Summary
Background
Post-polypectomy hemorrhage is one of the complications of colonscopic polypectomy. And there is no definitive and convenient laboratory test that could be used to predict risk of delayed post-polypectomy hemorrhage. This research aimed to study risk prediction of delayed post-polypectomy hemorrhage using serum C-reactive protein (CRP) level as a marker.
Material/Methods
In a retrospective, case-controlled study, 302 cases of post-polypectomy patients were divided into hemorrhage group and non-hemorrhage group. The CRP levels 24-hours after colonscopic treatment were compared between the two groups to assess whether elevated serum CRP levels in addition to other risk factors such as age, gender, smoking, alcohol consumption, hypertension (AHT) and size of polyps may predict risk of delayed post-polypectomy hemorrhage.
Results
The hemorrhage group had significantly higher levels of serum CRP (32.50±17.34 mg/L vs. 6. 32±6.02 mg/dL) and were also having a higher incidence of hypertension compared to the non- hemorrhage group (both P<0.05). Patients with elevated serum CRP levels (≥10mg/L) after colonscopic treatment are at a higher risk of developing post-polypectomy hemorrhage (OR 1.329, 95%CI 1.125–1.571) as compared with patients whose CRP levels were not increased.
Conclusions
A higher level of serum CRP may serve as an indicator of delayed post-polypectomy hemorrhage and there appears to be a direct relationship between the serum CRP levels and the risk of post-polypectomy hemorrhage: the higher CRP levels the higher the risk of post-polypectomy hemorrhage.
Keywords: CRP level, delayed post-polypectomy hemorrhage, risk prediction
Background
Colonscopic polypectomy is an effective approach for the treatment of colorectal polypoid lesions. Resection of potential malignant adenomas reduced the risk and incidence of colon cancer. However, colonscopic polypectomy is not without complications and the most frequent being post-polypectomy hemorrhage. A 1–3% incidence rate of hemorrhage after colonoscopy polypectomy is considered as reasonable [1–3], while a higher incidence of 3–10% is known to occur following endoscopic mucosal resection (EMR) and endoscopic submucosal dissection [4–6]. The occurrence of hemorrhage is most common during and immediately after the procedure though it is unlikely to cause significant clinical consequences if the patients are closely monitored. But, in an occasional instance, hemorrhage could occur several days after polypectomy that can be potentially serious and sometimes even life threatening. Delayed post-polypectomy hemorrhage is defined as hemorrhage occurring 24 hours after the colonscopic treatment that occurs in approximately 2% of all patients [7,8]. Several risk factors of delayed post-polypectomy hemorrhage have been identified that include: polyps-related factors such as large size and sessile form, and patients-related factors such as hypertension [7–9]. However, there is no definitive and convenient laboratory test that could be used to predict risk of delayed post-polypectomy hemorrhage. In this study, we evaluated the efficacy of serum C-reactive protein (CRP) that is a sensitive biomarker for bacterial infection, inflammation, infarction and injury to predict the occurrence of delayed post-polypectomy hemorrhage.
Material and Methods
Patients
We performed a case-control study of 302 patients who underwent colonoscopic polypectomy from January 2004 to November 2009. Detailed medical records were reviewed, including size and location of polyps removed, macroscopic type of polyps, histopathological findings, resection methods, presence or absence of delayed hemorrhage and clinical characteristics of patients. Written consent was taken from each patient according to the Ethics Committee of School of medicine, Zhejiang University.
The following exclusion criteria were used in our study: (1) hemorrhagic disorders, a recent history of taking anticoagulants or anti-platelet drugs, or abnormal result of coagulation tests (platelet count less than 100,000/mL or prothrombin time longer than 12 second, within 2 weeks prior to colonoscopy). (2) Presence of recent surgery, trauma, febrile disorders, acute or chronic inflammatory disease, autoimmune diseases, or a prior myocardial infarction (MI) and acute coronary syndrome (ACS). (3) Presence of polyposis syndrome. Furthermore, patients older than 60 years or those with known heart disease were advised to have made electrocardiographic examination (ECG) before treatment and were continuously monitored while undergoing treatment. Long term users of anticoagulants or anti-platelet drugs were asked to stop these medications for 1 week prior to polypectomy. Patients with hypertension were included in the study only if blood pressure is below 140/90mmHg prior to treatment.
