Elevated plasma D-dimer level is associated with short-term poor outcome in patients with acute ischemic stroke: a prospective, observational study

Abstract

Background

Epidemiological investigations have concluded that stroke is a leading cause of adult disability and mortality, it poses a serious public health burden worldwide [1-3]. Recently the multicenter Global Burden of  Disease (GBD 2016) Study found that risk of ischemic stroke was 18.3% ，the risk of hemorrhagic stroke was 8.2% among adults 25 years of age or older [4]. As a predominant stroke subtype in Chinese populations[5], AIS was up to 66.4% among the stroke subtypes between September 2007 and August 2008 in the Chinese  National Stroke Registry  [6]. Because of the high morbidity of AIS and high risk of disability after AIS, the estimation of prognosis is an emergent issue when physicians confront with these concerns from patients and families after AIS. Recent studies have found prognostic factors such as glycemic index, BMI and uric acid, but their prognostic values on AIS was inconsistent [7-12]. For better specific management of stroke rehabilitation regarding neurological functional outcomes, identifying more powerful predictors of clinical prognosis is indispensable.

D-dimer is a final soluble fibrin degradation product and derived from the cross-linked fibrin network undergoes plasmin-mediated degradation. As D-dimer level reflects increases in blood thrombosis and degradation of fibrin, D-dimer could be a biological marker of hemostatic abnormalities and thrombosis[13]. Elevated D-dimer level is reportedly a determinant of stroke progression [14], and infarction volume [15] and the incidence of stroke [16]. There are recently many studies about whether D-dimer is a determinant of poor functional outcomes after AIS, however, the conclusions of studies were controversial [17-20]. Some investigators found that D-dimer level could predict independently poor functional outcomes in patients with AIS[17, 18], other investigators reported the conflicting results[19, 20].

Accordingly, the aim of this study was to investigate whether elevated D-dimer level could be a significant determinant of poor outcome after admission for AIS.

Methods

Study population

This was a prospective study based on retrospectively collected data. We collected the records of acute ischemic stroke patients at Renmin Hospital of Wuhan University from January 2017 to August 2018. All patients were admitted within 72 hours of experiencing a new focal or global neurological event. Acute ischemic stroke was diagnosed according to the World Health Organization criteria [21] combined with brain computed tomography or magnetic resonance confirmation within 72 hours. Patients were excluded if any of the following criteria were met: a delay of 72 hours from symptom recognition to admission, age younger than 18 years, preexisting significant disability (defined as modified Rankin scale, mRS2) from any condition, intracranial hemorrhage, malignancy, febrile disorders, acute or chronic inflammatory disease at study enrollment. Each participant was followed up after 3 months via telephone, email, and face to face. The study protocol complied with the Declaration of Helsinki and approved by the Wuhan University Ethics Committee.

Demographic and clinical assessment

Socio-demographic, self-reported medical history and vascular risk biomarker data were assessed and included: age, sex, body mass index (BMI), histories of hypertension, diabetes, alcohol consumption, smoking, dyslipidemia, atrial fibrillation, previous stroke, and coronary artery disease (CAD). The National Institutes of Health Stroke Scale (NIHSS) scores were used by stroke neurologists to assess neurological deficit when the patients were admitted [22]. Stroke subtype was

classified according to Trial of Org 10172 in acute stroke treatment (TOAST classification) criteria [23], which distinguished large-artery arteriosclerosis, small-artery occlusion, cardio-embolism, other causative factor, and undetermined causative factor.

Fasting plasma glucose (FPG) and plasma D-dimer were measured on the first morning of admission after at least 8 h of fasting. Plasma D-dimer levels were assessed for all patients upon admission with a particle-enhanced, immunoturbidimetric assay in a calibrated SYSMEX7000 analyzer (Sysmex Corporation, Hyogo, Japan). The normal range of morning plasma D-dimer concentration in our hospital laboratory is 0–0.55 mg/L.

