Notas Médica
Antiagregantes
Anticoagulados
Biología Molecular
Cardiología
CoagulopatíasCongénitas
Coagulopatías Adquiridas
Endocrinología
Endotelio
Fibrinolisis
Genética
Ginecología - Obstetricia
Hemofilias
Hemostasis
Manuales
Medicina Interna
Nefrología
Neurología
Oftamología
Oncología
Pediatria
Plaquetas
Terapéuticas Actuales
Traumatología
Trombosis
Trabajos Publicados
Inicio Carné de Salud Libreta de Chofer Estudios de Hemostasis y Trombosis Odontología
 
Imprimir pagina Notas sobre Oncología
FromTrousseau to targeted therapy:newinsightsandinnovations in thrombosis and cancer
Ver Documento en formato PDF
M. N. LEVINE,* A. Y. LEEy and A. K. KAKKARz
*Departments of Clinical Epidemiology & Biostatistics and *yMedicine, McMaster University, Hamilton, Ontario, Canada; and zDepartment of Surgical Oncology and Technology, Imperial College, London, UK
Correspondence: Dr M. Levine, Room 9, 90 Wing, Main Level Henderson Hospital, 711 Concession St., Hamilton, Ontario, Canada L8V 1C3. Tel.: þ1 905 527 4322, ext. 42176; fax: þ1905 389 9288; e-mail: mlevine@ mcmaster.ca
Summary. Venous thromboembolism (VTE) commonly occurs in patients with malignant disease. At the 1997 ISTH
meeting, cancer and thrombosis was discussed in a state-of-theart symposium. Since then, there have been many new developments on this topic. Tumors, through expression of tissue factor can activate coagulation. Furthermore, local peritumor activation of coagulation may have important effects on the biology of cancer. A randomized trial has been conducted which evaluated extensive screening to detect underlying malignancy
vs. no screening in patients presenting with idiopathic VTE. No statistically significant difference was detected in cancer-related mortality between the two groups. A trial has evaluated extended prophylaxis in patients undergoing surgery for abdominal malignancy. There was a statistically significant reduction in venographically detected deep vein thrombosis in favor of 4 weeks of treatment. In contrast, there is clearly a need for
more information on the use of thromboprophylaxis in medical cancer patients. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the first line treatment in the majority of patients with acute VTE. Many cancer patients with acute VTE can be treated safely at home with subcutaneous LMWH without admission to hospital. The results of a recent trial demonstrated that long-term low molecular weight heparin administered over a 6-month period substantially reduced the rate of recurrent VTE compared with oral anticoagulant therapy
with no increase in bleeding. Finally, the first trial specifically designed to evaluate the anticancer effect of long-term LMWH in cancer patients has been conducted and will no doubt stimulate future research.
Keywords: cancer, thrombosis.

Introduction
For many years it has been recognized that venous thromboembolism (VTE) is a common occurrence in patients with malignant disease. Compared with other groups of patients with VTE, the cancer population is unique because the pathogenesis of thrombosis differs, the frequency of VTE is greater, and the clinical management required is more complex. In 1997 at the ISTH meeting in Florence, cancer and thrombosis was discussed in a state-of-the-art symposium entitled, Venous thromboembolism and cancer, a two–way clinical association [1].
The topics considered included: the pathogenesis of thrombosis in cancer [1], the association of VTE and occult cancer [2], the prevention of thrombosis in cancer patients undergoing surgery [3] and in those receiving chemotherapy [4], and the treatment of acute VTE in cancer patients [5,6]. Since then, substantial progress has been made both in scientific research and clinical care as they relate to VTE in the cancer patient. In this chapter we provide an update on those topics discussed in the Florence symposium.

The pathogenesis of thrombosis in cancer
In 1865 Professor Armand Trousseau first reported on the association between cancer and thrombosis [7]. The pathogenic mechanisms of thrombosis in the cancer patient involve a complex interaction between the tumor cell, the patient, and the hemostatic system. Since the 1997 symposium, there have been much new basic research data not only on the pathogenesis of thrombosis in cancer but also on the important role the hemostatic system plays in tumor growth and metastases.
Tumors, through expression of the procoagulant molecule tissue factor (TF), are capable of activating blood coagulation; the systemic manifestation of which is clinical thromboembolic disease. The human TF molecule is a single-chain 263-amino acid, 47-kDa transmembrane glycoprotein [8]. It acts as both a surface receptor and cofactor for activated coagulation protease factor (F) VIIa. Upon binding of FVIIa to TF, blood coagulation
is initiated with downstream generation of activated coagulation serine proteases, FXa and FIIa (thrombin). TF activity is dependent upon its expression in conjunction with a suitable lipid surface that can be provided by a variety of tumor cells [9].
TF is seldom expressed in normal epithelial tissue, but is frequently expressed as a result of malignant transformation.
For example, TF is expressed in the ductal epithelium of pancreatic adenocarcinoma [10] and a number of other tumors.