Follow-up and dietary advise
All patients were kept under close observation for 4 hours immediately after colonoscopic polypectomy in the event of immediate bleeding and were followed-up for the next 14 days by telephone contact. Follow-up for a period of 2 weeks from the day of polypectomy was achieved of all patients included in the study. Delayed postpolypectomy bleeding was defined as occurrence of tarry stool and/or bleeding during the follow-up period. All patients with tarry stool and/or bleeding should go through a second colonoscopy to confirm the reason and location of hemorrhage.
All patients who underwent colonoscopic polypectomy were advised to follow strict diet control that included absolute abstain from alcohol and avoidance of food rich in protein or fat for 2 weeks. In addition, these patients were also advised to avoid intense physical activity and long-distance travel.
Colon preparation and polypectomy methods
Colon preparation was conducted using polyethylene glycol electrolyte solution. Three resection approaches were used according to the size and macroscopic appearance of polyps. Polyps that were less than 0.5 cm were removed using hot biopsy; protruding polyps of less than 2.5 cm in size were resected by snare polypectomy; broad-based polyps that were less than 2 cm and IIc lesions (slightly depressed without ulcer) were treated by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) methods; pedicled polyps which were larger than 2.5 cm were resected by snare polypectomy [9–11]. The treatment for sessile polyps larger than 2.5 cm were determined according to the mucosal pit pattern classification. EMR was chosen if canceration was excluded, otherwise we would choose ESD for polyps with cancerous tendency pit pattern. Additional surgery was employed if endoscopic treatment failed.
All colonoscopic polypectomies were performed by one experienced endoscopist. The nurses all had standard training and did the snare following close instructions of the endoscopist. To reduce current of injury as much as possible, conduction time was regulated for different types of polyps.
Definitions of polyp-associated and patient-associated factors
The polyp size was determined by comparing to open forceps (5 mm) before polypectomy. The macroscopic type was classified based on the criteria of the Paris endoscopic classification of superficial neoplastic lesions [12]. Hypertension was defined as systolic/diastolic blood pressure of ≥140/90 mmHg (according to the criteria of The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [13]; those who smoke daily for over 6 months were defined as smokers according to WHO suggestions for standard smoking investigation methods, and alcohol consumption was considered to be present when the subject consumed 5 or more drinks per week as previously described.
CRP assay
Three milliliter peripheral blood was drawn to detect CRP level for each patient 24 hours after colonoscopic polypectomy. The normal reference range for the assay is <10.0 mg/L. We monitored CRP level of patients with delayed post-polypectomy bleeding or elevated CRP value (CRP ≥10mg/L) once in every 1~3 days until bleeding was controlled or CRP value returned to normal. Serum CRP level was determined using immunoturbidimetry method with an automatic biochemical analyzer (OLYMPUS AU5400, JAPAN).
Statistical analysis
Statistical analysis was performed by SPSS 16.0 software for Windows XP system. Data were expressed as mean ± standard deviation (SD). Independent Sample T-test was performed to analyze quantitative data and qualitative data was analyzed by Chi square test. Logistic regression including variables with P-value less than 0.05. The variables in this study were: age, sex, smoking, alcohol, hypertension disease, size, type and location of polyps and CRP level. Confidence intervals (CIs) were set for the 95% level and statistical significance was indicated if P value was less than 0.05.
Results
Baseline characteristics of patients and polyps in the study
302 patients with lesions were included in the study, averaging 56±13 years old; of all the patients, 181 (59.9%) were male, 59 (19.5%) were smokers and 40 (13.2%) were alcohol consumers; 47 (15.6%) have arterial hypertension (AHT), the average CRP level is 7.18±8.12 mg/L.
All the 302 Patients received endoscopic treatment. Of all, 258 were having adenoma, while 32 had hyperplastic polyps, 7 juvenile polyps and 5 colorectal cancer (Table 1).