Patient follow-up was performed at 90 days after stroke onset. The prognosis outcome was assessed with mRS by telephone interview by a trained research nurse or neurologist, a good functional outcome was defined as a mRS of 0–2 points, whereas a poor outcome was defined as a mRS of 3–6 points.

Statistical analysis

For continuous variables, data are expressed either as the means ± standard deviations (SD) or medians (interquartile ranges, IQR). Discrete variables are expressed as frequencies and percentages. The patients were categorized into two groups according to prognosis outcome (good outcome group vs poor outcome group) and four quartiles groups according to their median plasma D-dimer levels at admission. The statistical significance of inter-group differences was assessed by χ2 tests, unpaired Student t-test, one-way analysis of variance (ANOVA) and Mann–Whitney U tests, as appropriate. In this study, we collected variables associated with functional outcomes of AIS included sex, age, BMI, vascular risk factors smoker, Alcohol drinker, atrial fibrillation, diabetes, hypertension, CAD, dyslipidemia, previous stroke, baseline Systolic pressure , baseline Systolic pressure , FBG , baseline NIHSS scores and stroke subtype. Multivariate analysis adjustment for variables was performed for the relationship between the quartiles of D-dimer and poor outcome by logistic regression analysis, which used methods from previous studies [24, 25] . Results were expressed as adjusted odds ratios (OR) with the corresponding 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of D-dimer to predict AIS poor neurological outcomes. The area under the curve (AUC) was calculated as measurements of the accuracy of the test. All statistical analysis was performed with SPSS for Windows, version 22.0 (SPSS Inc., Chicago, IL, USA). P<0.05 was considered statistically significant.

A total of 877 AIS patients (median age 64 years,68.5% male) who met the inclusion criteria were recruited for this study，median D-dimer level on admission was 0.56 (0.24-1.79) mg /L, and the median NIHSS score on admission was 5(3–8). Among the 877 patients, 575(65.6%) presented with good outcomes, 302 (34.4%) presented with poor outcomes and 109 (8.8%) had died by 90 days. The baseline characteristics and outcomes of the patients with AIS are described in Table 1. The sex, age, BMI, smoker, history of atrial fibrillation, FBG, D-dimer, baseline NIHSS scores and stroke etiology were markedly associated with the outcomes of AIS at 90 days (P<0.05 for all).

Figure 1 shows the plasma D-dimer levels between two functional outcome groups. In the patients with pour outcome, plasma D-dimer levels were significantly higher compared with those in patients with good outcome [0.88(IQR, 0.42–2.72) mg/L vs 0.46 (IQR, 0.21–1.32) mg/L; P=0.001]

Correlation between D-dimer and 90-Day functional outcome

Patients were stratified into four groups according to D-dimer quartiles: Plasma D-dimer level 0.24, 0.25–0.56, 0.57–1.78, and 1.78mg /L (Table 2). Among the four groups, there were no significant differences in the history of hypertension, diabetes, dyslipidemia, previous stroke, Alcohol drinker, FBG, and baseline Systolic pressure (P0.05 for all). Age, sex, BMI, smoker, atrial fibrillation, baseline Diastolic pressure, baseline NIHSS scores, stroke etiology, and mortality differed among the four groups (P<0.05 for all). The unadjusted comparisons of the four groups revealed more poor outcomes among the higher quartiles of D-dimer (Figure 2).

Univariate analysis shows a clear relationship between admission D-dimer and functional outcome (Figure 3). Furthermore, the associations between D-dimer and pour outcome after adjustment are detailed in Tables 3. In patients with high D-dimer, the risk of poor functional outcome at 90 days was significantly increased as compared with the group with low D-dimer (P trend = 0.000, OR = 3.800, 95% CI = 2.420-5.965 for Q4: Q1; adjusted for age, sex and BMI). Additional adjustment for smoker, Alcohol drinker, atrial fibrillation, diabetes, hypertension, CAD, dyslipidemia ,previous stroke, baseline Systolic pressure , baseline Systolic pressure , FBG , baseline NIHSS scores and stroke etiology did not influence this finding, an overall OR of 2.257 (P trend = 0.004, 95% CI = 1.349-3.777 for Q4: Q1) was found for patients with high D-dimer.

