Thrombosis in Cancer: A Medical Professional's Guide to Cancer Associated Thrombosis

Ever since the association between cancer and thrombosis was reported in the early 19th century multiple studies have confirmed the relationship between cancer and thrombosis. Cancer patients, especially in the first few months after diagnosis and those with distant metastasis, have an elevated risk for VTE, and conversely, the risk of cancer diagnosis is high within the first 2 years of idiopathic VTE. VTE has an important impact on the prognosis of cancer patients. Thrombosis was the second leading cause of death (9.2%) after the cancer progression (70.9%) itself. The risks of recurrent VTE and bleeding are higher in patients with cancer-associated venous thrombosis than patients with venous thrombosis but without cancer.

Virchow’s triad of venous stasis, vascular damage, and blood hypercoagulability is the hallmark of VTE formation. Despite many studies done in recent times, the exact pathophysiology of cancer and VTE is still unknown. Various Tumor related, treatment-related and patient-related risk factors (RF) have been identified. Tissue-factor (TF), microparticles (MPs), inflammatory cytokines, and cancer procoagulants (CP) are some of the tumor-related risk factors. Tumor cellderived TNFa, IL-1b, and VEGF also contribute to cancer-induced hypercoagulability by other mechanisms, firstly they induce TF expression on monocytes. Several tumorrelated characteristics such as tumor site, type, stage (especially metastasis), histological variance and duration, are considered risk factors for the development of cancer-associated VTE. Surgery is the most important treatment-related risk factor in VTE in cancer patients along with other risk factors like hospital admission, chemotherapy, hormonal therapy, radiation therapy. patient-related factors such as age, gender, race, performance status, comorbidities, prior thrombosis, and prothrombotic mutations, are associated with an increased VTE risk in cancer patients. Several biomarkers have been investigated to quantitate and to predict the risk of VTE in cancer patients most important being D dimer, RF. Elevated levels of Ddimers are predictive of a higher risk of recurrent VTE in patients with cancer. Prechemotherapy platelet count has been shown associated with increased VTE risks in at least one study.

Incidence of venous thromboembolism (VTE) is more common in cancer patients compared to non-cancer patients. Various factors that influence the incidence of VTE are patient population, duration of follow-up, patient-related factors, type and stage of tumor, chemotherapy agent or the treatment modality used, presence of central venous catheters, detection methods, and reporting. Mortality is increased by various factors such as delay or withdrawal of chemotherapy treatment, directly VTE-related complications like pulmonary embolism. Development of VTE within 2 years was found to be a significant risk factor for increased mortality and the rate was high among patients with localized disease. For the prevention of VTE in patients with cancer LMWH is given increased consideration, specifically Dalteparin [26, 27]. Further studies are necessary to determine the effectiveness of thromboprophylaxis in the reduction of mortality or thromboembolic complications in these high-risk populations.

Idiopathic VTE comprises about 40% of total VTE cases and may be an early sign of occult cancer. In patients with acute unprovoked VTE, the risk of having occult cancer is increased by four-folds compared to patients with provoking risk factors. Despite evidence that occult malignancy may be associated with unprovoked VTE cases, there is a paucity of data and no specific guideline regarding whether to perform occult cancer screening and what investigations to include. The National Institute for Health Care Excellence (NICE) guidelines suggest that idiopathic VTE cases should undergo extensive history taking, a comprehensive physical examination, a chest X-ray, basic laboratory investigations, and urinalysis. For now, only ageappropriate cancer screening along with complete history, and physical examination are advised in idiopathic VTE cases, with more focused evaluation depending on the initial findings. Further studies are required to assess the extent and benefits of extensive occult cancer screening in patients with idiopathic VTE.

Chemotherapy is a known independent risk for the development of VTE which is also known to increase the risk of recurrence of VTE in malignancy by fourfolds. Factors that influence the incidence of VTE in chemotherapy are the type, location of the tumor, type of chemotherapy, the presence of agents such as hormonal agents, targeted therapies. Chemotherapy can worsen the pro-thrombotic state by various mechanisms. Various scoring system such as Khorana’s model and Ottawa score has been recommended to predict the risk of VTE with chemotherapy. Low molecular weight heparin (LMWH) has been shown be to effective in VTE prophylaxis in patients with active cancer undergoing chemotherapy. There is however limited evidence currently regarding the use of direct oral anticoagulants in the prophylaxis of cancer-associated thrombosis.

