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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study

BMC Cancer201717:351

https://doi.org/10.1186/s12885-017-3326-1

Received: 21 January 2017

Accepted: 5 May 2017

Published: 19 May 2017

Abstract

Background

Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.

Methods

We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.

Results

Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1–8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7–51.9; P = 0.011), respectively.

Conclusions

The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

Keywords

Antineoplastic agentsAntithrombin III-protease complexBiomarkersBlood coagulationFibrinolysisPatient admissionPlasmin-plasmin inhibitor complexProspective studiesRisk factorsVenous thromboembolism

Background

Cancer causes hypercoagulable states and thromboembolism [1]. No less than 11% of Western cancer patients develop thromboembolism, which is a secondary cause of cancer death [2, 3]. Hospitalization and chemotherapy are important risk factors for venous thromboembolism (VTE) [1, 4]. Prophylactic anticoagulation is generally recommended to hospitalized Western cancer patients [5, 6].

So far even VTE prevalence in Japanese cancer patients remains undetermined. Asian people have been recognized to have lower risk for VTE [7], however, estimated VTE incidence is definitely increasing in Japan [8]. It also remains unclear whether Asian cancer patients should receive prophylactic anticoagulation.

Increased plasma levels of coagulation activation markers, D-dimer and prothrombin fragment 1 + 2 (F1 + 2), were reported to be useful in prediction of VTE development [912]. Thrombin-antithrombin complex (TAT) reflects hypercoagulable states directly as with F1 + 2, and plasmin α2-plasmin inhibitor complex (PIC) reflects hyperfibrinolytic states [13]. What are the prevalence and incidence of VTE in hospitalized Japanese patients receiving chemotherapy? What are the biomarkers predicting VTE development? The purpose of this study is to investigate VTE rates prospectively and to predict the development using activation markers of coagulation and fibrinolysis.

Methods

Study population

We enrolled patients with histologically or cytologically confirmed malignancies admitted to Tonan Hospital, Sapporo, Japan, between April and December 2014 to receive a new-for-them chemotherapy regimen. Patients were required to have an acceptable hematologic, hepatic, and renal function for chemotherapy, and adequate performance status. Exclusion criteria included symptomatic thromboembolism, prophylactic anticoagulation, active infection, and pregnancy. Patients with asymptomatic VTE without anticoagulation diagnosed at enrollment were eligible in this study.

Study protocol

All patients received inpatient chemotherapy. We prospectively observed the patients for three months. The main endpoint was an objectively confirmed VTE. We also collected following data: age, sex, body mass index, mobility, previous chemotherapy or hormone therapy, time from tumor onset, central venous access device, using anti-vascular endothelial cell growth factor antibody, recent trauma, surgery, or radiation therapy, complications including acute infection, tumor subtype, distant metastases, and laboratory data.

Diagnostic imaging

All patients were examined for VTE by chest-abdomen-pelvic computed tomography (CT) and whole-leg compression ultrasonography before chemotherapy and three months later. The following veins were examined by a high frequency liner transducer of an Aplio XG SSA-790A ultrasound device (Toshiba Medical Systems, Toshiba Medical Systems Co., Ltd., Otawara, Japan): femoral, popliteal, and posterior tibial vein. Deep vein thrombosis (DVT) was diagnosed using compression maneuver and Doppler ultrasound technique, if the vein was non-compressible and blood flow compromised.

VTE was also diagnosed by direct visualization of a thrombus in CT scans of blood vessels. Arterial-phase scans covering pulmonary arteries were not performed for patients without PE symptoms. Contrast enhanced CT was also not performed in patient without adequate renal function, which means estimated glomerular filtration rate by Japanese equation is 45 mL/min/1.73 m2 or over [14].

Laboratory data

Only at baseline, we measured CBC and serum levels of activation markers of coagulation and fibrinolysis: D-dimer, TAT, and PIC. D-dimer and PIC were measured by latex immunoassay kits: LIAS AUTO D-dimer NEO and LIAS AUTO PIC, respectively (Sysmex Co., Ltd., Kobe, Japan). TAT was determined by a chemiluminescent enzyme immunoassay kit: STACIA CLEIA TAT (LSI Medience Co., Ltd., Tokyo, Japan). The cut off values of each CBC and D-dimer were set based on Khorana and Vienna VTE risk assessment score, validated models to estimate the risk in Western patients receiving chemotherapy [15, 16]. Those of TAT and PIC were at 2.1 ng/mL and 1.8 μg/mL, 50th and 75th percentile of our data, respectively.

