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    -  Pan XT
    -  Cheng X
    -  Lu Y

 
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ORIGINAL ARTICLE
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Characteristics and significance of changes of thrombomodulin and plasma protein C in patients with cancer before and after PICC


 Department of Hematology and Oncology, Taicang Hospital Affiliated to Suzhou University, Taicang, China

Correspondence Address:
Ye Lu,
Department of Hematology and Oncology, Taicang Hospital Affiliated to Suzhou University, Taicang
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_252_18

PMID: 31736467

  Abstract 

Objective: This study aimed to evaluate the changes and clinical significance of thrombomodulin (TM) and plasma protein C (PC) in patients with cancer before and after peripherally inserted central catheter placement (PICC).
Materials and Methods: The levels of plasma TM and PC in 35 patients with cancer before and after PICC were measured by enzyme-linked immunosorbent assay, and the significance of the differences was analyzed.
Results: TM was 3.57 ± 1.01 μg/L at 1 day after catheterization, which was significantly lower than the value of 4.41 ± 1.26 μg/L before catheterization; these values were 4.30 ± 1.81 and 4.73 ± 0.97 μg/L at 30 and 90 days after catheterization, respectively (F = 4.14, P < 0.05). PC was 3.32 ± 1.35 μg/L at 1 day after catheterization, which was significantly lower than the value of 5.32 ± 2.12 μg/L before catheterization; these values were 4.64 ± 2.44 and 5.83 ± 3.14 μg/L at 30 and 90 days after catheterization, respectively (F = 6.28, P < 0.01). There were no significant differences in platelet (PLT) counts, plasma D-D, and coagulation parameters among the four time points before and after catheterization. There was a positive correlation between TM and PC (r = 0.5420, P < 0.01) on day 1 after PICC line insertion. The levels of TM and PC were not related to PLT, plasma D-dimer, or various coagulation parameters.
Conclusions: The levels of TM and PC in the patients 1 day after PICC were significantly decreased and showed a positive correlation, but were not related to PLT, plasma D-dimer, or coagulation function.


Keywords: Peripherally inserted central catheter, plasma D-dimer, plasma proteins, solid tumors, thrombomodulin



How to cite this URL:
Yan M, Pan XT, Cheng X, Lu Y. Characteristics and significance of changes of thrombomodulin and plasma protein C in patients with cancer before and after PICC. Indian J Cancer [Epub ahead of print] [cited 2019 Nov 22]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=270358





  Introduction Top


Vascular thromboembolism (VTE) is an important and common disease endangering human health.[1] Many types of tumors may cause a hypercoagulable state of the bloodstream in patients, leading to the occurrence of VTE.[2],[3],[4] Peripherally inserted central catheter placement (PICC) plays important supporting roles in chemotherapy against cancer; however, intravenous therapy increases the risk of VTE.[5],[6],[7] Although a correlation between PICC and thrombosis formation in cancer patients, as well as with the plasma D-dimer (D-D), has been reported,[8],[9],[10] studies of the correlation and changes between PICC and thrombomodulin (TM) or protein C (PC), including D-D and thrombosis, are limited. Therefore, we measured the levels of plasma TM and PC in 35 patients undergoing chemotherapy for tumors by enzyme-linked immunosorbent assay (ELISA). We also measured the plasma D-D level, platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), antithrombin (AT), and fibrinogen (FN) and the correlations among these factors to explore the characteristics of PC and TM before and after PICC and their clinical significance in thrombosis.


  Materials and Methods Top


Patient data collection and population

From January 2014 to January 2015, a total of 35 patients with solid tumors, treated at the Oncology Department of Hematological and Oncology Center in our Hospital, were enrolled. All patients were pathologically confirmed, including 21 men and 14 women with ages of 28-77 years (mean age 46.8 years). The primary diseases included intestinal cancer in 13 cases, gastric cancer in 10 cases, and breast and lung cancer in 6 cases. The Khorana score of all the patients showed low risk. Patients with chronic liver, kidney, or other diseases that may significantly affect blood coagulation and patients with PLT <100.0 × 109/L or >300.0 × 109/L at the first visit were excluded. The ultrasound-guided modified Seldinger technique was used for catheterization. A small amount of unfractionated heparin was used for PICC sealing. No heparin was used in the vein or subcutaneously in any patient.