TF expression not only correlates with the degree of histological dedifferentiation in a number of solid tumors, but it also appears to alter tumor cell phenotypic behavior. For instance, overexpression of TF using techniques of gene transfer results in both enhanced tumor cell invasion in vitro and primary tumor growth in vivo in experimental animal models [11], as well as enhancing metastatic potential in such in vivo models [12].
Interestingly, in experiments where the effects of TF gene expression on the constitutive expression of potential proand anti-angiogenic genes has been studied, overexpression of TF appears to be associated with a switch in angiogenic balance towards a more pro-angiogenic phenotype with upregulation of vascular endothelial growth factor (VEGF) and downregulation of the antiangiogenic thrombospondin (TSP) [13]. Other cellular biological manifestations of procoagulant expression are dependent upon signaling of TF upon binding to its extracellular ligand FVIIa. These include stimulation of the interaction of TF cytoplasmic tail by actin-binding protein 280
(ABP-280), with subsequent reorganization of intracellular actin filaments [14]. Similar TF–FVIIa interactions on the surface of SW979 pancreatic adenocarcinoma cells (a high constitutive expressor of TF) in vitro result in the upregulation of expression of the urokinase plasminogen activator receptor gene, which results in the production of the proteolytic enzyme plasmin, capable of extracellular proteolysis and matrix degradation; thus potentially promoting tumor cell invasion and endothelial invasion towards the tumor as part of the process of angiogenesis [15].
The downstream-activated coagulation proteases also appear to have direct biological effects on tumor cell behavior. FXa appears to be able to induce signaling events in vascular endothelial cells [16] potentially mediated through proteaseactivated receptor 2 (PAR-2), and in HeLa cells via a PAR-1- dependent mechanism resulting in expression of the angiogenesis- promoting genes Cyr-61 and connective tissue growth factor (CTGF) [17]. Thrombin, ultimately generated as a result of the conversion of prothrombin by the prothrombinase complex, interacts with PAR-1 expressed on a number of epithelialderived tumor cell lines. Indeed, PAR-1 appears to be preferentially expressed in highly metastatic cell lines [18]. The binding of thrombin to its receptor has a number of cellular effects in cancer including upregulation of TF expression and enhanced procoagulant activity in colon adenocarcinoma cell lines [19]; the enhanced expression of urokinase plasminogen activator in prostatic carcinoma [20] and enhanced invasive potential of breast carcinoma cells [21]. Thrombin also upregulates expression of the VEGF receptor on endothelial cells [22].
Clearly, local peritumor activation of coagulation may have important effects in the biology of cancer and interference with this activation by antithrombotic agents may result in alterations in tumor biology.

The association between VTE and occult cancer
Patientswho present with idiopathic deep vein thrombosis (DVT) have an increased risk of subsequently developing cancer compared with patients with secondary DVT and to patients with symptoms of DVT, but who are not found to have DVT [23]. The evidence for this association was discussed by Dr Prins at the 1997 symposium. Since that time, additional studies have supported the association. In a population-based study conducted in Sweden for patients hospitalized between 1965 and 1983, Baron et al. calculated the standardized incidence ratios (SIRs) for cancer in patients with VTE [24]. The SIR at 1 year following the diagnosis ofVTE was 4.4. In a study using a similar databaselinkage strategy on Danish hospital and cancer registries for the
years 1977–92, Sorensen et al. found the SIR to be 1.3 for VTE [25]. The SIRs were highest within the first 6 months and dropped close to 1.0 beyond 12 months of presentation with VTE. Finally, Schulman and Lindmarker used the Swedish cancer registry to determine the incidence of subsequent cancer diagnosis in patients from a trial on the duration of anticoagulant therapy [26]. The SIR for the development of cancer was approximately
4.0 in the first year after an idiopathic thromboembolic event. The cumulative probability of cancer over 6 years of follow-up in those subjects categorized as having idiopathic VTE was 17%, compared with 5% in patients with secondary VTE.
Based on the reported association between VTE and occult cancer, it has been suggested that patients presenting with idiopathic thrombosis should undergo extensive investigations for an underlying cancer. There has been much discussion concerning this issue because the potential benefit of screening for occult malignancy must be weighed against potential harms such as procedure-related morbidity, the psychological burden
of a false-positive test and the cost of screening procedures. A small randomized trial evaluating extensive screening vs. no screening in patients presenting with idiopathic VTE has been conducted [27]. The battery of tests used in the extensively screened group included: ultrasound and computed tomography of the abdomen and pelvis, a fecal occult blood test, gastroscopy, colonoscopy, sputum cytology, mammography, a pelvic
examination, a prostate examination, and tumor markers. Thirteen of the 99 patients in the extensively screened group had cancers detected initially compared with none of the 102 patients in the control group. However, 10 patients in the control group and one in the screened group developed cancer during the 2-year follow-up period. There was no statistically signifi- cant difference detected in cancer-related mortality in the two
groups, 3.9% vs. 2%, respectively.
