Cancer and Thrombosis
Journal of Hematology & Thromboembolic Diseases

Journal of Hematology & Thromboembolic Diseases
Open Access

ISSN: 2329-8790

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Review Article - (2014) Volume 2, Issue 6

Cancer and Thrombosis

Zahra Mozaheb*
Department of Hematology-Oncology, Imam-Reza hospital, Mashhad University of Medical Science, Iran
*Corresponding Author: Zahra Mozaheb, Department of Hematology-Oncology, Imam-Reza hospital, Mashhad university of Medical Science, Iran, Tel: +98 5138023024 Email:


Venous thromboembolism (VTE) is a common and life-threatening condition in patients with cancer. The incidence rate depends on the tumor type. Many of risk factors for development of VTE are common in patients with cancer, which include cancer related factors and treatment related factors. In this review we define VTA to include deep vein thrombosis (DVT), pulmonary embolism (PE), superficial vein thrombisis (SVT), Splanchnic vein thromboses (SPVT), Involving the splenic, portal, mesenteric, or hepatic veins. Prophylactic anticoagulation therapy recommended for patients with active cancer who do not have a contraindication are Low molecular Wight heparins, fondaparinox, and subcutaneous Unfractionated Heparin, warfarin, and aspirin only for low risk multiple myeloma. In cancer patients low-molecular-weight heparin monotherapy has been identified as a simple and efficacious regimen compared with an initial parenteral anticoagulant followed by long-term therapy with a vitamin K antagonist.

Keywords: Venous thromboembolism; Heparin monotherapy


The close relationship between venous thromboembolism and cancer has been known since at least the 19th century by Armand Trousseau [1]. Thrombosis is a major cause of morbidity and mortality in patients with cancer [2]. One study showed that approximately 3-12% of adult cancer patients with neutropenia depending on the type of malignancy, experienced VTE during their first hospitalization [3]. The occurrence of VTE has been reported in 12.6% of ambulatory patients during 12 month from initiation of chemotherapy [4]. Increasing age, cancer prevalence, and greater thrombogenicity of chemotherapeutic regimens, enhanced detection of incidental thrombosis. Venous thromboemboly has been reported to increase the likelihood of death for cancer patients by 2-6 fold [5], and also has been reported VTE to be the most common cause of death at 30-days follow-up among cancer patients undergoing surgery [6]. A study showed increase in the incidence of cancer-associated thrombosis during the recent decades [3] that may be related to the cancer treatment.

Risk Factors

Several reasons induce thrombosis in cancer patients, which many of them are common in cancer patients [7]. Active cancer itself is often the underlying mechanism. The type of cancer is one of the most important risk factor for venous thromboembolism occurrence. The stage of cancer and the histological grade of a tumor have been found to be associated with the occurrence of cancer- related VTE, also the regional lymph node metastases are a strong risk factor for VTE. Patients with regional or distant metastasis have significantly higher levels of factor VIII, D dimer, p-selectin, platelets, and lower hemoglobin levels than those with local stage [8-10]. When monocyte or macrophage lineage cells interact with malignant cells, they release tumor necrosis factor, and interleukins (1 and 6), causing endothelial damage and converting to thrombogenic surface. The interaction between tumor cells and macrophages also activates platelets, factors X and XII, which leads to the thrombin generation. Procoagulant substances in tumor cells such as cysteine proteases and tissue factor can directly activate factor X and factor VII respectively. Aggressive chemotherapy with commonly used agents such as platinum compounds, high dose fluorouracil, mitomycin, and hormonal therapy with tamoxifen, angiogenetic agents, and growth factors increase the risk of thrombosis [11]. Central venous catheters inserted for chemotherapy and hyperalimentation, are also associated with a risk of thrombosis. The thrombogenic surface of these catheters induce platelets and serine proteases activation. Gram-negative organisms that infect central venous catheters can release endotoxin, and gram-positive organisms can release bacterial mucopolysaccharides, that can activate factor XII, induce a platelet-release reaction, and cause sloughing of endothelial cells; and increase the risk of thrombosis. Also endotoxin induces the release of tumor necrosis factor, tissue factor, and interleukin-1, which can incite thrombogenesis [12]. We can see other risk factors in Table 1.

