Expression and Release of Tumor Cell Tissue Factor Triggers Recurrent Thromboembolism in a Patient with Endometrial Cancer

Abstract

Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19–9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.

Zusammenfassung

Obwohl die tumorassoziierte Thrombose (CAT) eine häufige Komplikation bei Patienten mit malignen Erkrankungen darstellt, bleibt ihre Behandlung in der täglichen Praxis eine Herausforderung. Wir berichten über den klinischen Fall einer 51-jährigen Patientin, die sich mit einer hochgradig thrombogenen paraneoplastischen Gerinnungsstörung vorstellte. Trotz therapeutischer Antikoagulation mit verschiedenen Präparaten, unter anderem Rivaroxaban, Fondaparinux und niedermolekulares Heparin, entwickelte die Patientin rezidivierende venöse und arterielle Thromboembolien. Es konnte ein lokal fortgeschrittenes Endometriumkarzinom nachgewiesen werden mit starker Expression von Gewebefaktor (Tissue-Faktor, TF) auf den Tumorzellen. Es fanden sich zudem signifikant erhöhte Konzentrationen von TF-tragenden Mikrovesikeln im Plasma der Patientin. Die Koagulopathie konnte nur durch eine kontinuierliche intravenöse Antikoagulation mit dem direkten Thrombininhibitor Argatroban kontrolliert werden. Eine multimodale antineoplastische Behandlung, einschließlich einer neoadjuvanten Chemotherapie mit anschließender Operation und postoperativer Strahlentherapie, führte zu einer klinischen Remission des Tumors, welche mit einer Normalisierung der Tumormarker CA125 und CA19–9, der D-Dimere und der TF-exprimierenden Mikrovesikel einherging. Somit könnte die Kombination aus kontinuierlicher Antikoagulation mit Argatroban und multimodaler Krebstherapie erforderlich sein, um eine TF-vermittelte paraneoplastische Koagulopathie mit rezidivierender CAT bei Patientinnen mit Endometriumkarzinom zu kontrollieren.

Keywords

cancer-associated thrombosis - paraneoplastic coagulopathy - tissue factor - endometrial cancer - microvesicle

Schlüsselwörter

Krebs-assoziierte Thrombose - paraneoplastische Koagulopathie - Gewebefaktor - Endometriumkarzinom - Mikrovesikel

Introduction

Cancer-associated thrombosis (CAT) is a frequent complication in patients with solid tumors or hematological malignancies.[1] CAT significantly reduces quality of life and indicates an unfavorable clinical outcome of the underlying malignancy.[1] [2] [3] Furthermore, CAT directly contributes to mortality in hematology and oncology patients.[3] [4]

In general, the risk of venous thromboembolism (VTE) is increased four- to ninefold in patients with cancer.[1] [5] However, the risk is highly heterogeneous among individual cancer entities, with highest VTE incidence rates reported in tumors of pancreatic, gastric, brain, or genitourinary (excluding prostate) origin.[6] Moreover, in up to 11% of spontaneous VTE cases, an underlying malignancy is identified.[7] Finally, prevention and treatment of CAT are challenging since cancer patients are at particularly high risk for both, recurrent thrombosis and bleeding, during anticoagulant therapy.[3] [8]

Here, we present the case of a 51-year-old woman who developed recurrent VTE and arterial thromboembolism (ATE) despite standard therapeutic anticoagulation as the initial manifestation of advanced endometrial cancer.

Case Presentation

A 51-year-old woman (175 cm, 70 kg) was transferred to our institution in August three years ago for suspected paraneoplastic coagulopathy due to cancer of unknown primary (CUP) with peritoneal and lymphatic metastases. The patient had no history of symptomatic COVID-19. In addition, twice weekly PCR testing for SARS-CoV-2 remained negative during hospitalization.

