**2.5.1**

Pathophysiology and Clinical Aspects of 76 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

a. **Age:** Older age has been shown to be associated with VTE in hospitalized cancer patients, but not in ambulatory patients (35-37). The rate of VTE in patients older than 60 years of age undergoing surgery for various solid tumors was significantly higher

b. **Gender:** Among cancer patients, most studies have identified male gender as a significant predictor of VTE. (19-20) However, A recent pooled retrospective study of VTE rates in a large cohort of hospitalized cancer patients reported a higher rate in

c. **Race:** In the general population, the incidence of VTE varies by race. In the USA, it is

d. **Previous thrombotic episode:** Cancer patients with a past history of VTE have a 6–7 fold increased risk of developing VTE compared to those with no history of VTE (38). e. **Obesity** has been confirmed to be an important risk factor in cancer-associated thrombosis. Body mass index ≥35 kg/m2 was identified as one of five variables in a risk

f. **Chronic co-morbid Medical Conditions:** The presence of chronic medical co-morbid conditions such as chronic renal disease, chronic liver disease, hypertension and chronic heart failure has a marked effect on the incidence of cancer-associated thrombosis and survival. The presence of three or more chronic medical conditions was the strongest risk factor for development of VTE among the patients with gliomas and ovarian cancer, and was the second strongest risk factor among patients with breast or colon

a. **Tumor type:** certain tumors are strongly associated with VTE. In the retrospective cohort study of hospitalized cancer patients. Khorana et al (38), reported that sites of cancer with the highest proportion of patients with VTE were pancreas, brain and endometrial or cervical were 12.1%, 9.5% and 9%, respectively (California Cancer Registry). The incidence of VTE in pancreatic cancer patients is at least 10-fold higher than the rate in patients with prostate cancer. Histological subtype also predicts the increased risk of VTE in some types of malignancy. The incidence of VTE in patients with non-small cell lung cancer was 9.9% in patients with adenocarcinoma subtype versus 7.7% in patients with squamous cell carcinoma (HR 1.9, CI 1.7–2.1) (27, 26). Although mucin production was once proposed as the common feature and the thrombogenic mechanism amongst these mucin-producing tumors, the exact

pathogenesis of the prothrombotic state of mucin is still not fully understood. b. **Initial cancer stage:** Patients diagnosed with local-stage cancer, in general, have a very low incidence of VTE, whereas the incidence is much higher in patients diagnosed with

c. **Biological aggressiveness of cancer:** The observed differences in the incidence of VTE between different cancer types correlate with the biological behavior of the cancer. A very strong correlation was found between the 1- year fatality rate and the 1-year cumulative incidence of VTE (41). In addition, presence of metastatic disease at the time

than that in younger patients by multivariate analysis (OR 2.6) (36-38).

highest among blacks and lowest among Asian-Pacific Islanders (40).

prediction model proposed by Khorana et al with an OR of 2.1 (38)

**2.3 Patient-related factors and risk of VTE** 

females (OR 1.1, p < 0.0001) (39)

**2.4 Cancer-related factors to incidence of VTE** 

metastatic disease at time of diagnosis (24-27).

cancer (39-40).

Chemotherapy is one of the most important treatment-related factors in the aetiology of cancer-associated VTE as cancer alone is associated with a four-fold risk of thrombosis, while chemotherapy increases the risk by six-fold (45-47)

Several different mechanisms have been reported to explain the prothrombotic states induced by chemotherapy including (a) damage to the vascular endothelium (48-49), (b) reduction of endogenous, physiological, anticoagulant factors (56-59), (c) increase of levels of procoagulants (54-57), (d) induction of tumor and endothelial level apoptosis and cytokine release that, in turn, lead to increased expression and hence activity of TF (56-57), (e) induction of platelet activation (58) and (f) direct induction of expression of monocytemacrophages TF (59).

