Going with the Flow: Anticoagulants Can Reduce Blood Clot Risks for Patients With Cancer

CURE, Hematology Special Issue (October), Volume 1, Issue 1

Anticoagulants can reduce a heightened risk of blood clots in cancer patients.

Four years ago, James Smith was being treated for neuropathy when he began to experience difficulty breathing. He was rushed to his local emergency room, where a life-threatening embolism (a large blood clot), located just where the pulmonary artery splits, was discovered to be cutting off the blood supply to his pulmonary circulation. The now 62-year-old, who is president of a small gas exploration company in Corpus Christi, Texas, was treated with anticoagulation therapy and survived. But his health problems didn’t stop there.

Already aware that his neuropathy and certain proteins in his blood could indicate multiple myeloma, Smith discovered he had a tumor on his lower back. That led him to visit MD Anderson Cancer Center, in Houston, where he was diagnosed with the blood cancer and began treatment.

Like Smith, people with hematologic cancers — leukemia, lymphoma and multiple myeloma — are at increased risk for dangerous blood clots that can often be prevented by, and treated with, intravenous or oral anticoagulation therapies. In most blood cancers, the normal blood cell development process is impeded by the uncontrolled growth of abnormal types of blood cells. These abnormal, or cancerous, cells prevent blood from performing many of its normal functions, meaning that the patient will be prone to excess bleeding and may not be able to fight infections.

Jean Connors, M.D., assistant professor of medicine at Harvard Medical School, says there’s a balance in the body between pro-clotting and anti-clotting activity, and that cancer skews that balance in favor of clotting because it increases inflammation and compresses blood vessels. That’s why many cancer patients are routinely started on an ongoing preventive anticoagulation therapy routine.

CLOTTING RISK FACTORS

Normal blood clotting, or coagulation, occurs when platelets (a type of red blood cell) combine with proteins in the blood to form clots that stop the bleeding at the site of an injury. Once an injury is healed, clots dissolve. Clotting takes place in the veins and arteries that are part of the circulatory system. Arteries carry oxygen and blood from the heart to other parts of the body, and veins do the opposite, carrying deoxygenated blood away from the body’s organs and back to the heart. Arterial clots usually occur as a result of plaque build-up or hardening of the arteries that can cause a rupture that precipitates a heart attack or stroke. Venous blockages can also damage the heart.

Deep vein thrombosis (DVT) is a blood clot that forms in a deep vein in the leg, arm or pelvic area. When a DVT detaches from a vein, breaks up, travels to the heart and is pumped into the lungs, a pulmonary embolism (PE) occurs. A thrombosis is a blood clot that develops locally and an embolism is a thrombosis that has broken off and traveled elsewhere. Together, DVTs and PEs are known as venous thromboembolism, or VTE.

Michael H. Kroll, M.D., professor of medicine and chief of the Section of Benign Hematology at MD Anderson Cancer Center, says that VTE is relatively common in all cancers, compared with the incidence in the general population, and can have a major impact on the survival of patients with cancer.

According to Connors, the overall incidence of clots in cancer patients is generally low, at 5 to 6 percent — and that, she adds, can be decreased by 50 percent through anticoagulation at low doses.

But some patients with cancer face a much higher risk of clots: those with acute leukemia, myeloma and cancers of the pancreas, stomach and brain, Kroll says. Patients with lymphoma, lung cancer and colorectal cancer are at intermediate risk, he says, and those who have undergone stem cell transplant or have breast cancer, prostate cancer or melanomas are at lower risk. Kroll adds that risk increases with the stage of cancer.

Blood clots can also be precipitated by cancer treatments. For instance, patients who have central venous catheters, or central lines that are inserted into the large vein in the chest or upper arm and are used to put medicines, blood products, nutrients or fluids into the blood, may be at higher risk for clots.