Detection time

Blood samples were collected from all patients at four time points (1 day before PICC (T1), 1 day after PICC (T2), 30 days after PICC (T3), and 90 days after PICC (T4)). Among the patients, only 25 patients had complete indices at T4.

Index detection

Fasting blood samples were collected in the early morning, placed in a test tube, and stored at −80°C to detect the concentrations of plasma TM and PC by ELISA simultaneously. Reagents were supplied by Shanghai Tianyu Trade Development Co. (Shanghai, China), and the instrument was from Beckman Coulter (Brea, CA, USA). The samples for detecting PLT, plasma D-D, and coagulation indices were collected simultaneously with TM and PC blood samples. Plasma D-D was detected by ELISA, and PLT was determined by routine methods. The normal reference ranges of PLT, D-D, and various blood coagulation indices were listed as references.

Statistical analysis

The SPSS13.0 software package (SPSS, Inc., Chicago, IL, USA) was used for statistical analysis, and one-way analysis of variance (the F-test) was conducted. The q-test (Newman–Kuels) and Spearman rank correlation analysis were used for intergroup comparison.


  Results Top


Determination of various coagulation parameters

Various coagulation parameters were determined in 35 patients by ELISA at four time points [Table 1]. The results revealed significant differences in levels of TM and PC on day 1 after PICC compared to baseline and other time periods, but not among the remaining indices (P > 0.05). The correlation between group TM and group PC at four different time points was analyzed by the q-test [Table 2]. The levels of TM and PC on T2 were significantly lower than those on T1, T3, and T4 (P < 0.05 and P < 0.01, respectively). However, there was no significant difference among the values of T1, T3, and T4 (P > 0.05).
Table 1: Results of various coagulation parameters

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Table 2: Comparison of TM and PC levels among different groups (q)

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TM levels were decreased in 26 cases (72.3%), increased in 2 cases (5.7%), and unchanged in 7 cases (20.0%). PC levels were decreased in 27 cases (77.1%), increased in 3 cases (8.6%), and unchanged in 5 cases (14.3%).

Correlation analysis

Correlation between PC and TM

There was a positive correlation between PC and TM on day 1 post-PICC (r = 0.5420, t = 7.3046, P < 0.001). The specific results are shown in [Figure 1].
Figure 1: Correlation between PC and TM (P = 0.000)

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Correlation of TM/PC with blood coagulation indices

Correlation analysis revealed that TM and PC levels were not correlated with the other indices (PLT, D-D, PT, APTT, TT, AT, and FN) (P > 0.05) [Table 3].
Table 3: Correlation of TM/PC with blood coagulation indexes (r)

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Clinical observation

One case showed VTE above the catheter. TM and PC levels at T1, T2, T3, and T4 were 3.95, 3.0, 3.14, and 5.53 μg/L and 9.61, 4.38, 5.0, and 8.32 μg/L, respectively. None of the 48 cases without PICC during this period showed thrombosis (P = 0.42).


  Discussion Top


Because PICC is an invasive treatment, it is generally considered to be associated with thrombosis in patients.[8],[11] Agnelli [12] reported that intravenous therapy can increase the risk of VTE, which is the major procoagulant factor in surgeries in patients without cancer; this risk can be increased by two fold in patients with cancer. Chopra et al[5] also showed that the incidence of PICC-related upper extremity venous thrombosis was 0.32-64.52%. VTE is the major cause of pulmonary embolism or even death. Thus, PICC-induced thrombosis is an important problem. Therefore, we examined the changes in blood TM and PC before and after PICC and analyzed the correlation of TM and PC with PLT, DD, or other blood coagulation indices to understand the correlation between these factors and thrombosis.