General risk factor Treatment related risk factor
Active cancer Major surgery
Advance stage of cancer Central venous catheter
Cancer type at higher risk Chemotherapy such as:
Brain Thalidomide,Lenalidomide,
Pancreas High dose dexamethason
Stomach Exogenoushormonaltherapysuch as:
Bladder Hormone replacement
Gynecologic Contraceptives
Lung Tamoxifen/roloxifen
Lymphoma Diethylstilbestrol
Myeloproliferative neoplasm Modifiable risk factor
Kidney Smoking, tobacco
Metastatic cancer Obesity
Regional bulky lymphadenopathy withextrinsic vascular compression Activity level        
Acquired hypercoaglability
Medical comorbidity
Poor performance status
Older age
High Risk outpatients on chemotherapy
Active cancer with high incidence VTE: stomach, pancreas, lung,lymphoma, gynecoloyic, bladder, and testicular
PrechemotherapyPlatelet count>300000/mcl
Prechemotherapy WBC>11000/mcl
Hemoglobin<10 g/dl
Prior VTE

Table 1: VTE Risk factor in cancer patients (The NCCN guidelines 2014).

Risk-assessment models may offer improved outcomes for oncology patients. Estimating an individual patient's risk for VTE is clinically more relevant because it allows physicians to target thromboprophylaxis in those who are most at risk for venous thromboembolism. Five independent risk factors were identified for symptomatic VTE during the first four cycles of chemotherapy: site of cancer, platelet count and leukocyte count (pre-chemotherapy), hemoglobin level or the use of red cell growth factors, and body mass index (BMI), that predicted VTE. Risk score model containing these five clinical and laboratory items was developed (Table 1) and based on these total risk score patients are classified into three categories: low-risk (score 0; VTE risk 0.3-0.8%), intermediate-risk (score 1 or 2; VTE risk 1.8-2.0%), or high-risk (score 3 or higher; VTE risk 6.7-7.1%). There are some limitation in this model scoring, the model may not be predictive of VTE development based on age and in some tumor types or in those who have advanced disease and a poor performance status. Also such new drugs (e.g., bevacizumab or thalidomide) cannot be considered as a risk factor in this model (Table 2) [10].

Patient characteristic Risk score
Site of primary cancer  
Very high risk(stomach, pancreas) 2
High risk(lung, lymphoma, gynecologic, bladder, testicular) 1
Platelet count prechemotherapy more than 350000/µl 1
Leukocyte count prechemotherapy more than 11000/µl 1
Hemoglobin less than 10g/dl or using red cell growth factor 1
Body Mass Index35 kg/m2or higher 1
Total score Risk category Risk of symptomatic VTE  
0 Low 0.8-3%  
1, 2 Intermediate 1.8-8.4%  
3 or higher High 7.1-41%  

Table 2: Khorana predictive model for chemotherapy associated VTE[13].

Prevention of VTE in cancer: Hospitalized cancer patients are at high risk for venous thromboembolism, and ambulation in this patients is inadequate to reduce VTE risk [14]. The recommended prophylactic anticoagulation therapy for inpatients/ outpatients with active cancer who do not have a contraindication are Low molecular Wight heparins (LMWHs) (dalteparin 5000 units subcutaneous daily or enoxaparin40 mg subcutaneous daily), fondaparinox (factor Xa inhibitor) (2.5 mg subcutaneous daily), and subcutaneous Unfractionated Heparin (UFH) (5000 units 3 times/day), aspirin 81-325 mg daily (only for low risk multiple myeloma outpatients, warfarin (adjusted to INR 2-3). A meta-analysis of comparisons of a variety of low molecular-weight heparins with unfractionated heparin for deep-vein thrombosis showed that dalteparin was associated with fewer major bleeding episodes and a lower mortality rate than unfractionated heparin [15]. And also a study showed that the incidence of recurrent thromboembolism in the dalteparin group was half that in the warfarin group. An additional benefit is that dalteparin, has been deemed safe for use in the elderly (those older than 65 years of age) by the Food and Drug Administration. The multicenter trial reported by Lee et al. suggested that low-molecular-weight heparin should become the therapeutic and prophylactic agent of choice in cancer-associated thromboembolic disease [12].

All inpatients adult with cancer prior to the initiation of thromboprophylaxis should be undergo the following evaluation: comprehensive medical history and physical examination, complete blood count with platelet count, prothrombin time, activated partial thromboplastin time, and liver and kidney function tests.

Different studies showed that a high proportion of VTE occurs in the cancer outpatients setting [16]. Cancer patients with high risk for VTE could be consider for outpatients VTE prophylaxis on an individual basis (based on Khorana risk assessment score 3 or higher) (NCCN guideline 2014). Cancer patients undergoing abdominal or pelvic surgery have higher risk of VTE and should be considered for outpatients prophylaxis [6,17].

