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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 2  |  Page : 86-91

D-dimer levels as marker of deep vein thrombosis in patients with cervical cancer: A study of a northern Nigerian patient population


1 Department of Obstetrics and Gynaecology, Gynaecological Oncology Unit, Ahmadu Bello University, Zaria, Nigeria
2 Department of Haematology, Ahmadu Bello University, Zaria, Nigeria
3 Department of Radiology, Ahmadu Bello University, Zaria, Nigeria

Date of Submission15-Aug-2017
Date of Acceptance17-Jun-2018
Date of Web Publication20-Jun-2019

Correspondence Address:
Dr. Marliyya Sanusi Zayyan
Department of Obstetrics and Gynaecology, Gynaecological Oncology Unit, Ahmadu Bello University, Zaria
Nigeria
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DOI: 10.4103/smj.smj_59_17

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  Abstract 


Background: Cervical cancer is the most common genital tract malignancy in Nigeria and an important cause of cancer-related death in women. Patients with advanced cervical cancer are often victims of deep venous thrombosis (DVT) that increases morbidity and mortality. Strategies at screening and early diagnosis enable prompt treatment which improves quality of life. Objectives: The objective of this study is to determine the plasma D-dimer level in patients with cervical cancer and its relationship to the presence of DVT, Well's score, and stage of malignancy. Materials and Methods: It is a prospective cross-sectional descriptive study of patients with histological diagnosis of cervical cancer in a Nigerian population. Patients' clinical, laboratory, and radiological data were obtained, and their body mass index (BMI) was calculated. Well's chart 17 was used to categorize patients using a cutoff of 2. Plasma D-dimer was quantified by immunoturbidimetric method and interpreted as significant if >0.099 g/dl. High-resolution ultrasound with 5–10 MHZ linear probe was used to evaluate the lower limbs veins of the patients. Data were analyzed with SPSS version 20. The test of association was done using Chi-square with a P < 0.05 considered statistically significant. Results: A total of 77 patients were enrolled, but 67 patients had complete data. The mean age was 54.7 ± 11.2 years. The average parity was 7.5 ± 3.1. Majority (47.8%) had normal BMI. D-dimer was positive in 58 (87%). Of the 17 (25%) with both elevated D-dimer and high probability of DVT, 5 (29%) had DVT. The incidence of DVT among our study population was 7.5%. There was statistically significant relationship between stage of disease and an elevated D-dimer value (χ2 = 5.82, α = 0.016, 95% confidence interval). Conclusion: Deep vein thrombosis occurred only in patients with high D-dimer and high Well's score, which makes their combination relevant in early diagnosis. Advanced age, high parity advanced stage of disease was the main associated risk factors. All cases with DVT occurred in patients with squamous cell cancer.

Keywords: Cervical cancer, D-dimer, deep vein thrombosis, well's clinical score


How to cite this article:
Zayyan MS, Katung GK, Abdul-Aziz H, Igashi JB. D-dimer levels as marker of deep vein thrombosis in patients with cervical cancer: A study of a northern Nigerian patient population. Sahel Med J 2019;22:86-91

How to cite this URL:
Zayyan MS, Katung GK, Abdul-Aziz H, Igashi JB. D-dimer levels as marker of deep vein thrombosis in patients with cervical cancer: A study of a northern Nigerian patient population. Sahel Med J [serial online] 2019 [cited 2019 Sep 23];22:86-91. Available from: http://www.smjonline.org/text.asp?2019/22/2/86/260840




  Introduction Top


Deep venous thrombosis (DVT) is an important complication in cervical cancer patients. The global incidence is 0%–34%, occurring especially in patients with advanced disease due to an imbalance in the Virchow's triad.[1],[2] Venous thrombosis embolism (VTE) increases morbidity and mortality from cervical cancer and treatment with therapeutic doses of anticoagulants could worsen vaginal bleeding and anemia. DVT in cervical cancer is related to cancer stage, histological type, and treatment modality used. In about 50% of cases, DVT occurs without symptoms, besides its occurrence may occasionally prelude the diagnosis of cancer. Approximately 20% of all new cases of VTE are associated with the presence of underlying cancer whereas 26% of incident cases of cancer already have idiopathic DVT.[3]

Cervical cancer is the most common genital tract malignancy with 528,000 new cases every year and 266,000 deaths.[4] Africa and the rest of the developing countries bear more than 80% of the global disease burden. Nigeria along with four other countries contributes 50% of the global mortality burden.[5] Cervical cancer flourishes in Africa despite a decline in many parts of the world because of poverty, ignorance, inadequate screening, and intervention programs. Majority of the patients present in advanced stages[6],[7],[8] of the disease with high susceptibility to complications including DVT.

