Cancer, Chemotherapy and Their Impact Coagulation

by Donna Castellone, MS, MT(ASCP)S • May 08, 2023

The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

INTRODUCTION:

In 1865 the relationship between cancer and thrombosis was first described by Armand Trousseau due to a clinical association between thrombosis and an undiagnosed cancer.1 Cancer has specific impacts on all three elements of Virchow's triad including stasis, endothelial injury and hypercoagulability. Those with active cancer are at a risk of both arterial and venous thromboembolism. Particular cancers are associated with a high risk of thrombosis including pancreatic, stomach, metastatic, gynecological, lung, brain, hematologic, and genitourinary cancers (excluding prostate).2

Cancer patients have a seven-fold increased risk of developing a VTE. This rate is complicated by use of more thrombogenic therapy regimens as well as an aging population. Thrombosis can be the first sign of malignant disease preceding the clinical detection of cancer by months or years.1

Coagulation issues in cancer are caused by risk factors that are general to coagulation impairment and other factors such as tumor type and stage of disease. This can include immobility, old age and surgery, and risk factors specific of cancer, such as the cancer type, advanced disease stage and anti-cancer therapies. Cancer and coagulation are interconnected in several ways. Cancer cells can activate the coagulation system, and the hemostatic factors play a role in tumor progression. Identification of biomarkers that can be used to classify subjects at a higher risk can be used to aid in the prevention of thrombohemorrhage events.1

PATHOGENESIS:

The pathogenesis of blood coagulation in cancer is complicated and a role is played by the expression of tumor associated clotting which leads to the activation of the clotting cascade, the generation of thrombin and fibrin, the stimulation of platelets, leukocytes and endothelial cells exposing cellular procoagulants properties.1

Coagulation disorders in cancer patients can be liked to several process that occur in cancer. This may occur due to tumor specific growth, noenagiogenesis with impaired endothelial lining, defective myelopoiesis, hypoproteinemia or metastatic lesions growth with organ dysfunction. Additionally, treatment strategies such as radiation therapy may also contribute to both bleeding and thrombosis since it may affect liver function and decrease the function of coagulation factors. The most impacted coagulation parameter due to chemotherapy is platelet synthesis.3 Patients with solid tumors were the most likely to have thrombotic events, however complications have also been seen in hematological malignancies. Hemorrhages and DIC can be fatal in acute leukemia.4

Abnormality of coagulation testing results show a process of fibrin formation and fibrinolysis parallels the malignancy and increasing in patients with metastases. High levels of plasma by-products of clotting such as prothrombin fragment 1.2, fibrinopeptide A, thrombin-antithrombin complex and D-dimer or an acquired protein C resistance may be seen. Patients may have high levels of circulating microparticles shed by tumor cells and platelets.1

The release of cytokines which can be caused by the activation of leukocytes to the vessel wall can promote the activation of blood coagulation and clot formation. Many cases have supported the incidence of thrombotic microangiopathy in patients with high-dose chemotherapy. This is caused by enhanced platelet adhesion to the endothelium leading to platelet aggregation and activation causing consumptive thrombocytopenia. The platelet thrombi in the vasculature result in impaired organ function including renal insufficiency or neurological disease. The prognosis of this is poor with mortality of about 30%.5

Tissue factor (TF) can be expressed by endothelial cells as well as tumor cells. These procoagulant molecules can form a complex with FVIIIa to activate FIX and X and a cancer procoagulant (CP). This is a cysteine protease with factor X activating properties. CP is found in the plasma of patients with solid tumors and can contribute to the pathogenesis of cancer related DIC. Endothelial cells are damaged by chemotherapy increasing the risk of thrombosis. Endothelium is the primary source of von Willebrand factor (vWF) which is responsible for the interaction between glycoprotein 1b receptor on the platelet surface and vessel wall. There may be enhanced plasma levels of vWF which may contribute to increased platelet-vessel wall interaction.5

One of the complications in cancer patients is the activation of coagulation resulting in disseminated intravascular coagulation (DIC). This leading to the simultaneous activation of coagulation and the consumption of coagulation proteins and platelets resulting in bleeding and or thrombosis. DIC in cancer may be less intense than in other situations and patients may be asymptomatic. Consumption of factors and platelets may occur slowly and then result in bleeding at the site of the tumor or metastases. Additionally, thrombotic complications may arise clinically and manifest as vascular thrombosis to microvascular platelet plugs. Treatment for DIC in these patients is to treat the disease, however additional strategies may be needed to control the DIC.6

