Malignancy-associated Thrombosis Research Articles

Important Considerations in the Intensive Care Management of Acute Leukemias.

In the realm of hematologic disorders, acute leukemia is approached as an emergent disease given the multitude of complications and challenges that present both as a result of inherent disease pathology and adverse events associated with antineoplastic therapies and interventions. The heavy burden of leukemic cells may lead to complications including tumor lysis syndrome, hyperleukocytosis, leukostasis, and differentiation syndrome, and the initiation of treatment can further exacerbate these effects. Capillary leak syndrome is observed as a result of antineoplastic agents used in acute leukemia, and L-asparaginase, a bacterial-derived enzyme, has a unique side effect profile including association with thrombosis. Thrombohemorrhagic syndrome and malignancy-associated thrombosis are also commonly observed complications due to direct disequilibrium in coagulant and anticoagulant factors. Due to inherent effects on the white blood cell milieu, leukemia patients are inherently immunocompromised and vulnerable to life-threatening sepsis. Lastly, the advents of newer therapies such as chimeric antigen receptor (CAR) T-cells have clinicians facing the management of related toxicities on unfamiliar territory. This review aims to discuss these acute leukemia-associated complications, their pathology, and management recommendations.

Advances in Management of the Stroke Etiology One-Percenters.

Uncommon causes of stroke merit specific attention; when clinicians have less common etiologies of stoke in mind, the diagnosis may come more easily. This is key, as optimal management will in many cases differs significantly from "standard" care. Randomized controlled trials (RCT) on the best medical therapy in the treatment of cervical artery dissection (CeAD) have demonstrated low rates of ischemia with both antiplatelet and vitamin K antagonism. RCT evidence supports the use of anticoagulation with vitamin K antagonism in "high-risk" patients with antiphospholipid antibody syndrome (APLAS), and there is new evidence supporting the utilization of direct oral anticoagulation in malignancy-associated thrombosis. Migraine with aura has been more conclusively linked not only with increased risk of ischemic and hemorrhagic stroke, but also with cardiovascular mortality. Recent literature has surprisingly not provided support the utilization of L-arginine in the treatment of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); however, there is evidence at this time that support use of enzyme replacement in patients with Fabry disease. Additional triggers for reversible cerebral vasoconstriction syndrome (RCVS) have been identified, such as capsaicin. Imaging of cerebral blood vessel walls utilizing contrast-enhanced MRA is an emerging modality that may ultimately prove to be very useful in the evaluation of patients with uncommon causes of stroke. A plethora of associations between cerebrovascular disease and COVID-19 have been described. Where pertinent, authors provide additional tips and guidance. Less commonly encountered conditions with updates in diagnosis, and management along with clinical tips are reviewed.

Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes.

Platelets, the primary operatives of hemostasis that contribute to blood coagulation and wound healing after blood vessel injury, are also involved in pathological conditions, including cancer. Malignancy-associated thrombosis is common in ovarian cancer patients and is associated with poor clinical outcomes. Platelets extravasate into the tumor microenvironment in ovarian cancer and interact with cancer cells and non-cancerous elements. Ovarian cancer cells also activate platelets. The communication between activated platelets, cancer cells, and the tumor microenvironment is via various platelet membrane proteins or mediators released through degranulation or the secretion of microvesicles from platelets. These interactions trigger signaling cascades in tumors that promote ovarian cancer progression, metastasis, and neoangiogenesis. This review discusses how interactions between platelets, cancer cells, cancer stem cells, stromal cells, and the extracellular matrix in the tumor microenvironment influence ovarian cancer progression. It also presents novel potential therapeutic approaches toward this gynecological cancer.

Prophylaxis and treatment of hematological malignancy-associated thrombosis

Hematologic malignancies, particularly acute myeloid leukemia, are associated with thrombocytopenia as well as hyperfibrinolytic disseminated intravascular coagulation, which increases the risk of death due to bleeding. Conversely, thromboembolism is known to complicate certain proportions of patients and lead to a poor prognosis; however, prophylaxis and treatment with anticoagulants received little attention. This article discusses the risk factors for thromboembolism in hematologic malignancies, such as acute leukemia, malignant lymphoma, and multiple myeloma, as well as thromboembolism prevention and treatment. Meta-analyses have revealed that second- and third-generation BCR-ABL tyrosine kinase inhibitors increase the risk of cardiovascular events in patients with chronic myeloid leukemia, and this article discusses strategies to prevent these events, which are regarded as a major clinical issue.

