Dig Dis Sci DOI 10.1007/s10620-015-3701-1
ORIGINAL ARTICLE
Persistent Reactive Thrombocytosis May Increase the Risk of Coronary Artery Disease Among Inflammatory Bowel Disease Patients Sudeep Dhoj Thapa1 • Hiba Hadid1 • Waseem Imam1 • Ahmad Hassan1 Muhammad Usman1 • Syed-Mohammed Jafri2 • Jason Schairer2
•
Received: 15 March 2015 / Accepted: 2 May 2015 Ó Springer Science+Business Media New York 2015
Abstract Background IBD patients are at increased risk of coronary artery disease in the absence of traditional risk factors. However, the disease-related risk factors remain poorly understood although increased inflammation seems to increase cardiovascular disease risk in IBD. Thrombocytes are involved in the pathogenesis of coronary artery disease, and a subset of IBD patients have reactive thrombocytosis. Aim The aim of our study was to investigate the effect of persistent reactive thrombocytosis on the development of coronary artery disease in IBD. Methods We evaluated a retrospective cohort of 2525 IBD patients who were evaluated at the Henry Ford hospital from 2000 to 2004. We performed a case–control study comparing patients with persistent thrombocytosis and patients without persistent thrombocytosis. Cases (n = 36) and controls (n = 72) were matched for age and gender. Coronary artery disease incidence was compared between the two groups. Results Cases (n = 36) and controls (n = 72) were matched for age and gender. Cases and controls were similar in age at onset of IBD (41.5 vs. 35.5, p value 0.11) and smoking status (33.3 vs. 27.8 %, p value 0.66). Persistent thrombocytosis was less common among Caucasian patients (44.44 vs. 62.5 %, p value 0.09) and more common in patients who had exposure to steroids during the study follow-up period. Coronary artery disease occurred & Sudeep Dhoj Thapa [email protected]; [email protected] 1
Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
2
Department of Gastroenterology, Henry Ford Hospital, Detroit, MI, USA
in 13 (36.1 %) patients with persistent thrombocytosis compared to only seven (9.7 %) patients in the control group. Conclusions Persistent reactive thrombocytosis among IBD patients is associated with increased risk of coronary artery disease. Further studies should characterize the clinical and molecular associations of this phenomenon and determine appropriate therapeutic measures. Keywords Platelets Inflammatory bowel disease Coronary artery disease Ulcerative colitis Crohn’s disease Abbreviations IBD Inflammatory bowel disease HDL High-density lipoprotein LDL Low-density lipoprotein RT Reactive thrombocytosis CD Crohn’s disease UC Ulcerative colitis BMI Body mass index
Introduction Reactive thrombocytosis (RT) is defined as an increase in platelet count associated with conditions other than chronic myeloproliferative or myelodysplastic disorders and is the most common etiology of thrombocytosis in the general population [1]. It is induced by multiple inflammatory conditions including inflammatory bowel disease [2, 3]. Thrombocytosis is common among IBD patients. Thrombocytosis in IBD is a marker of inflammation, and platelets themselves exhibit proinflammatory properties
123
Dig Dis Sci
including secretion of inflammatory cytokines [4]. Platelets also have a long-established role in the pathogenesis of coronary artery disease, and thrombocytosis is known to increase the risk of coronary artery disease [5, 6]. The clinical significance of RT which is observed in IBD patients remains poorly understood. There is growing evidence that patients with IBD are at increased risk of coronary artery disease in the absence of traditional risk factors [7]. A study by Aggarwal et al. [8] showed that the age, body mass index, and smoking which are strong predictors of coronary artery disease in the general population have a lower impact among IBD patients, further supporting the role of atypical cardiovascular risk factors among IBD patients. However, the disease-specific risk factors remain poorly understood. We hypothesized that persistent thrombocytosis is associated with increased coronary artery disease incidence in IBD. Therefore, we sought to investigate the difference in coronary artery disease incidence among patients with and without persistent thrombocytosis.
Methods The study population consisted of patients with either Crohn’s disease or ulcerative colitis who were evaluated at Henry Ford hospital from January 1, 2000 to December 31, 2004. Patients were initially identified using ICD-9 codes 555.xx and 556.xx, and chart review was done to identify patients with histological evidence of CD or UC. Patients between 30 and 74 years of age on initial presentation with follow-up data available for at least 10 years were further identified. Patients with history of cardiovascular and cerebrovascular disease (coronary artery disease, congestive heart failure, ischemic stroke, transient ischemic attack, and peripheral vascular disease) were excluded. We also excluded patients with any lymphoproliferative disorder in order to include only those patients who had RT. Study design and patient selection are displayed in Fig. 1. Henry Ford hospital electronic medical records were reviewed to abstract demographic and clinical data. Thrombocytosis was defined as blood platelet count greater than 450 cells per deciliter. We defined persistent thrombocytosis as platelet count more than 450 cells per deciliter for at least four separate occasions with each episode occurring 3 or more months apart to avoid falsely elevated single laboratory values and thrombocytosis due to other acute illness. We conducted a case–control study of IBD patients with thrombocytosis and patients without thrombocytosis. Two controls were selected for every case after matching for age and gender. Demographic information including age, gender, race, body mass index, and smoking history (smoker or non-
123
smoker) were abstracted for all study participants. Patient charts were reviewed for hypertension, diabetes mellitus, chronic kidney disease, inflammatory bowel disease subtype (CD vs. UC), and disease extent. Baseline lipid levels including total cholesterol, high-density lipoprotein, lowdensity lipoprotein, and triglyceride levels were collected. Histopathology and colonoscopy results on extent of intestinal involvement were also reviewed. IBD-related medication use during any time prior to the development of coronary artery disease including 5-ASA, steroids, thiopurines, and TNF antagonist was collected. Disease-related surgery during the follow-up period was also recorded. Hematological laboratory tests were reviewed for platelet count and myeloproliferative disorders. Patient records were abstracted for coronary catheterizations, echocardiograms, stress tests, and coronary CT scans to identify patients who developed coronary artery disease during the follow-up period. Statistical Analysis We used R statistical software, version 3.1.2, for all statistical analyses. Continuous variables were summarized using medians and IQR, and categorical variables were expressed as absolute values and percentage. Categorical variables were analyzed using the Fisher’s exact test, and continuous variables were analyzed using the Mann– Whitney test. Further analysis was done with univariate logistic regression to identify variables significantly associated with coronary artery disease development. Variables which were significantly associated with coronary artery disease in the univariate model were adjusted using multivariate logistic regression analysis. A p value of 0.05 was used as the threshold of significance.
