**5. VTE in haematological malignancies**

Although the association between malignancy and thrombosis has been well recognized, less is known about the risk of thrombosis in patients with acute leukemia and the impact of VTE on survival. Certainly there is abundant biochemical evidence for thrombin generation and disseminated intravascular coagulation in patients with leukemia (184). The few singlecenter reports of the incidence of venous thrombosis in patients with leukaemia have focused primarily on children with acute lymphoblastic leukaemia. These studies have suggested the cumulative incidence varies between 2% and 10.6% (185-186).

Patients with haematologic malignancies are at high risk of thrombotic or haemorrhagic complications. The incidence of VTE events varies considerably and is influenced by many factors, including the type of disease, chemotherapy used, and whether a central venous device is inserted. As in solid tumors, a number of clinical risk factors have been identified and contribute to the increasing thrombotic rate in haematologic malignancies. Biologic Pathophysiology and Clinical Aspects of 90 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

• Gender • Race

• Previous thrombotic episode • Obesity: BMI ≥ 35 kg/m2

• Initial cancer stage

agents

• Surgery

• Radiation

• D-Dimer

Although the association between malignancy and thrombosis has been well recognized, less is known about the risk of thrombosis in patients with acute leukemia and the impact of VTE on survival. Certainly there is abundant biochemical evidence for thrombin generation and disseminated intravascular coagulation in patients with leukemia (184). The few singlecenter reports of the incidence of venous thrombosis in patients with leukaemia have focused primarily on children with acute lymphoblastic leukaemia. These studies have

Patients with haematologic malignancies are at high risk of thrombotic or haemorrhagic complications. The incidence of VTE events varies considerably and is influenced by many factors, including the type of disease, chemotherapy used, and whether a central venous device is inserted. As in solid tumors, a number of clinical risk factors have been identified and contribute to the increasing thrombotic rate in haematologic malignancies. Biologic

Biomarkers • Leukocyte count ≥ 11x109 /L

• Hormonal therapy

• Clotting factor VIII

• Tissue factor (TF) • Soluble P-selectin • C-Reactive protein

• Rate of metastatic spread

• Chronic co-morbid Medical Conditions

• Anti-angiogenic and immunomodulatory

• Biological aggressiveness of cancer

• Use of Hemopoetic growth factors

• Indwelling central venous catheters

• Platelet count ≥ 350 x109 /L

• The prothrombin fragment

**Factor** 

Patient Related Factors • Age - > 60 years

Disease Related Factors • Tumors type

Treatment Related Factors • Chemotherapy

Table 1. Summary of the Risk Factors for VTE in Cancer Patients

suggested the cumulative incidence varies between 2% and 10.6% (185-186).

**5. VTE in haematological malignancies** 

**CLINICAL RISK FACTORS** 

 **BIOMARKERS** 

properties of the tumor cells can influence the hypercoagulable state of patients with these malignancies by several mechanisms. Of interest, oncogenes responsible for haematological neoplastic transformation in leukemia also may be involved in haemostatic activation.

#### • **VTE in Central Nervous System Lymphoma**

Patients with brain tumors are at particularly high risk for VTE, and many studies found that the hazard for deep vein thrombosis in patients with malignant glioma may reach 28% (187-188) This high risk is maintained throughout the course of an active disease and during treatment, and not just in the immediate postoperative period (188). Risk factors for VTE in patients with glioma include the presence of paraparesis, a histologic diagnosis of glioblastoma multiforme, age ≥ 60 years, large tumor size, the use of chemotherapy, and length of surgery of > 4 hours. Because of the high incidence of VTE, patients who are treated for brain tumors are usually considered for long term prophylactic anticoagulation as deemed appropriate for a particular patient (189-190).

#### • **VTE in Non-Hodgkin Lymphoma**

The incidence of clinical VTE in patients with malignant lymphoma reportedly ranges between 6.6% and 13.3% (187, 190-194) In one study, 50% of patients had a bulky tumor compressing a vein, 25% of patients had a central catheter at the thrombosed vein, and, in the other patients, thrombosis was attributed to paraneoplasia or to chemotherapy (187)

Conlon SJ et al (194) reported the results of retrospective analysis of patients with a total of 18 653 cases on the NCI Working Formulation: there were 5496 low grade NHL, 12 251 aggressive NHL and 906 high-grade lymphoma cases. The cumulative incidence (CI) of VTE 24 months from diagnosis was 4.0%. The CI of VTE at 24 months were significantly different for the distinct lymphoma groups (p< 0.001, Chi-square and comparisons showed this difference to be significant only between the low grade and other histologies. Of 742 cases that had VTE, 454 died within 2 years (61%). For those without VTE, 7274 of 17911 (41%) died within 2 years. This difference was statistically significant (p < 0.001, Chi-square).