Chemotherapies increase the risk for developing VTE to different extents, but patients with acute lymphoblastic leukemia tend to be more likely to get clots when being treated with the chemotherapy drug asparaginase. Lymphoma patients are susceptible because lymph nodes compress the veins. Medications such as the thalidomide derivatives Revlimid (lenalidomide), an immunomodulator that is used to treat myeloma, increase the risk of clots. In addition, sometimes medications that alone don’t increase clot risk do so when combined with other drugs. For example, says Connors, a high dose of steroids and thalidomide for the treatment of myeloma can result in VTE rates as high as 20 to 30 percent.

In fact, thalidomide-based drugs are among two classes of medications that have the worst reputations for causing clots. Kroll says, however, that the VTE risk associated with the immunomodulatory drugs (Imids) and Avastin (bevacizumab), an angiogenesis inhibitor, is misunderstood. These drugs are thought to cause the vascular endothelium (cells lining blood vessels) to develop properties that promote thrombosis. Avastin therapy is only a small risk factor for developing VTE, while Imids, when they are combined with other therapies, are big risk factors for developing thrombosis. In neither case, however, are these drugs — when they are expected to be useful or known to be working — avoided or discontinued because of their effect on the risk of developing VTE. Treatment of VTE almost always accommodates the best cancer treatments available.

Judith Lin, M.D., assistant professor of hematology and oncology and a specialist in coagulation at the Icahn School of Medicine at Mount Sinai in New York, says that blood clots can be a serious complication to the care and survival of patients with hematologic malignancies. Arterial blood clots are generally difficult to ignore, as they often cause rapid tissue or organ damage, stroke or heart attack. Venous clots, however, occur more commonly in patients with cancer, and depending on their extent, size and location, can cause a range of symptoms from subtle and initially difficult to recognize to disabling with painful swelling or breathlessness to sudden death by pulmonary embolism. Treating clots with anticoagulants also adds to the medical burden for patients by increasing their risk of internal bleeding and may delay their cancer treatment plans.

WHAT IS ANTICOAGULATION?

Anticoagulation is the use of oral, intravenous or subcutaneous treatments to prevent, stop or slow down the formation of blood clots. These medications can offer the body time to at least partially digest the thrombus through the natural process known as thrombolysis and restore an intact vascular lining of endothelial cells.

Clotting, says Connors, starts with a cascade of factors that come together to create what she calls a “perfect storm.” One clot, she says, can set off another, or a clot can get bigger. The risk for additional clots is higher for a patient who has already had one. Specific medications, drug dosages and protocols for treatment of clots are determined by symptoms and the various manifestations of cancer.

A main side effect of anticoagulation is bleeding, and some with cancer are at higher risk for that than the average patient, especially if their platelet counts are low. Other side effects can include gangrene of the skin, rash, diarrhea, bloating, jaundice, hair loss and itchy or painful feet. The following are the various types of anticoagulants, as outlined by Kroll:

Warfarin: An oral drug, warfarin (marketed under the brand names Coumadin and Jantoven) is used to treat VTE in patients with cancer. It works by inhibiting the metabolism of vitamin K in the liver that is required by the liver to produce blood-clotting proteins. The drug is sensitive to changes in diet and medications, so a doctor needs to determine the best option for each individual and monitor its use carefully through blood testing (prothrombin time). It takes about five days before full anticoagulation develops.

Low Molecular Weight Heparin (LMWH): Injected under the skin, often by patients themselves at home, LMWHs inhibit the activity of a specific coagulation factor (activated factor X, or Xa). This class of drugs is used to prevent and treat VTE in patients with cancer. Fragmin (dalteparin) is the only LMWH that is FDAapproved for treatment of VTE in patients with cancer using a once-a-day dose. It doesn’t require routine monitoring, and is often used as the first line of therapy for cancer-associated VTE, because it may be more effective than warfarin in preventing recurrent blood clots. Although not approved specifically for use in patients who have cancer, Lovenox (enoxaparin) is also often used.