Statistical analysis

This study was conducted as a preliminary assessment of VTE prevalence, incidence, and its risk factors. Continuous variables were expressed as mean ± standard division, mean ± standard error, or median (interquartile range), as appropriate, which were categorized because linearity on the logit scale could not be achieved with all continuous covariates. Odds ratio (OR) with 95% confidence interval (CI), calculated using Woolf’s method, is presented as risk ratio of VTE prevalence and incidence between groups. OR with the CI were calculated using Woolf-Haldane correction when an observed frequency has a value of zero. The difference in VTE prevalence and incidence between groups was analyzed with chi-square test. Pearson’s test with Yates’s continuity correction was used when expected frequencies were all over 5, otherwise data were analyzed with Fisher’s exact test. We used multivariate logistic regression model to confirm the interaction between TAT and PIC for VTE prevalence. The predictor variables were increased TAT, non-increased PIC, and the first-order interaction term (increased TAT × non-increased PIC). Selected risk factors for VTE prevalence and incidence were analyzed by the multivariate model. We assumed that TAT, PIC, or the combination would affect VTE prevalence and incidence. Therefore, these three factors and other factors which were P < 0.10 in the univariate analysis were selected for the multivariate analysis. TAT and PIC were analyzed separately from the combination to avoid multicollinearity by the multivariable analysis. Multicollinearity was assessed by using the variance inflation factor, which greater than 4.0 may be a cause for concern. All statistical tests were two-sided, and P < 0.05 was considered statically significant. All analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Stastical Computing, Vienna, Austria) [17]. More precisely, it is a modified version of R commander designed to add Stastical functions frequently used in biostatistics.

Results

Patient characteristics

A total of 99 patients were enrolled, of which 2 patients could not be followed up. Remaining 97 patients were observed for the three-month period. Table 1 summarizes baseline clinical characteristics available for analysis. All patients were Japanese with practically equal male-female distribution. Most patients had a central venous access device and did not require bedrest for three days. Part of the patients (18%) was treated with anti-vascular endothelial cell growth factor antibody. Few patients (9%) had a history of surgery or radiation therapy within one month. Practically no patients had obesity, chronic heart failure, rheumatic arthritis, or acute infection. No patients had a previous history of coagulation defects, VTE, chronic respiratory failure, nephrosis syndrome, or hormone therapy including erythropoietin. The majority (67%) had distant metastases, and a few patients (20%) had a history of chemotherapy. Time from tumor onset as well as specific tumor subtypes varied widely: the median was three months, and the majority subtypes (68%) were colorectal, breast, and stomach cancer.
Table 1

Baseline clinical characteristics (n = 97)

Characteristic

No. of patients

(%)

Age (yr.)

65

±12.1a

Sex ratio (M:F)

47

:50

Body mass index (kg/m2)

22

± 3.4a

Reduced mobilityc

10

10

Previous chemotherapy

19

20

Time from tumor onset (yr.)

3

(1–12)b

Using anti-VGEF antibody

17

18

Recent (≤1 month) surgery

6

6

Recent (≤1 month) radiation

3

3

Complication

 Rheumatic arthritis

3

3

 Chronic heart failure

1

1

Tumor type

Digestive cancer

 Colon or rectum

26

27

 Stomach

18

19

 Esophagus

6

6

 Pancreas

7

7

 Otherd

2

2

Female reproductive system cancer

 Breast

22

23

 Ovary

3

3

Other tumor

 Lung cancer

2

2

 Urinary tract cancer

2

2

 Urachus cancer

1

1

 Cancer of unknown primary

4

4

 Sarcomae

3

3

 Lymphoma

1

1

Distant metastases

65

67

VEGF vascular endothelial cell growth factor

aMean ± standard deviation. bMedian (interquartile range). cBedrest with bathroom privileges for at least three days, either due to patient’s limitation or on physician’s order. dLiver and biliary tract. ethymus and prostate.