Three months earlier, the patient had developed deep vein thrombosis (DVT) of the right lower extremity ([Fig. 1]). Anticoagulation with rivaroxaban was initiated, but despite reliably good adherence the patient experienced an acute episode of amaurosis fugax, abdominal pain, tachycardia, and shortness of breath 4 weeks later requiring hospital admission. Computed tomography scanning of the chest and abdomen revealed right-sided pulmonary embolism (PE), embolic infarction of the right upper kidney, and a suspicious lymph node located in perisigmoid fat tissue with no evidence for a primary cancer. In addition, a thrombus in the right atrium was revealed by echocardiography. There was no sign for an atrial shunt or atrial fibrillation. Investigations for primary tumor site, including gastroscopy, colonoscopy, and gynecological examination, remained unremarkable. Thus, anticoagulation was continued with the vitamin K antagonist, phenprocoumon, at dosages titrated to maintain the international normalized ratio between 3 and 4, and the patient was discharged home from hospital. Several days later, painful swelling of the left leg occurred, and DVT of the upper and lower extremity was confirmed by ultrasound ([Fig. 1]). Moreover, progressive PE and cerebral infarctions in addition to new thrombotic deposits on mitral valve leaflets were observed. Anticoagulation was continued with fondaparinux at 7.5 mg once daily (OD), and extensive laboratory workup ruled out antithrombin deficiency, overt disseminated intravascular coagulation, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, and autoimmune (or spontaneous) heparin-induced thrombocytopenia ([Table 1]). In addition, molecular testing for JAK2^V617F, prothrombin G20210A, and factor V gene mutation Leiden was negative. Tumor markers CA125, CA15–3, CA19–9, and CEA were elevated. Follow-up computed tomography and magnetic resonance imaging studies of abdomen and pelvis revealed progressive tumor manifestations with multiple pelvic lymphatic and peritoneal lesions. Moreover, suspicious endometrial alterations were suggestive of a gynecological cancer. Because of clinically progressive coagulopathy, anticoagulation with fondaparinux was intensified to 7.5 mg three times daily, and the patient was transferred to our institution for further diagnostic workup.

Table 1 Laboratory workup of the patient in July

	Value	Reference range
Blood counts
Hemoglobin, g/dL	12.4	14.0–17.5
Leukocytes, 109/L	10.5	3.8–11.0
Platelets, 109/L	159	150–350
Clinical chemistry
Creatinine, mg/dL	0.5	0.6–1.3
LDH, U/L	292	87–241
Coagulation parameters
Prothrombin time, %	88	80–130
INR	1.0	0.85–1.15
aPTT, s	21	25–38
Thrombin time, s	16	16–22
Fibrinogen, g/L	3.7	1.8–4.0
D-dimer, mg/L	> 20	< 0.5
Antithrombin, %	103	83–118
PC activity, %	59	70–140
Free PS antigen, %	52	60–114
Ratio APC resistance	1.1	> 0.7
Factor VIII:C, %	129	70–150
Factor XIII:C, %	123	70–140
Plasminogen, %	110	75–140
Plasmin inhibitor, %	117	80–120
Tumor markers
CA125, kU/L	1,378	< 35
CA15–3, kU/L	92.4	< 25
CA19–9, kU/L	4,271	< 37
CEA, µg/L	47.3	< 3.8
Autoantibodies
IgM–aCL, U/mL	2.3	< 10
IgG–aCL, U/mL	2.7	< 10
IgM–anti-β2GPI, U/mL	< 0.9	< 7
IgG–anti-β2GPI, U/mL	0.8	< 7
LA	Negative	Negative
Genetic analysis
JAK2, pV617F	Negative	Negative
F5 mutation, Leiden	Negative	Negative
Prothrombin G20210A mutation	Negative	Negative

Abbreviations: aCL, anticardiolipin; anti-β₂GPI, anti-β₂-glycoprotein-I; APC, activated protein C; aPTT, activated partial thromboplastin time; CA, cancer antigen; CEA, carcinoembryonic antigen; F5, gene for coagulation factor V; INR, international normalized ratio; JAK2, Janus kinase 2; LDH, lactate dehydrogenase; LA, lupus anticoagulant; PC, protein C; PS, protein S.

Notes: EDTA-anticoagulated whole blood was used for genetic analysis and blood counts. Clinical chemistry parameters were measured in lithium heparin-anticoagulated plasma and coagulation parameters were measured in platelet-poor plasma obtained by centrifugation of sodium citrate-anticoagulated whole blood for 15 minutes at 2,755 × g and 15 °C. Serum was used to quantify tumor markers and antiphospholipid antibodies.

Fig. 1 Clinical course of the patient. ASA, acetylsalicylic acid; AT, arterial thrombosis; CT, cardiac thrombosis; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist. Asterisk indicates time point of laboratory workup ([Table 1]).

Anticoagulation was switched to the direct thrombin inhibitor, argatroban ([Fig. 1]). Compared with healthy controls, significantly elevated concentrations of microvesicle-associated tissue factor procoagulant activity (MV TF PCA) were detected in patient plasma ([Fig. 2A]), as assessed by a previously described chromogenic Xa generation endpoint assay.[9] High dosages of argatroban were required to maintain the activated partial thromboplastin time within the upper therapeutic target range ([Fig. 2B]). With the exception of an additional transient ischemic attack at the beginning of argatroban therapy, which prompted initiation of antiplatelet therapy with acetylsalicyclic acid (ASA) 100 mg OD, no further thrombotic events occurred ([Fig. 1]). Positron emission tomography scanning confirmed a tumorous process located in the uterus with cervical, rectal, and bowel infiltrations and multiple lymphatic and peritoneal metastases. While initial endometrial and cervical biopsy specimens were nondiagnostic, a percutaneous core biopsy of a peritoneal tumor manifestation revealed a highly estrogen and progesterone receptor positive endometrial adenocarcinoma, thus confirming the paraneoplastic etiopathogenesis of coagulopathy.

