Cancer associated thromboembolism

Approximately 15% of cancer patients have clinically significant thromboses.

It is estimated that 20%-30% of initial thromboses are cancer associated, but early evaluation reveals only 4-5%of such patients have cancer.

The presence of cancer increases the risk of VTE by nine fold.

The incidence of VTE has increased over the last few decades in patients with cancer, and in patients who receive chemotherapy or targeted therapy and is increasingly common.

VTE and arterial thromboembolism have been reported as the second most common cause of death in cancer patients after tumor progression.

Long-term followup reveals cancer in 17-23% of cases.

The six month VTE risk in patients with cancer is up to 12 fold higher than in the general population and up to 23 fold higher in patients with cancer receiving chemotherapy or targeted therapy.

VTE in patients with cancer can interfere with treatment, increase mortality risk, increase costs, and can also adversely affect cancer patients’ quality of life.

Pancreatic, renal, ovarian, lung, and gastric cancer is associated with the highest rates of cancer associated thrombosis among solid tumors.

Multiple myeloma and lymphoma have the highest risk of cancer associated thrombosis among hematologic malignancy.

Cancer associated thromboembolism (CAT) risk increases as cancer stage increases, with metastasis, and with cancer treatments, including surgery, chemotherapy, hormonal therapy, and targeted therapy.

Other important related factors for CAT include advanced age, male gender, history of venous thromboembolism, and obesity.

More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. 

The three essential list of categories that lead to VTE  and cancer include: stasis of blood flow, vascular injury, and hypercoagulability.

Patients with cancer have a 4-6 fold increased risk for thrombosis compared with the general community.

More than half of CAT events occur in the first three months after a cancer, diagnosis, and the risk subsequently declines.

Patients with active cancer have a 5-6 fold increase risk of venous thromboembolism.

Chemotherapy, antiangiogenic therapy, protein kinase Inhibitors, and immunotherapy all have been shown to increase the risk of VTE.

Among patient with active malignancy, the two-year risk of developing venous thromboembolism is up to 12%, depending upon the type of cancer.

Autopsy studies reveal that 20-50% of patients with metastatic cancer have thromboses.

Thrombosis is second most common cause of death of hospitalized cancer patients.

Higher associated thrombosis risks occur with pancreatic cancer, lymphoma, ovarian cancer, and is lower in those with melanomas.

Thromboembolism is the second leading cause of death in patients with cancer.

Annual incidence of VTE in patients with cancer ranges from 0.5% to 20% and is the second leading cause of death in this population.

Once a patient with cancer has a VTE, they are at increased risk of having another, with more serious consequences.

Patients with VTE are 2-3 times more likely to have recurrent VTE than non-cancer patients with VTE and 2-6 times more likely to have hemorrhagic complications.

Patients with advanced or metastatic cancer have a higher risk of VTE.

Cancer patients suffering with a VTE have a worse survival of cancer patients without VTE.

Many patients with unprovoked VTE‘s, may already have cancer, just at early stage and undetectable at the time of the VTE.

Patients with cancer who experience VTE have substantially higher in patient mortality than those without a VTE and a greater risk of death in the presence of metastatic disease and than patients with localized disease.

Hospitalized cancer patients have an incidence of VTE of 0.6-7.8 percent, with higher rates among patients on chemotherapy and with those with cancer of the pancreas, ovary, kidney, lung, stomach and brain.

Almost one fifth of all new cases of venous thromboembolism are associated with active cancer.

While the incidence of venous thromboembolism (VTE) estimated to be 1 event per 1000 patients annually it is estimated to occur in 1 of every 200 cancer patients annually.

The incidence of VTE is not equally distributed among malignancies with some lesions associated with a 1% risk and reaching up to 20% or more in most pro thrombotic malignancies like pancreatic cancer and malignant gliomas.

Approximately 20% of all patients with venous thromboembolism in the general population have cancer, and approximately 10% of patients with idiopathic venous thromboembolism with be diagnosed with cancer within the next 12 months.

Cancer patients have a seven fold higher incidence of VTE than patients hospitalized with other disease processes.

The absolute risk of venous thrombosis in cancer patients varies from 1-8% depending on the patient population, the duration of follow-up, and the method of detecting and reporting venous thrombotic events.

Pancreatic cancer and brain tumors of the highest rates of venous thromboembolism among all cancer types, with cumulative incidences of 5.3-26% at one 1.6-26%, respectively.

Incidence of VTE in certain types of lymphoma is as high as 59.5%.

Incidence of VTE in multiple myeloma is as high as 68% in patients treated with highly prothrombotic agents.

Lung cancer associated with rates of VTE from 1.6-13.6%.

Colorectal cancers have low rates of VTE at 3.1-10.2%.