Given such results, it is premature to recommend extensive screening in patients who present with idiopathic VTE.

Prevention of thrombosis in cancer
Surgical prophylaxis
Cancer patients undergoing surgery are at increased risk for postoperative thrombosis compared with non-cancer patients[28]. Clinical trials have demonstrated the efficacy of subcutaneous unfractionated heparin (UFH) in preventing DVT and pulmonary embolism (PE) in patients undergoing major surgery [29,30]. In these studies, many of the patients had cancer [29]. Mismetti et al. have conducted a meta-analysis of trials that compared a low molecular weight heparin (LMWH) to UFH in high-risk major surgery [31]. In the analysis of the eight trials
that included patients undergoing surgery for cancer, no differences in asymptomatic DVT, clinical PE, death or major bleeding were detected between LMWH and UFH. The results of these studies provide evidence that once-daily LMWH is as safe and effective as several injections of UFH per day for the prevention of postoperative DVT in cancer patients. The onceper- day injection is attractive because of the comfort for patients and convenience for medical staff. In recent years, a number of trials have shown that the incidence of venographic DVT can be reduced with extended out-of-hospital prophylaxis withLMWHin patients undergoing major joint-replacement surgery. A meta-analysis of these trials has suggested that the rate of clinical DVTafter hip replacement
is also reduced with the longer treatment [32]. Based on the results of these trials and the notion that the risk of VTE extends beyond the immediate postoperative period in patients undergoing cancer surgery, Bergqvist et al. studied extended prophylaxis in cancer surgery. In the Enoxacan II study, patients undergoing surgery for abdominal malignancy received one week of enoxaparin and were then randomized to enoxaparin or placebo for another 21 days [33]. Bilateral venography was performed at the end of treatment. There was a statistically
significant reduction in DVT from 12% with placebo to 4.8% with extended prophylaxis.
Extended prophylaxis in cancer surgery is potentially an important advance in the care of cancer patients undergoing surgery. However, further research is required to show that continuing anticoagulant therapy beyond hospitalization will also reduce the risk of clinically important VTE.
Prophylaxis in the medical cancer patient
There are far fewer data available on prophylaxis in ambulatory cancer patients. Since the discussion by Levine at the 1997 symposium [4], there has been further information on the risk of thrombosis in various cancer populations. Although it was recognized that tamoxifen was thrombogenic in women with breast cancer, the results of the Breast Cancer Prevention Trial conducted by the NSABP provided an opportunity to estimate
the thrombogenic effect of tamoxifen alone [34]. In this trial, healthy women at risk for developing breast cancer were randomized to either tamoxifen or placebo for 5 years. There was an increased risk of DVT in the tamoxifen group compared with placebo: 0.13% per year vs. 0.084% per year. The corresponding rates for PE were 0.069% and 0.023%, respectively. In this trial, the highest rates of thrombosis associated with the use of tamoxifen were observed in women >50 years of age.
Clinicians are often faced with the scenario of a patient with a past history of VTE who develops breast cancer and requires therapy with a hormonal agent. Based on the results of a recent trial, an aromatase inhibitor that has a much lower risk of thrombosis than tamoxifen can be used [35].
Another group of patients that has emerged to be at high risk for thrombosis are patients with brain tumors who are on extended follow-up. In a review by Marras et al. rates of symptomatic VTE as high as 18% per year were reported [36]. Weijl et al. reported that 8.4% of 179 patients with germ cell tumors who received platinum-based chemotherapy developed thromboembolism [37]. Finally, interest in the thrombogenicity of anticancer agents has been rekindled amongst medical oncologists because of the unexpectedly high rate of VTE in cancer patients receiving novel anticancer agents aimed at specific molecular targets in the cancer cell, e.g. anti-VEGF,
anti-EGFR, and thalidomide [38–43].
Unfortunately, there have been no new studies evaluating the primary prevention of VTE in ambulatory medical cancer patients since the trial of Levine et al., which evaluated lowdose warfarin [44]. There is clearly a need for more research in this area and several trials are currently studying primary prevention of VTE in medical cancer patients.

Central vein catheter thrombosis
Thrombosis associated with central vein catheters can beparticularly problematic in the cancer patient. At the time of the 1997 symposium, the results of two relatively small trials were available. Studies of warfarin (1 mg per day) and of LMWH (dalteparin 2500 units daily) had demonstrated significant reductions in catheter thrombosis [45,46]. Many of the thrombotic events were asymptomatic. Despite the results of these trials, routine prophylaxis is not practiced and there is substantial variation in the use of antithrombotic regimens.
Recently, the results of two randomized trials in patients with central vein catheters were reported: one compared dalteparin with placebo [47] and the other compared low-dose warfarin (1 mg) with placebo [48]. The rates of clinically relevant thrombosis were very low (4% and less) in both patient groups and no difference was detected between groups in either study.