Retrospective Assessment of Outcomes Following Superficial Vein Thrombosis in Cancer Patients

Background: Superficial vein thrombosis (SVT) has been historically considered to have a low risk of distal embolization and mortality, typically not warranting anticoagulation in the absence of underlying risk factors for thrombosis. However, recent studies of outcomes of SVT in patients without malignancy revealed significantly increased incidence of deep venous involvement at the time of presentation, as well as higher than expected rates of complications, reported in up to 10% of patients (Decousus et al. Ann Int Med(152)2010:218-224). However, outcomes of SVT in patients with cancer have not been well studied, despite the known increased risk of malignancy-associated thrombosis. In this study, we examined the rate of complications in patients who developed SVT in the setting of active malignancy. Methods: A retrospective single-center chart review of electronic medical records along with a corresponding database of radiology reports from NYU Winthrop Hospital from 2013 to 2019 was performed to identify patients with cancer who also had image-confirmed SVT. Patients were included if they had a synchronous or subsequent deep vein thrombosis (DVT) or pulmonary embolism (PE) during treatment, but excluded if they had a history of thrombosis prior to their cancer diagnosis, primary hypercoagulable disorder, or on therapeutic anticoagulation at the time of SVT diagnosis. Descriptive statistics for the overall sample, as well as a subgroup of subjects who were not treated at SVT diagnosis, were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: 490 patients were noted to have a diagnosis of SVT and cancer, and of these, 40 met the enrollment criteria. Demographic data are shown in the table below. Among the 40, 21 patients had upper extremity, and 19 had lower extremity SVT. As shown in the table, 15 patients (37.5%) had a concurrent thromboembolism at the time of SVT diagnosis. An intervention was provided in 26 (69% full dose and 11% prophylactic dose anticoagulation, 15.3% antiplatelet therapy, and 3.8% vena cava filter placement). Of these 26 patients, one who received prophylactic anticoagulation developed a subsequent DVT. This patient had stage IV colon cancer and recent surgical resection, and developed SVT associated with intravenous access. Among the 14 patients with SVT who were not treated, 6 (43%) developed subsequent complications including one with DVT at the same extremity, 2 with DVT at a different location, and 3 with recurrence of the underlying SVT. Five of these were stage IV gastrointestinal cancers (including 3 patients with pancreatic cancer, 1 with gastric, and 1 with cholangiocarcinoma), and one had stage IV ovarian cancer. Considering the 8 patients who were not treated and did not develop complications, there was no dominant cancer type (3 were stage IV breast cancer, 1 had stage I pancreatic cancer, 1 had stage III hepatocellular carcinoma, and one had chronic lymphocytic leukemia). Conclusions: This study reveals a greater degree of concurrent SVT complications in the setting of malignancy compared to prior reports in patients without cancer. The rate of complications were higher in those patients who did not receive treatment (either prophylactic or therapeutic) for their SVT or who had metastatic disease. Although the overall incidence of SVT in cancer patients is low, data presented here suggest a higher than expected rate of complications within a 3 month span following SVT diagnosis in the setting of malignancy compared to prior reports of patients without malignancy. Prospective studies are needed to assess the benefit of anticoagulation in decreasing the risk for SVT complications in patient with active cancer. Table Disclosures Braunstein: Celgene: Consultancy, Other: Advisory boards; Takeda: Consultancy, Other: Advisory Board; Amgen: Consultancy, Other: Advisory Board; AstraZeneca: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board, Research Funding; Verastem: Consultancy, Other: Advisory Board.

VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Temporary and Permanent Inferior Vena Cava Filters in the Oncology Population