To further evaluate the predictive values of Plasma D-dimer levels in patients with AIS, the ROC curves and AUCs were created and are depicted (Figure 4). Based on the ROC curve, the optimal cut-off value of plasma D-D levels as an indicator for diagnosis of unfavorable functional outcome was projected to be 0.315 mg/L, which yielded a sensitivity of 83.8% and a specificity of 41.4%, the area under the curve was 0.657 (95%CI, 0.620–0.694; P=0.000).

Discussion

In the present study, higher D-dimer level on admission was a significant independent determinant of short-term neurological dysfunction in patients with AIS within 90 days in the Chinese population. After adjusting for various confounders, the association remained significant.

Previous prospective epidemiological investigations have concluded that there is a positive association between D-dimer levels and stroke [26-28]. In some studies, the results showing that D-dimer was associated with stroke severity [29, 30], infarct volume [15, 31, 32] and progression of stroke status [14, 33, 34]. While in the patient with AIS, there are not many studies about the association between D-dimer levels and poor outcomes.

The available investigations of stroke have shown a correlation between D-dimer levels and functional outcomes and the prognostic value of D-Dimer in several different types of population with AIS [35-39]. Nam et al. [35] and Nezu et al. [36] found a predictive role of D-dimer only in patients with cryptogenic stroke. A Canadian study by Kim et al. [37] reported prognostic Value of plasm D-Dimer in patients with noncardioembolic stroke. In the study of the Chinese population complicating coronary heart disease, the result indicated that higher D-dimer levels had worst outcomes within 90 days after initial onset of AIS[38]. A Swiss study by Hsu et al. reported high plasma D-dimer indicates unfavorable outcome of in patients with AIS receiving intravenous thrombolysis[39]. But review previous literature, we also found that some other studies have reported conflicting results in comparison. A report by Squizzato et al. [19] revealed that D-dimer levels with AIS probably do not predict the functional outcome after adjustment for age and stroke subtype. Furthermore, two other studies even did not find a meaningful association between D-dimer and the prognosis of patients with AIS[40, 41].

In this study, because the prognostic did not alter even if adjusted various confounders such as age, sex, BMI, vascular risk factors, baseline NIHSS scores, and stroke etiology, our results revealed D-dimer is an independent biological prognostic marker of AIS. Actually, the positive value of plasm D-Dimer in patients with all subtypes of AIS was indicated in the previous several studies [33, 41, 42], which is consistent with our findings.

D-dimer derived from the cross-linked fibrin network is a final soluble fibrin degradation product undergoes plasmin-mediated degradation [13]. D-dimer could be elevated in population with thrombotic diseases such as pulmonary embolism and venous thromboembolism [42, 43], however, the mechanism remains unclear. There are several possible explanations for why D-dimer levels might be relevant to poor functional outcomes in patient with AIS. First of all, D-dimer level increases in blood coagulation and degradation of fibrin and could be a marker of thrombosis based on the underlying mechanisms [44, 45]. Moreover, high D-dimer levels may result in resistant to the endogenous fibrinolytic system and influence thromboembolism formation [40, 46]. Furthermore, D-dimer also stimulates the immune system and lead to changes in inflammatory mediators levels such as IL-1, TNF-alpha, IL-6, and IL-8 [47, 48]. Activated inflammation may contribute to the pathological alteration in patients with AIS [49]. In addition, infarct volume, initial stroke severity, and progression of stroke status were correlated with high D-dimer levels [14, 29-34], therefore elevated D-dimer levels may predict poor outcomes through the aggravation of cerebral tissue damage by disturbing recanalization and increasing reperfusion injury. Additionally, D-dimer level in patients with AIS may identify patients who may benefit from additional interventions, targeting some of the mechanisms mentioned above. This need be explored in further studies.