VTE

Figure 1 shows prevalence of VTE, which was detected in 29 patients (31%), 12 male and 17 female. VTE of 17 patients was detected before chemotherapy, and 12 (12%), 4 male and 8 female, were developed in the three-month observation period. VTE incidence was then 49 per 1000 person-years. Figure 2 shows VTE details of the 29 patients: 18 of which had distal DVT, 12 had proximal DVT, and 2 had PE. Three patients had both proximal and distal DVT, one had both distal DVT and PE, and one had both proximal DVT and PE. Almost all distal DVT was detected in soleus vein. Of the 12 proximal DVT, 9 were in lower extremity: iliac, femoral, or popliteal vein, 3 were catheter-related, 1 was in internal jugular vein, 1 in inferior vena cava, and 1 in portal vein. All VTE was asymptomatic, and only patients with proximal DVT and/or PE received anticoagulant therapy except where contraindicated or with limited life expectancy. One patient with proximal DVT was inserted inferior vena cava filter. No DVT progressed in size or number, and no patients suffered bleeding due to anticoagulation therapy.
Fig. 1

VTE prevalence in hospitalized patients receiving chemotherapy for malignancy (n = 97). VTE, venous thromboembolism; PE, pulmonary embolism

Fig. 2

Details of total VTE (n = 29). Abbreviations are as in Fig. 1. There is some overlap. No deep vein thrombosis was found in upper-extremities

Predictor analysis of VTE prevalence

Table 2 shows univariate OR of risk factors for VTE prevalence, which was significantly higher in patients with reduced mobility (OR, 6.9; 95% CI, 1.6–29.0; P = 0.007). Elderly (≥70 years old) female was not a significant risk factor compared to male and female <70 years old, but lower limit of 95% CI of the OR was over 1.0 (3.7; 95% CI, 1.1–12.2; P = 0.054). Other factors were not significant risks. Figure 3 shows interaction between increased TAT and non-increased PIC, which was significant. VTE prevalence in patients with non-increased PIC was high (41%) with increased TAT levels, but low (16%) in patients without increased TAT. Lower limit of 95% CI of the OR was almost over 1.0 in a combination of non-increased PIC with increased TAT (OR, 2.6; 95% CI, 1.0–6.6; P = 0.082) by univariate analysis. Table 3 shows VTE prevalence of a high- and low-risk group based on tumor subtypes [6, 18]. The absolute rates of the high- and low-risk group were 38% and 25%, respectively, which is not a significant difference.
Table 2

Univariable analysis of risk factors for total VTE of 29 patients

Variable

No. of patients

(%)

OR

(95% CI)

P

Sex and age (yr.)

  < 70

17

/64

27

1.0

(ref.)

 

  ≥ 70 male

4

/19

21

0.7

(0.2–2.5)

0.77

  ≥ 70 female

8

/14

57

3.7

(1.1–12.2)a

0.054

BMI

  < 25

21

/74

28

1.0

(ref.)

 

  ≥ 25

8

/23

35

1.4

(0.5–3.6)

0.75

Reduced mobilityb

 No

22

/87

25

1.0

(ref.)

 

 Yes

7

/10

70

6.9

(1.6–29.0)a

0.007*

Previous chemotherapy

 No

24

/78

31

1.0

(ref.)

 

 Yes

5

/19

26

0.8

(0.3–2.5)

0.92

Time from tumor onset (mo.)

  < 6 or >12

23

/85

27

1.0

(ref.)

 

 6–12

6

/12

50

2.7

(0.8–9.2)

0.17

Central venous access device

 No

1

/ 7

14

1.0

(ref.)

 

 Yes

28

/90

31

2.7

(0.3–23.6)

0.67

Using anti-VEGF antibody

 No

26

/80

33

1.0

(ref.)

 

 Yes

3

/17

18

0.5

(0.1–1.7)

0.26

Distant metastases

 No

7

/32

22

1.0

(ref.)

 

 Yes

22

/65

34

1.8

(0.7–4.9)

0.33

Developing acute infectionc

 No

18

/67

27

1.0

(ref.)