BackgroundThe use of both temporary and permanent inferior vena cava (IVC) filters continues to rise yet randomized data regarding efficacy and complication rates are limited, especially in cancer patients. Temporary IVC filters are associated with higher costs and can have more long-term complications than permanent IVC filters. In this study, we examined the use of temporary and permanent IVC filters in the cancer population, a group at high risk for venous thromboembolism (VTE) as well as complications of anticoagulation.MethodsThis single-institution study included patients with active malignancy receiving adjuvant chemotherapy or considered for future chemotherapy that received an interventional radiology (IR) placed temporary (N=179) or permanent (N=207) IVC filter from 2009 to 2013. Patients were followed prospectively from the time of filter placement. The database included patient demographics, type of malignancy, indication for filter placement, time to filter retrieval, complications of placement/retrieval, rates of VTE recurrence and cause of death (if applicable).ResultsPatient demographic information is shown in Table 1. The most common reasons cited for filter placement included a contraindication to anticoagulation from bleeding (36%), recent or upcoming procedure (19%), thrombocytopenia (17%), and surgical prophylaxis (8%). 21% of filters were placed in patients with no contraindication to anticoagulation or failure of anticoagulation. Of these, 35% of the temporary filters were not removed. IVC filters were most frequently placed in patients with underlying hematologic malignancies (22%), gastrointestinal malignancies (22%) and lung cancer (16%). The majority of patients had stage III or IV cancer (62%).Of the 179 temporary filters placed, 60% were not retrieved. The most common reasons for failure of filter retrieval included: progressive disease/clinical deterioration (51%), continued contraindication to anticoagulation (23%) and loss of follow-up (8%). Only 2% of filters could not be removed because of mechanical reasons. Of the 81 attempted filter removals, 5 had in-filter thrombus, 4 had surrounding fibrin sheaths, 4 had filter tilt, 1 had IVC in-growth, 1 had broken struts and 1 had a procedure-related infection.The rate of recurrent VTE in all patients studied was 23% (21% in temporary filter group, 24% in permanent filter group), including 20 pulmonary emboli (PE) and 14 thromboses within the IVC filter. The majority of recurrences occurred off of anticoagulation (58%). Only 34% could be maintained on therapeutic anticoagulation. By study end, 72% of patients had died, most commonly due to progressive cancer. Median time from filter placement to death was 2.9 months (range: 0.1-64.7 months). Seventy-five patients (19%) died within 30 days of filter placement. They were more likely to have stage IV disease (78% vs. 54%). Of these 75 patients, three experienced recurrent VTE, two with lower extremity DVTs and one with an IVC thrombus. Data on filter costs were also collected. Costs were attributable to the placement and retrieval procedures when applicable ($10,983.00 and $8,824.00, respectively) as well as the device itself ($1,576.00).ConclusionsMalignancy-associated thrombosis is common and associated with a high rate of recurrence. While most recurrent VTE after IVC filter placement were deep vein thromboses, a relatively large number of PE's occurred after filter placement as well. A significant number of patients with malignancy-associated thrombosis who underwent IVC filter placement had no contraindication to anticoagulation or recurrent VTE while on anticoagulation. Better prospective studies are needed to assess the safety and efficacy of IVC filters in the setting of hemodynamic compromise, extensive clot burden or for surgical prophylaxis, especially in the oncology population. In this cohort, the majority of filters were placed in patients with advanced cancer with likely short life expectancies, suggesting the patient selection for filter placement could be optimized. Finally, the cost of filter placement and retrieval is substantial, further emphasizing the need for better prospective data to identify the subset of patients who will derive the most benefit from filter use. [Display omitted] DisclosuresStein:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lewandowski:Cook Medical: Consultancy; Boston Scientific: Membership on an entity's Board of Directors or advisory committees.

Clinical Use of Anti-Xa Monitoring in Malignancy-Associated Thrombosis.

Introduction. Low molecular weight heparin (LMWH) is preferred for malignancy-associated venous thromboembolism (VTE). Many providers monitor LMWH with anti-Xa levels, despite little validation on correspondence with patient outcome. Methods. This is a retrospective, single institution study of anti-Xa measurement in malignancy-associated thrombosis. Cases were identified using the Electronic Data Warehouse, and inclusion was confirmed by two independent reviewers. Malignancy type, thrombotic history, measurement rationale and accuracy, clinical context, and management changes were evaluated. Results. 167 cases met inclusion criteria. There was no clear rationale for anti-Xa testing in 56%. Impaired renal function (10%), documented or suspected recurrent thrombosis despite anticoagulation (9%), and bleeding (6%) were the most common reasons for testing. Incorrect measurement occurred in 44%. Renal impairment was not a significant impetus for testing, as 70% had a GFR > 60. BMI > 30 was present in 40%, and 28% had a BMI < 25. Clinical impact was low, as only 11% of patients had management changes. Conclusions. Provider education in accuracy and rationale for anti-Xa testing is needed. Our study illustrates uncertainty of interpretation and clinical impact of routine anti-Xa testing, as management was affected in few patients. It is not yet clear in which clinical context providers should send anti-Xa levels.