This current study has several limitations. First, this is a single-center, observational study. The sample sizes of patients are small, and selection bias was a major concern, therefore limiting the power to generalize our results. Second, the D-dimer levels were recorded only at admission, recording the serial change of D-dimer levels might be better explored the correlation between D-dimer and outcomes after AIS. Finally, our study did explore short-term outcomes whose end-point was defined at 90 days. The relationship between D-dimer levels and long-term prognosis require further confirmation in our study population. Therefore, further larger sample size, multicenter studies are needed to carry out.

1 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS et al: Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013, 127(1):e6-e245.

2. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T et al: Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet (London, England) 2014, 383(9913):245-254.

3. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England) 2015, 386(9995):743-800.

4. VL F, G N, K C, CO J, T A, PG P, AA A, KH A, F A-A, AN A et al: Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. The New England journal of medicine 2018, 379(25):2429-2437.

5. Wang Y, Liu M, Pu C: 2014 Chinese guidelines for secondary prevention of ischemic stroke and transient ischemic attack. International Journal of Stroke Official Journal of the International Stroke Society 2017, 12(3):302.

6. Yongjun W, Liying C, Xunming J, Qiang D, Jinsheng Z, Yilong W, Yong Z, Xingquan Z, Chunxue W, Liping L: The China National Stroke Registry for patients with acute cerebrovascular events: design, rationale, and baseline patient characteristics. International Journal of Stroke Official Journal of the International Stroke Society 2011, 6(4):355-361.

7. Wolfram D, Johannes S, Anker SD, Jochen S, Audebert HJ: Overweight and obesity are associated with improved survival, functional outcome, and stroke recurrence after acute stroke or transient ischaemic attack: observations from the TEMPiS trial. European Heart Journal 2013, 34(4):268-277.

8. Luitse MJ, Velthuis BK, Kappelle LJ, Van dGY, Biessels GJ, Group DS: Chronic hyperglycemia is related to poor functional outcome after acute ischemic stroke. International Journal of Stroke 2017, 12(2):180.

9. Mapoure YN, Ayeah CM, Doualla MS, Ba H, Hbm N, Mbahe S, Luma HN: Serum Uric Acid Is Associated with Poor Outcome in Black Africans in the Acute Phase of Stroke. Stroke Res Treat 2017, 2017(11):1935136.

10. Sun W, Huang Y, Xian Y, Zhu S, Jia Z, Liu R, Li F, Wei JW, Wang JG, Liu M: Association of body mass index with mortality and functional outcome after acute ischemic stroke. Sci Rep 2017, 7(1):2507.

11. Sung JY, Chen CI, Hsieh YC, Chen YR, Wu HC, Chan L, Hu CJ, Hu HH, Chiou HY, Chi NF: Comparison of admission random glucose, fasting glucose, and glycated hemoglobin in predicting the neurological outcome of acute ischemic stroke: a retrospective study. Peerj 2017, 5(9):e2948.

12. Wang YF, Li JX, Sun XS, Lai R, Sheng WL: High serum uric acid levels are a protective factor against unfavourable neurological functional outcome in patients with ischaemic stroke. Journal of International Medical Research 2018, 46(5):1826-1838.

13. Weitz JI, Fredenburgh JC, Eikelboom JW: A Test in Context: D-Dimer. Journal of the American College of Cardiology 2017, 70(19):2411.

14. Mark B, Peter L, Ann R, Lowe GDO, Stott DJ: Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression. Stroke 2004, 35(6):1421-1425.

15. Mari M, Manabu S, Shuhei O, Shigetaka F, Masafumi T, Hideki E, Takeshi S, Toshiki Y, Hideki M, Kazuo K: Relationship between plasma (D)-dimer level and cerebral infarction volume in patients with nonvalvular atrial fibrillation. Cerebrovascular Diseases 2013, 35(1):64-72.

