper by Drabik et al., regard to TAFI and t , but had lower PAI-1 activity (5.3 who reported prolonged CLT and increased PAI-1 levels in 50% [4.1–12.6] vs. 11.5 [6.5–19.3] IU/dL, respectively, p = 0.04). subjects with non-valvular AF [24]. Impaired fibrinolysis, A median postoperative chest tube drainage volume was improved by oral anticoagulants, was also reported by other 440 ml with no AS–MS intergroup difference (Table  2.). investigators exploring fibrinoysis in AF [25, 26]. Only few In patients who required re-exploration for bleeding the patients with progressed MS will present without AF, and median chest-tube output was more than twofold higher than AF contributes to blood stasis in the left atrium in the set- in remaining patients (1120 [650–2000] vs. 420 [320–590] ting of MV stenosis—another component in Virchow’s triad mL, respectively; p = 0.0002). In the whole group (n = 121) equation. The observation that even in MS patients AF is a the postoperative drainage volumes correlated inversely potent enough factor to significantly alter fibrinolysis pro- with platelet count (r = − 0.29, p = 0.002), BMI (r = − 0.25, vides additional evidence for the necessity of anticoagula- p = 0.007), fibrinogen (r = − 0.26, p = 0.006) and PAI-1:Ag tion in this disorder. Nevertheless, MS was a predictor of (r = − 0.22, p = 0.02). Patients with high drainage volumes t independently of AF in this study. 50% (≥ 1000 mL; n = 8, 7%), compared with those with lower The preoperative history of VKA therapy in both groups volumes (n = 113) had lower PAI-1:Ag (by 40%, p = 0.02), warrants a comment. While the groups differed regarding but there were no differences in any other parameters. VKA use, it is unlikely that VKAs influenced the results of t test, markedly elevated in MS patients. Previously, 50% the permeability of the fibrin network was shown to rise in 1 3 200 P. Mazur et al. parallel to elevations of INR and shortening of CLT in AF latter: form of TAFI following the completion of its biologi- patients [25], thus, it could be expected that in the setting cal function of C-terminal arginine and lysine cleavage from of VKA use, t would be shorter. Also LMWHs prolong partially degraded fibrin). A novel observation in the current 50% clot formation and increase the clot susceptibility to lysis study is that the MS is associated with higher TAFI activity [27], and as all anticoagulated patients in this study received than AS, and this finding is independent of AF presence. LMWH bridging prior to operation, t shortening could The similar TAFIa/TAFIai values might be explained by 50% be expected. That notwithstanding, patients with MS, who “compensatory” changes in inactivated TAFI levels in both in this study were most often subjected to anticoagulation, groups, leading to similar ratios. A role of TAFI in hypofi- also had the most “prothrombotic” fibrin clot phenotype (and brinolysis in valvular disorders warrants further studies. longest t ). One might speculate that the effects of VKAs 50% and LMWHs on clot susceptibility to lysis are, arguably, Limitations abolished by MS and AF. On the other hand, our findings point to the importance of anticoagulation in MS, especially The MS and AS groups are representative to patients in eve- with concomitant AF. The prothrombotic state, as presented ryday practice, however they were not matched, and differed by us, is associated with MS, to some extent irrespectively of in some aspects. MS subjects are underrepresented, although AF. Further studies are needed to verify the hypothesis that this reflects the trends in open heart surgery, with a high patients with advanced MS, but with no documented AF, prevalence of AS in patients requiring surgical intervention would benefit from anticoagulant therapy, and to indicate [6]. Still, small sample size of MS patients might be a reason which treatment modality would be most beneficial. for underpowering. Long term follow-up to seek for throm- Furthermore, plasma PAI-1 was associated with enhanced botic complications was beyond the scope of the current bleeding after cardiac surgery in a study by Ozolina et al. on study. Despite sharing many risk factors [2, 5], degenerative 79 cardiosurgical patients (as few as 29 underwent valvular AS and MS likely differ in the underlying pathology. Most surgery) [28]. We demonstrated that plasma PAI-1:Ag is MS patients had AF. inversely correlated with chest-tube output. Yet, even with significant differences in PAI-1:Ag between AS and MS patients, we failed to show any differences in drainage vol- Conclusions umes. Our results confirm that fibrinolysis is a contributor to post-operative blood loss after cardiac surgery, but not We demonstrated that degenerative MS is associated with potent enough to reveal clinical effects after elective valvular more pronounced impairment of global fibrinolytic capac- surgery. It should be mentioned that the bleeding tendency ity than AS at the stage of surgical intervention. AF likely in AS [29] is largely driven by the imbalance in von Wille- contributes to fibrinolysis impairment in MS, but the role brand factor high molecular weight multimers [30]. In our of fibrinolysis in valvular disorders in terms of progression study, the postoperative blood loss was also associated with of the disease and thromboembolic complications requires preoperative fibrinogen level, PLT and BMI. Among the further studies. The relationship between the preoperative factors like fibrinogen or PLT, the cardiosurgical bleeding fibrinolysis activation, antifibrinolytic treatment, and postop- and transfusion risk scores consequently list low BMI/body erative outcomes in cardiac surgery needs to be investigated. weight as a risk factor [31]. Interestingly, PAI-1:Ag and BMI were positively associated in our study, and this association Acknowledgements This work was supported by a grant from the is in line with previous reports [32]. Inhibition of b fi rinolysis Polish Ministry of Science (N N402 383338 to Anetta Undas) and has long been a target of strategies aimed at bleeding reduc- a Grant from the National Science Centre (2012/05/N/NZ5/00846 to tion in cardiac surgery, but there is no obvious consensus on Piotr Mazur). the antifibrinolytic therapy in cardiac surgery. Our results suggest that different groups of patients might require a dif- Compliance with ethical standards ferent antifibrinolytic regimen for optimal outcomes, with Conflict of interest The authors declare that they have no conflicts of adjustment according to the diagnosis-dependent activity of interest. fibrinolysis. In the current report, along with t we studied TAFI, 50%, Ethical approval All procedures were in accordance with the ethical another important fibrinolysis inhibitor, using three assays standards of the institutional ethical committee and with the 1964 Hel- sinki declaration and its later amendments. [33]. This aspect of fibrinolyis was not studied yet in the context of VHD. TAFI:Ag measures all forms of TAFI in Informed consent Informed consent was obtained from all individual plasma: pro-TAFI, active and inactivated TAFI. TAFI:Act participants included in the study. reflects only the active form of TAFI, while TAFIa/TAFIai reflects the ratio of active and inactivated TAFI levels (the 1 3 Impaired fibrinolysis in degenerative mitral and aortic valve stenosis 201 Open Access This article is distributed under the terms of the Crea- 15. Marin F, Roldan V, Monmeneu JV, Bodi V, Fernandez C, de Bur- tive Commons Attribution 4.0 International License (http://creat iveco gos FG, Marco P, Sogorb F (1999) Prothrombotic state and ele- mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- vated levels of plasminogen activator inhibitor-1 in mitral stenosis tion, and reproduction in any medium, provided you give appropriate with and without atrial fibrillation. Am J Cardiol 84:862–864 credit to the original author(s) and the source, provide a link to the 16. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias Creative Commons license, and indicate if changes were made. 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Journal of Thrombosis and Thrombolysis – Springer Journals

Published: May 31, 2018

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