Table 1.
General information of colorectal polyps and CRP levels after treatment.
| Spectrum of diseases | No. of patients | Macroscopic type of polyp | Size of polyp (cm) | Treatment | Mean CRP value (mg/L) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Protruding | Flat | Depressed | ||||||||||
| Is | Isp | Ip | IIa | LST | IIc | IIc+IIa | IIa+IIc | |||||
| Colorectal cancer | 5 | 1 | 1 | 1 | 2 | 1.68±0.80 (0.4~2.5) | EMR or ESD | 5.78±2.13 | ||||
| Adenomatous polyps | 258 | 89 | 72 | 42 | 34 | 19 | 1 | 1 | 0.99±0.70 (0.4~3.5) | Hot biopsy polypectomy EMR or ESD | 7.40±8.48 | |
| Hyperplastic polyps | 32 | 6 | 9 | 4 | 10 | 3 | 0.75±0.32 (0.4~1.5) | Polypectomy EMR | 6.01±6.33 | |||
| Juvenile polyps | 7 | 2 | 2 | 2 | 1 | 1.36±1.02 (0.6~3.0) | Polypectomy | 5.87±2.45 | ||||
Of all 302 patients studied, CRP was raised in 46 (15.2%). Delayed post-polypectomy hemorrhage occurred in 10 (3.3%) and their CRP level ranged from 14.8 mg/L to 64.0 mg/L with an average of 32.50±17.34 mg/L.
Risk factors for delayed post-polypectomy bleeding
Patients with hemorrhage had significantly higher levels of CRP value (32.50±17.34mg/L vs. 6.32±6.02 mg/L; P<0.05), compared with the non- hemorrhage group. It was also observed that a higher incidence of hypertension in those who had post-polypectomy hemorrhage compared with those who did not have hemorrhage (P<0.05). No significant differences were found between the two groups with respect to age, gender, smoking, alcohol consuming, size, type and location of polyps (Table 2).
Table 2.
Univariate analysis between patients with hemorrhage and without hemorrhage.
| Variables | No hemorrhage | Hemorrhage | Univariate P value |
|---|---|---|---|
| No. | 292 | 10 | |
| Gender (male/female) | 131/85 | 7/3 | 0.510 |
| Mean age (years) | 56±13 | 63±11 | 0.089 |
| Smoking | 55 (18.8%) | 4 (40.0%) | 0.098 |
| Alcohol | 38 (13.0%) | 2 (20.0%) | 0.523 |
| Hypertension | 42 (14.4%) | 5 (50.0%) | 0.002 |
| Size of polyps (cm) | 1.01±0.84 | 1.24±0.61 | 0.386 |
| Location of polyps | 0.376 | ||
| Ileocecal junction | 14 | 0 | |
| Ascending colon | 53 | 0 | |
| Transverse colon (including hepatic flexure and splenic flexure) | 64 | 3 | |
| Decending colon | 52 | 4 | |
| Sigmoid colon | 65 | 2 | |
| Rectum | 44 | 1 | |
| Macroscopic type of polyp | 0.103 | ||
| Protruding(Is, Isp, Ip) | 224 | 5 | |
| Flat(IIa, LST) | 63 | 5 | |
| Depressed(IIc, IIa+IIc, IIc+IIa) | 5 | 0 | |
| Histopathology of polyp | 0.623 | ||
| Colorectal Cancer | 5 | 0 | |
| Adenomatous Polyps | 248 | 10 | |
| Hyperplastic Polyps | 32 | 0 | |
| Juvenile Polyps | 7 | 0 | |
| CRP values (mg/L) | 6.32±6.02 | 32.50±17.34 | <0.001 |
Logistic regression analysis showed that raised CRP value is a significant risk factor that predicts the development of post-resection hemorrhage with an odds ratio of 1.329(95% CI, 1.125–1.571) (P<0.001, Table 3). Presence of hypertension was not significant in the logistic regression analysis.
Table 3.