 

 Yes

11

/30

37

1.6

(0.6–3.9)

0.46

Platelet count (/μL)d

  < 350,000

25

/87

29

1.0

(ref.)

 

  ≥ 350,000

4

/10

40

1.7

(0.4–6.4)

0.48

Hemoglobin (g/dL)d

  ≥ 10

26

/84

31

1.0

(ref.)

 

  < 10

3

/13

23

0.7

(0.2–2.6)

0.75

Leukocyte count (/μL)d

  < 11,000

29

/93

31

1.0

(ref.)

 

  ≥ 11,000

0

/ 4

0

0.2

(0.0–4.7)

0.31

D-dimer (μg/mL)de

  < 1.5

7

/36

19

1.0

(ref.)

 

  ≥ 1.5

19

/58

33

2.0

(0.8–5.4)

0.24

TAT (ng/mL)de

  < 2.1

10

/50

20

1.0

(ref.)

 

  ≥ 2.1

16

/44

36

2.3

(0.9–5.8)

0.12

PIC (μg/mL)d, e

  ≥ 1.8

7

/21

33

1.0

(ref.)

 

  < 1.8

19

/73

26

0.7

(0.2–2.0)

0.70

TAT ≥2.1 ng/mL and PIC <1.8 μg/mLd, e

 No

14

/65

22

1.0

(ref.)

 

 Yes

12

/29

41

2.6

(1.0–6.6)

0.082

VTE venous thromboembolism, OR odds ratio, CI confidence interval, BMI body mass index, VEGF vascular endothelial cell growth factor, TAT thrombin-antithrombin complex, PIC plasmin α2-plasmin inhibitor complex

* P < 0.05. a95% CI over 1.0. bBedrest with bathroom privileges for at least three days at baseline, either due to patient’s limitation or on physician’s order. cDuring the three-month observation period. dMeasured at baseline, just before the first cycle of chemotherapy. eUnmeasured in three patients

Fig. 3

Change of VTE prevalence by non-increased PIC level in patients with and without increased TAT level. VTE, venous thromboembolism; TAT, thrombin-antithrombin complex; PIC, plasmin α2-plasmin inhibitor complex. Two crossing line graphs suggest interaction between increased TAT and non-increased PIC for VTE prevalence, which was significant (P = 0.043) Only in patients with increased TAT, non-increased PIC affects high prevalence of VTE

Table 3

Number of patients with total VTE according to underlying specific tumor subtypes

 

Total VTE

No. of patients

Prevalence

Tumor type

(n = 29)

(n = 97)

(%)

High-risk group for VTE

 Stomacha

5

18

 

 Pancreasa

3

7

 

 Ovarya

1

3

 

 Lunga

2

2

 

 Urinary tracta

1

2

 

 CUPb

1

4

 

 Sarcomab

2

3

 

 Lymphomaa

0

1

 

 Total

15

40

38c

Low-risk group for VTE

 Colon or rectum

6

26

 

 Breast

5

22

 

 Esophagus

3

6

 

 Biliary tract

0

1

 

 Liver

0

1

 

 Urachus

0

1

 

 Total

14

57

25

VTE venous thromboembolism, CUP cancer of unknown primary

aListed as a risk factor for VTE in National Comprehensive Cancer Network Guidelines 2016 [6]. bListed as a risk factor for VTE in Asian patients [18]. cOdds ratio was 1.84 vs. low-risk group for VTE (95% confidence interval, 0.8–4.4; P = 0.25).

Left side of Table 4 shows the multivariate OR of selected five risk factors. Non-increased PIC with increased TAT was the only significant risk factor (OR, 3.2; 95% CI, 1.1–8.2; P = 0.034). Lower limit of 95% CI of the OR was almost over 1.0 in elderly female (OR, 3.3; 95% CI, 0.9–12.4; P = 0.066), reduced mobility (OR, 4.9; 95% CI, 1.0–24.9; P = 0.057), and increased TAT (OR, 2.4; 95% CI, 0.9–6.4; P = 0.092). No evidence of multicollinearity between the five factors was found.
Table 4