COAGULATION PARAMETERS IN SPECIFIC CANCERS

Underlying mechanisms pre-disposing cancer patients to thrombosis are poorly understood. A study looked at extracellular vesicles (EV) and found they are elevated in patients with colorectal cancer in comparison with normal healthy controls. EV come from blood, endothelial cells or the underlying tumor. As a result, this may contribute to the activation of coagulation and propagation by exposing tissue factor which provides a surface for coagulation factors to interact. EV levels also correlated with D-dimer levels. Another study demonstrated that in patients with advanced colorectal cancer chemotherapy attenuates coagulation activation as indicated by a decline of D-dimer levels and number of EV.7

It has been shown that thromboembolism occurs in children who have been diagnosed with acute lymphoblastic leukemia (ALL) after chemotherapy is initiated. This suggests an interaction of disease and therapy. A study looked at 37 ALL patients matched with normal controls. Coagulation testing was performed on day 0, day 14 and day 28. Testing included PT, aPTT, fibrinogen, protein C and protein S activity (clot based), D-dimer, AT, tPA and PAI-1 levels. There were no major changes in the PT and aPTT during treatment, however fibrinogen levels decreased significantly following L- asparaginase treatment. D-dimer levels were statistically significantly elevated at diagnosis, and induction therapy while PC, PS and AT were reduced initially during induction increasing in the second half of therapy, reaching baseline levels. TPA level were reduced at diagnosis and throughout while PAI-1 levels were the same as controls initially and rose during therapy. This study demonstrated that both the malignant process and drugs used in combined chemotherapy cause thrombin activation, decrease in natural inhibitors, hypofibrinolysis resulting in hypercoagulability. These results support that ALL is a hypercoagulable state and prothrombotic condition at the time of diagnosis and increased during induction chemotherapy.8

Ovarian cancer patients are at high risk of thrombosis particularly during chemotherapy. Ovarian cancers are associated with a very high rate of venous thromboembolism (VTE) with cumulative incidence rates of 20% in the first year following diagnosis, Ovarian tumours release procoagulant material which is associated with VTE. The thrombin generation assay can be used as both a tool to investigate this procoagulant activity as well as a predictor of VTE. Measuring thrombin generation before and after the addition of thrombomodulin (TM) was analyzed. Lower levels of ETP and peak thrombin were found in the neoadjuvant group when compared to both chemo naïve and benign groups, however after TM was added ETP and peak thrombin were higher in this group. This indicated an increase in aPC resistance resulting in higher levels of TM and lower levels of protein S, as well as increased levels of factor V. This supports chemotherapy resulting in the induced procoagulant activity due to an acquired aPC resistance. The protein C pathway is a regulator of thrombin production. Binding of thrombin to TM on the endothelial cell surface leads to the activation of protein C which is accelerated by the endothelial protein C receptor (EPCR). Additionally, aPC, with cofactor protein S can inactivate cofactors FVa and FVIIIa shutting down the prothrombinase and tenase complexes.9

CHEMOTHERAPEUTIC DRUGS AND COAGULATION:

Treatment of acute myeloid leukemia (AML) by the antineoplastic drugs including Idarubicin (IDR), cytarabine (AraC), and tamibarotene (Am80) are effective, however they can cause either DIC or VTE during induction chemotherapy. These drugs were investigated using endotheIial cell lines focusing on tissue factor (TF), phosphatidylserine (PS), and thrombomodulin (TM). IDR induced procoagulant activity on the surface of vascular endothelial and AML cell lines they expressed TF, TM and PS. Am80 decreased TF and procoagulant activity and may suppress blood coagulation through downregulation of TF expression and induction of TM expression.10