Results We identified 36 IBD patients who demonstrated persistent RT and compared them to 72 age- and gender-matched controls selected from the initial cohort of IBD patients. Baseline characteristics are given in Table 1. The proportion of Caucasian patients was lower in persistent thrombocytosis group compared to the control group (44.44 vs. 62.5 %, p value 0.09); however, it was not statistically significant. The two groups were also similar in IBD subtype with similar proportion of CD and UC between the two groups (Table 2). Furthermore, cases and controls were similar in HDL level, hypertension, choric kidney disease, and diabetes mellitus (Table 2). Additionally, patients with persistent thrombocytosis had lower total cholesterol and LDL levels compared to the control group (Table 2).
Dig Dis Sci Fig. 1 Study design and patient selection
2525 inial paents
444 final paents 2081 paents excluded -
No histological diagnosis 74 years of age lymphoproliferave disorders Loss of follow up Prior cardiovascular disease
36 paents with persistent thrombocytosis
72 paents without persistent thrombocytosis
13 (36.1%) paents developed coronary artery disease
7 (9.7%) paents developed coronary artery disease
Table 1 Baseline demographic characteristics Characteristics Age, median (IQR)
Persistent thrombocytosis (n = 36)
p value
47.5 (36, 57)
0.74
Age at onset, median (IQR) Caucasian race, n (%)
41.5 (32, 53.3) 16 (44.44 %)
35.5 (29, 46) 45 (62.5 %)
0.11 0.09
BMI, median (IQR)
27.2 (24.2, 30.3)
27.9 (24.5, 31.9)
0.3
21 (58.33 %)
40 (55.6 %)
0.84
Female gender, n (%)
49 (38.3, 57.3)
No thrombocytosis (n = 72)
Obese, n (%)
10 (27.8 %)
29 (40.3 %)
0.29
Smoker, n (%)
12 (33.3 %)
20 (27.8 %)
0.66
The age at diagnosis and anatomical disease extent were also similar between the cases and controls (Table 2). Patients with RT were more likely to receive steroid therapy during the follow-up period compared to the control group (55.6 vs. 33.3 %, p value 0.04). There was no difference in thiopurine use (16.7 vs. 13.9 %, p value 0.78) or TNF antagonist use (19.6 vs. 18.1 %, p value 1) between the two groups. There was also no difference in disease-related surgery between patients with and without persistent thrombocytosis (38.9 vs. 27.8 %, p value 0.28). We evaluated the extent of baseline cardiovascular risk factors between the cases and the controls. There was no difference in the median body mass index (BMI) (27.2 vs 27.9, p value 0.3) or number of hypertensive patients (27.8 vs. 26.4 %, p value 1) between the two groups. Framingham risk score (2008) was calculated for all the study subjects. The score predicts the 10-year risk of developing cardiovascular disorders including coronary artery disease [9]. The median Framingham risk score was similar between the
cases and controls (4.09 vs. 6.53, p value 0.35), signifying similar traditional risk of developing coronary artery disease between the two groups. There was a significant difference in coronary artery disease incidence between the cases and controls (36.1 vs. 9.7 %, p value 0.002) Further analysis was done using univariate logistic regression to identify variables associated with the development of coronary artery disease. Female gender (OR 0.34, 95 % CI 0.12, 0.91; p value = 0.04) was associated with decreased coronary artery disease incidence, whereas higher Framingham risk score (OR 1.08, 95 % CI 1.03, 1.15; p value = 0.005) and persistent thrombocytosis (OR 5.25, 95 % CI 1.91, 15.53; p value = 0.002) were associated with increased risk. Framingham risk score (OR 1.1, 95 % CI 1.04, 1.18; p value = 0.003) and persistent thrombocytosis (OR 3.1, 95 % CI 2.29, 24.15; p value = 0.001) were included in the multivariate logistic regression model and were significantly associated with coronary artery disease. The results are given in Table 3.
123
Dig Dis Sci Table 2 Clinical characteristics Characteristics
Persistent thrombocytosis (n = 36)
No thrombocytosis (n = 72)
p value
IBD type UC, n (%)
20 (55.6 %)
45 (62.5 %)
CD, n (%)
16 (44.4 %)
27 (37.5 %)
Total cholesterol, median (IQR)
186 (161.8, 201.8)
Low-density lipoprotein, median (IQR)
100.5 (80, 116.75)
High-density lipoprotein, median (IQR)
56.5 (41, 68.5)
Triglyceride level, median (IQR) Platelet count (K/mL), median (IQR) Chronic kidney disease, n (%) Diabetes mellitus, n (%) HTN Framingham score, median (IQR)
0.54
203.5 (173, 230.8)
0.01
119.5 (95.3, 147.3)
0.002
53 (43.8, 64.3)
0.49
92 (79.5, 137.8)
115 (80.75, 167.8)
0.26
573 (523.2, 672.5)
284 (238.5, 370.2)
\0.001
4 (11.1 %)
4 (5.6 %)
0.44
7 (19.4 %)
11 (15.3 %)
0.59
10 (27.8 %) 4.09 (2.62, 8.42)
19 (26.4 %) 6.53 (2.9, 12.17)
1 0.35
13 (65 %)
19 (42.2 %)
0.11
7 (35 %)
26 (57.8 %)
4 (25 %)
11 (40.7 %)
12 (75 %)
16 (59.3 %)
UC disease location, n (%) Pancolonic UC Left sided and proctitis CD disease behavior, n (%) Stricturing Inflammatory CD disease location, n (%)
0.22 0.43
Ileal
2 (12.5 %)
Colonic
4 (25 %)
2 (7.5 %) 12 (44.4 %)
Ileocolonic
10 (62.5 %)
13 (48.1 %)
5-ASA, n (%)
27 (75 %)
45 (62.5 %)
Steroid, n (%)
20 (55.6 %)
24 (33.3 %)
0.04
6 (16.7 %)
10 (13.9 %)
0.78
Thiopurine (azathioprine or 6-mercaptopurine), n (%) TNF antagonist, n (%) Surgery, n (%) Coronary artery disease, n (%) Death, n (%)
7 (19.6 %)
13 (18.1 %)
1
14 (38.9 %) 13 (36.1 %)
20 (27.8 %) 7 (9.7 %)
0.28 0.002
3 (8.3 %)
2 (2.8 %)
0.33
Discussion We conducted this study with the aim of investigating the role of chronic thrombocytosis in coronary artery disease incidence among IBD patients. Thrombocytosis is a commonly encountered condition among IBD patients and is a marker of disease activity [10]. We discovered increased need for steroid treatment and coronary artery disease incidence among IBD patients with persistent thrombocytosis. Furthermore, persistent thrombocytosis remained significantly associated with coronary artery disease after adjusting for disease-related risk factors in univariate and multivariate logistic regression analysis. These findings suggest that persistent thrombocytosis may serve as a biomarker of increased coronary artery disease risk among IBD patients. Coronary artery disease risk in the general population is influenced by certain modifiable (cholesterol level,
123
0.28