Multivariable analysis of risk factors for total VTE of 29 patients and newly developed VTE of 12 patients (n = 97)

 

Total VTE

Newly developed VTE

Variable

OR

(95% CI)

P

OR

(95% CI)

P

Elderly femalea

3.3

(0.9–12.4)

0.066

 

-

 

BMI ≥25b

 

-

 

2.5

(0.5–12.0)

0.25

Reduced mobilityc

4.9

(1.0–24.9)

0.057

 

-

 

6–12 months from tumor onsetd

 

-

 

3.0

(0.6–15.8)

0.19

Increased TATe

2.4

(0.9–6.4)f

0.092

3.8

(0.7–20.8)g

0.12

Non-increased PICh

1.2

(0.3–4.0)

0.78

 

-

 

Increased TATe and non-increased PICh

3.0

(1.1–8.2)i

0.034*

9.4

(1.7–51.9)j

0.011*

Abbreviations are as in Table 2. VIF variance inflation factor

* P < 0.05. a ≥ 70 yr. vs. male and female <70 yr., adjusted for reduced mobility and non-increased PIC with increased TAT (VIF, 1.0). bAdjusted for 6–12 months from tumor onset, and non-increased PIC with increased TAT (VIF, 1.0). cAdjusted for elderly female and non-increased PIC with increased TAT (VIF, 1.0). dAdjusted for BMI ≥25 and non-increased PIC with increased TAT (VIF, 1.1). e ≥ 2.1 ng/mL. fAdjusted for elderly female and non-increased PIC (VIF, 1.1). gAdjusted for BMI ≥25 and 6–12 months from tumor onset (VIF, 1.1). h < 1.8 ng/mL, adjusted for elderly female and increased TAT (VIF, 1.2). iAdjusted for elderly female and reduced mobility (VIF, 1.0). jAdjusted for BMI ≥25 and 6–12 months from tumor onset (VIF, 1.1)

Predictor analysis of VTE incidence

Table 5 shows univariate OR of risk factors for VTE incidence in the three-month observation period, which was significantly higher in patients with high body mass index (OR, 4.0; 95% CI, 1.2–14.0; P = 0.030), 6–12 months from tumor onset (OR, 8.0; 95% CI, 2.0–31.8; P = 0.006), increased TAT (OR, 5.3; 95% CI, 1.1–26.6; P = 0.042), and non-increased PIC with increased TAT (OR, 12.0; 95% CI, 2.4–61.0; P = 0.001). Other factors did not show significantly higher OR.
Table 5

Univariable analysis of risk factors for newly developed VTE of 12 patients in three-month observation period

Variable

No. of patients

% per three months

OR

(95% CI)

P

Sex and age (yr.)

 < 70

7

/64

11

1.0

(ref.)

 

 ≥ 70 male

1

/19

5

0.5

(0.05–3.9)

0.67

 ≥ 70 female

4

/14

29

3.3

(0.80–13.2)

0.10

BMI

 < 25

6

/74

8

1.0

(ref.)

 

 ≥ 25

6

/23

26

4.0

(1.2–14.0)a

0.030*

Reduced mobilityb

 No

11

/87

13

1.0

(ref.)

 

 Yes

1

/10

10

0.8

(0.1–6.7)

1.00

Previous chemotherapy

 No

9

/78

12

1.0

(ref.)

 

 Yes

3

/19

16

1.4

(0.4–5.9)

0.70

Time from cancer onset (mo.)

 < 6 or >12

7

/85

8

1.0

(ref.)

 

 6–12

5

/12

42

8.0

(2.0–31.8)a

0.006*

Central venous access device

 No

0

/7

0

1.0

(ref.)

 

 Yes

12

/90

13

2.4

(0.1–44.5)

0.59

Using anti-VEGF antibody

 No

11

/80

14

1.0

(ref.)

 

 Yes

1

/17

6

0.4

(0.1–3.3)

0.69

Distant metastases

 No

3

/32

9

1.0

(ref.)

 

 Yes

9

/65

14

1.6

(0.4–6.2)

0.75

Developing acute infectionc

 No

24

/67

56

1.0

(ref.)