TM mainly exists on the surface of vascular endothelial cells. As a thrombin receptor, it can form a complex with thrombin in a 1:1 ratio and then cleave PC to form activated PC (APC). PC is produced by the liver; after cleavage into APC, it uses protein S as a cofactor to inactivate Factor V and Factor VIII, prevent the binding of Factor Xa with PLT, and promoting fibrinolysis, thereby playing a role in anticoagulation. Pathological conditions such as vascular injury, liver disease, DIC, malignancies, or severe infections can lead to decrease in PC activity and the depletion of consumptive PC, thus failing to produce APC to inactivate Factor Va and Factor VIIIa. Additionally, tissue factors can cause Factor Xa to increase, during which period leukocytes can participate in the local reaction and aggravate the vascular endothelial injury response. This decreases free protein S, which further reduces the anticoagulant regulatory function of PC and causes the body to remain in a hypercoagulable state, prompting VTE.

Our study showed that the PC level on T2 was significantly lower than those on T1, T3, and T4 (P < 0.01, 0.05, and <0.01, respectively), but there was no significant difference in PC levels among T1, T3, and T4. The TM level on T2 was significantly lower than those on T1, T3, and T4 (P < 0.01, 0.05, and <0.01, respectively), but there was no significant difference in PC levels among T1, T3, and T4. Additionally, there was a positive correlation between TM and PC (r = 0.5420, t = 7.3046, P < 0.001), indicating that the coagulation system is activated within minutes or hours after PICC, and the body enters a low-coagulation phase shortly after experiencing a transient hypercoagulable state, which is manifested as the depletion of PC and TM. Therefore, the levels of PC and TM decreased one day after PICC. After that, the body's self-regulation gradually restored these two factors to their original levels. In one case, VTE occurred after catheterization at the top of the catheter; none of the remaining 48 cases without PICC during the same period showed thrombosis, but the result was not significant (P = 0.42). Therefore, the clinical application of PICC is still safe and feasible. The levels of PC and TM change within a few hours after PICC, which may lead to thrombosis, and thus clinics must closely monitor coagulation indices and observe limb status to prevent thrombosis and provide solutions in a timely manner. We also found that the levels of PC and TM remained relatively stable for a long time after catheterization (30-90 days), suggesting that PICC only causes short-term PC and TM reduction that can be restored quickly, demonstrating that PICC is generally safe and feasible. However, if TM and PC decrease rapidly or show a persistent decrease, thrombosis may occur.

In future studies, we will measure PC and TM levels starting immediately after PICC and for one month, particularly at different time points in the same week, to determine the changes in PC and guide effective observation of the relevant changes in the disease.

Most patients with tumors show increased plasma D-D, an important factor in thrombosis in patients with tumors and an important indicator of prognosis.[13],[14],[15],[16],[17] This study mainly explored the changes in TM and PC before and after PICC and their correlation with thrombosis, rather than the prognosis of tumors. Multiparametric analysis by Ay [18] showed that an increased D-D increases the risk of VTE (hazard ratio = 1.8, 95% confidence interval 1.0-1.2, P = 0.048); Laporte et al.[19] reported that 20% of VTE cases occurred in patients with tumors, and the incidence of VTE in tumor patients was 4-7-fold higher than that in patients without tumors. Stender et al.[20] reported that the one-year incidence of VTE in patients with tumors and D-D >0.3 mg/L was as high as 20% (95% confidence interval = 12.0-31.0%) compared to other patients. However, we found no significant difference in the PLT, plasma D-D, or coagulation parameters before and after PICC (all P > 0.05), indicating that PICC has no obvious effect on these factors and supporting that PICC has little effect on coagulation. Additionally, PC and TM showed no correlation with the PLT, D-D, or other coagulation indices, further supporting that PC and TM do not affect coagulation. Therefore, PICC is not the main factor in thrombosis in patients. Patients' PLT levels were normal, while D-D levels were significantly increased; thus, tumors may significantly elevate plasma D-D, resulting in abnormal coagulation. The above-mentioned facts show that cancer patients are in hypercoagulable state.

In conclusion, PICC can cause immediate, short-term changes in PC and TM in patients, but these values quickly recover and are maintained at stable levels by regulatory mechanisms in the body. An important factor in thrombosis in patients with tumors is the tumor itself. Thus, PICC is safe and feasible.

Ethical approval

This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Suzhou University. Written informed consent was obtained from all participants.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Ay C, Vormittag R, Dunkler D, Simanek R, Chiriac AL, Drach J, et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: Results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009;27:4124-9.  Back to cited text no. 18
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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