Fig. 2 Characterization of paraneoplastic coagulation disorder. (A) Tissue factor–dependent procoagulant activity of plasma microvesicles (MV TF PCA) was assessed by a chromogenic factor Xa generation assay. MVs were isolated from patient plasma on four distinct occasions during early anticoagulation with argatroban. Plasma MVs obtained from three sex-matched healthy individuals served as controls. For MV isolation, sodium citrate-anticoagulated whole blood was centrifuged within 1 hour after collection twice at 2,050 × g and 4 °C for 10 minutes to obtain platelet-poor plasma (PPP). Subsequently, MVs were isolated from PPP by double high-speed centrifugation at 16,100 × g and 4 °C for 30 minutes. (B) Time course of activated partial thromboplastin time (aPTT) and argatroban dosages. Target range is defined as 1.5- to 3.0-fold prolongation of the patient's baseline aPTT and highlighted by horizontal dashed lines. (C) Time course of tumor markers CA125 and CA19–9. Application of each cycle of neoadjuvant chemotherapy (CTx) and upper limit of the reference range of tumor markers (dashed lines) are indicated. Time course of patient MV TF PCA (D) and D-dimer levels (E) are shown. In panel (E), the upper limit of the D-dimer reference range is indicated by a dotted line. Correlations of D-dimer with MV TF PCA (F) and tumor markers CA125 (G) and CA19–9 (H). All data were normally distributed using the Shapiro–Wilk test. p-Values are according to two-sample t-test (***, p < 0.001) in panel (A). Correlation coefficients (r) and p-values are according to the method of Pearson in panels F–H.

The endometrial cancer was classified as stage FIGO IVB, and the patient received neoadjuvant chemotherapy with carboplatin and paclitaxel. Inhibition of tumor angiogenesis with the monoclonal vascular endothelial growth factor antibody, bevacizumab, was waived because of recurrent thromboembolic events. The patient showed a good clinical response with decreasing tumor markers ([Fig. 2C]). Consistently, release of MV TF PCA ([Fig. 2D]) and D-dimer levels ([Fig. 2E]) steadily declined during chemotherapy. In addition, MV TF PCA ([Fig. 2F]), CA125 ([Fig. 2G]), and CA19–9 ([Fig. 2H]) strongly correlated with plasma D-dimers. Since tumor response was accompanied by an improvement in coagulopathy, anticoagulation was continued with the low-molecular-weight heparin (LMWH), enoxaparin, at supratherapeutic dosages (1.25 mg/kg twice daily [BID]). After completion of all six chemotherapy cycles, the enoxaparin dosage was reduced to 1 mg/kg BID. Cancer therapy was continued with debulking surgery, resulting in complete resection of gross tumor lesions, followed by adjuvant percutaneous and local radiotherapy. Immunohistochemical staining of the resected mass confirmed endometrial cancer with tumor cells showing abundant TF expression ([Fig. 3]). At 15 months of follow-up, the patient is still in complete remission. No further thrombotic events have occurred.

Fig. 3 Histopathological analysis of resected tumor. (A, B) Histopathological analysis of tissue specimens obtained from debulking surgery revealed an endometrioid adenocarcinoma. (C, D) Immunohistochemical staining of tumor cells for TF using a specific rabbit monoclonal IgG antibody (clone, EPR22548–240; Abcam, Cambridge, UK). Images were captured with ×2 magnification in panels (A) and (C), and ×10 magnification in panels (B) and (D).

Discussion

In the patient discussed in this study, recurrent thromboembolism was triggered by advanced endometrial cancer. Endometrial cancer is the 7th leading type of cancer in women worldwide with even higher prevalence in developed countries of the western hemisphere.[10] In the majority of cases, endometrial cancer is diagnosed at localized stages, since abnormal uterine bleeding typically occurs early in affected women.[10] [11] Bleeding, however, was absent in our patient, and thrombotic coagulopathy was the first manifestation of the hitherto occult malignancy. VTE rates of up to 11.5% have been reported in endometrial cancer, with highest risks observed in patients with advanced tumors.[12] [13] [14] [15] In addition, endometrial cancer was the third leading tumor entity identified in women with VTE and occult cancer.[16] Also, VTE occurrence is associated with an adverse outcome in this patient population.[13]