Mechanical prophylaxis: In patients with contraindication to pharmacologic agents in patients at very high risk of VTE, intermittent pneumatic compression devices and graduated compression stockings are mechanical prophylaxis option [18].

VTE Treatment

Options for the initial treatment of cancer-associated thrombosis include LMWH, unfractionated heparin (UFH), or, in some cases, fondaparinux in patients without contraindications to anticoagulantion. In a meta-analysis of trial comparing outcomes with UFH, LMWH, and fondaparinox as initial treatment of VTE in cancer patients, LMWH was associated with no significant reduction was found in mortality rate at 3-month follow up compared with UFH, but without significant difference in recurrence of VTE, or bleeding. Therefore LMWHs are preferred for acute management of VTE in cancer patients because they do not require hospitalization or monitoring, and also are preferred option for long term therapy [19,20].

Several studies comparing the efficacy and safety of oral warfarin and LMWH in chronic VTE treatment. In comparing of enoxaparin and warfarin, major bleeding and VTE recurrence within 3-month in the enoxaparin using was significantly lower than the warfarin [21]. In another study, no significant differences were observed within 6-month threament with warfarin and enoxaparin [22]. Kaplan-meier study showed VTE recurrence risk within 6-month study significantly decreased with dalteparin compared with oral anticoagulant and no significant difference in bleeding risk was seen for two groups [23]. Vitamin K antagonists are less effective in patients with cancer, with rates of recurrent VTE threefold higher than in patients without cancer, despite maintenance of the international normalized ratio (INR) within the therapeutic range [24]. LMWH also offers other advantages including: no need for laboratory monitoring of its anticoagulant activity; a shorter half-life that facilitates temporary interruption for procedures or thrombocytopenia; limited drug interactions; and no food interactions. As a result, LMWH is recommended for both initial and long-term anticoagulant therapy in cancer-associated thrombosis by major consensus guidelines [25]. The use of oral factor Xa inhibitors has also been evaluated for extended anticoagulation therapy in patients who had VTE, but using of them in cancer patient remains to be investigated in future prospective trials [26].

Superficial venous thrombosis(SVT): Anticoagulation therapy with intravenous UFH or LMWH at least for 6 weeks is a recommendation with a non-peripheral catheter SVT in close proximity to the deep venous thrombosis, and 12 weeks treatment if SVT in close to the femoral vain. catheter removal, anti-inflammatory medications, warm compresses, and limb elevation in peripheral catheter related SVT is recomended.

Splanchnic vein thromboses (SPVT), Involving the splenic, portal, mesenteric, or hepatic veins, are uncommon in the general population, but significant rates have been reported in patients with intra-abdominal malignancies [27]. In a single-institution study, incidental splanchnic vein thrombosis was present in 23% [28]. A retrospective study showed that, the presence of malignancy was significantly associated with decreased survival for patients with SPVT, both in univariate and multivariate analysis [29]. Management of the patients with SPVT depends on the duration, location and extent of the thrombosis. In acute SPVT, which is associated with presenting sign and symptoms ≤8 weeks duration, without portal cavernoma and portal hypertension, anticoagulation with UFH or low molecular weight heparin (preferred) should be initiated, followed by oral agents for at least 6 months [29,30]. Anticoagulant therapy appears to lower the risk for recurrent thrombosis in patients with SPVT without increasing the risk for severe bleeding [31,32]. NCCN guideline recommends lifelong anticoagulation for SPVT in patients with active cancer, underlying thrombophilia, and idiopathic thrombosis. Thrombolytic therapy may be most useful when administered locally in patients with acute thrombosis; but should be used with caution because of major bleeding complications [33]. In chronic SPVT, the presence of portal hypertention may increase the risk of bleeding from esophageal varices and splenomegaly may decreased platelet counts, that increase the risk of bleeding in patients treated with anticoagulation [34]. An important management of patients with chronic mesenteric or portal thrombosis is risk reduction for and prevention of bleeding [35].