The need for early diagnosis necessitates detection of asymptomatic cases. This can be achieved by risk score assessment using the Wells score, a clinical model that predicts the risk of developing DVT and enables the further test to be carried out with a cutoff mark of two.[9]

D-dimer, a by-product of fibrinolysis is a marker of DVT with high negative predictive value and sensitivity in addition to a moderate specificity.[10] When combined with Doppler ultrasound, its sensitivity is increased and enables early diagnosis thereby reducing morbidity. The development of DVT in conjunction with a gynecologic malignancy connotes a poor prognosis, especially in patients with cervical cancer.[11],[12]

The aim of this study was to determine the serum levels of D-dimer in cervical cancer patients in addition to their clinical assessment using the Well's chart. Doppler ultrasound assessment was performed on patients with high D-dimer, and high Wells score to detect DVT. Early detection of DVT in patients with cervical cancer will ensure early institution of treatment thereby reducing morbidity and mortality.

Study setting

The study was conducted in Ahmadu Bello University Teaching Hospital (ABUTH), a tertiary health institution equipped for research and clinical service. Although it provides primary clinical care, it mainly serves as a referral center for specialist services in Nigeria and neighboring West African countries such as Niger and Chad. It is a referral center for oncology and one of seven centers in Nigeria with facilities for complete radiotherapy. Ethical approval (ADM/E 22/A/VOL. VII/ 1161) was obtained on 15th June, 2015 from Health Research and Ethics Committee of Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Patients gave informed written consent. All the procedures have been carried out as per the guidelines given in Declaration of Helsinski 2013. Authors approve sharing and use of data in this article for purpose of research and learning.


  Materials and Methods Top


This is a prospective cross-sectional descriptive study of consenting consenting patients with histological diagnosis of cervical cancer at ABUTH Zaria in Northern Nigeria between August and December 2015.

Consecutive consenting patients with cervical cancer were enrolled according to sample size.[13] Patients on anticoagulants, hemoglobinopathy, and family history of thrombophilia or coexisting pregnancy were excluded from this study.

The patients had their body mass index (BMI) (kg/m2) measured using RGZ-120 stadiometer (Jiangsu Shusong Medical Company, China). Those with BMI <18, 18–24.9, 25–29.9, 30–34.9, and ≥35 kg/m2 were categorized as underweight, normal, overweight, obese, and morbidly obese, respectively.

A Well's chart 17 was used to categorize patients into high- or low-risk group using cut off of two.[9],[14] The standard clinical method was used to examine all patients in supine position. Patients with tender swollen calf had it measured at 10 cm below the tibial tuberosity and considered significant if 3 cm larger than the asymptomatic leg. If both legs were swollen, the larger of the two was measured.

D-dimer was determined by immunoturbidimetry using OET-100 nephelometer (Beijing Share Sun). D-Dimer level of <0.099 g/dl was considered negative while levels of ≥0.099 g/dl positive.[15] The machine was calibrated using samples from 50 normal local individuals to obtain the normal value of ≤0.099 g/L. A control recalibration was done with every batch of samples to ensure quality control.

Patients with the significant D-dimer result and high clinical pretest probability score had compression Doppler ultrasound of the lower limb veins to assess for venous thrombosis. A high-resolution ultrasound machine, Mindray DC-8 2011, China, with a 5-10 MHZ linear probe was used to assess the iliac, femoral, great saphenous, popliteal, peroneal, posterior tibial, and anterior soleal veins bilaterally. The iliac and femoral veins were assessed in a supine position, while all other veins were assessed in upright position.

In order to eliminate intraobserver variability, the same consultant radiologist (I. J) did the ultrasound scans.

The primary criterion used for diagnosis of DVT was lack of coaptation of the walls of the vein with compression on grey scale imaging. Color Doppler was also used to confirm occlusion in the vein and demonstrate the clot.

Data obtained were checked for completeness, entered serially into the SPSS version 20 IBM, Armonk, New York United States of America software package and analyzed using mean and standard deviation of variables. The test of association using Chi-square was also done to further analyze the relationship between and within variables. P < 0.05 was considered statistically significant.


