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Cancer and Blood Clots: Who Is at Risk and How Do We Treat?

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This article was written in collaboration with Yan Liu MD, Ph.D., Director of Cardio-Oncology, Ascension Seton, Medical Director, Ascension Texas Cardiovascular Seton Northwest, Assistant Professor of Medicine, Dell Medical School, The University of Texas at Austin, Ascension Texas.

Venous thrombosis as manifested by superficial thrombophlebitis, deep vein thrombosis (DVT), and pulmonary embolism (PTE or the killer clot) represents the most common cardiovascular complication of cancer. In a series of patients evaluated for the first time DVT or PTE, the presence of cancer increased the rate of venous thrombosis by seven-fold. Hematologic malignancies increased the odds ratio twenty-eight-fold and both lung and gastrointestinal tumors (pancreas, stomach) increased the odds twenty-fold, with the risk being highest in the first year.

Moreover, as cancer progresses from localized to remote or metastatic, the cumulative incidence of VTE (Venous Thrombo-Embolism) increases proportionally and up to nineteen-fold.

Thrombosis in cancer patients is also characterized by a high clot burden involving bilateral lower extremity DVT, upper limb DVT, and sometimes the presence of clots in the large veins such as the superior vena cava or the inferior vena cava. 

Patients with cancer have significantly increased rates of VTE recurrence. In an Italian registry that included over 19,000 patients, the relative risk of recurrence was 2.4-fold for DVT and two-fold for PTE. The high rate of recurrence has led to recommendations for long-term anticoagulation. 

Cancer therapeutics can often directly and further increase the risk of VTE in cancer patients. Though a wide spectrum of cancer therapies have been shown to increase VTE risk, certain types of chemotherapies or targeted therapies, such as Platinum-Based Agents (Cisplatin), angiogenesis inhibitors (Nilotinib, Ponatinib, etc) were associated with a significantly higher risk of VTE compared to other regimens. Other modalities such as hormonal therapies and immunotherapies are also linked to a higher risk of VTE in cancer patients.

VTE in a Special Population: How to Treat Patients with Multiple Myeloma or Patients with Brain Cancer?

VTE affects more than 10% of patients affected with multiple myeloma. There are several reasons for patients to develop VTE, and, in general, they can be divided into 3 groups: (assign 1 point for each of these factors)

  1. Patient related-factors: Age > 75, BMI > 25, Caucasian, a previous history of VTE, a central venous catheter, a blood clotting disorder, comorbidities (DM, COPD, renal or liver impairment)
  2. Diagnosis of multiple myeloma, evidence for increased viscosity or thick blood
  3. Treatment-related risks such as the use of immunomodulatory therapy whether associated with low or high dose steroids, as well as the use of Erythropoietin to treat a low blood count

Common immunomodulating agents include Thalidomide, some proteasome inhibitors like Bortezomib (Velcade) or Carfilzomib (Kyprolis), and Ixazomib. Some monoclonal antibodies have been designed to target proteins on the surface of the myeloma cells and have been used in combination with chemotherapy and steroids.

In patients with a low risk of VTE (0-1 point), 100 mg of aspirin is usually prescribed to prevent a VTE. For patients at high risk (> 1 points), low molecular weight heparin at a smaller prevention dose (enoxaparin 40 mg sc daily) or warfarin is prescribed. DOACs are becoming more and more popular, and there is clinical evidence that apixaban 2.5 mg twice daily can reduce VTE episodes with minimal bleeding risk. The major limitation is the presence of renal failure, particularly when the creatinine clearance is <30 mL/min.

Brain cancer causes a higher risk of VTE compared to other types of cancer. The incidence of VTE can reach 30% in patients with high-grade glioma type of brain cancer and 20% in metastatic brain cancer (where cancer originated elsewhere). Due to the concern about long-term anticoagulation and the risk of intracranial bleeding, the use of prophylactic anticoagulation for primary prevention as an outpatient is not recommended. The use of LMWH is usually recommended in the perioperative period, however. 

How Do We Treat VTE Acutely, and How Do We Prevent Its Recurrence?