Clinical Use Of Anti-Xa Monitoring In Malignancy-Associated Thrombosis

IntroductionLow molecular weight heparin (LMWH) is currently the preferred anticoagulant for malignancy-associated venous thromboembolism (VTE) given improved outcomes compared to warfarin. However, recurrent thrombosis still occurs in up to 9% of patients despite use of this preferred agent. Data to guide clinical decisions-making in the setting of recurrent thrombosis despite use of LMWH is lacking. Unlike warfarin or unfractionated heparin (UFH), LMWH typically does not require monitoring to determine efficacy or safety. However, many providers will still check a LMWH anti-Xa level, despite little clinical validation on how these values should be interpreted and how they correspond with patient outcome. Therefore, the levels have the potential to be used or interpreted incorrectly. The aim of this study was to evaluate how LMWH anti-Xa levels are currently incorporated into clinical practice, with emphasis on whether the lab was drawn correctly, the indication for checking the level, and whether testing impacted clinical decision making. MethodsThis is a single-institution, retrospective study. Cases of malignancy-associated thrombosis occurring between 1/1/2006 and 12/31/2011 were identified using current procedural terminology (CPT) codes and the Northwestern University Electronic Data Warehouse. This cohort was then screened for those who had a LMWH anti-Xa level checked at any point in that time frame. All resultant cases had charts reviewed by 2 independent investigators to confirm active malignancy, treatment with LMWH, and history of VTE. Patients were excluded from analysis if the anti-Xa level was checked while on unfractionated heparin and if the last dose of anticoagulation was given as an outpatient. ResultsAn anti-Xa level was checked 447 times in patients with malignancy-associated thrombosis in the specified time frame. Analysis thus far was limited to the 247 patients with malignancy-associated VTE who had only one LMWH anti-Xa level checked during the study period. After reviewing for exclusion criteria, 167 cases were eligible. LMWH anti-Xa testing was sent most frequently in those with hematologic malignancy (25%) and lung cancer (13%). The indication for testing was not documented or was unclear in 88 (53%) of cases. Impaired renal function (10%), documented or suspected recurrent thrombosis despite anticoagulation (9%), and bleeding (6%) were among the more common reasons that LMWH anti-Xa levels were checked. 40% of the patients had a body mass index (BMI) ≥30. Optimal timing for testing is 4-6 hours after the third dose. In this study, the timing of the lab draw was correct in only 55% of cases, leading to potentially imprecise results in the remaining 45%. Of those drawn correctly, 76% were in the reported “therapeutic target range.” In the majority of cases, there was no change in the type or dose of anticoagulation in the 24 hours after the anti-Xa level was drawn. ConclusionsDespite widespread use in routine clinical practice, the role for checking LMWH anti-Xa levels in those with malignancy-associated thrombosis being treated with LMWH is not clear. Our data indicate that providers may not be aware of how the lab should be drawn, with regard to peak levels. In addition, a majority of anti-Xa levels were checked in overweight and obese patients, despite no definitive evidence that these patients require extra monitoring. Finally, when tested correctly, the majority of patients were already in what is reported to be the therapeutic range, bringing to question if the level needed to be checked at all. This strongly suggests a role for provider education if testing is felt to be clinically indicated. At present, though testing is widely available, it is not yet clear in which clinical contexts (if any) providers should send LMWH anti-Xa levels. Prospective studies are needed to better clarify whether anti-Xa levels correlate with clinical outcomes in those with malignancy-associated thrombosis, and how the results should be incorporated clinical practice. Disclosures:No relevant conflicts of interest to declare.

PL-13 Tissue factor isoforms in cancer and coagulation: May the best isoform win

Tissue factor (TF), the trigger of blood coagulation, is a 47 kDa membrane protein that also impacts on non-hemostatic processes, such as atherosclerosis, primary tumor growth and metastasis. TF binding to its ligand FVIIa induces activation of protease-activated receptor-2 and this event is thought to considerably influence atherosclerosis and tumor angiogenesis. TF-dependent activation of the coagulation cascade, rather than PAR-2 activation, then leads to the potentiation of metastasis. Importantly, a soluble alternatively spliced isoform of TF (asTF) has been discovered, but the function of asTF in hemostatic and non-hemostatic events is poorly understood. In this review, we aim to present a side-by-side evaluation of normally-spliced, full length TF (flTF) and asTF with regard to coagulant function, atherosclerosis, tumor progression and malignancy-associated thrombosis.