Multivariate logistic regression analysis for risk factors of hemorrhage after colonoscopic treatment.
| Variables | Odds ratio | 95% Confidence Interval | P value |
|---|---|---|---|
| Hypertension | 0.984 | 0.099–9.763 | 0.989 |
| CRP value (mg/L) | 1.329 | 1.125–1.571 | <0.001 |
Dynamic monitoring of CRP level in patients with elevated CRP values
In order to know dynamic relationship between serum CRP levels and development of post-polypectomy hemorrhage, we monitored serum CRP levels in 46 cases with elevated CRP values (CRP ≥10 mg/L) once in every 1~3 days. It was noted that serum CRP values began to increase on the first day of treatment and returned to normal within 2~13 days (average 4±2 days).
While comparing patients with elevated CRP values, we noted that CRP levels were higher in hemorrhage group than in non-hemorrhage (32.50±17.34 mg/L vs. 18.72±7.62 mg/L, P<0.05, Table 4), and it took more time for CRP levels returning to normal in those with post-polypectomy hemorrhage than those without hemorrhange (6±3 days vs. 4±2 days, P<0.05, Table 4). It was noted that serum CRP levels returned to normal even in those who had post-polypectomy hemorrhage once the hemorrhage ceased.
Table 4.
Univariate analysis in patients with elevated CRP values.
| Variables | No hemorrhage | Hemorrhage | Univariate P value |
|---|---|---|---|
| CRP values (mg/L) | 18.72±7.62 | 32.50±17.34 | <0.05 |
| Time for CRP to return to normal (day) | 4±2 | 6±3 | <0.05 |
Treatment of patients with elevated CRP level
There were 10 patients who had late-phase delayed bleeding, the details of which are given in Table 5. Post-polypectomy hemorrhage was seen within two weeks of therapy. In all patients, hemorrhages could be controlled in time without any complications. In all these patients with or without hemorrhage CRP decreased to normal within two weeks.
Table 5.
Details of the ten patients with delayed post-polypectomy hemorrhage.
| No. | Sex | Age | Treatment | Complication | Causes of complication | Polyp type | Site of polyp | Size of polype (cm) | Histopathology |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Male | 67 | Colon polypectomy | Delayed hemorrhage | Intaking food too early | IIa | Transverse colon | 0.5 | Adenoma |
| 2 | Male | 67 | EMR | Delayed hemorrhage | Intaking food too early | LST | Transverse colon | 2.5 | Adenoma |
| 3 | Male | 74 | Colon polypectomy | Delayed hemorrhage | Long term antihypertensive vasodilator grugs administration due to AHT | Is | Sigmoid colon | 0.7 | Adenoma |
| 4 | Male | 67 | Colon polypectomy | Delayed hemorrhage | Intense movement after endoscopic therapy too early | Is | Transverse colon | 1.2 | Adenoma |
| 5 | Female | 41 | Colon polypectomy | Delayed hemorrhage | Long term grug administration of hydrocortisone due to SLE | IIa | Decending colon | 0.8 | Adenoma |
| 6 | Female | 61 | Colon polypectomy | Delayed hemorrhage | Long term antihypertensive vasodilator grugs administration due to AHT | IIa | Decending colon | 1.5 | Adenoma |
| 7 | Male | 57 | EMR | Delayed hemorrhage | Muscular propria injured by endoscopic therapy | IIa | Sigmoid colon | 1 | Adenoma |
| 8 | Male | 81 | Colon polypectomy | Delayed hemorrhage | Long term antihypertensive vasodilator grugs administration due to AHT | Isp | Decending colon | 1 | Adenoma |
| 9 | Male | 57 | Colon polypectomy | Delayed hemorrhage | Long term antihypertensive vasodilator grugs administration due to AHT | Is | Rectum | 1.2 | Adenoma |
| 10 | Female | 56 | EMR | Delayed hemorrhage | Polype base containing pulsatile vessel | Ip | Hepatic flexure of colon | 2 | Adenoma with moderate dysplasia |
Discussion
C-reactive protein (CRP) is an acute phase reactant synthesized by liver that has a regulatory role on other inflammatory markers such as IL-2, IL-6, TNF-α, is one kind of sensitive marker of inflammation and tissue injury [14–17]. CRP is considered as a valuable predictor of occurrence and prognosis of myocardial infarction (MI), acute coronary syndrome (ACS) and other cardiovascular diseases [18–20]. Recent studies revealed that CRP has a role in the pathobiology of thrombosis and may module the behavior of endothelial progenitor cells (EPCs). In vitro experiments revealed that CRP inhibited vasodilatation by attenuating the release of endothelial nitric oxide (eNO) [21,22]; Verma S et al. observed that human recombinant CRP directly inhibited EPC differentiation, survival, and function, key components of angiogenesis. Thus, those with chronic ischemia with elevated levels of CRP may have compromised eNO production and attenuated proliferation of EPC that may impedes healing process [22]. This is supported by the observation that mice with elevated levels of CRP showed a significantly faster and higher rate of arterial thrombosis [23]. Furthermore, volunteers receiving recombinant human CRP (rh-CRP) showed inappropriately activated coagulation system [24].