 

 Yes

5

/30

20

0.4

(0.1–1.1)

0.10

Platelet count (/μL)d

 < 350,000

12

/87

12

1.0

(ref.)

 

 ≥ 350,000

0

/10

0

0.3

(0.0–5.2)

0.60

Hemoglobin (g/dL)d

 ≥ 10

10

/84

12

1.0

(ref.)

 

 < 10

2

/13

15

1.4

(0.3–7.0)

0.66

Leukocyte count (/μL)d

 < 11,000

12

/93

13

1.0

(ref.)

 

 ≥11,000

0

/4

0

0.7

(0.0–14.3)

1.00

D-dimer (μg/mL)d, e

 <1.5

3

/36

8

1.0

(ref.)

 

 ≥1.5

7

/58

12

1.5

(0.4–6.3)

0.74

TAT (ng/mL)d, e

 < 2.1

2

/50

2

1.0

(ref.)

 

 ≥ 2.1

8

/44

18

5.3

(1.1–26.6)a

0.042*

PIC (μg/mL)d, e

  ≥ 1.8

0

/21

0

1.0

(ref.)

 

  < 1.8

10

/73

14

7.1

(0.4–126.5)

0.11

TAT ≥2.1 ng/mL and PIC <1.8 μg/mLd, e

 No

2

/65

3

1.0

(ref.)

 

 Yes

8

/29

28

12.0

(2.4–61.0)a

0.001*

Abbreviations and footnotes are as in Table 2.

Right side of Table 4 shows the multivariate OR of selected four risk factors. Non-increased PIC with increased TAT was the only significant risk factor (OR, 9.4; 95% CI, 1.7–51.9; P = 0.011), which had a good characteristic for predicting VTE development, 80% (8/10) of sensitivity with 75% (63/84) of specificity. No evidence of multicollinearity between the four factors was found.

Discussion

In this study, we made two important clinical observations. First, the prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. The overall prevalence was 31%, high compared to that in Western countries. The prevalence of thromboembolism in Western cancer patients was reported to be about 11% [2, 3]. As for with VTE incidence, it was 49 per 1000 person-years in our study, also high compared to Western countries. In a meta-analysis, VTE incidence was estimated to be 13 (95% CI, 7–23) and 68 (95% CI, 48–96) per 1000 person-years among Western cancer patients at average and high risk for VTE, respectively [19]. VTE incidence in our study, 49 per 1000 person-years, was also high compared to Asian countries. From a nation-wide analysis in Taiwan, VTE incidence in hospitalized cancer patients was 1.9 per 1000 person-years [18]. In Japan, though from a questionnaire survey, estimated VTE incidence was 0.18 per 1000 person-years in 2006 [20]. These incidence rates of both Taiwan and Japan can be considered similar to relative risks of cancer and hospitalization in the Western counties, which was 4.7 (hazard ratio) and 2.63 (OR), respectively [4, 21]. Even considering these relative risks, VTE incidence in our study was high and equivalent to that of average- or high-risk for VTE in Western countries.

One important thing is that all patients in this study underwent whole-leg compression ultrasonography before and after inpatient chemotherapy. As far as we could find, no other study includes the ultrasonography for each hospitalized patient receiving chemotherapy for malignancy. This is one of the reasons why we observed such a lot of VTE patients. Hospitalized cancer patients receiving chemotherapy in Western countries must have more asymptomatic VTE than in Asia. The prevalence and incidence have been definitely underestimated. Despite the frequency, the natural history of asymptomatic distal DVT and their real risk of thromboembolic complications are still uncertain because of the scarcity of prospective, blind, nonintervention studies. In fact, no distal DVT in this study progressed after three months from inpatient chemotherapy without anticoagulation. Therefore it is still debated whether we should make the diagnosis and treatment. However, prophylactic anticoagulation in cancer patients may prevent symptomatic VTE, which is associated with a substantial risk of bleeding [22, 23]. For beneficial thromboprophylaxis, we need to define high-VTE risks.