The reason for the observed low rates of thrombosis in these trials are unclear. One possible explanation is that newer generations of catheters and improved catheter care have reduced the rates of associated thrombosis. Clearly, further research is required.

Treatment of VTE
Treatment of cancer patients with VTE is difficult because these patients have an increased risk of recurrent VTE and also of anticoagulant-induced bleeding compared with non-cancer patients. In addition, many cancer patients have a compromised quality of life and the occurrence of thrombosis has an additional negative impact on their quality of life.
Since the symposium in 1997, more data have confirmed that cancer patients with acute VTE are at increased risk of recurrent VTE and anticoagulant-induced bleeding compared with non-
cancer patients [49,50]. In addition, cancer patients who develop VTE have increased mortality compared with cancer patientswithout VTE [51].

Risk of recurrence and bleeding
Hutton et al. performed a retrospective analysis of the rates of recurrent thrombosis and bleeding for patients who received at least 3 months of oral anticoagulant therapy in two large randomized clinical trials that compared LMWH with UFH for the initial therapy of acute VTE [49]. The incidence of recurrent thrombosis in patients with cancer was 27.1 per 100 patient-years vs. 9.0 per 100 patient-years in those without cancer, P ¼ 0.003. The risk of bleeding was approximately six times higher in cancer patients (13.3 per 100 patient-years) than in patients without cancer (2.1 per 100 patient-years) (P¼0.002).
More recently, Prandoni et al. reported on the outcomes of anticoagulant treatment in a cohort of 842 patients who received initial UFH orLMWHfollowed by oral anticoagulants for acute VTE [50]. The 12-month cumulative incidence of recurrent thromboembolism in the 181 cancer patients was 20.7% vs. 6.8% in patients without cancer, for a hazard ratio of 3.2. The 12-month cumulative incidence of major bleeding was 12.4% in
patients with cancer compared with 4.9% in patients without cancer, for a hazard ratio of 2.2. Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy.

Initial treatment of VTE
Based on the results of numerous randomized controlled trials, LMWH has replaced UFH as the first-line treatment in the majority of patients with acute VTE. Large meta-analyses of these clinical trials have shown that weight-adjusted subcutaneous LMWH is safer and probably more effective than UFH administered by continuous intravenous infusion and monitored by the activated partial thromboplastin time [52–55] (Table 1).
Despite the observed efficacy and safety of LMWH in these trials, it should be noted that only about 20% of patients in these studies had cancer. Nonetheless, it would seem reasonable to generalize the results of these trials to cancer patients with acute VTE. In terms of optimizing treatment, the use of LMWH avoids intravenous administration of anticoagulant therapy and the need for laboratory monitoring, thereby improving the
quality of life of the patient.
Three clinical trials have demonstrated that patients with acute proximal DVT can be treated safely at home with subcutaneous LMWH without admission to hospital [56–58] (Table 2). In these trials, some of the patients were treated entirely at home and some were admitted to hospital for a short while and then discharged home early. In these trials, approximately 400 cancer patients received either LMWH or UFH. Therate of recurrent VTE at 3 months was approximately 10% in both treatment arms. Additional cohort studies have shown that about 80% of unselected outpatients with newly diagnosed DVT can be treated entirely at home, and up to 50% of these
patients had cancer [59,60]. Hence, use of LMWH at home in the cancer patient with acute VTE is recommended because of the substantial positive impact on quality of life. Clearly, some patients with acute VTE will require hospitalization because of symptoms and other complications related to their cancer. If patients are to be treated at home, they must be reliable and compliant, and have a good support system.
In contrast to DVT, relatively few trials have compared LMWH with UFH in patients with acute PE. Simmoneau
et al. compared the LMWH tinzaparin with intravenous (i.v.) UFH in hospitalized patients with PE, and no difference was detected in recurrent VTE and bleeding between treatment groups [61]. In the trial performed by the Columbus Investigators,

which found no difference in these outcomes between the LMWH reviparin and UFH, the majority of patients were treated at home, and 27% of all patients had PE [58]. In these two trials, 10% and 23% of patients had cancer, respectively.
Finally, in a prospective cohort study, Kovacs et al. treated 108 patients with PE as outpatients with the LMWHdalteparin; 22% had cancer [62]. The rate of recurrent thrombosis was 5.6%, and major bleeding occurred in 2.9% of the patients. Hence, based on this evidence and the large experience with LMWHs in DVT, it seems reasonable to manage acute PE patients who are hemodynamically stable by treating them with outpatient
LMWH. However, in patients with acute PE who are hemodynamically unstable, the use of i.v. UFH should be considered because such patients were excluded from the clinical trials that compared LMWH with UFH.
