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  In this article
 »  Abstract
 » Introduction
 »  The Epidemiology...
 »  Pathophysiology ...
 »  The Association ...
 »  Cancer Treatment...
 » Diagnosis
 » Treatment
 »  Mechanical Throm...
 »  Current Manageme...
 » Conclusion
 »  Tumors most Freq...
 »  References

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REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 308-312
 

Venous thromboembolism in cancer patients – magnitude of problem, approach, and management


1 Department of Radiotherapy, VMMC and Safdarjung Hospital, New Delhi, India
2 Department of Radiotherapy, Maulana Azad Medical College, New Delhi, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. G Singh
Department of Radiotherapy, VMMC and Safdarjung Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_101_17

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 » Abstract 

Cancer is hypercoagulable state. Patients with cancer are at high risk to develop venous thromboembolism (VTE). Relative risk of developing VTE is approximately seven times higher in patients with active cancer. The incidence of occult malignancy is 7%–12% in patients with idiopathic deep vein thrombosis (DVT). However, little research has been focused on cancer with thromboembolism. Lowmolecularweight heparin most frequently used pharmacologic agents as recommended by established guidelines. The aim was to evaluate the magnitude of problem in cancer patients and treatment option as per established guidelines. EMBASE, MEDLINE, and PubMed search of the literature were done to evaluate the association of DVT with various malignancy, magnitude of problem, approach, and various guidelines for the management of DVT. References of all publication were also searched to enrich this article for recent update. Thromboprophylaxis in cancer patient is gray zone area. This need lot of investigational work to find highrisk patients who would benefit from primary thromboprophylaxis.


Keywords: Deep vein thrombosis, malignancy, thromboprophylaxis


How to cite this article:
Singh G, Rathi A K, Singh K, Sharma D. Venous thromboembolism in cancer patients – magnitude of problem, approach, and management. Indian J Cancer 2017;54:308-12

How to cite this URL:
Singh G, Rathi A K, Singh K, Sharma D. Venous thromboembolism in cancer patients – magnitude of problem, approach, and management. Indian J Cancer [serial online] 2017 [cited 2020 Mar 31];54:308-12. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/308/219529



 » Introduction Top


Deep vein thrombosis (DVT) refers to the formation of one or more blood clots (a blood clot is also known as a “thrombus,” while multiple clots are called “thrombi”) in one of the body's large veins, most commonly in the lower limbs (e.g., lower leg or calf). The clot can cause partial or complete blocking of circulation in the vein, which in some patients leads to pain, swelling, tenderness, discoloration or redness of the affected area, and skin. The association between cancer and venous thromboembolism (VTE) was well discussed by the famous Parisian physician Armand Trousseau in 1865.[1] VTE significantly affects the morbidity and mortality associated with cancer still; it remains under diagnosed and under treated in cancer patients.[2],[3] VTE in cancer has an increased incidence due to the presence of a large number of associated risk factors suggest that the absolute risk depends on the tumor type, the stage or extent of cancer, and treatment with antineoplastic agents. Furthermore, age, surgery, immobilization, and other comorbid features will also influence the overall likelihood of thrombotic complications as they do in patients without cancer.[4] Cancer alone was associated with a 4.1-fold risk of thrombosis, whereas chemotherapy increased the risk 6.5-fold.[5]

This increased risk can be attributed to several factors, including the prothrombotic nature of malignancy, advanced stage of cancer, malignancies such as pancreatic, gastric, ovarian, renal, brain, bladder, kidney, lung, hematologic malignancies, particularly leukemia, lymphoma, regional bulky lymphadenopathy with extrinsic vascular compression, familial or acquired hypercoagulability, infection, renal disease, pulmonary disease, congestive heart failure, poor performance status, older age etc. There are several treatment-related risk factors such as major oncological surgery, administration of chemotherapy, use of vascular access devices modifiable risk factors associated with VTE are smoking, obesity, activity level/exercise (National Comprehensive Cancer Network 2015).[6]


 » The Epidemiology of Venous Thromboembolism in Patients With Cancer Top


There is a very strong association between the presence of cancer and the development of acute VTE. In a large population-based epidemiological study, approximately 20% of all new cases of VTE are associated with underlying cancer.[7] The relative risk of developing VTE is approximately seven times higher in patients with active cancer. According to population-based case–control studies, the 2-year cumulative incidence of VTE is between 0.8% and 8%. Patients with the highest 1-year incidence rate of VTE are those with advanced disease of the brain, lung, uterus, bladder, pancreas, stomach, and kidney. For these histotypes, the rate of VTE is 4–13 times higher among patients with metastatic disease as compared with those with localized disease.[8] While receiving chemotherapy, cancer patients have a 7-fold risk of developing VTE as compared with other patients without cancer. Cancer patients, once hospitalized, are at an even higher risk of developing VTE. In a recent retrospective study involving more than 66,000 adults with cancer, 5.4% of patients developed VTE over the 8 years of the study.[9] Furthermore, in a retrospective study, cancer patients were found to have a 3-fold higher risk for recurrent VTE than patients who had an initial VTE in the absence of malignancy. The probability of readmission for recurrent VTE within 183 days was 22% for cancer patients compared with 6.5% for those without malignancy.[10]