16. Zhang J, Song Y, Shan B, He M, Ren Q, Zeng Y, Liu Z, Liu H, Xu J: Elevated level of D-dimer increases the risk of stroke. Oncotarget 2018, 9(2):2208-2219.

17. Paul W, Mark B, Peter L, Ann R, Lowe GDO, Stott DJ: Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovascular Diseases 2009, 27(3):247-253.

18. Dougu N, Takashima S, Sasahara E, Taguchi Y, Toyoda S, Hirai T, Nozawa T, Tanaka K, Inoue H: Predictors of poor outcome in patients with acute cerebral infarction. Journal of Clinical Neurology 2011, 7(4):197-202.

19. Squizzato A, Ageno W, Finazzi S, Mera V, Romualdi E, Bossi A, Venco A: D-dimer is not a long-term prognostic marker following acute cerebral ischemia. Blood Coagulation & Fibrinolysis 2006, 17(4):303-306.

20. Haapaniemi E, ., Tatlisumak T, . Is D-dimer helpful in evaluating stroke patients? A systematic review. Acta Neurologica Scandinavica 2010, 119(3):141-150.

21. Listed N: Stroke--1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke; a journal of cerebral circulation 1989, 20(10):1407.

22. Brott T, ., Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, ., Spilker J, ., Holleran R, ., Eberle R, ., Hertzberg V, . Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989, 20(7):864-870.

23. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, 3rd: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993, 24(1):35-41.

24. Deng QW, Wang H, Sun CZ, Xing FL, Zhang HQ, Zuo L, Gu ZT, Yan FL: Triglyceride to high-density lipoprotein cholesterol ratio predicts worse outcomes after acute ischaemic stroke. Eur J Neurol 2017, 24(2):283-291.

25. Luitse MJ, Velthuis BK, Kappelle LJ, van der Graaf Y, Biessels GJ: Chronic hyperglycemia is related to poor functional outcome after acute ischemic stroke. International journal of stroke : official journal of the International Stroke Society 2017, 12(2):180-186.

26. Di Castelnuovo A, Agnoli C, de Curtis A, Giurdanella MC, Sieri S, Mattiello A, Matullo G, Panico S, Sacerdote C, Tumino R et al: Elevated levels of D-dimers increase the risk of ischaemic and haemorrhagic stroke. Findings from the EPICOR Study. Thrombosis and haemostasis 2014, 112(5):941-946.

27. Folsom AR, Gottesman RF, Appiah D, Shahar E, Mosley TH: Plasma d-Dimer and Incident Ischemic Stroke and Coronary Heart Disease: The Atherosclerosis Risk in Communities Study. Stroke 2016, 47(1):18.

28. Hamatani Y, Nagai T, Nakai M, Nishimura K, Honda Y, Nakano H, Honda S, Iwakami N, Sugano Y, Asaumi Y et al: Elevated Plasma D-Dimer Level Is Associated With Short-Term Risk of Ischemic Stroke in Patients With Acute Heart Failure. Stroke 2018, 49(7):1737-1740.

29. Berge E, Friis P, Sandset PM: Hemostatic Activation in Acute Ischemic Stroke ☆. Thrombosis Research 2001, 101(2):13-21.

30. Barbieri A, ., Giuliani E, ., Carone C, ., Pederzoli F, ., Mascheroni G, ., Greco G, ., Stucchi C, ., Genedani S, . Clinical severity of ischemic stroke and neural damage biomarkers in the acute setting: the STROke MArkers (STROMA) study. Minerva Anestesiologica 2013, 79(7):750.

31. Young-Woo P, Eun-Jeong K, Ha-Young C: Correlation between Serum D-Dimer Level and Volume in Acute Ischemic Stroke. Journal of Korean Neurosurgical Society 2011, 50(2):89.

32. Zi WJ, Shuai J: Plasma D-dimer levels are associated with stroke subtypes and infarction volume in patients with acute ischemic stroke. Plos One 2014, 9(1):e86465.