smoking, and hypertension) and non-modifiable (age and gender) risk factors. There are also several established risk score calculators that are used in clinical medicine [9, 11]. The most well established of them is the Framingham risk score which predicts 10-year risk of developing general cardiovascular diseases and is based on age, gender, smoking status, high-density lipoprotein, and total cholesterol level [9]. We used the Framingham risk score to calculate the baseline risk of developing coronary artery disease between the cases and controls. We selected our study dates to allow for a 10-year follow-up period. In addition, we aimed to study patients who developed new onset coronary artery disease during the follow-up period. Therefore, we excluded patients with known cardiovascular and cerebrovascular disease prior to the study start date. Furthermore, to avoid ‘‘loss of followup bias,’’ we selected only those patients who had followup data available for at least 10 years. In addition, we
Dig Dis Sci Table 3 Logistic regression analysis
Characteristics
Univariate analysis OR (95 % CI)
Multivariate analysis p value
Age
1.03 (0.99, 1.08)
0.17
Age at onset
1.01 (0.98, 1.05)
0.49
Caucasian race
0.63 (0.23, 1.76)
0.37
Body mass index
0.94 (0.85, 1.03)
0.21
Female gender
0.34 (0.12, 0.91)
0.04
Smoking
1.78 (0.63, 4.85)
0.26
Obesity
0.53 (0.16, 1.51)
0.26
IBD type (UC vs.CD)
0.59 (0.19, 1.62)
0.32
Total cholesterol, median (IQR)
1.01 (0.99, 1.02)
0.48
High-density lipoprotein
0.97 (0.94, 1.01)
0.09
Triglyceride level Chronic kidney disease
1.01 (0.99, 1.01) 2.93 (0.56, 13.14)
0.17 0.17
OR (95 % CI)
p value
Diabetes mellitus
0.86 (0.18, 2.98)
0.83
HTN
2.78 (0.99,7.69)
0.05
Framingham score
1.08 (1.03, 1.15)
0.005
1.1 (1.04, 1.18)
0.003
Persistent thrombocytosis
5.25 (1.91, 15.53)
0.002
3.1 (2.29, 24.15)
0.001
5-ASA
2.29 (0.76, 8.5)
0.17
Steroid
0.96 (0.35, 2.57)
0.94
Thiopurine
0.59 (0.09, 2.36)
0.51
TNF antagonist
1.62 (0.47, 4.95)
0.41
Surgery
0.48 (0.13, 1.46)
0.23
excluded patients with myeloproliferative disorders and essential thrombocytosis to include only those patients with RT. We also wanted to select a subset of patients with persistent thrombocytosis secondary to IBD which we defined as platelet count more than 450 cells per deciliter for at least four separate occasions with each episode occurring 3 or more months apart to avoid isolated episodes of thrombocytosis which could be secondary to other acute conditions such as infection and could also be secondary to laboratory error. IBD is marked by chronic inflammation affecting the gastrointestinal and extra-intestinal tissue [12]. It is characterized by increase in effector macrophages, neutrophils, and T cells into the inflamed intestine, where they are activated and release proinflammatory cytokines [13]. Reactive thrombocytosis level and elevated thrombopoietin level is a common finding in IBD [3] and is associated with elevated levels of IL-6 level [17]. Platelets themselves are known to play a proinflammatory function [14]. A study by Voudoukis et al. showed a positive correlation between absolute platelet count and disease activity [15]. Furthermore, platelet count increases during periods of active inflammation [4]. The increased frequency of steroid use among patients with persistent thrombocytosis that we observed in our study is likely because of increased inflammation requiring steroid treatment among them
compared to the control group. Platelets also play an integral role in the pathogenesis of coronary artery disease [16]. Reactive thrombocytosis has been reported to lead to coronary artery disease [5, 6], but it is not regarded as a major risk factor for thromboembolism unlike essential thrombocytosis where increased risk has been firmly established. Furthermore, increased inflammation is associated with increased coronary events in IBD patients [17]. Coronary artery disease itself is increasingly recognized as an inflammatory process, and various endothelial, lymphocyte-mediated, and cytokine-mediated factors have been shown to be involved in coronary atherosclerotic plaque formation [18]. Accordingly, coronary artery disease occurs at a higher frequency among patients with systemic inflammatory diseases [19]. Therefore, persistent thrombocytosis may mark a state of sustained inflammation and thrombogenicity which forms a self-perpetuating loop with inflammation increasing thrombocytosis and vice versa. This can ultimately lead to increased risk of coronary artery disease in IBD as we observed in our study. An association between increased IBD disease activity and coronary artery disease has also been established [17, 20]. However, studies investigating the difference in cardiovascular disease incidence between IBD patients and the general population have been inconclusive. A study by Singh et al. [21] showed modestly increased risk of
123
Dig Dis Sci
cardiovascular morbidity (from CVA and IHD, especially in women). Another study by Osterman et al. [22] showed that inflammatory bowel disease is not associated with increased risk of myocardial infarction. Therefore, the findings from prior studies have been contradictory. Furthermore, traditional risk factors have a smaller role in the development of coronary artery disease among IBD patient [7, 8], but atypical risk factors have not been clearly identified. Our study raises three important questions. Firstly, is there a subset of IBD patients who are at increased risk of coronary artery disease? The contradictory findings of previous studies, with some studies showing increased cardiovascular disease in IBD [7, 21] and others showing no such difference [22], are likely because coronary artery disease risk is not uniformly increased in all IBD patients but only in certain subsets of patients with certain diseaserelated cardiovascular risk factor/factors. IBD-related cardiovascular risk factors have not been identified so far. Reactive thrombocytosis is associated with chronic inflammation. Both thrombocytosis and chronic inflammation have been shown to be risk factors for the development of coronary artery disease. Based on our study findings, IBD patients with persistent RT form a unique subset of patients who are at increased risk of developing coronary artery disease. This hypothesis is further substantiated by the fact that patients in the RT group had higher coronary artery disease incidence despite having significantly lower total cholesterol and LDL levels which are powerful predictors of coronary artery disease risk. This