Breast cancer associated with rates of VTE from 0.4-8.1%.

Prostate cancer associated with low rates of VTE at 0.5-1.3%.

Leukocytosis in cancer patients associated with a twofold increase risk of VTE.

Patients with thrombocytosis and malignancy have a 2.5 fold increase in the risk of developing VTE during hospitalization.

In a study of Medicare patients it was found that within 183 days of initial hospitalization, there was a 0.29 probability of death for patients with VTE alone compared with 0.94 probability of death for patients with cancer and VTE (Levitan N et al).

VTE is the second most common cause of death among patients with cancer (Khorana AA et al).

Cancer patients with VTE have twice the mortality than cancer patients without DVT.

Almost 50% of patients with cancer associated VTE have metastases at the time of diagnosis of VTE.

Up to 78% of thromboembolic phenomenon occur in cancer patients in the outpatient setting.

In a case-control study of 3,220 consecutive patients 18-70 years of age with a first episode of DVT of the leg or a pulmonary embolism compared to 2100 control patients-the overall risk of venous thrombosis was increased 7 fold in patients with cancer compared to patients without cancer (Blom).

Active cancer strongly associated with arm or intra-abdominal DVT or intra-abdominal DVT alone compared with leg DVT or pulmonary embolism and with bilateral leg DVT compared with unilateral leg DVT.

Patients with cancer have a 3-4 fold increased chance of recurrence of venous thromboembolism than patients without cancer.

Even with anticoagulant therapy patients with malignancy have an approximate 3 fold increased risk of recurrent VTE.

Presence of VTE in a patient with malignancy decreases survival up to 6-fold compared to patients without VTE.

Patients with cancer undergoing surgery have a 2 fold higher risk of postoperative venous thromboembolism than control patients.

Majority of such lesions are venous in origin and arterial thromboembolic events reported to account for 10-30% of complications.

Approximately 90% of patients with cancer have disorders of coagulation.

More anaplastic cancers are more hypercoaguable.

Substances in malignant cells such as tissue factor and cysteine proteases have procoagulant activity.

Likelihood of death for cancer patients increased by 2-8 fold.

Venothromboembolism most common cause of death at 30 day follow-up for cancer patients undergoing surgery.

Patients with gynecological cancers and pulmonary embolus are 6 times at increased risk of death within 2 years compared to patients without pulmonary embolism.

Tissue factor a transmembrane glycoprotein active in angiogenesis and metastases and activates factor X.

Tissue factor binds plasma factor VII/VIIa triggering blood coagulation following vascular injury and in certain diseases.

Tissue factor likely the key mediator in hypercoagulability in patients with cancer.

Abnormal expression of tissue factor in tumors and related vascular endothelial cells may contribute to excessive clot formation in patients with cancer.

Tissue factor is expressed by many cancer cells, particularly of epithelial origin, and can’t spontaneously release micro-particles bearing tissue factor.

Cancer cells may generate thrombin and subsequently fibrin necessary for the development of deep vein thrombosis.

Factors contributing to risk of venous thromboembolism include type and stage of cancer, presence of surgery, age, patient mobility, treatment modalities, and procoagulant effects of cancer cells.

In a retrospective study of 66,000 hospitalized neutropenic adult patients with cancer 5.4% of patients developed VTE over the 8 years of the study (Khorana).

Up to 50% of cancer patients having major surgery will have an associated VTE in the absence of anticoagulant prophylaxis.

The highest risk related to major surgery.

Tamoxifen, mitomycin, high dose fluorouracil and growth factors increase risk.

Annual incidence of VTE in nonsurgical cancer patients 3-15%.

Spontaneous upper extremity DVT 2.6-8 times more likely to occur than in patients in the general population, and the presence of a central venous catheter significantly increases the risk.

Patients with pancreas, kidney, brain or ovarian cancer have the highest incidence of thromboembolism while patients with lung, colorectal or breast cancers have the highest prevalence.

Brain tumors, hematologic malignancies, adenocarcinomas of tenancies, uterus, ovary stomach , lung and kidney considered to carry the highest risk of associated thromboembolism.

Thrombosis in lung cancer 20 times higher than the risk for the general population and the risk for adenocarcinoma of the lung three times higher than with squamous cell cancer, and an annualized rate of 7%.

Recent studies suggest that patients with neutropenic lymphomas and leukemias have represented more than one-third of patients with such events and hospital mortality for these patients approaches 15%.

One autopsy study revealed that one in every seven hospitalized cancer patients died from pulmonary embolism and not from cancer, and 60% of those that died of pulmonary embolism had localized or limited metastatic disease subject to possible treatment.

Patients with cancer and a VTE episode are more likely to have metastases than those without such a process.