Central venous catheters (CVC) are important for the infusion of chemotherapy, intravenous medications, and blood products. Catheter-related thrombosis (CRT) is common among cancer patients. The lower rates of CRT underreported as many are asymptomatic. Many patient-related factors such as age, venous anatomy, tumor characteristics (histology, size, and location, and catheter-specific features) have been attributed to CRT. Also, limitations of the diagnostic criteria exist. Doppler ultrasound is the common initial test but can be non-diagnostic. Contrast venography is the ‘gold standard’ and considered once Doppler negative but with strong clinical suspicion. Newer diagnostic tools such as contrast CT or MRI has emerged as promising alternatives but with occasional use. Anticoagulation is the treatment of choice once DVT is confirmed but there are no established standard guidelines. The catheter should be preserved with low molecular weight heparin for a minimum of three months. No anticoagulants are advised for routine prophylaxis but can be considered in high-risk groups.

Anticoagulation options remain the same in those with or without cancer. It is used for the prevention and/or treatment of thrombus in those with low bleeding risk. No anticoagulation is recommended in active bleeding, recent surgery, pre-existing bleeding disorders, coagulopathy, or platelet count <50,000/microL. The immediate treatment options include low molecular weight heparin (LMWH) or unfractionated heparin (UFH) plus long-term management with LMWH, vitamin K antagonists, or direct oral anticoagulants. The acute VTE with malignancy requires initial anticoagulation therapy for 5-10 days, LMWH is the medication of choice unless contraindicated. The patient characteristics such as renal function, compliance, diet adherence determine drug selection. Fondaparinux and direct oral anticoagulants can also be initial treatment choices. UFH is preferred if a rapid anticoagulation reversal is required in circumstances such as renal disease, high bleeding risk, and for patients undergoing procedures. The factor Xa inhibitors are currently approved for initial DVT and acute PE treatment. They eliminate the need to monitor anticoagulation effectiveness. For those who are poor candidates for long-term LMWH, indirect oral anticoagulant (warfarin) is acceptable for chronic management. DOACs can be an alternative for those unable to use LMWH for reasons such as renal impairment (creatinine clearance less than 30mL/min), cost, non-compliance, or fear of needles. The duration of anticoagulation treatment is a minimum of 3 months. For those with malignancy and VTE with contraindications to anticoagulants, the only therapeutic option can sometimes be mechanical devices such as inferior vena cava filter (IVCF).

Thrombosis and thrombocytopenia are common in malignancy due to microangiopathic disorders (thrombocytopenic purpura, immune disorder, immune thrombocytopenic purpura, and heparin-induced thrombocytopenia), chemotherapy side effect, or direct cancer effect. Recurrent VTE (while on anticoagulation) is also common, risk factors include metastasis, young age, and short interval between cancer diagnosis and VTE. VTE remains a major challenge among those with renal impairment. Incidental VTE is an unexpected thrombosis detected in a patient undergoing imaging study for other indications. Incidental VTE has been attributed to malignancy or chemotherapy side effects. Philadelphia chromosome-negative Myeloproliferative Disorders (Polycythemia Vera (PV), Essential thrombocytosis (ET), and Primary Myelofibrosis (PMF) has been implicated with high risk for both venous and arterial thromboembolism. Venous thromboembolism (VTE) has been increasingly associated with hematological malignancy as well.

Heparin was isolated from the liver and heart in 1916. Heparin was demonstrated as an anticoagulant in the presence of heparin-cofactor, a plasma component. Over years many heparin molecules have been manufactured due to their anti-tumor properties. Heparin sulfate, an essential component of the extracellular matrix when degraded by heparanase secreted by tumor cells has shown to increase tumor invasiveness. The anti-angiogenic properties of heparin are due to its effect on decreasing fibrin level and inhibition of thrombin formation. Natural killer (NK) cells destroy circulating tumor cells. The anti-tumor properties of heparin have been demonstrated in various studies. Among various forms of heparin, butanoylated heparin has the lowest anticoagulation strength but much stronger anti-tumor activity compared with UFH at higher doses. The anti-tumor effects between LMWH and butanoylated heparin are yet to be compared.

Cancer patients have an increased risk of VTE and its complications. It has been of utmost importance to identify high-risk patients. The Khorana score, which stratifies cancer patients into low and high risk, includes cancer type, chemotherapy regimen, hematological factors, and combinations of clinical and lab factors. In hospitalized cancer patients with limited mobility, pharmacologic prophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) is recommended. In those with contraindications to anticoagulation, mechanical prophylaxis can be used. In cancer patients undergoing surgery, perioperative VTE prophylaxis using pharmacologic anticoagulation is recommended, unless a minor procedure or an anticoagulant contraindication exists. In outpatients, the American Society of Clinical Oncology (ASCO) did not recommend routine anticoagulation in cancer patients except in high risk (e.g., Khorana score ≥2, or multiple myeloma, receiving thalidomide or lenalidomide). Those patients should be offered VTE prophylaxis with apixaban, rivaroxaban, or LMWH. Also, ASCO recommended periodic assessment of cancer patients for VTE risk and educating them about VTE's signs and symptoms.