1. Introduction

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Deep vein thrombosis (DVT) is a severe postoperative complication. It often occurs in patients undergoing total hip replacement, and studies have been conducted to elucidate the relationship between DVT and total hip replacement [1-3]. The levels of D-dimer, a highly sensitive marker of venous thromboembolism, have been studied among these patients to measure the risk of DVT [4-6]. Although patients undergoing lymphadenectomy for metastatic melanomas have been reported to develop DVT [7], the rate of the development of this condition among patients undergoing skin surgery has not been studied. In our daily practice, we have often experienced elevation in D-dimer levels in hospitalized patients undergoing surgery. This prompted us to study this phenomenon for better management. For this purpose, we focused our study on patients with the same disease and the same affected anatomical region. Therefore, in this study, we analyzed the postoperative rate of DVT development and changes in plasma D-dimer levels before and after the surgical treatment of stage IA extramammary Paget’s disease (EMPD) involving perineal regions.

2. Methods

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We retrospectively selected all patients with stage IA EMPD involving perineal regions, who were surgically treated in Kurume University Hospital between 2011 and 2014. Although 15 patients with stage IA EMPD were treated during the study period, 3 were excluded because data on D-dimer levels were unavailable. We collected clinical data including age, sex, body mass index (BMI), a comorbidity requiring antithrombotic treatment, hospitalization duration, anesthesia type, operation time, skin graft or skin flap performance, postoperative thrombus, postoperative heparin use, and D-dimer levels from all enrolled patients. We divided the cohort into 2 groups in terms of each clinical parameter, and a t-test was performed to compare the maximum D-dimer levels between 2 groups. A level of p< 0.05 was considered significant. Analysis was performed using JMP® Pro 11.0.0 (SAS Institute Inc., Cary, NC, U.S.A.). This study was approved by the Ethical Committee of Kurume University.

3. Results

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Clinical data are shown in Table 1, and the line chart of D-dimer levels for each patient is shown in Figure 1. Twelve patients were included (4 males and 8 females), with a mean age of 74.1 ± 11.3 years and a mean BMI of 23.8 ± 3.8. All patients wore compression stockings after the operation. No patient developed post-operative symptomatic DVT, but D-dimer levels were elevated in all patients post-operatively (Figure 1). Postoperative heparin was used in 2 patients for a couple of days to prevent DVT development based on the decision of the dermatologist in charge. The mean maximum D-dimer level was 4.1 ± 2.7 μg/ml (normal, ≤1.0 μg/ml). The mean post-operative day when the maximum D-dimer level was reached was 10.6 ± 4.9 days. Antithrombotic agents were used in 4 patients with a comorbidity of cerebrovascular disease, deep vein thrombus, or transient ischemic attack. The mean hospitalization duration was 31.3 ± 14.0 days. Lumbar anesthesia was used in 3 patients, and general anesthesia was used in the other 9. The mean operation time was 3 ± 1 h. A skin graft was used in 6 patients, and a skin flap was used in 1 patient. All patients spent 2 to 5 years without symptomatic thromboembolism after the surgery.

Figure 1    Table 1

To elucidate the relationship between the D-dimer level and each clinical parameter, the post-operative maximum D-dimer level was analyzed using a t-test in terms of sex (male vs. female), age (< 75 years old vs. ≥75 years), BMI ( < 25 vs. ≥25), hospitalization duration (< 4 weeks vs. ≥ 4weeks), anesthesia type (lumbar anesthesia vs. general anesthesia), operation time (≤3 hours vs. >3 h), and skin graft/flap (used vs. not used) (Table 2). Although no significant difference was found in any parameter, older patients (≥75 years) tended to have higher maximum D-dimer levels than younger patients (< 75 years).

Table 2

4. Discussion

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Stage IA EMPD is defined as an in situ lesion without lymph node involvement or metastatic lesions [8,9]. The first line therapy for noninvasive lesions of EMPD is wide excision [10]; therefore, patients are usually hospitalized, and their physical activities often diminish. Immobilization is a known risk factor for DVT [11]; it particularly increases in hospitalized patients after surgical treatment, which seems to be one of the reasons for the high incidence of DVT in patients undergoing total hip replacement [1-3].

In our hospital, patients scheduled to be on bed rest for a couple of days are given compression stockings. Because we do not have criteria for postoperative heparin use, it was used according to the decision made by each attending physician; hence, the use of postoperative heparin was inconsistent in this study.

Previous studies have reported that DVT occurs mainly between days 4 and 6 post operation in patients undergoing total hip replacement and that the risk of DVT decreases over 2 weeks after surgery [1,12]. We measured D-dimer levels during this period in most patients and found that the maximum D-dimer level was obtained 11 days or more after the operation in 9 of the 12 patients. Thus, a relatively long period seems necessary for monitoring D-dimer levels. A previous study has revealed that a cutoff D-dimer level of 10.0 μg/ml (normal, ≤1.0 μg/ml) on postoperative day 7 shows high specificity in making a diagnosis of DVT after total hip replacement.[5] The mean maximum D-dimer level of 4.1 ± 2.7 μg/ml in the present study was relatively low compared to the previously reported cutoff level for DVT; this may be the reason for symptomatic DVT not developing.

The high sensitivity and low specificity of D-dimer levels in predicting DVT have been previously highlighted [13,14]. Previous studies have revealed that D-dimer levels increase in elderly individuals [15,16]. In addition, recent major surgery, trauma, infection, arrhythmias, cancer, pregnancy, and liver disease can elevate D-dimer levels [17-20]. Thus, the elevation in D-dimer levels in the present study may not be associated with DVT but rather with the operation itself and the high mean age because older patients tended to have higher D-dimer levels than younger patients.

This retrospective study has a limitation that patients were not examined by duplex ultrasonography or venography; hence, non-symptomatic DVT was not detected. However, most previous studies have dealt with only symptomatic DVT [1-3,14], reflecting the difficulty in studying non-symptomatic DVT. Another limitation is the inconsistent postoperative heparin use. Although most patients undergoing total hip replacement are postoperatively treated with antithrombotic agents such as enoxaparin according to the guidelines regardless of D-dimer levels [21-23], no standard guideline is available in patients undergoing skin surgery. It may be debatable whether heparin should have been used in non-symptomatic patients undergoing skin surgery with elevated D-dimer levels in this study.

5. Conclusion

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No patient developed symptomatic DVT; however non-symptomatic DVT could not be excluded. Although elevated D-dimer levels may not be associated with DVT in this context, further studies may disclose cutoff D-dimer levels for predicting DVT in patients undergoing skin surgery, as a previous orthopedic study revealed in patients undergoing total hip replacement[5].

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