33. Mark B, Peter L, Ann R, Lowe GDO, Stott DJ: D-dimer predicts early clinical progression in ischemic stroke: confirmation using routine clinical assays. Stroke; a journal of cerebral circulation 2006, 37(4):1113-1115.

34. Zang R, Zhang H, Xu Y, Zhang S, Liu X, Wang J, Gao Y, Shu M, Mei B, Li H: Serum C-reactive protein, fibrinogen and D-dimer in patients with progressive cerebral infarction. Translational Neuroscience 2016, 7(1):84-88.

35. Nam KW, Kim CK, Kim TJ, An SJ, Demchuk AM, Kim Y, Jung S, Han MK, Ko SB, Yoon BW: D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. European Journal of Neurology 2016, 24(1).

36. Nezu T, Kitano T, Kubo S, Uemura J, Yamashita S, Iwanaga T, Inoue T, Hosomi N, Maruyama H, Matsumoto M: Impact of D-dimer levels for short-term or long-term outcomes in cryptogenic stroke patients. Journal of Neurology 2018, 265(3):1-9.

37. Kim TW, Song IU, Chung SW: Prognostic Value of Serum D-Dimer in Noncardioembolic Ischemic Stroke. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques 2017, 44(4):404-409.

38. Wang Y, Hafeez A, Meng F, Zhang R, Wang X, Chen X, Kong Q, Du H, Ma X: The correlation of D-dimer levels with patient outcomes in acute ischemic cerebrovascular disease complicating coronary heart disease. Neurological Research 2016, 38(6):524-532.

39. 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(1-2):117-121.

40. Lip GY, Blann AD, Farooqi IS, Zarifis J, Sagar G, Beevers DG: Sequential alterations in haemorheology, endothelial dysfunction, platelet activation and thrombogenesis in relation to prognosis following acute stroke: The West Birmingham Stroke Project. Blood Coagulation & Fibrinolysis 2002, 13(4):339-347.

41. Rallidis LS, Vikelis M, ., Panagiotakos DB, Liakos GK, Krania E, ., Kremastinos DT: Usefulness of inflammatory and haemostatic markers to predict short-term risk for death in middle-aged ischaemic stroke patients. Acta Neurologica Scandinavica 2010, 117(6):415-420.

42. Keller K, Beule J, Balzer JO, Dippold W: D-Dimer and thrombus burden in acute pulmonary embolism. The American journal of emergency medicine 2018, 36(9):1613-1618.

43. Sartori M, Migliaccio L, Favaretto E, Cini M, Legnani C, Palareti G, Cosmi B: D-dimer for the diagnosis of upper extremity deep and superficial venous thrombosis. Thromb Res 2015, 135(4):673-678.

44. Matsuo T, ., Kobayashi H, ., Kario K, ., Suzuki S, . Fibrin D-dimer in thrombogenic disorders. Seminars in Thrombosis & Hemostasis 2000, 26(01):101-107.

45. Kogan AE, Mukharyamova KS, Bereznikova AV, Filatov VL, Koshkina EV, Bloshchitsyna MN, Katrukha AG: Monoclonal antibodies with equal specificity to D-dimer and high-molecular-weight fibrin degradation products. Blood Coagulation & Fibrinolysis 2016, 27(5):542-550.

46. Urbach H, ., Hartmann A, ., Pohl C, ., Omran H, ., Wilhelm K, ., Flacke S, ., Schild HH, Klockgether T, . Local intra-arterial thrombolysis in the carotid territory: does recanalization depend on the thromboembolus type? Neuroradiology 2002, 44(8):695.

47. Shorr AF, Thomas SJ, Alkins SA, Fitzpatrick TM, Ling GS: D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients. Chest 2002, 121(4):1262.

48. Robson SC, Shephard EG, Kirsch RE: Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 2010, 86(2):322-326.

49. Mar C, José C, García MM, Rogelio L, Joaquín S, Angel C, Antoni D: Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke 2002, 33(4):982-987.