increased risk could be because RT may be a surrogate marker of increased disease-related inflammation which in turn increases the risk of coronary artery disease. Reactive thrombocytosis could also lead to a prothrombotic state and hence increased coronary artery disease incidence. However, it is not possible to elucidate the exact mechanism based on our investigation and should be researched in future studies. Secondly, does race play a role in the development of persistent thrombocytosis in IBD? We observed a higher proportion of non-Caucasian population in the persistent thrombocytosis group. This could be because of unique disease phenotype in the non-Caucasian population which predisposes this group to develop RT. It is well known that there are significant racial differences in IBD phenotype [23]. The increased thrombocytosis in IBD could also be because of lack of access to IBD-related treatment among the non-Caucasian population, leading to persistent inflammation and thrombocytosis. Thirdly, which management strategies would be effective in reducing cardiovascular disease risk in IBD patients with persistent thrombocytosis? Risk reduction in this subset of patients could be achieved most effectively by reducing the underlying disease-related inflammation. This strategy
123
would be consistent with findings from other studies which have shown increased cardiovascular events in IBD patients who have active disease [17], and therefore, it is likely that decreasing the disease activity would decrease the cardiovascular disease burden. Antiplatelet drugs such as aspirin or clopidogrel could also form effective medications for risk reduction. Aspirin is the standard of care for reducing thromboembolic risk in patients with essential thrombocytosis [24], and it is highly likely that the same protective effect would extend to patients with RT. However, concerns have been raised about the safety of NSAIDs in IBD, and further studies are needed to understand the safety profile of low-dose aspirin use in IBD patients. A major limitation of our study is its retrospective design. Due to the retrospective nature of the study, we could not correlate the risk of coronary artery disease with the degree of thrombocytosis or the relation between the timing of thrombocytosis and coronary artery disease. We did not include patients younger than 30 years or older than 74 years in the study because the Framingham risk score is applicable only to the 30- to 74-year age group. Therefore, we cannot predict whether thrombocytosis is associated with increased coronary artery disease among younger patients. Furthermore, we had a small sample size which could have led to selection bias. In conclusion, we identified persistent RT in IBD patients as a strong risk factor for coronary artery disease. Prospective studies are needed to determine the optimum strategy for cardiovascular risk reduction among IBD patients in this subgroup of IBD patients. Conflict of interest
None.
References 1. Santhosh-Kumar CR, Yohannan MD, Higgy KE, al-Mashhadani SA. Thrombocytosis in adults: analysis of 777 patients. J Intern Med. 1991;229:493–495. 2. Heits F, Stahl M, Ludwig D, Stange EF, Jelkmann W. Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease. J Interferon Cytokine Res. 1999;19:757–760. 3. Kapsoritakis AN, Potamianos SP, Sfiridaki AI, et al. Elevated thrombopoietin serum levels in patients with inflammatory bowel disease. Am J Gastroenterol. 2000;95:3478–3481. 4. Collins CE, Rampton DS. Platelet dysfunction: a new dimension in inflammatory bowel disease. Gut. 1995;36:5–8. 5. Virmani R, Popovsky MA, Roberts WC. Thrombocytosis, coronary thrombosis and acute myocardial infarction. Am J Med. 1979;67:498–506. 6. Dumrongmongcolgul N, Mankongpaisarnrung C, Sutamtewagul G, Hosiriluck N, Chen T, Trujillo A, et al. Reactive thrombocytosis associated with acute myocardial infarction following STEMI with percutaneous coronary intervention. Case Rep Cardiol. 2013;2013:707438. doi:10.1155/2013/707438.
Dig Dis Sci 7. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol. 2011;106:741–747. 8. Aggarwal A, Atreja A, Kapadia S, Lopez R, Achkar J-P. Conventional risk factors and cardiovascular outcomes of patients with inflammatory bowel disease with confirmed coronary artery disease. Inflamm Bowel Dis. 2014;20:1593–1601. 9. D’Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117:743–753. 10. Danese S, de la Motte CC, Fiocchi C. Platelets in inflammatory bowel disease: clinical, pathogenic, and therapeutic implications. Am J Gastroenterol. 2004;99:938–945. 11. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611–619. 12. Van Sommeren S, Janse M, Karjalainen J, et al. Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways. Inflamm Bowel Dis. 2014;20:987–994. 13. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407. doi:10.1038/ncpgasthep0528. 14. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost. 2014;112:678–691. 15. Voudoukis E, Karmiris K, Oustamanolakis P, et al. Association between thrombocytosis and iron deficiency anemia in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2013;25:1212–1216.
16. Siddiqui TI, Kumar KSA, Dikshit DK. Platelets and atherothrombosis: causes, targets and treatments for thrombosis. Curr Med Chem. 2013;20:2779–2797. 17. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death—a Danish nationwide cohort study. PLoS One. 2013;8:e56944. 18. Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease. Postgrad Med J. 2008;84:368–371. 19. Roifman I, Beck PL, Anderson TJ, Eisenberg MJ, Genest J. Chronic inflammatory diseases and cardiovascular risk: a systematic review. Can J Cardiol. 2011;27:174–182. 20. Srinivas M, Basumani P, Muthusamy R, Wheeldon N. Active inflammatory bowel disease and coronary artery dissection. Postgrad Med J. 2005;81:68–70. 21. Singh S, Singh H, Loftus E V, Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:382–93.e1: quiz e22. 22. Osterman MT, Yang Y-X, Brensinger C, Forde KA, Lichtenstein GR, Lewis JD. No increased risk of myocardial infarction among patients with ulcerative colitis or Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9:875–880. 23. Basu D, Lopez I, Kulkarni A, Sellin JH. Impact of race and ethnicity on inflammatory bowel disease. Am J Gastroenterol. 2005;100:2254–2261. 24. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015;90:162–173.