Risk of venous thrombosis highest in the first few months after the diagnosis of malignancy.

The presence of distant metastases further increases the risk of thrombosis by 20 fold.

A prospective study of with newly diagnosed patients with venothromboembolism with or without cancer treated with unfractionated or low molecular weight heparin followed by oral warfarin revealed a recurrent venous thrombosis among cancer patients of 20.7% compared with 6.8% among patients without cancer.

Carriers of factor V Leiden or patients with Prothrombin 20210A variant who also have cancer have a 12 fold increased risk of thromboembolism

Despite anticoagulation therapy cancer patients have a threefold higher incidence of recurrent VTE.

Chemotherapy can increased risk of thromboembolic disease by damaging the endothelium and by decreasing natural inhibitors of coagulation.

Prothrombotic factors in cancer include ability of malignant cells to produce procoagulant or fibrinolytic substances and inflammatory cytokines, interaction of cancer cells with monocytes, platelets, neutrophils and endothelial cells, generation of acute phase reactants and necrosis.

Administration of dalteparin (Fragmin), a low molecular weight heparin, for 1 month followed by 75% of the initial dose for 5 more months decreases the risk of recurrent thromboembolism compared to conventional treatment with dalteparin followed by warfarin by 50%.

In patients with cancer and thromboembolism the risk of symptomatic recurrence is significantly lower with dalteparin compared to oral anticoagulant therapy (Lee et al.)

Prophylactic anticoagulation significantly reduces the incidence of thrombotic complications.

VTE prophylaxis is under utilized in cancer patients and admission to the hospital associated with a lower likelihood of such treatment (Kahn).

The rate of venous thromboembolism in ambulatory chemotherapy patients in individuals with platelet counts of less than 200,000/m3 is about 0.5% a month, while the rate is 1.7% per month is patients with platelet counts of 350,000/mm3 suggesting the use of prophylactic anticoagulation in the latter situation (Leizorovicz).

Low molecular weight heparin has supplanted vitamin K antagonists as preferred treatment for acute VTE in cancer patients, with a 50% reduction in recurrent VTE.

Decreased efficacy of of warfarin in cancer patients is difficulty maintaining a stable INR in setting of use of chemotherapy, inconsistent dietary intake due to anorexia, nausea, vomiting, low body weight, and low albumin.

Cancer patients who undergo major surgery should receive thrombo-prophylaxis before surgery, followed by the seven-10 days postoperatively.

Guidelines recommend extended anticoagulant prophylaxis for up to four weeks after a major abdominal or pelvic cancer surgery.

For cancer patients undergoing major abdominalor pelvic surgery with high risk features up to 4 weeks of continued treatment should be considered.

For patients with multiple myeloma receiving treatment with anti-angiogenesis agents and for dexamethasone should also receive thromboprophylaxis.

In a review of all anticoagulant therapy for adults with malignancy and no history of venous thromboembolism on anti-cancer treatments the following conclusions were made (Aronow W):

Warfarin versus placebo: evidence suggested warfarin did reduce pain is from Moe embolism and some patients, but increase the risk of major bleeding, there was no difference in mortality between warfarin and placebo.

Warfarin versus aspirin: no differences in benefits between warfarin and aspirin and very low quality of evidence between reduction in venous thromboembolism.

Apixaban versus placebo: evidence suggested that Apixaban versus placebo did not prevent thromboembolic events and increased the risk of bleeding

Apixaban vs enoxaprin: no differences in thromboembolic events of bleeding between Apixaban and enoxaparin.

Rivaroxaban versus enoxaparin: No difference in thromboembolic events but rivaroxaban increased the risk of bleeding.

The conclusion from the above studies is that guidelines recommend against routine use of oral anticoagulants for the prevention of venous thromboembolism in patients receiving systemic anti-cancer therapy.

American Society of Hematology strongly recommends using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.


It is recommended using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk

DOACs have become the anticoagulant of choice for patients for the treatment and prevention of VTE  in the general population and in cancer patients.

Among patients with cancer and VTE, direct oral anticoagulants, were non-inferior to low molecular weight heparin for for preventing recurrent VTE over a six month follow up (CANVAS investigators).

Apixaban therapy resulted in significant lower rate of venousthromboembolism than did placebo among intermediate to high-risk ambulatory patients with cancer who were starting chemotherapy (AVERT study).

Apixaban for the treatment of Venous thromboembolism associated with cancer was non-inferior to subcutaneous dalteparin without an increased risk of major bleeding (Caravaggio Onvestigators).
Risk directed primary thromboprophylaxis in adults with lung and G.I. cancers, who have high risk profiles of elevated fibrinogen and d-dimer levels receive clinical benefit (Alexander M).

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