Published: 2021-04-28

Gall bladder carcinoma associated with anticoagulation-resistant, progressive, multi-focal venous thrombosis and gangrene of all limbs: a case report and review of literature

Manisha Aggarwal, Janitta Kundaikar, Dinesh Manchikanti, Shaji Thomas, Ashish Arsia, Rahul Pusuluri, Sanjay Kumar


Cancer being a prothrombotic state, frequently has vascular complications, venous thrombosis, embolism, recurrent venous thromboembolism and a high frequency of anticoagulant failure. We present a rare case of anticoagulant-resistant, progressive, multifocal venous thrombosis and gangrene in all four limbs in a patient with carcinoma gallbladder. A 49 year old lady with locally advanced gallbladder cancer who had been on routine perioperative deep venous thrombosis (DVT) prophylaxis presented two months later with deep venous thrombosis of both lower limbs progressing to venous gangrene of both feet, despite being on anticoagulation. 7 days later, she presented with venous gangrene of both hands. Shortly thereafter, she developed right facial paralysis due to thrombus in the segmental branch of the left MCA despite being on anticoagulation. The hypercoagulable state in cancer involves procoagulant molecules produced by tumor cells, suppression of fibrinolytic activity and platelet activation and is contributed by interactions between the coagulation cascade, complement pathway and immune system. Upto 15% of patients with cancer will develop DVT following surgery, despite standard DVT prophylaxis. Extended DVT prophylaxis should be considered in high-risk patients. Patients with metastases should continue with indefinite anticoagulant therapy after a thrombotic event. In patients without metastasis, anticoagulant treatment is recommended for as long as the cancer is active and while the patient is receiving antitumor therapy. This rare case has been presented to highlight the hypercoagulable state of cancer, the importance of long-term anticoagulation in advanced and metastatic cancers and the high rate of anticoagulation failure associated with unfavourable tumor biology.


Cancer-associated thrombosis, Venous thrombosis, Gangrene, Pulmonary thromboembolism, Prothrombotic state

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Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000;18(17):3078-83.

Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484-8.

Lee AYY, Khorana AA. Cancer Associated Thrombosis. In: DeVita VT, Lawrence TS, Rosenberg SA eds. DeVita, Hellman and Rosenberg’s Cancer Principles and Practice of Oncology. 10th ed. Philadelphia: Wolters Kluwer; 2015: 1969-75.

Kolev M, Towner L, Donev R. Complement in cancer and cancer immunotherapy. Arch Immunol Ther Exp. 2011;59(6):407-19.

Markiewski MM, Lambris JD. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 2009;30(6):286-92.

Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Parsa AT. Cancer and the complement cascade. Mol Cancer Res. 2010;8(11):1453-65.

Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI, et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood. 2005;105(4):1734-41.

Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009;27(29):4834-8.

Belting M, Ahamed J, Ruf W. Signaling of the tissue factor coagulation pathway in angiogenesis and cancer. Arterioscler Thromb Vasc Biol. 2005;25(8):1545-50.

Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest. 2003;112(6):853-62.

Weitz IC, Israel VK, Waisman JR, Presant CA, Rochanda L, Liebman HA. Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation. Thromb Haemost. 2002;88(2):213-20.

Lee AY, Levine MN. The thrombophilic state induced by therapeutic agents in the cancer patient. Semin Thromb Hemost. 1999;25(2):137-45.

Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715-22.

Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104(12):2822-9.

Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost. 2002;87(4):575-9.

Khorana AK, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24(3):484-90.

Khorana AK, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-7.

Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Moigne-Amrani AL, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346(13):975-80.

Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg. 2006;243(1):89-95.

Sweetland S, Green J, Liu B, de-González AB, Canonico M, Reeves G, et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ. 2009;339:4583.

Lyman GH , Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-204.

Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2):227.

Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, Muti P, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review. Cancer. 2008;113(7):1685-94.

Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.

Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6):454-545.

National Comprehensive Cancer Network. Fact sheet: Clinical practice guidelines in oncology. cancer-associated venous thromboembolic disease, 2020. Available at: /professionals/physician_gls/pdf/vte.pdf. Accessed 5 March 2021.

Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7(5):760-5.