Thrombosis and Malignancy: A Case-Based Review

The association between venous thromboembolism (VTE) and malignancy is well established. Recent interest has focused on standards of care for prophylaxis, diagnosis, and treatment of malignancy-associated thrombosis. Anticoagulant management in cancer patients has unique complexities such as prolonged hospitalization, extensive surgeries, extended periods of inactivity, indwelling central venous catheters (CVC), thrombocytopenia, and pro-thrombotic medications. Here we will explore current recommendations for various specific clinical scenarios for cancer-associated thromboses. We will make evidence-based recommendations wherever possible; however, several of the scenarios here were included because pertinent high-quality evidence does not exist.

Therapeutic Roles of Heparin Anticoagulants in Cancer and Related Disorders

Cancer represents a major cause of overall mortality, second to cardiovascular disorders. Cancer patients frequently encounter hypercoagulable states, with recurrent thromboembolic events due to the impact of cancer cells and chemotherapy/radiotherapy on the coagulation cascade. The expression of highly procoagulant proteins have been implicated to involve in tumor cell-induced thrombin generation, leading to platelet activation and fibrin clot formation. These include binding of heparin to angiogenic growth factors (e.g., basic fibroblast growth factor and vascular endothelial growth factor); modulation of tissue factor (TF); and enhanced TF-pathway-inhibitor release, and inhibition of matrix-degrading enzymes. The classical anticoagulant (unfractionated heparin; UFH), and its derived low-molecular-weight heparins (LMWH) are polypharmacologic agents. These anticoagulants are composed of oligosccharides with structural/molecular heterogeneity. Heparins bind to wide range of molecules via electrostatic interactions with the glycosaminoglycan chains, and hence possess numerous therapeutic properties beyond their anticoagulant effects, including anti-cancer potentials. Recent studies demonstrate that UFH and LMWH fractions interfere with various cellular/inflammatory processes and reduce mortality/morbidity in malignancy-associated thrombosis and vascular disorders. There are certain weaknesses of heparins, particularly when patients receiving prolonged therapy, including bleeding complications. Paradoxically, many individuals receiving heparin anticoagulants develop antibodies against the complex formed between heparin and platelet factor 4 because of massive platelet/cellular activation and hypercoagulable state, resulting in clinical manifestation referred to as heparin-induced thrombocytopenia (HIT) syndrome. Increased risk of venous thromboembolic events are likely in individuals with malignancy-associated thrombosis coupled with underlying HIT pathogenesis. This article will review the existing knowledge about the experimental/clinical anti-cancer properties of heparin anticoagulants and provide a rationale for future research.

Malignancy-Associated Thrombosis

Malignancy-Associated Thrombosis

Nitric Oxide and Asymmetric Dimethylarginine Levels in Malignancy Associated Thrombosis and Their Modulation by Anticoagulants

Nitric oxide (NO) is an important endothelially derived vasoactive mediator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. While an association between ADMA levels and cardiovascular diseases is known, no information on ADMA levels in cancer patients is available. It was hypothesized that endothelial dysfunction in cancer patients may result in increased ADMA levels. Plasma samples were analyzed from an open-label, multi-dose, active comparator study in which all patients (n=110) were initially treated with enoxaparin (E; 1 to 1.5 mg/kg SC). After 5 days of treatment, half of the patients continued to receive E and the other half received warfarin (W) for up to 12 weeks. Baseline (BL), 5 days post E (IPE) and 4–6 week blood samples from the E and W treated groups were analyzed for ADMA and NO levels (Cardiovasics, Palo Alto, CA; R&D Systems, Minneapolis, MN). Relative to aged matched controls, ADMA and NO levels were markedly elevated in cancer patients. The E treated group showed a marked decrease in ADMA levels throughout the treatment period. In the W converted group, ADMA levels rebounded to an increased level. The down-regulation of NO was similar for both E and W. These results suggest that patients with cancer and thrombosis exhibit simultaneous up-regulation of ADMA and NO. While enoxaparin and warfarin differentially regulate ADMA, both result in down-regulation of NO. These studies underscore the anti-inflammatory mechanisms by which low molecular weight heparins such as E mediate their therapeutic effects in cancer associated thrombosis.

Nitric Oxide and Asymmetric Dimethlyarginine Levels in Malignancy Associated Thrombosis and Their Modulaiton by Anticoagulants.