 » Pathophysiology of Venous Thromboembolism Top


DVT and pulmonary embolism (PE) are manifestations of the same pathological entity called VTE. VTE is associated with Virchow's triad.

Three conditions that predispose to thrombus formation.

  1. Endothelial damage
  2. Hypercoagulability
  3. Stasis:
    1. This is well known that malignancy is itself a prothrombic state or hypercoagulable state. Malignant cells can interact with the hemostatic system in multiple ways, but the two principal categories of interaction are the capacity to produce and release procoagulant and fibrinolytic activities as well as inflammatory cytokines
    2. The best-characterized procoagulants are tissue factor (TF) and cancer procoagulant. TF is the cellular procoagulant expressed in normal resting cells, including endothelial cells and monocytes–macrophages. These cells do not express TF under normal resting conditions, TF is produced in response to the cytokines interleukin (IL)-1b, tumor necrosis factor (TNF-a), and bacterial endotoxins.[11],[12] However, in contrast to normal cells, malignant cells express TF constitutively and thus have constant procoagulant activity
    3. Fibrinolytic molecules: Tumor cells can express everything required for the regulation of the fibrinolytic pathway on their cell surface. They possess both the urokinase-type and the tissue-type plasminogen activator and can also produce plasminogen activator inhibitor-1 (PAI-1) and PAI-2[13]
    4. Cytokines release: Tumor cells produce and secrete a number of different proinflammatory cytokines,[14] some of which can adversely affect the normal anticoagulant system in the vascular endothelium. For example, TNF-a and IL-1b (as well as bacterial endotoxins) can induce the expression of TF by vascular endothelial cells.[15] The release of vascular endothelial growth factor by tumor cells may account for the increased microvascular permeability found in a wide variety of tumors [16] and is considered to play a role in tumor angiogenesis [17] and chemotactic for macrophages
    5. Direct interaction with other blood cells, i.e., endothelial cells, platelets, and monocytes.



 » Tumors most Frequently Associated with Thrombosis Top


An extensive screening at the time of autopsy and retrospective reviews suggest that cancer of the pancreas, lung, and stomach, and adenocarcinomas of unknown primary, are most strongly associated with thrombosis [18],[19] leading to the view that mucin-producing cancers are the most often associated with VTE. Levitan et al. found the highest rates of VTE in cases of ovarian cancer (1.2%), brain tumors (1.2%), and cancer of the pancreas (1.1%).[10] Other malignancies such as prostate, colon, lung, and brain in men and the breast, lung, and ovary in women are also associated with high incidence of VTE.[20]


 » The Association between Venous Thromboembolism and Occult Cancer Top


The incidence of occult malignancy is 7%–12% in patients with idiopathic DVT.[21] VTE may be the earliest sign of cancer. Piccioli et al.[22] showed that the incidence of a newly diagnosed malignancy was DVT diagnosis with an additional incidence of 1% in the 2-year follow-up than when the patients were not screened (9.8%). Oudega et al.[23] in prospective trial of total 430 consecutive patients without known malignancy, but with proven DVT were included in the study and compared with a control group of 442 primary care patients. The 2-year incidence of a newly diagnosed malignancy in patients with idiopathic DVT was 7.4%.


 » Cancer Treatment and Incidence of Venous Thromboembolism Top


Chemotherapeutic drugs have been reported to damage the vascular endothelium, activate platelets, cause induction of TF in tumor cells, and downregulate anticoagulant proteins such as protein C and S.[24],[25],[26] According to Lyman et al. the overall incidence of VTE 3.5 months after starting chemotherapy was 7.3% (range 4.6%–11.6% across cancer locations) rising to 13.5% at 12 months (range 9.8%–21.3%).[27] Agent such as thalidomide and lenalidomide have been associated with increased VTE,[28] especially when combined with high-dose dexamethasone for the treatment of multiple myeloma. Routine thromboprophylaxis is recommended when using these combinations. Anti-angiogenic agents are associated with a higher risk of both arterial and venous thrombosis as well as an increased risk of bleeding.[29] Use of the erythropoietic-stimulating agents such as erythropoietin and darbepoietin increases the incidence of VTE in cancer patient,[30] especially for those receiving concurrent chemotherapy and radiation.