Mechanism(s) of delayed post-polypectomy hemorrhage is not known. There are no reliable indicators to predict the occurrence of delayed hemorrhage. Although location and size of polyps were regarded to be risk indicators for delayed post-polypectomy hemorrhage [7,8], while our data didn’t show significant relationship between location or size of polyps and post-polypectomy hemorrhage. The results of the present study revealed that those with significantly elevated plasma CRP levels had delayed post-polypectomy hemorrhage compared to those without delayed post-polypectomy hemorrhage. Logistic regression analysis showed that CRP value was a significant risk factor with a high predictive value with an odds ratio of 1.329 (95% CI, 1.125–1.571) (P<0.001). Hence, we regard elevated CRP values within 24 hrs after polypectomy is a reliable indicator and predictor of delayed post-polypectomy hemorrhage.
Conclusions
Based on the results of the present study, we propose that CRP is synthesized by the liver in response to vascular injury caused by polypectomy and a high CRP level 24 hours after treatment may suggest that vascular injury is incompletely repaired with potential risk of hemorrhage.
Hence, it is suggested that serum CRP level could be used as a surveillance marker to predict hemorrhage after colonoscopic treatment.
Footnotes
Conflict of interest
All the authors declare that they have no conflict of interest.
Source of support: This research was supported by grants from the National Health Key Special Fund (No. 200802112), the Health Department Fund (No. 2007A093), the Traditional Chinese Medicine Bureau Fund (No. 2007ZA018), the Natural Science Fund of Zhejiang Province (No.Y2080001, Z2080514 and Y12H160121), and the Key Project of Zhejiang Province (No. 2009C03012-5)
References
- 1.Waye JD. Management of complications of colonoscopic polypectomy. Gastroenterology. 1993;1:158–64. [PubMed] [Google Scholar]
- 2.Agha R, Miller M, George ML, Sabharwal T. Arterial embolisation to control haemorrhage following colonoscopic polypectomy. Int J Surg. 2008;6:420–21. doi: 10.1016/j.ijsu.2007.01.005. [DOI] [PubMed] [Google Scholar]
- 3.Vernava AM, Longo WE. Complications of endoscopic polypectomy. Surg Oncol Clin N Am. 1996;5:663–73. [PubMed] [Google Scholar]
- 4.Arebi N, Swain D, Suzuki N, et al. Endoscopic mucosal resection of 161 cases of large sessile or flat colorectal polyps. Scand J Gastroenterol. 2007;42:859–66. doi: 10.1080/00365520601137280. [DOI] [PubMed] [Google Scholar]
- 5.Saito Y, Uraoka T, Matsuda T, et al. Endoscopic treatment of large superficial colorectal tumors: a case series of 200 endoscopic submucosal dissections (with video) Gastrointest Endosc. 2007;66:966–73. doi: 10.1016/j.gie.2007.02.053. [DOI] [PubMed] [Google Scholar]
- 6.Pierluigi C, Carmelo L, Giuseppe S, et al. Efficacy, risk factors and complications of endoscopic polypectomy: Ten year experience at a single center. World J Gastroenterol. 2008;14(15):2364–69. doi: 10.3748/wjg.14.2364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kim DH, Lim SW. Analysis of Delayed Postpolypectomy Bleeding in a Colorectal Clinic. J Korean Soc Coloproctol. 2011;27(1):13–16. doi: 10.3393/jksc.2011.27.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kim HS, Kim KU, Park WK, et al. Delayed bleeding in a colonoscopic polypectomy: an experience with 5,236 polypectomies. J Korean Soc Coloproctol. 2000;16:462–68. [Google Scholar]
