Prophylaxis and Treatment of Venous Thromboembolism in Cancer Patients

The Case

A 62-year-old woman with a past medical history significant for metastatic adenocarcinoma of the lung presents to the ED with complaints of fever and shortness of breath. She has recently completed her first cycle of carboplatin, pemetrexed, and bevacizumab. Upon admission, she is found to have an absolute neutrophil count of 800 and a platelet count of 48,000. She is admitted for neutropenic fever and placed on IV antimicrobials. Sequential compression devices are initiated for DVT prophylaxis.

Key Clinical Questions

What risk do cancer patients have for VTE?

Patients with cancer have a risk of clinically significant VTE that is four to seven times that of patients without malignancy.1 This is due to a number of reasons:

  • Tumor cells produce procoagulant activity inducing thrombin formation;2
  • The cancer itself can compress or invade deep veins; and3
  • Some cancer therapies such L-asparaginase and thalidomide/lenalidomide, plus high-dose steroids, or anti-estrogen medications such as tamoxifen can also increase patients’ risk of VTE.3,4,5

What inpatients with cancer need VTE prophylaxis?

Much like other hospitalized medical patients, patients with cancer who have reduced mobility and are not on therapeutic anticoagulation should receive pharmacologic prophylaxis unless there is a contraindication.3,6,7,8 Cancer patients with acute medical illnesses should also likely receive prophylaxis if there are no contraindications, because the vast majority of these have factors increasing their VTE risk, including infection, kidney disease, or pulmonary disease.3,6,7,8 Patients undergoing major cancer surgery should also receive pharmacologic prophylaxis prior to surgery and for at least seven to 10 days post-operatively.3,6,7,8

For ambulatory cancer patients who are admitted for short courses of chemotherapy or for minor procedures, however, there is not enough evidence to recommend routine VTE prophylaxis.6,7 An exception to this is patients with multiple myeloma receiving thalidomide-based or lenalidomide-based chemotherapy, who should receive pharmacologic prophylaxis.6,7

Illustration shows vascularized cancer cells in the background upper left, with arteries going into it and a venous plexus coming off which joins up with a bigger vein with valves. larger pink molecular balls represent the procoagulation factor that tumor cells produce that directly jump starts the coagulation pathway. the procoagulation factor molecules are binding to regular leukocytes, endothelium and platelets that will then start producing tissue factor that also encourages coagulation. Also shown are tumor cells binding to endothelium which cause production of tissue factor, causing clots to form. two of the clots are shown embolizing. fibrinogen and platelets are throughout.

Image Credit: DNA ILLUSTRATIONS / SCIENCE SOURCE Illustration shows vascularized cancer cells in the background upper left, with arteries going into it and a venous plexus coming off which joins up with a bigger vein with valves. larger pink molecular balls represent the procoagulation factor that tumor cells produce that directly jump starts the coagulation pathway. the procoagulation factor molecules are binding to regular leukocytes, endothelium and platelets that will then start producing tissue factor that also encourages coagulation. Also shown are tumor cells binding to endothelium which cause production of tissue factor, causing clots to form. two of the clots are shown embolizing. fibrinogen and platelets are throughout.

What are the options available for VTE in hospitalized cancer patients?

The guidelines for VTE prophylaxis in hospitalized cancer patients recommend either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for prophylaxis when no contraindications exist.5 The only two LMWH that have been FDA approved for prophylaxis are enoxaparin and dalteparin. When deciding between UFH and LMWH, no evidence shows that one is better than the other in preventing VTE in hospitalized cancer patients.9 There is evidence that the use of LMWH results in a lower incidence of major hemorrhage when compared to UFH.10

What are the contraindications to pharmacologic VTE prophylaxis in cancer patients?

Contraindications for pharmacologic VTE prophylaxis in cancer patients include active major bleeding, thrombocytopenia (platelet count <50,000/µL), severe coagulopathy, inherited bleeding disorder, and at the time of surgery or invasive procedures (including lumbar puncture and epidural or spinal anesthesia).3,6,7 Those with contraindications to pharmacologic VTE prophylaxis should have mechanical prophylaxis instead.

What is the recommended treatment of VTE in cancer patients?

After the diagnosis of pulmonary embolism (PE) or DVT is found, LMWH is the preferred initial anticoagulant instead of UFH unless the patient has severe renal impairment (CrCl of less than 30 ml/min).6,7,8 LMWH is also preferred over warfarin for long-term anticoagulation during the initial six months of therapy.6,7,8 Following the initial six months, continued anticoagulation with either LMWH or warfarin could be considered in patients with active cancer, metastatic disease, or ongoing chemotherapy.6,7,8

When should IVC filters be considered in treating VTE in cancer patients?

IVC filter insertion should be reserved for those patients found to have a DVT or PE who have a contraindication to pharmacologic anticoagulation.3,6 It can be considered in patients who have recurrent VTE despite the appropriate use of optimally dosed LMWH therapy.6,8

What about the new oral anticoagulants?

At this point, because the majority of the major trials looking at the new oral anticoagulants (dabigatran, rivaroxaban, and apixaban) excluded cancer patients or included them only in small numbers, there is not enough evidence to support their use in cancer patients diagnosed with VTE.6,7,8

Back to the Case

On hospital day three, the patient is clinically improved. She is afebrile, her neutropenia has resolved, and her platelet count is up to 80,000. Her only complaint is pain and swelling of her left leg. A lower extremity Doppler is performed. She is found to have an acute left femoral DVT. The patient is then started on enoxaparin 1 mg/kg every 12 hours. Her left leg swelling and pain begin to improve, and she is discharged on enoxaparin and follows up with her oncologist in the next week. TH


Drs. Bell and O’Rourke are assistant professor of medicine in the division of hospital medicine at the University of California San Diego.

References

1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712-1723.
2. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715-722.
3. Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. J Natl Compr Canc Netw. 2013;11(11):1402-1429.
4. Payne JH, Vora AJ. Thrombosis and acute lymphoblastic leukaemia. Br J Haematol. 2007;138(4):430-445.
5. Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103(17):1299-1309.
6. Lyman GH, Khorana AA, Kuderer NM, 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):2189-2204.
7. Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33(6):654-656.
8. Farge D, Debourdeau P, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013;11(1):56-70.
9. Khorana AA. The NCCN clinical practice guidelines on venous thromboembolic disease: strategies for improving VTE prophylaxis in hospitalized cancer patients. Oncologist. 2007;12(11):1361-1370.
10. Mismetti P, Laporte-Simitisidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomized clinical trials. Thromb Haemost. 2000;83(1):14-19.

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