The use of IVC filters will reduce the short-term risk of PE, but is associated with an increased risk long-term of recurrent DVT, despite concurrent oral anticoagulant therapy. In a large randomized trial conducted in France, in which patients with proximal DVT were treated with anticoagulant therapy and randomized to receive an IVC filter or not, there was a statistically significant reduction in PE during the first 2 weeks of treatment [63]. By 1 year, however, there was a statistically significant increase in recurrent DVT in patients with a filter.
This was probably a result of thrombosis that developed around and proximal to the filter. Thus, the use of an IVC filter in a cancer patient presenting with acute VTE is not recommended.
Filters should be reserved for patients who are actively bleeding and cannot receive anticoagulant therapy, and for patients who develop multiple episodes of recurrent thromboembolism despite therapeutic LMWH.
There are recent reports on a new type of IVC filter (the Gunther Tulip retrievable vena caval filter), which could potentially be useful in a cancer patient who presents with acute VTE and is actively bleeding [64]. In such patients, a filter can be inserted and then removed within 7–10 days if the bleeding has stopped and is well-controlled. This would avoid the long-term potential complications of IVC filters. However, the results of
additional studies on cancer patients are required.

Long-term anticoagulant therapy
Long-term anticoagulant therapy using coumarin derivatives is required to prevent recurrent thrombosis. An oral anticoagulant such as warfarin is commenced on the first or second day of treatment and the aim is to achieve an international normalized ratio (INR) of between 2.0 and 3.0. Warfarin therapy is particularly complicated in the cancer patient for a number of reasons. It is often difficult to maintain the INR within the therapeutic range because cancer patients suffer from anorexia and vomiting. In addition, drug interactions (e.g. chemotherapy
and antibiotics) can influence the anticoagulant effect of vitamin K-dependent anticoagulants. Often it is necessary to frequently interrupt oral anticoagulant therapy because of thrombocytopenia and procedures such as thoracentesis and abdominal paracentesis. Finally, frequent blood sampling is required for the INR and venous access can often be difficult in the cancer patient.
There are certain features of long-term anticoagulant therapy with LMWH that are attractive in the cancer patient. LMWH does not require laboratory monitoring and can be administered once or twice daily, subcutaneously based on body weight.
There is the clinical impression that LMWH can be effective in warfarin resistance. Finally, based on preclinical data and metaanalyses, there is the potential for less bleeding. A number of trials have compared long-term oral anticoagulant therapy with long-term LMWH [65–70]. These trials were relatively small in size and had very few cancer patients. No definitive conclusions can be drawn from these trials concerning long-term treatment
with LMWH in the cancer patient.
Several recent randomized trials, however, have provided new information concerning the long-term treatment of cancer patients with VTE. In the trial reported by Meyer et al., cancer patients with acute VTE were randomized to 3 months of enoxaparin or warfarin at a targeted INR of 2.0–3.0 [71].
The primary outcome measure was a composite outcome consistingof major bleeding and recurrent VTE. In the 71 patients who received warfarin, the outcome event rate was 21% compared with 10.5% in the 67 patients who received LMWH, P ¼ 0.09. This observed difference was mainly as a result of the rates of major bleeding in the two groups; 16.9% in warfarin patients vs. 7.5% in theLMWHpatients. Recently, Levine et al. reported
the results of the CLOT trial in which cancer patients with acute VTE and/or PE were randomized to long-term dalteparin vs. long-term oral anticoagulant therapy [72]. Over the 6-month study period, 27 of 336 patients in the dalteparin group compared with 53 of 336 patients in the oral anticoagulant group experienced recurrent VTE. The probability of VTE at 6 months was reduced from 17.4% in the oral anticoagulant group to 8.8% in the dalteparin group, hazard ratio 0.48, P ¼ 0.0017. No statistically significant difference was detected in major bleeding between groups, 3.6% and 5.6%, respectively. Finally, in a subgroup analysis of a trial that compared long-term tinzaparin LMWH with oral anticoagulant therapy, both administered for 3 months, there was a statistically significant reduction in recurrent VTE in the subgroup of cancer patients [73]. Based on the results of these trials, long-term therapy with LMWH is an important advance in the management of cancer patients
with acute VTE. It substantially reduces the rate of recurrent VTE without an increase in bleeding, thereby improving the quality of life of the cancer patient.

Antineoplastic effect of anticoagulants
In the 1997 symposium the potential for anticoagulant therapy to reduce mortality in cancer patients as a result of an antitumor effect was briefly discussed [6]. Since then there have been a number of meta-analyses of trials of LMWH vs. UFH for the initial treatment of acute VTE that have all demonstrated a reduction in mortality in favor of LMWH [53,74–76]. The observed reduction was due to the effect in the subgroup of cancer patients. In these trials the difference was not explained by a reduction in fatal PE. Another trial, which compared a short course of LMWH with UFH for the prevention of postoperative thromboembolism in patients with breast and pelvic malignancies, showed a significantly improved 2-year survival in the patients who received the LMWH [77]. However none of these trials were designed with survival as the primary outcome.