The pathogenesis of cancer-associated coagulopathy is complex and involves a plethora of cellular and molecular mechanisms. These include aberrant expression and activation of coagulation factors, release of procoagulant MVs, and activation of platelets and leukocytes (i.e., monocytes and neutrophils) in the proinflammatory tumor microenvironment.[6] [17] [18] In particular, aberrant expression of TF, the physiologic initiator of the extrinsic coagulation protease cascade, on cancer cells and release of TF-bearing MVs have been associated with highly prothrombotic tumor entities and overt tumor cell-induced coagulation activation.[17] [18] [19] In addition, some tumor entities may also produce other coagulation factors, including coagulation factor VII (FVII) or cancer procoagulant,[20] [21] or initiate coagulation by activation of the contact-dependent intrinsic pathway.[22] In our patient, we identified strong tumor cell TF expression in tissue sections obtained from debulking surgery ([Fig. 3C, D]), a finding consistent with previous (pre-)clinical studies.[23] [24] Moreover, dramatically increased levels of MV TF PCA, presumably released by TF-expressing tumor cells, were measured in patient plasma at initial presentation to our institution, which steadily decreased during effective anticancer therapy ([Fig. 2A, D]) and strongly correlated with plasma D-dimers ([Fig. 2F]). Despite a limited number of data points, tumor markers CA125 and CA19–9 showed a strikingly close correlation with plasma D-dimer levels ([Fig. 2G, H]). It is thus tempting to speculate that TF expressed by tumor cells and cancer cell-derived MVs was the main driver of paraneoplastic coagulation activation. Similarly, high dosages of argatroban were required to control the hypercoagulable state ([Fig. 2B]), which is in line with significant TF-driven thrombin generation.

Interestingly, MV TF PCA had markedly decreased during anticoagulation with argatroban ([Fig. 2D]), suggesting that thrombin contributed to CAT pathogenesis by mechanisms additional to fibrin formation. Several previous (pre-)clinical studies have indicated that thrombin participates in primary tumor growth, cell proliferation and survival, metastasis, angiogenesis, inflammation, and oncogenesis, particularly via cleavage activation of protease-activated receptors (PARs).[25] [26] [27] [28] In the proinflammatory tumor microenvironment, thrombin also promotes leukocyte trafficking and activation of platelets and endothelial cells.[25] [26] [27] Moreover, thrombin inhibitors such as dabigatran or ximelagatran may reduce cancer growth and metastasis in mice, but effects are highly variable between individual tumor models and direct oral anticoagulant (DOAC) treatment schedules.[29] Similarly, rivaroxaban prevented FXa-mediated PAR2 activation on murine tumor-associated monocytes/macrophages, which has been implicated in immune evasion of cancer cells.[30] Thus, it is tempting to speculate that thrombin-directed anticoagulants may inhibit cancer progression, thereby enhancing their antithrombotic potency in CAT therapy. However, convincing data from prospective clinical trials are currently not available.[26]

Despite significant insights into the molecular basis of paraneoplastic coagulopathies over the past decades, prevention and treatment of CAT remain challenging. Consistent with our case report ([Fig. 1]), cancer patients are at increased risk of recurrent thrombosis, with risks correlating with tumor stage and entity.[1] [6] Thus, extended anticoagulation beyond 6 months is recommended, especially in patients whose cancer is still active and who carry a high thromboembolic risk.[31] [32] [33] [34] [35] In this population, current treatment guidelines recommend anticoagulation with LMWH or direct oral FXa inhibitors (i.e., apixaban, edoxaban, and rivaroxaban).[31] [32] [33] [34] In addition, effective treatment of the underlying malignancy is of utmost importance as it addresses the primary cause of the coagulopathy.

Another challenge is VTE recurrence despite therapeutic anticoagulation. Following exclusion of treatment nonadherence, switching the anticoagulant class (e.g., from LMWH to DOAC or vice versa) can be considered.[32] Alternatively, the dose of LMWH may be increased by 20 to 25%.[32]

In addition to VTE, cancer patients are at increased risk of ATE, including myocardial infarction, stroke, and peripheral arterial occlusions.[36] [37] Similar to VTE, the highest risks were observed in patients with brain, stomach, or pancreatic cancer.[36]

Our patient, however, developed recurrent ATE and VTE despite therapeutic anticoagulation with various agents ([Fig. 1]). While arterial embolic events were most probably caused by cardiac thrombotic manifestations, TF-driven coagulation activation by tumor cells and released MVs was likely the main pathway leading to venous thrombosis ([Fig. 2A, D, F]). Only continuous anticoagulation with argatroban in combination with antiplatelet therapy with ASA was sufficient to attenuate initial coagulation activation, while effective anticancer treatment was required for long-term control of the coagulopathy.

In conclusion, in patients with catastrophic paraneoplastic coagulation activation, synergistic effects of therapeutic anticoagulation and effective anticancer therapy may be required to control the thrombotic storm.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 24 October 2022

Accepted: 05 January 2023

Article published online:
02 March 2023