123
ORIGINAL ARTICLE
Persistent Reactive Thrombocytosis May Increase the Risk of Coronary Artery Disease Among Inflammatory Bowel Disease Patients Sudeep Dhoj Thapa1 • Hiba Hadid1 • Waseem Imam1 • Ahmad Hassan1 Muhammad Usman1 • Syed-Mohammed Jafri2 • Jason Schairer2
•
Received: 15 March 2015 / Accepted: 2 May 2015 Ó Springer Science+Business Media New York 2015
Abstract Background IBD patients are at increased risk of coronary artery disease in the absence of traditional risk factors. However, the disease-related risk factors remain poorly understood although increased inflammation seems to increase cardiovascular disease risk in IBD. Thrombocytes are involved in the pathogenesis of coronary artery disease, and a subset of IBD patients have reactive thrombocytosis. Aim The aim of our study was to investigate the effect of persistent reactive thrombocytosis on the development of coronary artery disease in IBD. Methods We evaluated a retrospective cohort of 2525 IBD patients who were evaluated at the Henry Ford hospital from 2000 to 2004. We performed a case–control study comparing patients with persistent thrombocytosis and patients without persistent thrombocytosis. Cases (n = 36) and controls (n = 72) were matched for age and gender. Coronary artery disease incidence was compared between the two groups. Results Cases (n = 36) and controls (n = 72) were matched for age and gender. Cases and controls were similar in age at onset of IBD (41.5 vs. 35.5, p value 0.11) and smoking status (33.3 vs. 27.8 %, p value 0.66). Persistent thrombocytosis was less common among Caucasian patients (44.44 vs. 62.5 %, p value 0.09) and more common in patients who had exposure to steroids during the study follow-up period. Coronary artery disease occurred & Sudeep Dhoj Thapa [email protected]; [email protected] 1
Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
2
Department of Gastroenterology, Henry Ford Hospital, Detroit, MI, USA
in 13 (36.1 %) patients with persistent thrombocytosis compared to only seven (9.7 %) patients in the control group. Conclusions Persistent reactive thrombocytosis among IBD patients is associated with increased risk of coronary artery disease. Further studies should characterize the clinical and molecular associations of this phenomenon and determine appropriate therapeutic measures. Keywords Platelets Inflammatory bowel disease Coronary artery disease Ulcerative colitis Crohn’s disease Abbreviations IBD Inflammatory bowel disease HDL High-density lipoprotein LDL Low-density lipoprotein RT Reactive thrombocytosis CD Crohn’s disease UC Ulcerative colitis BMI Body mass index
Introduction Reactive thrombocytosis (RT) is defined as an increase in platelet count associated with conditions other than chronic myeloproliferative or myelodysplastic disorders and is the most common etiology of thrombocytosis in the general population [1]. It is induced by multiple inflammatory conditions including inflammatory bowel disease [2, 3]. Thrombocytosis is common among IBD patients. Thrombocytosis in IBD is a marker of inflammation, and platelets themselves exhibit proinflammatory properties
123
Dig Dis Sci
including secretion of inflammatory cytokines [4]. Platelets also have a long-established role in the pathogenesis of coronary artery disease, and thrombocytosis is known to increase the risk of coronary artery disease [5, 6]. The clinical significance of RT which is observed in IBD patients remains poorly understood. There is growing evidence that patients with IBD are at increased risk of coronary artery disease in the absence of traditional risk factors [7]. A study by Aggarwal et al. [8] showed that the age, body mass index, and smoking which are strong predictors of coronary artery disease in the general population have a lower impact among IBD patients, further supporting the role of atypical cardiovascular risk factors among IBD patients. However, the disease-specific risk factors remain poorly understood. We hypothesized that persistent thrombocytosis is associated with increased coronary artery disease incidence in IBD. Therefore, we sought to investigate the difference in coronary artery disease incidence among patients with and without persistent thrombocytosis.
Methods The study population consisted of patients with either Crohn’s disease or ulcerative colitis who were evaluated at Henry Ford hospital from January 1, 2000 to December 31, 2004. Patients were initially identified using ICD-9 codes 555.xx and 556.xx, and chart review was done to identify patients with histological evidence of CD or UC. Patients between 30 and 74 years of age on initial presentation with follow-up data available for at least 10 years were further identified. Patients with history of cardiovascular and cerebrovascular disease (coronary artery disease, congestive heart failure, ischemic stroke, transient ischemic attack, and peripheral vascular disease) were excluded. We also excluded patients with any lymphoproliferative disorder in order to include only those patients who had RT. Study design and patient selection are displayed in Fig. 1. Henry Ford hospital electronic medical records were reviewed to abstract demographic and clinical data. Thrombocytosis was defined as blood platelet count greater than 450 cells per deciliter. We defined persistent thrombocytosis as platelet count more than 450 cells per deciliter for at least four separate occasions with each episode occurring 3 or more months apart to avoid falsely elevated single laboratory values and thrombocytosis due to other acute illness. We conducted a case–control study of IBD patients with thrombocytosis and patients without thrombocytosis. Two controls were selected for every case after matching for age and gender. Demographic information including age, gender, race, body mass index, and smoking history (smoker or non-
123
smoker) were abstracted for all study participants. Patient charts were reviewed for hypertension, diabetes mellitus, chronic kidney disease, inflammatory bowel disease subtype (CD vs. UC), and disease extent. Baseline lipid levels including total cholesterol, high-density lipoprotein, lowdensity lipoprotein, and triglyceride levels were collected. Histopathology and colonoscopy results on extent of intestinal involvement were also reviewed. IBD-related medication use during any time prior to the development of coronary artery disease including 5-ASA, steroids, thiopurines, and TNF antagonist was collected. Disease-related surgery during the follow-up period was also recorded. Hematological laboratory tests were reviewed for platelet count and myeloproliferative disorders. Patient records were abstracted for coronary catheterizations, echocardiograms, stress tests, and coronary CT scans to identify patients who developed coronary artery disease during the follow-up period. Statistical Analysis We used R statistical software, version 3.1.2, for all statistical analyses. Continuous variables were summarized using medians and IQR, and categorical variables were expressed as absolute values and percentage. Categorical variables were analyzed using the Fisher’s exact test, and continuous variables were analyzed using the Mann– Whitney test. Further analysis was done with univariate logistic regression to identify variables significantly associated with coronary artery disease development. Variables which were significantly associated with coronary artery disease in the univariate model were adjusted using multivariate logistic regression analysis. A p value of 0.05 was used as the threshold of significance.