 » Diagnosis Top


DVT diagnosis requires the proper clinical assessments, D-dimer test, and use of imaging such as ultrasound. In those with suspected DVT, a clinical assessment of probability can be useful to determine which tests to perform. The most studied clinical prediction rule is the Wells score.

Wells score or criteria (possible score −2–9):

  1. Active cancer (treatment within last 6 months or palliative): +1 point
  2. Calf swelling ≥3 cm compared to asymptomatic calf (measured 10 cm below tibial tuberosity): +1 point
  3. Swollen unilateral superficial veins (nonvaricose, in symptomatic leg): +1 point
  4. Unilateral pitting edema (in symptomatic leg): +1 point.


Previous documented DVT – +1 point:

  1. Swelling of entire leg: +1 point
  2. Localized tenderness along the deep venous system: +1 point
  3. Paralysis, paresis, or recent cast immobilization of lower extremities: +1 point
  4. Recently bedridden ≥3 days, or major surgery requiring regional or general anesthetic in the past 12 weeks: +1 point
  5. Alternative diagnosis at least as likely: −2 points.[31]


Those with Wells scores of two or more have a 28% chance of having DVT; those with a lower score have 6% odds. Alternatively, Wells scores can be categorized as high if >2, moderate if one or two, and low if <1, with likelihoods of 53%, 17%, and 5%, respectively.

Wells criteria/scoring for pulmonary embolism

  1. Clinical signs and symptoms of DVT: +3
  2. PE is No. 1Dx or equally likely Dx: +3
  3. Heart rate >100: +1.5
  4. Immobilization at least 3 days, or surgery in the previous 4 weeks: +1.5
  5. Previous objectively diagnosed PE or DVT: +1.5
  6. Hemoptysis: +1
  7. Malignancy with treatment within 6 months, or palliative: +1.


Wells score >4 – PE likely. Consider diagnostic imaging.

Wells score 4 or less – PE unlikely. Consider D-dimer to rule out PE.

D-dimer

D-dimer is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two cross-linked D fragments of the fibrin protein.[32]

D-dimer concentration may be determined by a blood test to help diagnose thrombosis, a negative result practically rules out thrombosis, a positive result can indicate thrombosis but does not rule out other potential causes. Its main use, therefore, is to exclude thromboembolic disease where the probability is low. In addition, it is used in the diagnosis of the blood disorder disseminated intravascular coagulation.

Imaging tests

Of the veins are used in the diagnosis of DVT, most commonly either proximal compression ultrasound or whole-leg ultrasound. Each technique has drawbacks: A single proximal scan may miss a distal DVT, while whole-leg scanning can lead to distal DVT overtreatment. Doppler ultrasound, computed tomography scan venography, magnetic resonance imaging (MRI) venography, or MRI of the thrombus are also possibilities.[33]


 » Treatment Top


Prophylaxis

Postoperative pharmacologic prophylaxis with anticoagulants for 1–2 weeks after major abdominal or pelvic cancer surgery can reduce the risk of VTE to 1.3% for symptomatic DVT and 0.4% for fatal PE.[34],[35] Thus, it is evident from these data that effective thromboprophylaxis is imperative in cancer patients undergoing surgery.[36] Different modalities are available for treatment of VTE, including pharmacological prophylaxis and mechanical prophylaxis.

Pharmacological prophylaxis

  1. Aspirin
  2. Warfarin
  3. Unfractionated heparin (UFH)
  4. Low-molecular-weight heparin (LMWH) - dalteparin, enoxaparin sodium, tinzaparin, nadroparin, bemiparin
  5. Factor Xa inhibitor - fondaparinux, idrabiotaparinux, idraparinux, rivaroxaban
  6. Direct thrombin inhibitor - dabigatran.


Mechanical prophylaxis

  1. Graduated compression stockings
  2. Electrical calf stimulation
  3. Venous foot pump devices
  4. Intermittent pneumatic compression devices.


Aspirin

Aspirin is a nonsteroidal anti-inflammatory drug, cornerstone of prevention in the setting of arterial thrombosis, due to antiplatelet property. Aspirin causes an irreversible inhibition of cyclooxygenase, an essential enzyme for the production of thromboxane A2 (TxA2) in the platelet. TxA2 is a powerful stimulant of platelet aggregation, and use of aspirin subsequently results in effective inactivation of the platelet. Large meta-analysis by the antiplatelet trialists collaboration [37] showed 22% risk reduction of a combined end-point of myocardial infarction, stroke, or vascular death in a of patients at increased risk for arterial thromboembolism of VTE. Only limited evidence is available regarding its protective role in hospitalized patients.[38] Hence, aspirin is not recommended as a primary modality of pharmacoprophylaxis by any of the guidelines.

