Tumor-Specific D-Dimer Concentration Ranges and Influencing Factors: A Cross-Sectional Study

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Abstract

D-dimer level in cancer patients is associated with risk of venous thromboembolism and deep venous thrombosis. Most cancer patients have “abnormal” D-dimer levels based on the current normal reference range. To investigate tumor-specific D-dimer reference range, we compared D-dimer levels for nine different tumour types with healthy controls by using simultaneous quantile regression and constructing a median, 5th percentile, and 95th percentile model of normal tumour D-dimer concentration. Associations with tumour primary site, stage, pathological type, and treatment were also explored. Additionally, 190 patients were tracked to reveal the relevance of initial D-dimer levels to cancer prognosis. D-dimer ranges (median, 5th, 95th) in various cancers (mg/L) were: liver 1.12, 0.27, 5.25; pancreatic 0.96, 0.23, 4.81; breast 0.44, 0.2, 2.17; gastric 0.65, 0.22, 5.03; colorectal 0.73, 0.22, 4.45; lung 0.7, 0.25, 4.0; gynaecological 0.61, 0.22, 3.98; oesophageal 0.23, 0.7, 3.45; and head and neck 0.22, 0.44, 2.19. All were significantly higher than that of healthy controls (0.18, 0.07, 0.57). D-dimer peaked 1–2 days postoperatively but had decreased to the normal range by 1 week. Additionally, cancer patients with high initial D-dimer were shown a tendency of poor prognosis in survival rate. In conclusion, D-dimer levels in cancer depend on patient age, tumour primary site, and tumour stage. Thrombosis prevention is necessary if D-dimer has not decreased to the tumor-specific baseline a week after surgery.

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Most cited references 21

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High D-dimer levels are associated with poor prognosis in cancer patients.

Peter Quehenberger, Christoph Zielinski, Oswald Wagner … (2012)

Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1(st), 2(nd) and 3(rd) quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4-1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.

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A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.

Jim Julian, Peter Gent, Hedda J. Weitz … (1999)

Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.

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A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.

Mark P. Nicol, H Walter, S Schulman … (1995)

The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate. We performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in patients who had a first episode of venous thromboembolism. Anticoagulant therapy consisted of warfarin or dicumarol. Of the 902 patients enrolled, 5 were later excluded because they had congenital protein C deficiency; 443 were randomly assigned to receive six weeks of oral anticoagulant therapy with a targeted international normalized ratio (INR) of 2.0 to 2.85, and 454 were randomly assigned to receive six months of such therapy. The initial diagnoses were confirmed by means of venography in cases of deep-vein thromboses (n = 790) and with perfusion-ventilation scanning or angiography in cases of pulmonary embolism (n = 107); recurrences were confirmed in the same way. After two years of follow-up, there had been 123 recurrences of venous thromboembolism that met the diagnostic criteria, 80 in the six-week group (18.1 percent; 95 percent confidence interval, 14.5 to 21.6) and 43 in the six-month group (9.5 percent; 95 percent confidence interval, 6.8 to 12.2). The odds ratio for recurrence in the six-week group was 2.1 (95 percent confidence interval, 1.4 to 3.1). There was no difference in mortality or the rate of major hemorrhage between the six-week and six-month groups. Six months of prophylactic oral anticoagulation after a first episode of venous thromboembolism led to a lower recurrence rate than did treatment lasting for six weeks. The difference between the two groups occurred between 6 weeks and 6 months after the start of treatment, and the rates of recurrence remained nearly parallel for 1 1/2 years thereafter.

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Author and article information

Contributors

Robert Hurst: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 11 November 2016

Publication date Collection: 2016

Volume: 11

Issue: 11

Electronic Location Identifier: e0165390

Affiliations

[1 ]The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China

[2 ]Department of Laboratory, Hubei Cancer Hospital, Wuhan, China

[3 ]Department of Microbiology, School of Basic Medical Sciences, Wuhan University; Wuhan, China

[4 ]Stago Diagnosis Company, Wuhan, China

[5 ]Department of Orthopaedics, Renmin Hospital, Wuhan University, Wuhan, China

[6 ]Laboratory of Immunology, University of Lorraine, Lorraine, France

University of Oklahoma Health Sciences Center, UNITED STATES

Author notes

Competing Interests: We have the following interests: Anming Yu is employed by Stago Diagnosis Company. Stago Diagnosis Company supplied partial D-dimer testing reagents and some technic supports. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: D. Li JY YW.
Performed the experiments: JY D. Lei FY FP HZ KW HC.
Analyzed the data: JY XT.
Contributed reagents/materials/analysis tools: AY XW LC.
Wrote the paper: JY D. Li.

* E-mail: wangyefu2014@ 123456sina.com

Article

Publisher ID: PONE-D-16-07690

DOI: 10.1371/journal.pone.0165390

PMC ID: 5105993

PubMed ID: 27835633

SO-VID: 5a7851c9-76e0-40b2-b472-5d556a6014a0

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 22 February 2016

Date accepted : 20 September 2016

Page count

Figures: 3, Tables: 5, Pages: 12

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 30901356

Award Recipient : Dongqing Dong Li

Funded by: Fundamental Research Funds for the Central Universities

Award ID: 3082008

Award Recipient : Dongqing Dong Li

Funded by: Programs Foundation of Ministry of Education of China

Award ID: 20090141120014

Award Recipient : Dongqing Dong Li

Funded by: Research Foundation of Health Department of Hubei Province

Award ID: JX4B67

Award Recipient : Dongqing Dong Li

This work was funded by grants from the National Natural Science Foundation of China (No. 30901356), Fundamental Research Funds for the Central Universities (No.3082008), Ph.D. Programs Foundation of Ministry of Education of China (No.20090141120014), and Research Foundation of Health Department of Hubei Province (No. JX4B67). The study sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Anming Yu is employed by Stago Diagnosis Company. Stago Diagnosis Company provided support by the supply of partial D-dimer testing reagents and some technic support and paid the salary for author AY, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Anming Yu is the one who supported technical support. This specific role of this author is articulated in the ‘author contributions’ section.

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Data Availability Relevant data are within the paper and its Information files. Identifying information has been removed to protect participant identities. Please contact the Corresponding Author with additional questions.

Tumor-Specific D-Dimer Concentration Ranges and Influencing Factors: A Cross-Sectional Study

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Abstract

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PLOS Climate

Most cited references 21

High D-dimer levels are associated with poor prognosis in cancer patients.

A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.

A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.

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