Kakkar et al. recently reported the results of a trial that was specifically designed to test the effect of LMWH on survival in patients with cancer [78]. In the famous trial 385 patients with advanced solid tumors were randomized to the LMWH dalteparin or placebo for up to 1 year. No difference was detected in
survival at 1 year. However, in a subgroup analysis of goodprognosis patients, there was a statistically significant improvement in survival in favor of the LMWH. These results are> encouraging, and further trials evaluating the antineoplastic effect of LMWH are warranted.

Conclusion
Since the 1997 symposium, there has been renewed enthusiasm in the area of thrombosis and cancer that has lead to much new research. LMWH administered once daily is effective, safe and convenient in cancer patients undergoing surgery. However, there are still some forms of cancer surgery in which clinicians are reluctant to use pharmacologic prophylaxis because of the concern for bleeding, and further research is required. There is
clearly a need for more information on long-term prophylaxis in medical cancer patients who receive radiation and chemotherapy, and in patients with central vein catheters. There have been many advances in the management of cancer patients with acuteVTE. SubcutaneousLMWHhas replaced i.v. UFH for the initial
treatment of VTE and in many instances, patients can be treated at home. The use of long-term LMWH instead of oral anticoagulants can substantially reduce the risk of recurrent VTE in this high-risk group of patients without causing increased bleeding. A number of novel agents that target specific coagulation proteases are currently undergoing investigation for both the prevention and treatment of VTE [79]. Such agents couldpotentially improve thrombosis management in cancer patients.
Finally, the first trial specifically designed to evaluate the anticancer effect of LMWH has been conducted and hopefully will be an impetus for further trials.

References
  1. Agnelli G. Venous thromboembolism and cancer: a two–way clinical association. Thromb Haemost 1997; 78 (Suppl.): 117–20.
  2. Prins MH, Hettiarachchi RJ, Lensing AW, Hirsh J. Newly diagnosed malignancy in patients with venous thromboembolism. Search or wait and see? Thromb Haemost 1997; 78 (Suppl.): 121–5.
  3. Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost 1997; 78 (Suppl.): 126–32.
  4. Levine MN. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost 1997; 78 (Suppl.): 133–6.
  5. Bona RD, Hickey AD, Wallace DM. Efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 1997; 78 (Suppl.): 137–40.
  6. Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost 1997; 78 (Suppl.): 141–4.
  7. Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l’Hotel- Dieu de Paris 3. Paris, France: JB Balliere et Fils, 1865: 654–712.
  8. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934–8.
  9. Van de Water L, Tracy PB, Aronson D, Mann KG, Dvorak HF. Tumour cell generation of thrombin via functional prothrombinase assembly. Cancer Res 1985; 45: 5521–5.
  10. Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RCN. Tissue factor expression correlated with histological grade in human pancreatic carcinoma. Br J Surg 1995; 82: 1101–4.
  11. Kakkar AK, Chinswangwatanakul V, Lemoine NR, Tebbutt S,Williamson RCN. Tissue factor expression enhances tumour cell invasion and growth of experimental pancreatic adenocarcinoma. Br J Surg 1999; 86: 890–4.
  12. Mueller BM, Reisfeld RA, Edgington TS, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 1992; 89: 11832–6.
  13. Zhang Y, Deng Y, Luther T, Muller M, Ziegler R,Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320–7.
  14. Ott I, Fischer EG, Miyagi Y, Mueller BM, RufW. A role for tissue factor in cell adhesion and migration mediated by interaction with actinbinding protein 280. J Cell Biol 1998; 140: 1241–53.
  15. Taniguchi T, Kakkar AK, Tuddenham EG, Williamson RC, Lemoine NR. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Cancer Res 1998; 58: 4461–7.
  16. Bono F, Schaeffer P, Herault JP, Michaux C, Nestor AL, Guillemot JC. Factor Xa activates endothelial cells by a receptor cascade between EPR-1 and PAR-2. Arterioscler Thromb Vasc Biol 2000; 20: 107–12.
  17. Riewald M, Kravechenko VV, Petrovan RJ, O’Brien PJ, Brass LF, Ulevitch RJ, Ruf W. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood 2001; 97: 3109–16.
  18. Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginsburg Y, Reich R, Vlodavsky I, Bar-Shavit R. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 1998; 4: 909–14.
  19. Tanimoto K, Parmley TH, Parham GB, O’Brien TJ. Heparin, a cell surface serine protease identified in hepatoma cells, is overexpressed in ovarian cancer. Cancer Res 1997; 57: 2884–7.
  20. Yoshida E, Verrusio EN, Mihara H, Oh D, Kwaan HC. Enhancement of the expression of urokinase-type plasminogen activator from PC-3 human prostate cancer cells by thrombin. Cancer Res 1994; 54: 3300–4.