Results We identified 36 IBD patients who demonstrated persistent RT and compared them to 72 age- and gender-matched controls selected from the initial cohort of IBD patients. Baseline characteristics are given in Table 1. The proportion of Caucasian patients was lower in persistent thrombocytosis group compared to the control group (44.44 vs. 62.5 %, p value 0.09); however, it was not statistically significant. The two groups were also similar in IBD subtype with similar proportion of CD and UC between the two groups (Table 2). Furthermore, cases and controls were similar in HDL level, hypertension, choric kidney disease, and diabetes mellitus (Table 2). Additionally, patients with persistent thrombocytosis had lower total cholesterol and LDL levels compared to the control group (Table 2).
Dig Dis Sci Fig. 1 Study design and patient selection
2525 inial paents
444 final paents 2081 paents excluded -
No histological diagnosis 74 years of age lymphoproliferave disorders Loss of follow up Prior cardiovascular disease
36 paents with persistent thrombocytosis
72 paents without persistent thrombocytosis
13 (36.1%) paents developed coronary artery disease
7 (9.7%) paents developed coronary artery disease
Table 1 Baseline demographic characteristics Characteristics Age, median (IQR)
Persistent thrombocytosis (n = 36)
p value
47.5 (36, 57)
0.74
Age at onset, median (IQR) Caucasian race, n (%)
41.5 (32, 53.3) 16 (44.44 %)
35.5 (29, 46) 45 (62.5 %)
0.11 0.09
BMI, median (IQR)
27.2 (24.2, 30.3)
27.9 (24.5, 31.9)
0.3
21 (58.33 %)
40 (55.6 %)
0.84
Female gender, n (%)
49 (38.3, 57.3)
No thrombocytosis (n = 72)
Obese, n (%)
10 (27.8 %)
29 (40.3 %)
0.29
Smoker, n (%)
12 (33.3 %)
20 (27.8 %)
0.66
The age at diagnosis and anatomical disease extent were also similar between the cases and controls (Table 2). Patients with RT were more likely to receive steroid therapy during the follow-up period compared to the control group (55.6 vs. 33.3 %, p value 0.04). There was no difference in thiopurine use (16.7 vs. 13.9 %, p value 0.78) or TNF antagonist use (19.6 vs. 18.1 %, p value 1) between the two groups. There was also no difference in disease-related surgery between patients with and without persistent thrombocytosis (38.9 vs. 27.8 %, p value 0.28). We evaluated the extent of baseline cardiovascular risk factors between the cases and the controls. There was no difference in the median body mass index (BMI) (27.2 vs 27.9, p value 0.3) or number of hypertensive patients (27.8 vs. 26.4 %, p value 1) between the two groups. Framingham risk score (2008) was calculated for all the study subjects. The score predicts the 10-year risk of developing cardiovascular disorders including coronary artery disease [9]. The median Framingham risk score was similar between the
cases and controls (4.09 vs. 6.53, p value 0.35), signifying similar traditional risk of developing coronary artery disease between the two groups. There was a significant difference in coronary artery disease incidence between the cases and controls (36.1 vs. 9.7 %, p value 0.002) Further analysis was done using univariate logistic regression to identify variables associated with the development of coronary artery disease. Female gender (OR 0.34, 95 % CI 0.12, 0.91; p value = 0.04) was associated with decreased coronary artery disease incidence, whereas higher Framingham risk score (OR 1.08, 95 % CI 1.03, 1.15; p value = 0.005) and persistent thrombocytosis (OR 5.25, 95 % CI 1.91, 15.53; p value = 0.002) were associated with increased risk. Framingham risk score (OR 1.1, 95 % CI 1.04, 1.18; p value = 0.003) and persistent thrombocytosis (OR 3.1, 95 % CI 2.29, 24.15; p value = 0.001) were included in the multivariate logistic regression model and were significantly associated with coronary artery disease. The results are given in Table 3.
123
Dig Dis Sci Table 2 Clinical characteristics Characteristics
Persistent thrombocytosis (n = 36)
No thrombocytosis (n = 72)
p value
IBD type UC, n (%)
20 (55.6 %)
45 (62.5 %)
CD, n (%)
16 (44.4 %)
27 (37.5 %)
Total cholesterol, median (IQR)
186 (161.8, 201.8)
Low-density lipoprotein, median (IQR)
100.5 (80, 116.75)
High-density lipoprotein, median (IQR)
56.5 (41, 68.5)
Triglyceride level, median (IQR) Platelet count (K/mL), median (IQR) Chronic kidney disease, n (%) Diabetes mellitus, n (%) HTN Framingham score, median (IQR)
0.54
203.5 (173, 230.8)
0.01
119.5 (95.3, 147.3)
0.002
53 (43.8, 64.3)
0.49
92 (79.5, 137.8)
115 (80.75, 167.8)
0.26
573 (523.2, 672.5)
284 (238.5, 370.2)
\0.001
4 (11.1 %)
4 (5.6 %)
0.44
7 (19.4 %)
11 (15.3 %)
0.59
10 (27.8 %) 4.09 (2.62, 8.42)
19 (26.4 %) 6.53 (2.9, 12.17)
1 0.35
13 (65 %)
19 (42.2 %)
0.11
7 (35 %)
26 (57.8 %)
4 (25 %)
11 (40.7 %)
12 (75 %)
16 (59.3 %)
UC disease location, n (%) Pancolonic UC Left sided and proctitis CD disease behavior, n (%) Stricturing Inflammatory CD disease location, n (%)
0.22 0.43
Ileal
2 (12.5 %)
Colonic
4 (25 %)
2 (7.5 %) 12 (44.4 %)
Ileocolonic
10 (62.5 %)
13 (48.1 %)
5-ASA, n (%)
27 (75 %)
45 (62.5 %)
Steroid, n (%)
20 (55.6 %)
24 (33.3 %)
0.04
6 (16.7 %)
10 (13.9 %)
0.78
Thiopurine (azathioprine or 6-mercaptopurine), n (%) TNF antagonist, n (%) Surgery, n (%) Coronary artery disease, n (%) Death, n (%)
7 (19.6 %)
13 (18.1 %)
1
14 (38.9 %) 13 (36.1 %)
20 (27.8 %) 7 (9.7 %)
0.28 0.002
3 (8.3 %)
2 (2.8 %)
0.33
Discussion We conducted this study with the aim of investigating the role of chronic thrombocytosis in coronary artery disease incidence among IBD patients. Thrombocytosis is a commonly encountered condition among IBD patients and is a marker of disease activity [10]. We discovered increased need for steroid treatment and coronary artery disease incidence among IBD patients with persistent thrombocytosis. Furthermore, persistent thrombocytosis remained significantly associated with coronary artery disease after adjusting for disease-related risk factors in univariate and multivariate logistic regression analysis. These findings suggest that persistent thrombocytosis may serve as a biomarker of increased coronary artery disease risk among IBD patients. Coronary artery disease risk in the general population is influenced by certain modifiable (cholesterol level,
123
0.28