  Results Top


A total of 77 patients were enrolled in the study. However, only 67 patients had complete data as two died on admission and eight were lost to follow-up. The mean age of the participants was 54.7 ± 11.2 years with a range of 27–77 years. The average parity was 7.5 ± 3.1 within a range of 3–11. Majority of the patients were grand multiparous 90% (60) while 10% (5) and 3% (2) were multiparous and primiparous, respectively.

The average duration of symptoms of cervical cancer was 13.5 ± 11.0 months. Only two (3%) patients had a history of recent surgery. Twenty-one (31.3%) patients had a history of coexisting medical condition, and there was none with a bleeding disorder. There was a history of DVT in one (1.5%) participant [Table 1].
Table 1: Distributions of comorbid factors

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Majority (32) 47.8% of the participants had normal BMI, but 19 (24.8%) were overweight [Table 2]. Most (60) 89.5% of the participants presented with the advanced cervical stage of at least cancer 2B [Table 3]. The most common histological variant was squamous cell carcinoma found in (55) 82% of patients. Adenocarcinomas occurred in (11) 16% of patients. There was a single case of signet ring carcinoma [Table 4].
Table 2: Distribution of body mass index among participants

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Table 3: Distribution of participants by stage of cervical cancer

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Table 4: Histological variants of cancer among participants

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Forty-six (46) 69% of participants had low probability (Wells) score while (21) 31% had high probability [Figure 1]. D-dimer was positive in (58) 87% of the patients while (9) 13% had normal values. The D-dimer value ranged from 0.099 mg/l to10.00 md/l with a mean value of 2.11 mg/dl ± 2.40 mg/l. There was no statistically significant association between an elevated D-dimer and a pretest probability for DVT when used alone (χ2 = 0.402, α =0.526, 95% confidence interval [CI]) [Figure 2].
Figure 1: Distribution of clinical probability test for deep venous thrombosis

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Figure 2: Chart showing relationship between D-dimer and Wells score

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There was a statistically significant relationship between stage of disease and an elevated D-dimer value (χ2 = 5.82, α =0.016, 95% CI) [Table 5].
Table 5: Relationship between deep venous thrombosis and stage of disease

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There were 17 (25%) patients with both elevated D-Dimer and high Well's score. Of these five had DVT (29%) while 12/17 (71%) were negative. Majority 3/5 (60%) occurred in the left internal iliac vein. The prevalence rate of DVT among our study population was therefore 7.5% (95% CI, 1.3%–13.7%).

There was positive correlation between an elevated D-dimer value, a high pretest probability score and an ultrasound diagnosis of DVT in the patients, but it was not statistically significant (χ2 = 3.535, α =0.171, 95% CI). There was no relationship between preexisting medical disorder and DVT.

Similarly, there was an association between mode of treatment and DVT (χ2 = 4.154, α =0.042) with the patient on concurrent chemoradiation contributing 40%.


  Discussion Top


Cervical cancer is an important health problem and a common cause of cancer-related death in Nigerian women. There are 9922 cases diagnosed annually with 8030 deaths. The incidence of cervical cancer in Nigeria is 250/100,000 women.[16],[17],[18] VTE is a life-threatening complication in patients with cervical cancer and studies have shown patients with this complication to have shorter survival rates and poorer prognosis.[12],[19] Strategies at identifying and reducing risk may improve survival and/or quality of life.

The prevalence of DVT in this study was 7.5%, which is comparable with the report by Thomas et al. of 8%.[20] but higher than 3.3% reported by Tsai et al. from Taiwan. Satoh et al. reported 4.8% incidence of DVT in patients with cervical cancer.[21],[22] The high incidence observed in our patients might be as a result of the generally very late presentation. Other local studies on DVT by Osime et al. and Sotunmbi et al. were not specific to cervical cancer.[23],[24] Cervical cancer has been shown to have the highest incidence of thrombosis compared to other gynecologic malignancies.[21]

The mean age of participants was 54.7 ± 11.2 years, which was higher than the mean age of 45 and 48 years, respectively, reported in previous studies from Zaria[6],[25] but similar to the 54.7 years report from Ilorin, North-West Nigeria.[8] Increasing age is known to be associated with an elevated D-dimer and increased risk of venous thrombosis[26] and may partly explain the higher prevalence of the disease in our study population.