Initial anticoagulation treatment is crucial for reducing mortality, preventing early recurrence, and improving long-term outcomes of cancer patients. Early treatment included intravenous heparin, followed in the 1980s with low molecular weight heparin (LMWH), and, since 2017, mostly Direct Oral Anticoagulants (DOACs).

In the HOKUSAI study, patients with cancer and VTE were treated with either Dalteparin followed by Edoxaban or Dalteparin sc. The rate of recurrence of VTE was reduced by 29% with the use of Edoxaban while the major bleeding risk was slightly elevated (6.9% vs 4% for Edoxaban vs dalteparin respectively).

Carravagio investigators studied the treatment of Apixaban 10 mg bid for 7 days followed by 5 mg bid compared to Dalteparin sc in cancer patients and VTE. They found a recurrent VTE in 5.6% in the apixaban group vs 7.9% in the dalteparin with a similar risk of major bleeding (3.9% vs 4%).
In another study, Rivaroxaban was shown to be a good alternative for LMWH (with similar bleeding risk but reduced recurrent thrombosis risk compared to LMWH)

How Do We Prevent VTE in Cancer Patients in Ambulatory Settings? Who Is at Risk and Who Is Likely to Benefit from Anticoagulation Prophylaxis?

In 2008, Dr. Khorana from the Cleveland Clinic developed and validated a score (Khorana score) that predicts thrombosis risk based on a collection of few variables:

  1. Type of cancer (very high risk like gastric or pancreas = 2 points, high-risk cancer lung cancer or lymphoma = 1 point)
  2. BMI (>35) (1 point)
  3. Complete blood count (Hb <10, Leukocyte count >11.000, Platelet count >350,000) (each 1 point when present)

Cancer patients with a Khorana score of 3 or greater are at increased risk of developing clots, more likely to have their cancer progress, and suffer earlier mortality.

In 2019, the Cassini investigators, led by Dr. Khorana, published their study of Rivaroxaban 10 mg daily for 6 months in ambulatory cancer patients at high risk of VTE (Khorana score >or =2) and who had no DVT. The results showed that DVT or death occurred in 6% in the Rivaroxaban group and 8.8% in the placebo and did not reach significance. The risk of major bleeding was 2% vs 1% for Rivaroxaban and placebo.

The same year, Dr. Marc Carrier and the Avert investigators reported their findings on the study of Apixaban 2.5 mg twice daily for 6 months in the same category of patients (Khorana score of 2 or greater) who were initiating chemotherapy. VTE was reported in 4.2% in the Apixaban group vs 10.4% in the placebo and these results were statistically significant. During the treatment period, major bleeding occurred in 2.1% of patients treated with Apixaban vs 1.1% with placebo.

This article was written in collaboration with Yan Liu MD, Ph.D., Director of Cardio-Oncology, Ascension Seton, Medical Director, Ascension Texas Cardiovascular Seton Northwest, Assistant Professor of Medicine, Dell Medical School, The University of Texas at Austin, Ascension Texas.