  21. Even-Ram S, Maoz M, Pokroy E, Reich R, Katz BZ, Gutwein P, Altevogt P, Bar-Shavit R. Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha vbeta 5 integrin. J Biol Chem 2001; 276: 10952–62.
  22. Zucker S, Conner C, DiMassmo BI, Ende H, Drews M, Seiki M, Bahou WF. Thrombin induces the activation of progelatinase A in vascular endothelial cells. J Biol Chem 1995; 270: 23730–8.
  23. Hettiarachchi RJ, Lok J, Prins MH, Buller HR, Prandoni P. Undiagnosed malignancy in patients with deep vein thrombosis: incidence, risk indicators, and diagnosis. Cancer 1998; 83: 180–5.
  24. Baron JA, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer. Lancet 1998; 351: 1077–80.
  25. Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338: 1169–73.
  26. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anticoagulation Trial. N Engl J Med 2000; 342: 1953–8.From Trousseau to targeted therapy 1461
  27. Piccioli A, Lensing AWA, Prins MH. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. In: Abstracts of the XVIII Congress of the
    International Society on Thrombosis and Haemostasis, July 2001, Paris, France (Abstract 900). Thromb Haemost (Serial on CD Rom).
  28. Kakkar VV, Howe CT, Nicolaides AN, Renney JT, Clarke MB. Deep vein thrombosis of the leg. Is there a ‘high risk’ group? Am J Surg 1970; 120: 527–30.
  29. Kakkar AK,Williamson RC. Prevention of venous thromboembolism in cancer patients. Semin Thromb Hemost 1999; 25: 239–43. 30 Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 1975; ii (7924): 45–51.
  30. Mismetti P, Laporte S, Darmon JY, Buchmuller A, Decousus H. Metaanalysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 2001; 88: 913–30.
  31. Hull R, Pineo G, Stein PD. Extended out-of-hospital low molecular weight heparin prophylaxis against deep vein thrombosis in patients after elective hip arthroplasty. Ann Intern Med 2001; 135: 858–69.
  32. Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne- Amrani A, Dietrich-Neto F; ENOXACAN II Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975–80.
  33. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371–88.
  34. The ATAC, Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131–9.
  35. Marras LC, Geerts WH, Perry JR. The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidencebased review. Cancer 2000; 89: 640–6.
  36. Weijl NI, Rutten MF, Zwinderman AH, Keizer HJ, Nooy MA, Rosendaal FR, Cleton FJ, Osanto S. Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncol 2000; 18: 2169–78.
  37. Marx GM, Steer CB, Harper P, Pavlakis N, Rixe O, Khayat D. Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock! J Clin Oncol 2002; 20: 1446–8.
  38. Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, Morris C, Toor A, Siegel E, Fink L, Tricot G. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98: 1614–5.
  39. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 2001; 344: 1951–2.
  40. Urbauer E, Kaufmann H, Nosslinger T, Raderer M, Drach J. Thromboembolic events during treatment with thalidomide. Blood 2002; 99: 4247–8.
  41. Kuenen BC, Rosen L, Smit EF. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine and SU5416 in patients with solid tumors. J Clin Oncol 2002; 20: 1657–67.
  42. Cropp GF, Hannah AL. SU5416, a molecularly targeted novel antiangiogenic drug: clinical pharmacokinetics and safety review. Clin Cancer Res 2002; 6: 95.
  43. Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, Samosh M, Bramwell V, Pritchard KI, Stewart D. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886–9.
  44. Bern MM, Lokich JJ, Wallach SR, Bothe A Jr, Benotti PN, Arkin CF, Greco FA, Huberman M, Moore C. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990; 112: 423–8.
  45. Monreal M, Alastrue A, Rull M, Mira X, Muxart J, Rosell R, Abad A. Upper extremity deep venous thrombosis in cancer patients with venous access devices – prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75: 251–3.
  46. Reichart P, Kretzschmar A, Biakhov M, Irwin D. A Phase III doubleblind, placebo-controlled study evaluating the efficacy and safety of daily low-molecular-weight heparins (dalteparin sodium, fragmin) in preventing catheter-related complications in cancer patients with central venous catheters. Clin Oncol 2002; 21: 1474 [Abstract].
  47. Couban S, Goodyear M, Burnell M, Dolan S. A randomized doubleblind placebo-controlled study of low dose warfarin for the prevention of symptomatic central venous catheter-associated thrombosis in patients with cancer. Blood 2002; 100: 2769 [Abstract].
  48. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Buller HR. Incidence of recurrent thromboembolic and bleeding complicationsamong patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078–83.
  49. Prandoni P, Lensing AWA, Piccioli A, Bernardi E. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8.
  50. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–50.
  51. Hettiarachchi RJ, Prins MH, Lensing AW, Buller HR. Low molecularweight heparin versus unfractionated heparin in the initial treatment of venous thromboembolism. Curr Opin Pulm Med 1998; 4: 220–5.
  52. Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Lowmolecular- weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800–9.