- 9.Christopher JF, Peter VD. Colonoscopic polypectomy and associated techniques. World J Gastroenterol. 2010;16(29):3630–37. doi: 10.3748/wjg.v16.i29.3630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Nicholls RJ, Zinicola R, Binda GA. Indications for colorectal resection for adenoma before and after polypectomy. Tech Coloproctol. 2004;8:291–94. doi: 10.1007/s10151-004-0179-9. [DOI] [PubMed] [Google Scholar]
- 11.Jerome DW. Colonoscopic Polypectomy. Diagnostic and Therapeutic Endoscopy. 1999;6:111–24. doi: 10.1155/DTE.6.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.The Paris workshop. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointestinal Endoscopy. 2003;58(6 Suppl):S3–43. doi: 10.1016/s0016-5107(03)02159-x. [DOI] [PubMed] [Google Scholar]
- 13.National Institutes of Health. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 04-5230. 2004:8. [Google Scholar]
- 14.Castell JV, Gomez-Lechon MJ, David MR, et al. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology. 1990;12:1179–86. doi: 10.1002/hep.1840120517. [DOI] [PubMed] [Google Scholar]
- 15.Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265:621–36. doi: 10.1042/bj2650621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Alenius GM, Eriksson C, Rantapää DS. Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis? Clin Exp Rheumatol. 2009;27:120–23. [PubMed] [Google Scholar]
- 17.Anna S, Zbigniew S, Wojciech G. The role of the immuno-inflammatory response in patients after cardiac arrest. Arch Med Sci. 2011;7(4):619–26. doi: 10.5114/aoms.2011.24131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Weber M, Hamm C. Redefinition of myocardial infarction – relevance of biomarkers. Herz. 2008;33:115–21. doi: 10.1007/s00059-008-3103-7. [DOI] [PubMed] [Google Scholar]
- 19.Kim DH, Shim JK, Hong SW, et al. Predictive Value of C-Reactive Protein for Major Postoperative Complications Following Off-Pump Coronary Artery Bypass Surgery. Circ J. 2009;73(5):872–77. doi: 10.1253/circj.cj-08-1010. [DOI] [PubMed] [Google Scholar]
- 20.Akbulut M, Kutlu M, Ozbay Y, et al. Efficacy of clopidrogel on reperfusion and high-sensitivity C-reactive protein in patients with acute myocardial infarction. Mediators Inflamm. 2009;2009:932515. doi: 10.1155/2009/932515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Uichi I, Yoshikazu M, Keiji Y, et al. C-Reactive protein augments inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes. Cardiovascular Research. 2002;56:86–92. doi: 10.1016/s0008-6363(02)00496-0. [DOI] [PubMed] [Google Scholar]
- 22.Verma S, Kuliszewski MA, Li SH, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease. Circulation. 2004;109:2058–67. doi: 10.1161/01.CIR.0000127577.63323.24. [DOI] [PubMed] [Google Scholar]
- 23.Haim D, Danenberg, Etty G, et al. Neointimal formation is reduced after arterial injury in human crp transgenic mice. Atherosclerosis. 2008;201(1):85–91. doi: 10.1016/j.atherosclerosis.2008.01.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of Inflammation and Coagulation After Infusion of C-Reactive Protein in Humans. Circ Res. 2005;96:714–16. doi: 10.1161/01.RES.0000163015.67711.AB. [DOI] [PubMed] [Google Scholar]