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d by superficial thrombophlebitis, deep vein thrombosis (DVT) and pulmonary embolism (PTE or the killer clot) represents the most common cardiovascular complication of cancer. In a series of patients evaluated for the first time DVT or PTE, the presence of cancer increased the rate of venous thrombosis by 7 fold. Hematologic malignancies increased the odds ratio 28 fold and both lung and gastrointestinal tumors (pancreas, stomach) increased the odds 20 fold with the risk being highest in the first year. Moreover, as the cancer progresses from localized to remote or metastatic, the cumulative incidence of VTE ( Venous Thrombo-Embolism) increases proportionally and up to 19 fold. Thrombosis in cancer patients is also characterized by a high clot burden involving bilateral lower extremity DVT, upper limb DVT and sometimes presence of clot in the large veins such as the superior vena cava or the inferior vena cava. Finally, patients with cancer have significantly increased rates of VTE recurrence. In an Italian registry that included over 19,000 patients, the relative risk of recurrence was 2.4 fold for DVT and 2 fold for PTE. The high rate of recurrence has led to recommendations for long term anticoagulation. How do we treat VTE acutely and how do we prevent its recurrence? Initial anticoagulation treatment is crucial for reducing mortality, preventing early recurrence and improving long term outcomes of cancer patients. Early treatment included intravenous heparin, followed in the 1980’s with low molecular weight heparin (LMWH) and since 2017, mostly Direct Oral Anticoagulants (DOAC). In the HOKUSAI study, patients with cancer and VTE were treated with either Dalteparin followed by Edoxaban or Dalteparin sc. The rate of recurrence of VTE was reduced by 29% with the use of Edoxaban while the major bleeding risk was slightly elevated (6.9% vs 4% for Edoxaban vs dalteparin respectively). Carravagio investigators studied the treatment of Apixaban 10 mg bid for 7 days followed by 5 mg bid compared to Dalteparin sc in cancer patients and VTE. They found a recurrent VTE in 5.6% in the apixaban group vs 7.9% in the dalteparin with a similar risk of major bleeding (3.9% vs 4%). VTE in a special population: how to treat patients with multiple myeloma or patients with brain cancer? VTE affects more than 10% of patients affected with multiple myeloma. There are several reasons for patients to develop VTE and in general they can be divided into 3 groups: (assign 1 point for each of these factors) 1) patient related-factors: age>75, BMI >25, caucasian, a previous history of VTE, a central venous catheter, a blood clotting disorder, comorbidities (DM, COPD, renal or liver impairment), 2) Diagnosis of multiple myeloma, evidence for increased viscosity or thick blood. 3) Treatment related risk such as the use of Immunomodulatory therapy whether associated with low or high dose steroids, as well as the use of Erythropoietin to treat a low blood count. Common immunomodulating agents include: Thalidomide, some proteasome inhibitors like Bortezomib (Velcade) or Carfilzomib (Kyprolis), Ixazomib. Some monoclonal antibodies have been designed to target proteins on the surface of the myeloma cells and have been used in combination with chemotherapy and steroids. In patients with low risk of VTE (0-1 point), 100 mg of aspirin is usually prescribed to prevent a VTE. For patients at high risk (> 1 points) Low molecular weight heparin at a smaller prevention dose (enoxiparin 40 mg sc daily) or warfarin is prescribed. DOACs are becoming more and more popular and there is clinical evidence that apixaban 2.5 mg twice daily can reduce VTE episodes with minimal bleeding risk. The major limitation is the presence of renal failure particularly when the Creatinine clearance is <30 mL/min. Brain cancer causes a higher risk of VTE compared to other types of cancer. The incidence of VTE can reach 30% in patients with high grade glioma type of brain cancer and 20% in metastatic brain cancer (where the cancer originated elsewhere). Due to the concern about long term anticoagulation and the risk of intracranial bleeding, the use of prophylactic anticoagulation for primary prevention as an outpatient is not recommended. The use of LMWH is usually recommended in the perioperative period however. How do we prevent VTE in cancer patients in ambulatory settings? Who is at risk and who is likely to benefit from anticoagulation prophylaxis? In 2008, Dr. Khorana from the Cleveland Clinic developed and validated a score (Khorana score) that predicts thrombosis risk based on a collection of few variables: 1) type of cancer (very high risk like gastric or pancreas = 2 points, high risk cancer lung cancer or lymphoma = 1 point), BMI (>35) and complete blood count (Hb <10, Leukocyte count >11.000, Platelet count >350,000) each = 1 point when present. Cancer patients with a Khorana score of 3 or greater are at increased risk of developing clots, more likely to have their cancer progress and earlier mortality. In 2019, the Cassini investigators, led by Dr. Khorana published their study of Rivaroxaban 10 mg daily for 6 months in ambulatory cancer patients at high risk of VTE (Khorana score >or =2) and who had no DVT. The results showed that DVT or death occurred in 6% in the rivaroxaban group and 8.8% in the placebo and did not reach significance. The risk of major bleeding was 2% vs 1% for rivaroxaban and placebo. The same year, Dr. Marc Carrier and the Avert investigators reported their findings on the study of Apixaban 2.5 mg twice daily for 6 months in the same category of patients (Khorana score of 2 or greater) and who were initiating chemotherapy. VTE was reported in 4.2% in the apixaban group vs 10.4% in the placebo and these results were statistically significant. During the treatment period, major bleeding occurred in 2.1% of patients treated with apixaban vs 1.1% with placebo.