The second clinical observation is that non-increased PIC with increased TAT may be an independent risk factor for VTE development. In this study, non-increased PIC with increased TAT was the only significant risk factor of both VTE prevalence and incidence. This is the first study to show the potential of the combination of coagulation and fibrinolytic activation markers to predict VTE development. Antithrombin III inactivates thrombin, which results in increased TAT levels and shows coagulation activation. α2-plasmin inhibitor inactivates plasmin, resulting in increased PIC levels, which shows fibrinolytic activation. In fact, other coagulation activation markers, F1 + 2 and D-dimer, were reported to be able to predict VTE [912]. Increased levels of F1 + 2 predicted a twofold increased risk of VTE in cancer patients [9]. Several studies indicate that D-dimer is associated with VTE risk in cancer patients [912], and the highest relative risk for VTE development (hazard ratio, 3.6) was found in patients with both increased F1 + 2 and D-dimer [9]. F1 + 2 and D-dimer are both coagulation activation markers, but D-dimer levels are also affected by fibrinolytic activation; D-dimer can be produced more in patients with pleural effusion, ascites, hematoma, or cancer itself. False-positive of D-dimer elevation for VTE is increased in patients with cancer patients. In disseminated intravascular coagulation, D-dimer levels are higher with advanced fibrinolysis than with suppressed fibrinolysis [24, 25]. F1 + 2 and D-dimer then complement each other in the identification of high-risk patients for VTE. In theory, the combination of TAT and PIC shows more simply and directly each activity of coagulation and fibrinolysis, respectively; non-increased PIC with increased TAT shows advanced coagulation with suppressed fibrinolysis, which means a state at high risk for thrombosis. False-positive for VTE can be decreased by the combination of TAT and PIC. According to our study, the interaction between increased TAT and non-increased PIC is also indicative of VTE related processes. Non-increased PIC with increased TAT might be a precise biomarker for VTE in patients with malignancies.

This study has two limitations. First, the number of VTE events was insufficient to detect differences in patients with and without each variable in multivariate analysis. The number of newly developed VTE events was only 12. This is a preliminary study to assess VTE prevalence, incidence, and its high-risk factors. Non-increased PIC with increased TAT was not adjusted for a number of VTE risk factors, except two: elderly female and reduced mobility. Second limitation is that blood sampling difficulties were not recorded. TAT levels are highly affected by the duration of needle puncturing; the more time it takes to collect blood, the more the TAT levels increase [26]. This artifact can result in a pseudo-positive VTE prediction. It would have been better to recollect blood in case of blood sampling taking too long, with too high levels of the activation markers, or clotted blood. F1 + 2 levels are less affected by the duration of needle puncturing than TAT levels, however, TAT and F1 + 2 reflect slightly different results of coagulation activation. The combination of TAT and PIC might have a unique role for predicting VTE development.

Conclusions

This study clearly showed that the prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies, and suggests that non-increased PIC with increased TAT is an independent risk factor for VTE development. Activation markers of coagulation and fibrinolysis are easy to be tested, and may be useful to define the high-risk group. It is worth being investigated further with a large number of patients and including other activation markers.

Abbreviations

CI: 

Confidence interval

CT: 

Computed tomography

DVT: 

Deep vein thrombosis

F1 + 2: 

Prothrombin fragment 1 + 2

OR: 

Odds ratio

PIC: 

Plasmin α2-plasmin inhibitor complex

TAT: 

Thrombin-antithrombin complex

VTE: 

Venous thromboembolism

Declarations

Acknowledgments

The authors would like to thank the patients and ultrasonographers who participated in this study. We also thank Mr. David Hochman for reviewing the language of our article.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Authors’ contributions

Study concepts and design: HK, YT; Data acquisition: HK, TK, JS, KK, MH, YT; Analysis and interpretation of data: HK, YN, YT; Drafting of manuscript: HK, TK, JS, KK; Revising manuscript critically for important intellectual content: YN, MH, YT; Approval of final manuscripts: all authors.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Institutional review board of Tonan Hospital approved the study protocol, and all participating patients provided written informed consent.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medical Oncology, Tonan Hospital
(2)
Department of Clinical Laboratory, Tonan Hospital
(3)
Department of Cardiovascular Medicine, Tonan Hospital
(4)
Department of Gastroenterology, Tonan Hospital

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© The Author(s). 2017

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