Nitric oxide (NO) represents one of the major endothelial derived vasoactive mediators. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase which inhibits NO production at Pathophysiologic levels. While the association of ADMA in cardiovascular diseases is known, no information on the ADMA levels is available in cancer patients. To test the hypothesis that endothelial dysfunction in cancer patients may result in increased ADMA levels, plasma samples were analyzed from an open label, multidose, active comparator designed study in which all patients (n=110) were initially treated with low molecular weight heparin, enoxaparin (E) at 1–1.5 mg/kg sc for 5 days. These patients were further subdivided. One group continued to receive E whereas the other group received warfarin (W) for up to 12 weeks. Baseline blood samples (BL), 5 days post E (IPE) and 4–6 week samples from the E and W were analyzed for ADMA and NO levels (Cardiovasics, Palo Alto, CA; R&D Systems, Minneapolis, MN, respectively). In comparison to the aged matched controls both the ADMA and NO levels were markedly elevated in cancer patients. The E treated group showed a marked decrease in the ADMA levels which persisted throughout the treatment period. However in the W converted group the ADMA levels rebounded to an increased level indicating that E differentially regulated ADMA in these patients. The down regulation pattern of NO was similar for both enoxaparin and warfarin. These results suggest that patients with cancer and thrombosis exhibit simultaneous up regulation of ADMA and NO. While enoxaparin and warfarin show a differential regulation of ADMA both result in down regulation of NO. The fact that E regulates ADMA is highly suggestive of its regulatory role in iNOX which may be involved in the inflammatory response in cancer patients. Furthermore, these studies underscore the anti-inflammatory mechanisms by which low molecular weight heparins such as E, mediate their therapeutic effects in cancer asscoiated thrombosis.GroupNitric Oxide (uM)ADMA (uM)Aged matched controls18±51.51±0.52BL63±185.34±1.5IPE22±92.81±0.94–6 weeks enoxaparin20±82.45±0.94–6 weeks warfarin25±83.67±1.1

Increased blood levels of inflammatory cytokines CRP, TNF-α, CD40L, MCP-1 and Nitric Oxide in malignancy-associated thrombosis and their modulation by a low molecular weight heparin, Enoxaparin

6077 Background: Endogenous generation of inflammatory cytokines and induction of NO synthase (NOS, EC 1.1.4. 13.49) resulting in enhanced formation of NO free radicals contribute to the pathogenes...

Increased blood levels of inflammatory cytokines CRP, TNF-α, CD40L, MCP-1 and Nitric Oxide in malignancy-associated thrombosis and their modulation by a low molecular weight heparin, Enoxaparin

6077 Background: Endogenous generation of inflammatory cytokines and induction of NO synthase (NOS, EC 1.1.4. 13.49) resulting in enhanced formation of NO free radicals contribute to the pathogenesis of vascular and thrombotic events in these patients. Patients recruited in an open label, multidose active comparator parallel design study were randomized to receive a low molecular weight heparin (LMWH) namely enoxaparin at a dose of 1–1.5 mg/kg SC for one week. Methods: Blood samples were collected prior to and 3–7 days after initiation of LMWH. These samples were analyzed for NO measurement utilizing a chemical method (Sievers 280i, Ionics Corp. Boulder, CO) and ELISA methods for MCP-1, CD40L, TNF-α (R&D Systems, Minneapolis, MN) and hsCRP (American Diagnostica, Stamford, CT). In addition to the control group (n=50), a group of medical patients with thrombosis without cancer were included (n=50). Results: The relative increase of these inflammatory markers in the cancer patients with thrombosis was higher in comparison to the two other groups. In particular, the CD40L levels were found to be 10-fold higher in comparison to normals. Patients with thrombosis without cancer exhibited only a 4-fold increase in comparison to normal. The MCP-1 levels showed a 5-fold increase in the cancer with thrombosis group, whereas cancer patients without thrombosis exhibited a 40% increase. HsCRP was much higher in the cancer patients with thrombosis when compared with cancer patients without thrombosis. The TNF-α levels were increased in both groups. Interestingly, the relative increase in the NO level was significantly higher in cancer patients with thrombosis 63.1± 50.1 μ M for ONCENOX and 39.8± 16.2 μ M for CORTES study. Cancer patients with thrombosis treated with LMWH for 3–7 days exhibited a marked downregulation of MCP-1, CD40L, hsCRP and NO. In the group of patients with thrombosis without cancer a decreased trend was noted. Conclusions: This observation clearly suggests that the pathogenesis of cancer-associated thrombosis is strongly influenced by inflammatory cytokines. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Mitsubishi; Pfizer