Direct Oral Anticoagulants: This new class of anticoagulants blocks the activity of clotting factor Xa. These drugs are being studied as treatments for VTE in patients with cancer, but the National Comprehensive Cancer Network and the American Society of Clinical Oncology guidelines discourage their use in patients with cancer at this time, due to a paucity of clinical data. Nevertheless, two classes of these pills have been FDA-approved for use for preventing and treating VTE:

> Direct Factor Xa Inhibitors: Oral drugs such as Xarelto (rivaroxaban), Eliquis (apixaban) and Savaysa (edoxaban) directly inhibit activated factor X. They have proven to be safer than, and at least as effective as, warfarin in preventing recurrent VTE. No monitoring is required and an antidote for use in case of lifethreatening bleeding or emergency surgery is expected to soon be FDA-approved. A patient should not stop taking this medication without speaking with a doctor first, as it may cause paradoxical rebound clotting if it is abruptly stopped.

> Direct Thrombin Inhibitor: Pradaxa (dabigatran) is taken orally and directly inhibits the enzyme thrombin in blood; thrombin causes the clotting of blood by converting the protein fibrinogen, produced by the liver, to insoluble fibrin, the main component of a venous thrombus or clot. Pradaxa is also as safe and effective as warfarin in preventing recurrent VTE. No monitoring is required, and an antidote is available for use in the case of life-threatening bleeding or emergency surgery. This medication should also not be stopped without speaking with a doctor first.

TREATMENT GUIDELINES

Treatment guidelines recommend that all hospitalized cancer patients receive thromboprophylaxis, or clot prevention, and that all patients who have cancer discuss the option of these preventive measures with their doctors. For most patients who have both cancer and VTE, the recommended length of treatment is at least six months, often continuing beyond that if the patient has active cancer and is undergoing chemotherapy treatment. Studies have shown that the dose of an anticoagulant can be safely reduced by about 30 percent after the first six weeks of treatment. While anticoagulation does sometimes take place in hospitals, most of these drugs can be selfadministered outside the hospital.

Although many may have heard aspirin referred to as a “blood thinner,” Lin clarifies that aspirin is not an anticoagulant and is not the standard of care for preventing VTE in patients with cancer. It is, however, standardly used for the prevention of arterial clots involved in heart attacks or thrombotic strokes in patients who don’t have cancer. Lin says that doctors recommend aspirin to prevent venous clots for patients with cancer in certain circumstances. For example, multiple myeloma patients receiving Revlimid may be given the option of aspirin instead of standard anticoagulant when they have no past history of clots or when standard anticoagulants may be contraindicated or not tolerated.

There are times, though they’re not frequent, when an anticoagulant can’t be used because a patient is already experiencing excess bleeding or facing heightened bleeding risk; patients whose platelet counts are low, who have ulcer/gastrointestinal bleeding or who have recently undergone stem cell transplants might fit into this category. In such rare circumstances, and when no other option exists, a filter can be inserted into the interior vena cava, a large vein that delivers blood from the legs to the heart, to capture clot fragments before they can travel to the heart and lungs.

When no longer needed, the filter is removed. Another option for those who can’t be given anticoagulants due to bleeding risk is thrombolytic therapy — treatment with a medication such as tissue plasminogen activator (TPA) that is administered through a catheter to break up clot fragments from a massive PE. A third but rare alternative, used when DVT is unusually severe and causing tissue injury, or when a patient is a poor candidate for other methods or has not responded to anticoagulation, is a thrombectomy, the surgical removal of a massive PE that’s become life-threatening. Connors says it’s important to know in advance if a patient who has been getting anticoagulation therapy needs to have surgery. This allows doctors to stop giving anticoagulants to these patients so they will not face an extra bleeding risk during surgery. If surgery is an emergency, patients must take an anticoagulant reversal medication beforehand, to protect against bleeding. According to Connors, current guidelines recommend that all patients with cancer receive intravenous thromboprophylaxis for one to four weeks after certain surgical procedures.

Other more common approaches to preventing clotting and keeping blood flowing include getting out of a hospital or other bed and moving around as often as possible, limiting the time spent sitting, staying well hydrated and knowing if there is a family history of clots. If there is, changes in diet and exercise can lessen the risk.

Kroll says he expects that ongoing research will keep improving the care of patients with cancer who suffer VTE, and he is optimistic that lives will be saved as we continue to improve the way cancer-associated VTE is prevented and treated.