  53. Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. Ameta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160: 181–8.
  54. van Den Belt AG, Prins MH, Lensing AW, Castro AA, Clark OA, Atallah AN. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.
    Cochrane Database Syst Rev 2: CD001100.
  55. Levine M, Gent M, Hirsh J, Leclerc J, Anderson D,Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecularweight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996, 2000; 334: 677–81.
  56. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous lowmolecular- weight heparin administered at home. The Tasman Study
    Group. N Engl J Med 1996; 334: 682–7.
  57. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657–62.
  58. Harrison L, McGinnis J, Crowther M, Ginsberg J, Hirsh J. Assessment of outpatient treatment of deep-vein thrombosis with low-molecularweight heparin. Arch Intern Med 1998; 158: 2001–3.
  59. Wells PS, Kovacs MJ, Bormanis J, Forgie MA, Goudie D, Morrow B, Kovacs J. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection.Arch Intern Med 1998; 158: 1809–12.
  60. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsch JL, Ferrari E, Bosson JL, Mottier D, Beau B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group:1462 M. N. Levine et al Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997; 337: 663–9.
  61. Kovacs MJ, Anderson D, Morrow B, Gray L, Touchie D, Wells PS. Outpatient treatment of pulmonary embolism with dalteparin. Thromb Haemost 2000; 83: 209–11.
  62. Decousus H, Leizorovicz A, Parent F, PageY, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, Huet Y, Simonneau G. A clinical trial of vena caval filters in the prevention of pulmonary embolism in
    patients with proximal deep-vein thrombosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl JMed 1998; 338: 409–15.
  63. Millward SF, Oliva VL, Bell SD, Valenti DA, Rasuli P, Asch M, Hadziomerovic A, Kachura JR. Gunther tulip retrievable venacava filter: results from the registry of the Canadian Interventional Radiology Association. J Vasc Interv Radiol 2001; 12: 1053–1.
  64. Pini M, Aiello S, Manotti C, Pattacini C, Quintavalla R, Poli T, Tagliaferri A, Dettori AG. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191–7.
  65. Das SK, Cohen AT, Edmondson RA, Melissari E, Kakkar VV. Lowmolecular- weight heparin versus warfarin for prevention of recurrentvenous thromboembolism: a randomized trial. World J Surg 1996; 20: 521–6.
  66. Lopaciuk S, Bielska-Falda H, Noszczyk W, Bielawiec M, Witkiewicz W, Filipecki S, Michalak J, Ciesielski L, Mackiewicz Z, Czestochowska E, Zawilska K, Cencora A. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: 26–31.
  67. Gonzalez-Fajardo JA, Arreba E, Castrodeza J, Perez JL, Fernandez L, Agundez I, Mateo AM, Carrera S, Gutierrez V, Vaquero C. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283–92.
  68. Veiga F, Escriba A, Maluenda MP, Lopez RM, Margalet I, Lezana A, Gallego J, Ribera JM. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84: 559–64.
  69. Hull R, Pineo G, Mah A. Long-term low molecular weight heparintreatment versus oral anticoagulant therapy for proximal deep vein thrombosis. Blood 2000; 96: 449 [Abstract].
  70. Meyer G, Marjanovic Z, Valcke J, Lorcerie B. comparison of lowmolecular- weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med 2002; 162: 1729–35.
  71. Levine MN, Lee AY, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles F, Jwlian J, Haley S, Kovacs M, Gent M. A randomized trial of long term dalteparin low molecular weight heparin versus oral anticoagulant therapy in cancer patients with venous thromboembolism. Blood 2002; 100: [Abstract 298].
  72. Hull RD, Pineo GF, Mah AF, Brant RF. A randomized trial evaluating long-term lowmolecular weight heparin therapy for three months versus intravenous heparin followed by warfarin sodium. Blood 2002; 100: 556
    [Abstract].
  73. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995; 155: 601–7.
  74. Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecularweight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996; 100: 269–77.
  75. Hettiarachchi RJ, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Buller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost 1999; 82:947–52.
  76. von Tempelhoff GF, Harenberg J, Niemann F, Hommel G, KirkpatrickCJ, Heilmann L. Effect of low molecular weight heparin (Certoparin)versus unfractionated heparin on cancer survival following breast andpelvic cancer surgery: a prospective randomized double-blind trial.Int J Oncol 2000; 16: 815–24.
  77. Kakkar AK, Kadziola Z, Williamson RCN, Levine MN, Low V, Lemoine NR. Low molecular weight heparin therapy and survival in advanced cancer. Blood 2002; 100: 557[Abstract].
  78. Hirsh J,Weitz JI. New antithrombotic agents. Lancet 1999; 353 (9162):1431–6. From Trousseau to targeted therapy 1463
Inicio | Carné de Salud | Libreta de Chofer | Laboratorio |Odontología | Hemostasis y Trombosis | Contáctos