Warfarin

Warfarin is a Vitamin K antagonist (VKA) and interferes with the synthesis of clotting factors and thus prevents thrombosis. Its use has been gradually replaced by UFH and now LMWH because of delayed onset of anticoagulant effect and prolonged duration, with clearance in patient with hepatic insufficiency, due to this frequent blood sampling for laboratory monitoring is needed to avoid excessive dosing.[39]

Unfractionated heparin

UFH inhibits the action of activated thrombin (factor IIa) and factor Xa and thus mediates an anticoagulant effect. Early trials, meta-analyses and multicenter trials strongly emphasized the benefit of UFH prophylaxis in surgical patients, especially in those patients who had cancer [40],[41],[42] but certain disadvantages limit the use of UFH. The pharmacokinetics of UFH are unpredictable and influenced by its binding to plasma proteins, endothelial cell surfaces, macrophages, and other acute phase reactants, thus causing variability in the anticoagulant response, which necessitates the monitoring of activated partial thromboplastin time (APTT) values in patients. In addition, the interaction of UFH molecules with platelet factor 4 and generation of heparin-dependent IgG antibodies can lead to an immune-mediated complication-heparin-induced thrombocytopenia (HIT), where the release of procoagulant microparticles such as thrombin occurs into the systemic circulation leads to disseminated arterial and venous thrombosis.[43]

Low-molecular-weight heparin

Dalteparin is recommend by most of the guidelines in a dose of 5000U of for prophylaxis.[44],[45] The benefit of LMWHs includes they can be administered at home, hospitalization is not needed, hence, overall low cost as compared to UFH.

Factor Xa inhibitors

Fondaparinux, idrabiotaparinux, and idraparinux are factor Xa inhibitors. Only fondaparinux is approved by the US Food and Drug Administration for pharmacoprophylaxis of VTE. Idrabiotaparinux and idraparinux both are under clinical trials.[46] The benefit of fondaparinux is lower incidence of HIT. Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for outpatients with cancer. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either LMWH or low-dose aspirin. Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery, and continuing for at least 7–10 days. Extending prophylaxis up to 4 weeks should be considered in those with high-risk features. LMWH is recommended for the initial 5–10 days of treatment for DVT and PE as well as for long-term (6 months) secondary prophylaxis. Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE.[47]


 » Mechanical Thromboprophylaxis Top


Compression stockings, electrical calf stimulation, intermittent pneumatic compression devices, and venous foot pump devices are used for mechanical thromboprophylaxis. Wells et al. showed that compression stockings are effective in reducing the risk of VTE by two-thirds in patients at moderate risk.[48] Compression devices can be reserved for such situations where anticoagulants are contraindicated. Whether mechanical methods in combination with anticoagulants result in added benefit is not clear.


 » Current Management Strategies for Venous Thromboembolism in Cancer Patients Top


Initial treatment of cancer-associated VTE includes LMWH, UFH, and fondaparinux. LMWH is administered by subcutaneous injection (once daily with dalteparin or tinzaparin, twice daily with enoxaparin or nadroparin) or UFH by intravenous injection or infusion, for 5–7 days. LMWH provides advantages over UFH, it has lower cost (because hospitalization and laboratory monitoring are not required) and simple dosing (because the total daily dose is based on body weight). LMWH is also associated with a lower risk for HIT.[49] If UFH is used, patients are generally required to remain in hospital for this period, and the dose of UFH administered is adjusted to maintain an APTT of approximately 1.5–2.5 times the normal. Treatment with a VKA, i.e., warfarin or another coumarin, is usually commenced on day 1 during initial LMWH/UFH therapy, adjusted to achieve an international normalized ratio of 2–3, and continued for 3–6 months, to reduce the risk of recurrent VTE. Current guidelines from the American College of Chest Physicians (ACCP) recommend the use of LMWH, specifically dalteparin or tinzaparin, for the long-term treatment of acute VTE, and that this should be continued for a minimum of 3–6 months.[50] Thus, first-line treatment of VTE in patients with cancer is LMWH for a minimum of 3–6 months. This approach is endorsed by the ACCP, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network.[6],[49]


 » Conclusion Top


Cancer is prothrombotic or hypercoagulable state because an alteration between the coagulation and fibrinolytic systems. Thromboprophylaxis in cancer patient is gray zone area. This need lot of investigational work to find high-risk patients who would benefit from primary thromboprophylaxis and also in patient of established VTE. VTE is best treated with LMWH for a minimum of 3–6 months, and treatment can be continued for as long as active cancer is present.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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