Specific Thrombophilia Work-Up Approach

Breast cancer is associated with an increased risk for venous thromboembolism (VTE). Among more than 13,000 women with breast cancer in four U.K. databases, the rate of VTE was 3.5 times that of age-matched controls.¹  Similarly, among more than 100,000 patients with breast cancer in two California databases, the one- and two-year incidences of VTE were 0.9 and 1.2 percent, with the incidence greatest in the first six months after diagnosis.²  VTE incidence also increased while patients were receiving chemotherapy, in the month after therapy was discontinued, and during the initial three months of treatment with tamoxifen.¹  Nonetheless, compared with cancers of the pancreas, stomach, ovary, lung, and kidney, as well as gliomas and lymphomas, this risk is relatively low.³ 

There remains a paucity of data regarding thromboprophylaxis in ambulatory patients with cancer in general and with breast cancer in particular. One relevant study, TOPIC-1, was halted prematurely because of no difference in VTE incidence between ambulatory breast cancer patients treated with low-molecular-weight heparin or placebo.⁴  It is noteworthy that neither the American Society of Clinical Oncology,⁵  the American College of Chest Physicians,⁶  nor the European Society of Medical Oncology³  currently recommend thromboprophylaxis in ambulatory patients with any cancer, unless the individual patient is considered to be at high risk.

In 2010, I discussed the treatment of an ambulatory patient with breast cancer with adjuvant chemotherapy who developed a central-line thrombosis. Based on the information available in 2016, I would not change my recommendations.

(Editor’s Note: The original question was submitted to Dr. Bennett through Consult a Colleague. He expanded his answer for print.)

I have been treating a 54-year-old woman with a resected breast cancer with adjuvant docetaxel, cyclophosphamide, and trastuzumab. She developed a central line thrombosis during treatment and was treated with warfarin for three months, after which the central line was removed. I plan to discontinue the warfarin in the next several weeks, assuming it is safe to do so while she is receiving trastuzumab. Should the patient undergo a workup for thrombophilia despite a negative family history, and should warfarin be restarted if she needs another central line to complete a one-year course of trastuzumab?

This is a common but complex situation. This patient has several predispositions to venous thrombosis, including breast cancer, chemotherapy, and an indwelling venous catheter. The thrombosis she experienced could have resulted from the cumulative effect of these factors, but I suspect the presence of the indwelling catheter was the major precipitating cause.

As you know, cancers — in particular malignancies of the brain, adenocarcinomas of the lung and gastrointestinal tract, and hematologic malignancies - are associated with a sixfold to sevenfold increase in the risk for venous thromboembolism (VTE).^1,2  Although this risk is greatest in the months following diagnosis and declines with time, the risk remains higher than in individuals without cancer even two years after diagnosis. Moreover, the risk for patients with metastatic disease is increased further compared to patients without. Although the risk for VTE in the first six months after a diagnosis of breast cancer is twofold to fourfold less than for patients with the malignancies noted above, the cumulative incidence of VTE for patients with breast cancer approaches that of the others, because patients with breast cancer live substantially longer. This raises the question whether prophylactic anticoagulation in a patient with breast cancer would be beneficial. This issue was addressed in the most recent American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.³  After reviewing the available data, the authors of the guidelines concluded that the evidence does not support routine thromboprophylaxis for the primary prevention of VTE in ambulatory patients such as this one.

Chemotherapy administration and hormonal manipulation are also associated with an increased risk of VTE. Therefore, it is surprising that there is a paucity of studies addressing the efficacy of thromboprophylaxis in ambulatory cancer patients who are receiving chemotherapy or hormonal therapy. One widely cited study from 1994 reported that giving low-dose warfarin (INRs of 1.3-1.9) in patients with stage IV breast cancer receiving chemotherapy resulted in a significant reduction in VTE.⁴  However, these results were not replicated in subsequent studies,⁵  and thromboprophylaxis is not currently recommended for patients with cancer receiving chemotherapy or hormonal therapy.³  With specific regard to trastuzumab, after reviewing the prescribing information and searching the literature, I could not find evidence that VTE is a common adverse event related to the use of this drug.

As I mentioned earlier, I think the central venous catheter itself, as a foreign body in the circulation, was the proximate cause of the thrombosis in your patient. So, it would seem logical to ask whether prophylactic anticoagulation could prevent this from happening again. There have been a number of studies addressing this question. However, a recently reported meta-analysis of eight randomized controlled trials of thromboprophylaxis in patients with cancer and central venous catheters concluded that thromboprophylaxis had no significant effect on the risk of catheter-related thrombosis.⁶  Similarly, in the WARP study of warfarin thromboprophylaxis in cancer patients with central venous catheters,⁷  it was found that neither fixed-dose warfarin at 1 mg per day nor dose-adjusted warfarin to maintain an INR of 1.5 to 2.0 reduced the incidence of catheter-related thromboses. Thus, the available evidence does not support the use of prophylactic anticoagulation should the central line be re-inserted.

Although your patient has several recognized predispositions to thrombosis, the currently available evidence does not support the use of thromboprophylaxis for her clinical situation. Further, on the basis of this conclusion, as well her age and history, I don’t see the utility of a thrombophilia work-up.