smoking, and hypertension) and non-modifiable (age and gender) risk factors. There are also several established risk score calculators that are used in clinical medicine [9, 11]. The most well established of them is the Framingham risk score which predicts 10-year risk of developing general cardiovascular diseases and is based on age, gender, smoking status, high-density lipoprotein, and total cholesterol level [9]. We used the Framingham risk score to calculate the baseline risk of developing coronary artery disease between the cases and controls. We selected our study dates to allow for a 10-year follow-up period. In addition, we aimed to study patients who developed new onset coronary artery disease during the follow-up period. Therefore, we excluded patients with known cardiovascular and cerebrovascular disease prior to the study start date. Furthermore, to avoid ‘‘loss of followup bias,’’ we selected only those patients who had followup data available for at least 10 years. In addition, we
Dig Dis Sci Table 3 Logistic regression analysis
Characteristics
Univariate analysis OR (95 % CI)
Multivariate analysis p value
Age
1.03 (0.99, 1.08)
0.17
Age at onset
1.01 (0.98, 1.05)
0.49
Caucasian race
0.63 (0.23, 1.76)
0.37
Body mass index
0.94 (0.85, 1.03)
0.21
Female gender
0.34 (0.12, 0.91)
0.04
Smoking
1.78 (0.63, 4.85)
0.26
Obesity
0.53 (0.16, 1.51)
0.26
IBD type (UC vs.CD)
0.59 (0.19, 1.62)
0.32
Total cholesterol, median (IQR)
1.01 (0.99, 1.02)
0.48
High-density lipoprotein
0.97 (0.94, 1.01)
0.09
Triglyceride level Chronic kidney disease
1.01 (0.99, 1.01) 2.93 (0.56, 13.14)
0.17 0.17
OR (95 % CI)
p value
Diabetes mellitus
0.86 (0.18, 2.98)
0.83
HTN
2.78 (0.99,7.69)
0.05
Framingham score
1.08 (1.03, 1.15)
0.005
1.1 (1.04, 1.18)
0.003
Persistent thrombocytosis
5.25 (1.91, 15.53)
0.002
3.1 (2.29, 24.15)
0.001
5-ASA
2.29 (0.76, 8.5)
0.17
Steroid
0.96 (0.35, 2.57)
0.94
Thiopurine
0.59 (0.09, 2.36)
0.51
TNF antagonist
1.62 (0.47, 4.95)
0.41
Surgery
0.48 (0.13, 1.46)
0.23
excluded patients with myeloproliferative disorders and essential thrombocytosis to include only those patients with RT. We also wanted to select a subset of patients with persistent thrombocytosis secondary to IBD which we defined as platelet count more than 450 cells per deciliter for at least four separate occasions with each episode occurring 3 or more months apart to avoid isolated episodes of thrombocytosis which could be secondary to other acute conditions such as infection and could also be secondary to laboratory error. IBD is marked by chronic inflammation affecting the gastrointestinal and extra-intestinal tissue [12]. It is characterized by increase in effector macrophages, neutrophils, and T cells into the inflamed intestine, where they are activated and release proinflammatory cytokines [13]. Reactive thrombocytosis level and elevated thrombopoietin level is a common finding in IBD [3] and is associated with elevated levels of IL-6 level [17]. Platelets themselves are known to play a proinflammatory function [14]. A study by Voudoukis et al. showed a positive correlation between absolute platelet count and disease activity [15]. Furthermore, platelet count increases during periods of active inflammation [4]. The increased frequency of steroid use among patients with persistent thrombocytosis that we observed in our study is likely because of increased inflammation requiring steroid treatment among them
compared to the control group. Platelets also play an integral role in the pathogenesis of coronary artery disease [16]. Reactive thrombocytosis has been reported to lead to coronary artery disease [5, 6], but it is not regarded as a major risk factor for thromboembolism unlike essential thrombocytosis where increased risk has been firmly established. Furthermore, increased inflammation is associated with increased coronary events in IBD patients [17]. Coronary artery disease itself is increasingly recognized as an inflammatory process, and various endothelial, lymphocyte-mediated, and cytokine-mediated factors have been shown to be involved in coronary atherosclerotic plaque formation [18]. Accordingly, coronary artery disease occurs at a higher frequency among patients with systemic inflammatory diseases [19]. Therefore, persistent thrombocytosis may mark a state of sustained inflammation and thrombogenicity which forms a self-perpetuating loop with inflammation increasing thrombocytosis and vice versa. This can ultimately lead to increased risk of coronary artery disease in IBD as we observed in our study. An association between increased IBD disease activity and coronary artery disease has also been established [17, 20]. However, studies investigating the difference in cardiovascular disease incidence between IBD patients and the general population have been inconclusive. A study by Singh et al. [21] showed modestly increased risk of
123
Dig Dis Sci
cardiovascular morbidity (from CVA and IHD, especially in women). Another study by Osterman et al. [22] showed that inflammatory bowel disease is not associated with increased risk of myocardial infarction. Therefore, the findings from prior studies have been contradictory. Furthermore, traditional risk factors have a smaller role in the development of coronary artery disease among IBD patient [7, 8], but atypical risk factors have not been clearly identified. Our study raises three important questions. Firstly, is there a subset of IBD patients who are at increased risk of coronary artery disease? The contradictory findings of previous studies, with some studies showing increased cardiovascular disease in IBD [7, 21] and others showing no such difference [22], are likely because coronary artery disease risk is not uniformly increased in all IBD patients but only in certain subsets of patients with certain diseaserelated cardiovascular risk factor/factors. IBD-related cardiovascular risk factors have not been identified so far. Reactive thrombocytosis is associated with chronic inflammation. Both thrombocytosis and chronic inflammation have been shown to be risk factors for the development of coronary artery disease. Based on our study findings, IBD patients with persistent RT form a unique subset of patients who are at increased risk of developing coronary artery disease. This hypothesis is further substantiated by the fact that patients in the RT group had higher coronary artery disease incidence despite having significantly lower total cholesterol and LDL levels which are powerful predictors of coronary artery disease risk. This