The global thrombosis test (GTT) is used to assess both platelet rich thrombus formation and lysis activities under physiological flow conditions. The impact of cisplatin-based chemotherapy on the thrombotic and it’s reaction in cancer. Samples from 34 patients using non-anticoagulated blood samples were tested using the occlusion time (OT) which is the time to form an occlusive thrombus, and the lysis time (LT) indicates the time of endogenous lysis of the thrombus. Testing was performed before and after chemotherapy to determine the impact of cisplatin on arterial thrombogenesis and endogenous fibrinolytic activity. Results showed that the OT was significantly shorted suggesting it enhanced platelet reactivity increasing the risk of thrombosis. The LT was initially reduced and did not change after treatment. Cisplastin based chemotherapy affected the thrombotic activity in patients.11

The drug bevacizumab is a recombinant monoclonal antibody directed against VEGF frequently used in treating colorectal cancer and is not without side effects. Thrombotic events were reported in up to 23% of patients. A study looked at its impact on coagulation and platelet parameters. It included 27 patients with a total number of 330 chemotherapy cycles. D-dimer levels significantly decreased beginning with the 12th cycle, however there was no difference in the PT, aPTT, fibrinogen and MPV. At the end of the treatment there was a significant increase in INR in females. Fibrinogen increased after the 8th cycle while a decrease in the MPV lasted until the 12th cycle in females. It is possible that females may be more sensitive to chemotherapy as compared to males.12

CONCLUSION:

Cancer and coagulation are complex and mechanisms are not well understood. It is important to understand how both cancer and the treatment for cancer impacts coagulation testing. Investigation of abnormal test results may be due to the disease and treatment and not an additional coagulopathy.

REFERENCES:

  1. Falanga, M. Marchetti, A. Vignoli, Coagulation and cancer: biological and clinical aspects, Journal of Thrombosis and Hemostasis, Volume11, Issue2, February 2013
  2. Mosarla RC, Vaduganathan M, Qamar A, Moslehi J, Piazza G, Giugliano R, Anticoagulation Strategies in Patients With Cancer: JACC Review Topic of the Week. J Am Coll Cardiol 2019;73:1336-134
  3. Slavica Kvolik 1, Marko Jukic, Marko Matijevic, Ksenija Marjanovic, Ljubica Glavas-Obrovac, An overview of coagulation disorders in cancer patients, Surg Oncol 2010 Mar;19(1):e33-46.Epub 2009 Apr 25. https://pubmed.ncbi.nlm.nih.gov/19394816/
  4. Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies. J Clin Oncol2009; 27: 4848– 57.
  5. Levi, Marcel1,2. Pathophysiology of Coagulopathy in Hematological Malignancies and in COVID-19. HemaSphere 5 (6):p e571, June 2021
  6. Marcel Levi, Disseminated Intravascular Coagulation in Cancer: An Update, Semin Thromb Hemost 2019 Jun;45 (4):342-347. https://pubmed.ncbi.nlm.nih.gov/31041800/
  7. Ludwig Traby, Hannah C. Puhr, Marietta Kollars, Kammer Michael, Gerald Prager, et al Effects of Chemotherapy on Extracellular Vesicles and Coagulation Activation in Colorectal Cancer Patients: A Pilot Study, Blood (2016) 128 (22): 1425.
  8. Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile during induction chemotherapy in childhood acute lymphoblastic leukemia. Indian J Pathol Microbiol 2017;60:50-6
  9. Ward, MP., Abu Saadeh, F., O’Toole, SA., Gleeson, S., Noris, LA., Procoagulant activity in high grade serous ovarian cancer patients following neo-adjuvant therapy – the role of the activated Protein C pathway, Thrombosis Research, Volume 200 April 2021
  10. Misae Tsunaka, Haruka Shinki, Takatoshi Koyama, Cell-based evaluation of changes in coagulation activity induced by antineoplastic drugs for the treatment of acute myeloid leukemia, April 13, 2017
  11. Wataru Shioyama, Toru Oka, Risa Kamada, Tatsuya Nishikawa, Makiko Oboshi etal, Assessment for dynamic effects of cisplatin-based cancer chemotherapy on coagulation and fibrinolytic system free access, J Am Coll Cardiol. 2020 Mar, 75 (11_Supplement_1) 2248
  12. Cemil Bilir, Hüseyin Engin, Yasemin Temi, Evaluation of Coagulation Parameters in the Use of Bevacizumab Based Chemotherapy for Metastatic Colorectal Cancer ANNALS OF ONCOLOGY, VOLUME 24, SUPPLEMENT 4, IV104, JUNE 2013

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