#### • **VTE In Patient with Acute Leukemia**

A population- based cohort study (1993-1999) to determine the incidence and risk factors associated with development of VTE among Californians diagnosed with acute leukemia (1993-1999) was reported in Blood 2009, by Ku GH et al (195). Among 5394 cases of AML, the 2-year cumulative incidence of VTE was 281 (5.2%) and 64% of VTE events occurred within 3 months of AML diagnosis. The authors reported that, in AML patients, female sex, older age, number of co-morbid conditions, presence of CVC were significant predictors for development of VTE within one year following diagnosis of acute leukemia but the event of VTE was not associated with poor survival in AML patients in the studied group. Among 2482 case of ALL, the 2-year incidence of VTE was 4.5% and risk factors in this group were presence of CVC, older age and number of chronic co-morbidities. In this study, development of VTE in ALL patients was associated with a 40% increase of dying within one year.

In the abstract #6595 published in JCO 2011 by Luong NV et al from MD Anderson Cancer Center, USA (196) of a retrospective chart review to determine the prevalence of VTE prior

Venous Thromboembolism in Cancer Patients 93

after a diagnosis of MGUS and MM was 3.3 and 9.2 respectively with excess risk of DVT in the first year of diagnosis. Compared to the background population, patients with multiple myeloma have a 9-fold increased risk of developing DVT especially during the first year of diagnosis while the risk for DVT in MGUS was stable at 3-fold increased risk over time with

Yang X et al (204), in 2009, reported a total of 7764 MDS patient who were prescribed Lenalidomide during the first two years of its commercial use in the USA. VTE was reported in 41 patients (rate of 0.53%) denoting a computed signal that did not exceed the statistical threshold for identification of a significant disproportional signal for VTE in MDS on Lenalidomide without erythropoietin. However, the authors found that a disproportional signal of VTE where erythropoietin was concurrently administered with

Life expectancy of patients with myeloproliferative neoplasms (MPNs) and particularly that of subjects with polycythemia vera (PV) and essential thrombocythemia (ET) has significantly increased over the last three decades, largely due to the use of cytoreductive treatments. Currently, PRV and ET are considered relatively benign diseases in which the main objective of treatment strategy is the prevention of thrombotic events. Widespread use of routine haematologic screening and novel diagnostic tools greatly facilitate disease recognition and treatment. This helps to prevent a significant number of early vascular events that still constitute the first disease manifestation in approximately one-third of patients (205). We can also expect that new therapeutic options and appropriate use of aspirin will result in a further reduction of morbidity and mortality. One of the unmet needs of PRV and ET is validated methods for vascular risk stratification. The evaluation of the thrombotic risk in the individual patients, as reported by Barbui et al. in their paper (206). The pathogenesis of thrombosis in myeloproliferative neoplasms has been extensively investigated by focusing in particular on the possible contribution of disease related haemostatic abnormalities. However, the pathogenesis of thrombosis appears to be multifactorial. Red blood cell, platelet, and leukocyte abnormalities, both qualitative and quantitative, are likely to play a key-role in myeloproliferative neoplasm thrombophilia. High shear stress of the vessel wall, due to blood hyperviscosity, accounts for chronic

Platelets and endothelial cells play a pivotal role in regulating blood flow, both cells might contribute to determine a prothrombotic microenvironment in myeloproliferative neoplasm patients by producing more soluble selectins and less nitric oxide, likely as a consequence of

According to the data of Barbui et al. (208) it is intriguing to consider the possibility that pentraxin 3 response to inflammation in subjects with high JAK2 burden might contribute to lower or enhance the thrombotic risk. More generally the association between JAK2 mutation, inflammation and thrombotic risk deserves scientific attention also for other

no statistical association between DVT in MGUS and risk for progression into MM.

• **VTE in Myelodysplastic Syndrome** 

• **VTE in Myeloproliferative Neoplasms** 

endothelial dysfunction and platelet and leukocyte activation.

Lenalidomide.

inflammation (207).

speculative and practical purposes.

to treatment and recurrence of VTE. Records of 299 ALL patients and 996 AML patients were included (Nov 1991-May 2005). The authors concluded that acute leukemia patients have a high prevalence of VTE but the occurrence of VTE prior to initiation of chemotherapy was not associated with poor prognosis similar finding to that reported by Ku GH et al.

Blast cells with their procoagulant properties, central venous catheters, chemotherapeutic agents (as discussed earlier in this chapter) concomitant infections, patient-and supportive treatment related factors are major determinants of haemostatic mechanism activation in acute leukemia. The clinical manifestations range from VTE to diffuse life-threatening hemorrhage. Anti-coagulant therapy in this clinical setting is fraud with major difficulties as the patients are at very high risk of haemorrhage because of thrombocytopenia. To date, no guidelines are available for prophylaxis or treatment of VTE in this group of patients (197)