  1. Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, et al. (2002) Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 162: 1245-1248.
  2. Khorana AA (2012) Cancer-associated thrombosis: updates and controversies. Hematology Am Soc Hematol Educ Program 2012: 626-630.
  3. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, et al. (2006) Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 24: 484-490.
  4. Khorana AA, Dalal M, Lin J, Connolly GC (2013) Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 119: 648-655.
  5. Chew HK, Wun T, Harvey D, Zhou H, White RH (2006) Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 166: 458-464.
  6. Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, et al. (2006) A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 243: 89-95.
  7. Cohen AT, Alikhan R, Arcelus JI, Bergmann JF, Haas S, et al. (2005) Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost 94: 750-759.
  8. Königsbrügge O, Pabinger I, Ay C (2014) Risk factors for venous thromboembolism in cancer: novel findings from the Vienna Cancer and Thrombosis Study (CATS). Thromb Res 133 Suppl 2: S39-43.
  9. Dickmann B, Ahlbrecht J, Ay C, Dunkler D, Thaler J, et al. (2012) Regional lymph node metastases are a strong risk factor for venous thromboembolism: results from the Vienna Cancer and Thrombosis Study. Haematologica 98: 1309-1314.
  10. Khorana AA, Connolly GC (2009) Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 27: 4839-4847.
  11. Lee AY (2010) Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulants. Hematology Am Soc Hematol Educ Program 2010: 144-149.
  12. Bick RL (2003) Cancer-associated thrombosis. N Engl J Med 349: 109-111.
  13. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW (2008) Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111: 4902-4907.
  14. Francis CW (2009) Prevention of venous thromboembolism in hospitalized patients with cancer. J Clin Oncol 27: 4874-4880.
  15. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, et al. (2004) Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). Journal of Clinical Oncology 22: 1944-1948.
  16. Young AM, Billingham LJ, Begum G, Kerr DJ, Hughes AI, et al. (2009) Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet 373: 567-574.
  17. Khorana AA, Dalal M, Tangirala K, Miao R (2011) Higher incidence of venous thromboembolism in the outpatient versus the inpatient setting among US cancer patients. ASH Annual Meeting Abstracts.
  18. Cohen AT, Nandini B, Wills JO, Ota S (2010) VTE prophylaxis for the medical patient: where do we stand“A focus on cancer patients. Thrombosis Research. 125: S21-S9.
  19. Lee AY, Peterson EA (2013) Treatment of cancer-associated thrombosis. Blood 122: 2310-2317.
  20. Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, et al. (2008) Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cancer 113: 1685-94.
  21. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, et al. (2002) Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 162: 1729-1735.
  22. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, et al. (2006) Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clinical and Applied Thrombosis/Hemostasis 12: 389-96.
  23. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, et al. (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349: 146-153.
  24. Connolly GC, Khorana AA (2010) Emerging risk stratification approaches to cancer-associated thrombosis: risk factors, biomarkers and a risk score. Thromb Res 125 Suppl 2: S1-7.
  25. Martino MA, Williamson E, Siegfried S, Cardosi RJ, Cantor AB, et al. (2005) Diagnosing pulmonary embolism: experience with spiral CT pulmonary angiography in gynecologic oncology. Gynecol Oncol 98: 289-293.
  26. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, et al. (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368: 699-708.
  27. Ogren M, Bergqvist D, Bjorck M, Acosta S, Eriksson H, et al. (2006) Portal vein thrombosis: Prevalence, patient characteristics and lifetime risk: A population study based on 23796 consecutive autopsies. World journal of gastroenterology 12: 2115.
  28. den Exter PL, Hooijer J, Dekkers OM, Huisman MV (2011). Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. Journal of Clinical Oncology 29: 2405-2409.
  29. Thatipelli MR, McBane RD, Hodge DO, Wysokinski WE (2010) Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol 8: 200-205.
  30. Hoekstra J, Janssen HL (2009) Vascular liver disorders (II): portal vein thrombosis. Neth J Med 67: 46-53.
  31. Plessier A, Darwish-Murad S, Hernandez-Guerra M, Consigny Y, Fabris F, et al. (2010) Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 51: 210-218.
  32. Dentali F, Ageno W, Witt D, Malato A, Clark N, et al. (2009) Natural history of mesenteric venous thrombosis in patients treated with vitamin K antagonists: a multi-centre, retrospective cohort study. Thromb Haemostasis 102: 501-4.
  33. Menon KV, Shah V, Kamath PS (2004) The Budd-Chiari syndrome. N Engl J Med 350: 578-585.
  34. Martinelli I, Franchini M, Mannucci PM (2008) How I treat rare venous thromboses. Blood 112: 4818-4823.
  35. Boley SJ, Kaleya RN, Brandt LJ (1992) Mesenteric venous thrombosis. Surg Clin North Am 72: 183-201.
Citation: Mozaheb Z (2014) Cancer and Thrombosis. J Hematol Thrombo Dis 2:176.

Copyright: © 2014 Mozaheb Z. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.