Majority of the patients were grand multiparous women, and high parity is known to increase not only risk of cervical cancer but also that of thrombosis. The mean parity found in this study was 8, and 90% of the participants were grand multiparous. It is estimated that the risk of cervical cancer increases 2.6 folds in women who had ≥3 deliveries compared with nulliparous women. This risk rises to 3.8 after ≥7 deliveries.[27]

The finding here stresses the need to be aware of the increased likelihood of thrombosis in the older grand multiparous woman presenting with advanced cervical cancer.

We found that only 10.5% of cervical cancer patients presented with the early disease while the average duration of symptoms before presentation was 13.5 months. Delay in presentation until advanced stages has been reported by many researchers in the developing world.[18],[28],[29] Since there is a positive correlation between the stage of cancer and the occurrence of DVT,[30],[31] late presentation could significantly increase the likelihood of DVT.[11] In this study, there was a statistical significant relationship between stage of disease and elevated D-dimer levels.

D-dimer, a marker of hypercoagulable state, is a stable end-product of fibrin degradation and its levels increase as a result of fibrin formation and fibrinolysis. However, both cancer and its treatment affect the specificity of D-dimer as a screening tool for VTE besides low hemoglobin, and high C-reactive protein raise the levels of D-dimer. Therefore, the specificity and positive predictive value of the assay is reduced in cancer patients. D dimer was elevated in 87% of our patients with an average value of 2.11 mg/L. Ahlbrecht et al.[32] reported a D-dimer level of 1.32 μg/mL as significantly associated with an increased risk of cancer-related DVT. There are a number of assays for D-dimer levels, and cutoff values depend on the assay. With the method used in this study, the negative predictive value has been reported as 100% using a cutoff of 1.32 μg/mL and a positive predictive value of >50% using a cutoff value of 3 μg/ml. Teismann et al. reported 3/37 cases of DVT in patients with negative D-dimer against 20 cases in 150 cases with positive D-dimer.[33]

High levels of D-dimer have also been evaluated as a prognostic factor for VTE recurrence and mortality. Legnani et al. reported elevated D-dimer as independent risk factor for recurrence of VTE in cancer patients.[34]

The addition of Well's probability test is to increase the sensitivity of D-dimer test. Using this simple clinical method has been shown in two prospective studies to have high negative predictive value.[35],[36],[37] None of our patients with low probability and low D-dimer were diagnosed with DVT. The estimation of D-dimer therefore in patients with high clinical probability score could enhance early diagnosis of DVT in patients with cervical cancer.

The use of other risk assessment tool, which incorporates peculiarities of cancer patients including like cytotoxic chemotherapy, radiotherapy, stage of disease, and histological variants might be more helpful in DVT risk assessment for cancer patients. Such a model as validated by Khorana and Connolly for cancer patients on chemotherapy.[38],[39] Khorana and Connolly found an incidence of VTE in a high-risk group of 6.7%–7.1%, which is similar to the prevalence of 7.5%. Although this study found 2/5 (40%) of the patients with DVT to be on chemoradiation (χ2 = 4.154, α =0.042) conclusion cannot be drawn on the importance of this association because of the small numbers involved. The observation may also be due to the stage of disease rather than treatment modality.

Tumor grade and histology have a significant effect on tumor biology and subsequent clinical effect. The histological type and variant of all patients that developed DVT in this study were large cell nonkeratinizing Squamous Cell carcinomas with moderate levels of differentiation. No patients with adenocarcinoma developed DVT. This is at variance with other reports, that adenocarcinoma is commonly associated with thromboembolism and poorer prognosis.[40],[41] This paradoxical finding here may be emphasizing the significance of thrombosis in late disease as 90% of our patients had advanced disease. A study from Japan identified the stage of the disease to be an independent risk factor for VTE in cervical cancer patients.[42]

Various clinical guidelines advocate Doppler ultrasounds scan of the lower limbs in patients with positive D-dimer and a low-pretest probability of having a DVT, but the economic cost and low yield in (patients with low probability and low D-dimer) on our largely indigent population precludes this use. Therefore, while Doppler ultrasounds scan were done only in patients with high pretest probability and positive D-dimer test enhanced computerized tomography might have been better than Doppler ultrasound, but economic considerations precluded its use.


  Conclusion Top


Deep vein thrombosis occurred only in patients with high D-dimer and high clinical probability score, which makes their combination relevant in screening and early diagnosis. Advanced age, high parity advanced stage of disease was the main associated risk factors. All cases with DVT occurred in patients with squamous cell cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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