increased risk could be because RT may be a surrogate marker of increased disease-related inflammation which in turn increases the risk of coronary artery disease. Reactive thrombocytosis could also lead to a prothrombotic state and hence increased coronary artery disease incidence. However, it is not possible to elucidate the exact mechanism based on our investigation and should be researched in future studies. Secondly, does race play a role in the development of persistent thrombocytosis in IBD? We observed a higher proportion of non-Caucasian population in the persistent thrombocytosis group. This could be because of unique disease phenotype in the non-Caucasian population which predisposes this group to develop RT. It is well known that there are significant racial differences in IBD phenotype [23]. The increased thrombocytosis in IBD could also be because of lack of access to IBD-related treatment among the non-Caucasian population, leading to persistent inflammation and thrombocytosis. Thirdly, which management strategies would be effective in reducing cardiovascular disease risk in IBD patients with persistent thrombocytosis? Risk reduction in this subset of patients could be achieved most effectively by reducing the underlying disease-related inflammation. This strategy
123
would be consistent with findings from other studies which have shown increased cardiovascular events in IBD patients who have active disease [17], and therefore, it is likely that decreasing the disease activity would decrease the cardiovascular disease burden. Antiplatelet drugs such as aspirin or clopidogrel could also form effective medications for risk reduction. Aspirin is the standard of care for reducing thromboembolic risk in patients with essential thrombocytosis [24], and it is highly likely that the same protective effect would extend to patients with RT. However, concerns have been raised about the safety of NSAIDs in IBD, and further studies are needed to understand the safety profile of low-dose aspirin use in IBD patients. A major limitation of our study is its retrospective design. Due to the retrospective nature of the study, we could not correlate the risk of coronary artery disease with the degree of thrombocytosis or the relation between the timing of thrombocytosis and coronary artery disease. We did not include patients younger than 30 years or older than 74 years in the study because the Framingham risk score is applicable only to the 30- to 74-year age group. Therefore, we cannot predict whether thrombocytosis is associated with increased coronary artery disease among younger patients. Furthermore, we had a small sample size which could have led to selection bias. In conclusion, we identified persistent RT in IBD patients as a strong risk factor for coronary artery disease. Prospective studies are needed to determine the optimum strategy for cardiovascular risk reduction among IBD patients in this subgroup of IBD patients. Conflict of interest
None.
References 1. Santhosh-Kumar CR, Yohannan MD, Higgy KE, al-Mashhadani SA. Thrombocytosis in adults: analysis of 777 patients. J Intern Med. 1991;229:493–495. 2. Heits F, Stahl M, Ludwig D, Stange EF, Jelkmann W. Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease. J Interferon Cytokine Res. 1999;19:757–760. 3. Kapsoritakis AN, Potamianos SP, Sfiridaki AI, et al. Elevated thrombopoietin serum levels in patients with inflammatory bowel disease. Am J Gastroenterol. 2000;95:3478–3481. 4. Collins CE, Rampton DS. Platelet dysfunction: a new dimension in inflammatory bowel disease. Gut. 1995;36:5–8. 5. Virmani R, Popovsky MA, Roberts WC. Thrombocytosis, coronary thrombosis and acute myocardial infarction. Am J Med. 1979;67:498–506. 6. Dumrongmongcolgul N, Mankongpaisarnrung C, Sutamtewagul G, Hosiriluck N, Chen T, Trujillo A, et al. Reactive thrombocytosis associated with acute myocardial infarction following STEMI with percutaneous coronary intervention. Case Rep Cardiol. 2013;2013:707438. doi:10.1155/2013/707438.
Dig Dis Sci 7. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol. 2011;106:741–747. 8. Aggarwal A, Atreja A, Kapadia S, Lopez R, Achkar J-P. Conventional risk factors and cardiovascular outcomes of patients with inflammatory bowel disease with confirmed coronary artery disease. Inflamm Bowel Dis. 2014;20:1593–1601. 9. D’Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117:743–753. 10. Danese S, de la Motte CC, Fiocchi C. Platelets in inflammatory bowel disease: clinical, pathogenic, and therapeutic implications. Am J Gastroenterol. 2004;99:938–945. 11. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611–619. 12. Van Sommeren S, Janse M, Karjalainen J, et al. Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways. Inflamm Bowel Dis. 2014;20:987–994. 13. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407. doi:10.1038/ncpgasthep0528. 14. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost. 2014;112:678–691. 15. Voudoukis E, Karmiris K, Oustamanolakis P, et al. Association between thrombocytosis and iron deficiency anemia in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2013;25:1212–1216.
16. Siddiqui TI, Kumar KSA, Dikshit DK. Platelets and atherothrombosis: causes, targets and treatments for thrombosis. Curr Med Chem. 2013;20:2779–2797. 17. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death—a Danish nationwide cohort study. PLoS One. 2013;8:e56944. 18. Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease. Postgrad Med J. 2008;84:368–371. 19. Roifman I, Beck PL, Anderson TJ, Eisenberg MJ, Genest J. Chronic inflammatory diseases and cardiovascular risk: a systematic review. Can J Cardiol. 2011;27:174–182. 20. Srinivas M, Basumani P, Muthusamy R, Wheeldon N. Active inflammatory bowel disease and coronary artery dissection. Postgrad Med J. 2005;81:68–70. 21. Singh S, Singh H, Loftus E V, Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:382–93.e1: quiz e22. 22. Osterman MT, Yang Y-X, Brensinger C, Forde KA, Lichtenstein GR, Lewis JD. No increased risk of myocardial infarction among patients with ulcerative colitis or Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9:875–880. 23. Basu D, Lopez I, Kulkarni A, Sellin JH. Impact of race and ethnicity on inflammatory bowel disease. Am J Gastroenterol. 2005;100:2254–2261. 24. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015;90:162–173.
123
