Detection of Prethrombotic State Malignant Neoplasms, Including Pancreatic Cancer, Using Clot Waveform Analysis

Research Article

Ann Hematol Onco. 2024; 11(1): 1444.

Detection of Prethrombotic State Malignant Neoplasms, Including Pancreatic Cancer, Using Clot Waveform Analysis

Mayu Kobayashi1; Hideo Wada2; Shunsuke Fukui1; Yasuaki Shimada1; Yuuichi Nakazawa1; Hiroki Mizutani1; Yuhuko Ichikawa3; Yuuki Nishiura1; Isao Moritani1; Yutaka Yamanaka1; Hidekazu Inoue1; Motomu Shimaoka4; Hideto Shimpo5; Katsuya Shiraki1,2

1Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi 510-8561, Japan

2Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi 510-8561, Japan

3Department of Central Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi 510-8561, Japan.

4Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan

5Mie Prefectural General Medical Center, Yokkaichi 510-8561, Japan

*Corresponding author: Katsuya Shiraki, MD, PhD Department of Gastroenterology, Mie Prefectural General Medical Center, 5450-132 Hinaga, Yokkaichi, Mie 510-8561, Japan.

Hideo Wada, MD, PhD Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, 5450-132 Hinaga,Yokkaichi, Mie 510-8561, Japan. Tel: +81-59-345-2321; Fax: +81-9-347-3500 Email: [email protected]; [email protected]

Received: December 06, 2023 Accepted: January 06, 2024 Published: January 13, 2024


Background: Cancer, especially pancreatic cancer, is frequently associated with thrombosis which is one of the causes of poor outcomes; moreover hypercoagulability can be present in cancer patients. Hypercoagulability is considered to be caused by a thrombin burst.

Methods: Activated Partial Tthromboplastin Time (APTT), small amount of tissue factor induced FIX activation assay (sTF/FIXa) and Thrombin Time (TT) assessment using Clot Waveform Analysis (CWA) were performed in 138 patients with malignant neoplasms, including pancreatic cancer.

Results: The first derivative peak (1st DP) time (1st DPT), 1st DP height (1st DPH) and 1st DPH/1st DPT ratio were increased in a clotting-factor-FVIII-dependent manner. Thrombosis was frequently associated with pancreatic cancer and was observed in the early stage. CWA-APTT and CWA-sTF/FIXa indicated that the peak times and heights were markedly longer and higher, respectively, in cancer patients, especially pancreas cancer patients, than in patients without cancer. The 1st DPH/1st DPT ratios of CWA-sTF/FIXa were significantly high in patients with pancreas cancer (median value 1.5). CWA-TT showed that the peak times were significantly shorter in cancer patients than in healthy volunteers and that the peak heights were significantly higher in cancer than in benign pancreas diseases. The cutoff value of the 1st DPH/ 1st DPT of sTF/FIXa for cancer patients with thrombosis vs. all patients without cancer was 1.3.

Conclusions: Cancer patients, including those with pancreatic cancer were frequently associated with thrombosis due to hypercoagulability caused by thrombin burst detected by CWA. A high 1st DPH/1st DPT ratio of sTF/FIXa may suggest an association with cancer or thrombosis.

Keywords: Cancer; Pancreatic cancer; CWA; sTF/FIXa; 1st DPH/ 1st DPT; sTF/FIXa ratio


Thrombotic complications such as Venous Thromboembolism (VTE), Acute Cerebral Infarction (ACI) and Acute Coronary Syndrome (ACS) have often been reported and studied as Cancer-Associated Thrombosis (CAT) by many physicians and researchers [1-3]. The incidence of VTE is <0.1% in the general population; it has been reported that approximately 20% of the overall VTE incidence might be caused by active cancer [4]. CAT, including ACS, ACI and VTE, is considered a main cause of noncancer death in patients with cancer [5]. VTE is one of the most important thrombotic complications in patients with cancer [6,7], and ACS and ACI are arterial thromboses that are mainly caused by platelet activation and atherosclerosis [8,9]. Trousseau syndrome [10,11] is a well-known thrombotic syndrome in cancer patients. CAT, including Trousseau syndrome is associated with various thrombotic diseases and has various factors, including leukocytosis, thrombocytosis, physical factors and increased coagulation factors, which have been proposed as risk factors for CAT [1].

Hypercoagulability including increased levels of coagulation factors, such as Tissue Factor (TF) and clotting factor VIII (FVIII), activated coagulation factors and TF-positive microparticles was proposed as a risk factor for CAT [1]. Activation of the coagulation cascade and platelets which is related to tumor growth and metastasis, may cause CAT [12,13]. Therefore, early diagnosis of hypercoagulability and prophylaxis for CAT may be important in the management of cancer [10].

Although increased D-dimer or Soluble Fibrin (SF) levels are useful for detecting thrombosis in patients with CAT [14-16], routine coagulation tests, such as Activation Partial Thromboplastin Time (APTT) and Prothrombin Time (PT), cannot detect hypercoagulable states [17]. A Clot Waveform Analysis (CWA) of APTT (CWA-APTT) has been developed to evaluate hemostatic abnormalities in patients with bleeding tendencies and to monitor anticoagulant therapy [17-19]. Furthermore, the use of a small scale of TF-induced FIX activation (sTF/FIXa) (CWA-sTF/FIXa) assay can evaluate hemostatic abnormalities including platelet abnormalities [17]. Hypercoagulability is considered to be caused by a thrombin burst [20,21] which is evaluated by thrombin time using a small amount of thrombin with a CWA (CWA-TT) [22].

In the present study, hypercoagulability and complications of thrombosis in patients with malignant neoplasms including pancreatic cancer were investigated using a CWA-APTT, CWA-sTF/FIXa and CWA-TT in comparison to patients without cancer or those with benign pancreatic diseases.

Materials and Methods

The study population included 138 patients with cancer and 66 patients without cancer who were managed at Mie Prefectural General Medical Center from August 21, 2020 to December 31, 2022. Cancer types were pancreatic cancer (n=30), uterine cancer (n=4), prostate cancer (n=7), hepatocellular carcinoma (n=15), malignant lymphoma (n=9), leukemia and myelodysplastic syndrome (leukemia/MDS) (n=11), lung cancer (n=11), breast cancer (n=5), biliary tract cancer (n=11), colon cancer (n=10), stomach cancer (n=12), esophageal cancer (n=5) and other cancer (n=8; origin unknown, n=3; bladder cancer, n=2; kidney cancer, n=2 and ovarian cancer, n=1) (Table 1). Noncancer patients included those with chronic hepatitis (n=31), anemia (n=9), bone marrow proliferative disease (n=6), pregnancy loss (n=3), fatty liver (n=3), carrier of hepatitis B virus (n=4), alcoholic liver damage (n=2), hepatic hemangioma (n=2), pancreatic cyst (n=3), benign pancreatic tumor (n=2) and pancreatitis (n=1). CWA was also performed in 20 healthy volunteers as controls. Disseminated intravascular coagulation (DIC) was diagnosed using the Japanese Ministry of Health Labor and Welfare criteria for DIC [23]. Acute cerebral infarction was diagnosed using computed tomography or magnetic resonance imaging, acute coronary syndrome was diagnosed using coronary angiography, electrocardiography was based on elevated troponin levels, and venous thromboembolism was diagnosed using computed tomography or venous ultrasound [24]. The stage of pancreatic cancer was determined in accordance with the established guidelines [25,26].