The Role of Heparin in Lung Cancer

Non-small cell lung cancer is a major health problem worldwide. Surgery is still the mainstay of treatment especially in early stages of the disease. Despite the fact that surgery is the potentially curative treatment, the recurrence and mortality rates are still high specifically with more advanced stages of cancer. Heparin has been suggested to have a positive impact on the outcome of various cancers through its anticoagulants properties and; in some instances; due to their antitumor activity. Recently, the molecular mechanisms of tumor cell spreading have been recognised. Metastasis is a complex process that could be therapeutically affected wherever certain extra-cellular matrix proteins could play an important role in prevention of tumor cell migration and invasion. Experimental studies have shown decreased metastases development after heparin use in rat models. We have reviewed the literature to study the role of anticoagulants in cancer patients in general and in patients with Non Small Cell Lung Cancer (NSCLC) specifically. DOI : 10.14302/issn.2639-1716.jn-17-1499 Corresponding Author: Dr. Walid Abu Arab, 3001, 12e Avenue Nord, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 4N5 Canada, Tel: 1 8193461110 ext. 12371, Fax: 1 8198206871, E-mail: walidabuarab@yahoo.com Running title: Heparin & lung cancer


History
Unfractionated heparin was developed during 1930s. Since that time it has been used by injections for more than sixty years. It requires coagulation monitor-ing, and it can be associated with heparin-induced thrombocytopoenia (HIT) and osteopoenia (11-13).
Vitamin K Antagonists (VKAs), as warfarin and acenocoumarol, were the first oral anticoagulants introduced into the market during 1950s. Warfarin has been the drug of choice for prevention and treatment of arterial and venous thrombotic disorders for more than 40 years. It was initially marketed as pesticide against rats and mice and is still popular for this purpose.
Although, VKAs are highly effective, they are difficult to manage well (14). These therapies require frequent monitoring and dose adjustment to limit adverse consequences and they have multiple food and drug interactions. Moreover, these factors may contribute to the frequent underuse of warfarin, especially in elderly patients, and low patient satisfaction (15). In addition, VKAs have a slow onset of action, and when used for Venous Thrombo-Embolism (VTE) treatment, bridging therapy with injected anticoagulants with a fast onset of action is required.
Ximelagatran was the first oral direct thrombin inhibitor and had proven efficacy for prevention and treatment of (VTE), stroke prevention with AF and recurrent coronary events after acute myocardial infarction (16,17). Its use was initially approved for short term prevention of (VTE) in patients who will undergo orthopedic surgery in Europe. It is not the case in more advanced stages as they have a higher risk of local recurrence. In particular, the recurrence rate is relatively low in stage II (37), but increases in stage IIIA, especially in N2 disease (38).
Overall, distant metastasis has to be considered as the leading cause of treatment failure in resected NSCLC. As a consequence, it is reasonable to hypothesize that the prevention of the metastatic spread (preoperatively, peri -operatively, and postoperatively) could represent the mainstay of improvement in chances of cure in those patients. Blood clotting components in micro vessels were found to play a significant role in the process of metastasis (39).

Venous Thrombo-Embolism in NSCLC patients
It has been recognised that venous thromboembolism (VTE) represents a common complication of malignancy. It was shown that the relative risk of VTE is increased about 4-6 folds in patients with cancer, compared to sex and age matched control (40). Previous studies have also showed that the development of symptomatic VTE in a cancer patient is associated with significant reduction of the overall survival (41).
The clinical importance of anticoagulant therapy in patients with cancer is readily apparent, in view of the prevalence of VTE in cancer patients, and its associated morbidity and mortality. Generally, in non-cancer patients, the acute VTE is treated with anticoagulants starting by using the unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for a period ranging from 5 to 7 days followed by oral anticoagulation via warfarin for at least 3 months (42).

Effects of Heparin on Immune System
Heparin can affect adhesion of leucocytes to endothelium at sites of inflammation or tumor invasion; hence it can interfere with the immune reactions.
Moreover, heparin can inhibit leukocyte activation and affect complement activation (68). In addition to the direct effect of heparin on the immune system, Gorelik et al. (51) has suggested that heparin inhibits metastasis by rendering cancer cells more vulnerable to cytotoxic effects of natural killers (NK) cells. Recently, Abu Arab et al. (85)