The following chemotherapeutic agents are associated with high risk for VTE:

## • **Cisplatin based regimens**

Weiji et al (60), in a retrospective review of VTE in germ cell cancer patients treated with cisplatin and bleomycin-based chemotherapy reported an estimated risk of thrombosis of 8.4%. In a prospective study of VTE in non-small cell lung cancer patients treated with cisplatin and gemcitabine, Numico et al (61) reported VTE incidence of 17.6%.

The mechanisms by which cisplatin induces thrombosis is not well known but in vitro studies suggest increase in the level of TF (48), platelet activation (50) and increased levels of von Willebrand factor suggesting endothelial injury (58). The latter perhaps explain the cisplatin induced arterial thrombosis. Moore et al (62) conducted a large retrospective analysis to determine the incidence of venous and arterial thromboembolic events in patients treated with cisplatin-based chemotherapy and confirmed the unacceptable incidence of those events and recommend randomized studies to examine the question of prophylactic anticoagulation in patients with cancer treated with chemotherapy.

#### • **L-Asparaginase**

L-Asparaginase (ASNase) has been a mainstay in the treatment of paediatric patients with acute lymphoblastic leukemia since the 1960's and there are several reports of ASNase containing regimen used in the treatment of paediatric ALL achieving a higher survival rate than non-ASNase treatment regimens used for ALL in adults and adolescents (63-65).

Venous Thromboembolism in Cancer Patients 79

For intracranial thrombohemorrhagic complications, the use of AT concentrates and/or cryoprecipitates to replace both AT and fibrinogen, respectively, is a reasonable approach. In case of unavailability of AT, fresh frozen plasma (FFP) at a dose of 20 ml/kg can raise the AT level by approximately 20%. However, FFP may also replenish asparagine and, thereby, counteract the anti-leukemic effect of ASNase. There is no clear indication from the literature about whether further administration of ASNase should be stopped in adults after a thrombotic event while on therapy. In children, ASNase is continued under cover of low-molecular-weight heparin. Patients with thrombotic events after ASNase have been successfully re-challenged with ASNase without recurrence of thrombosis (75). In the Dana-Farber Cancer Institute review (63) confirms that, after venous thromboembolic events, asparaginase can be restarted after demonstrating clot stabilization or improvement by imaging with close monitoring of anticoagulation. Therefore, a history of venous thromboernbolic events does not seem to adversely impact

The expert panel, Wendy Stock et al (81) in their excellent article published in Leukemia and Lymphoma, 2011 detailed the management of ASNase associated VTE and put down the

1. In adults, activated partial thromboplastin time (APTT), international normalized ratio (INR), AT, and fibrinogen levels should be measured prior to ASNase therapy for

2. Between doses of native ASNase and for 1 week after pegASNase therapy, these tests,

3. AT concentrates and cryoprecipitate infusions should be considered for treatment of thrombohemorrhagic events due to AT and fibrinogen deficiency, respectively. 4. For non-urgent thrombohemorrhagic episodes, fresh frozen plasma should be avoided since it contains asparagine and may counteract the anti-leukemic effect of ASNase. However, careful follow up is advised for possible evolution of the

5. For a clinically significant DVT, the patient should be anticoagulated with or without AT supplementation, and whether or not it is associated with a central venous line. 6. Early diagnostic imaging, CT scan and or MRI should be performed in patients with a suspected CNS event related to ASNase therapy and urgent consultation of the

7. For CNS thrombosis, the patient should be anticoagulated with or without AT

8. Anti-epileptic medications in patients with thrombohemorrhagic complications should be administered prophylactically or therapeutically as appropriate at the discretion of

9. ASNase is discontinued for all clinically significant bleeding or thrombosis and whether it is resumed depends on the nature and resolution of the thrombohemorrhagic event

This synthetic pyrimidine analogue is an important chemotherapeutic agent for treatment of various solid tumors. The incidence of VTE in patients treated for colorectal cancer with this

as well as factor Xa, should be serially monitored as clinically indicated.

neurologist/ neurosurgeon should be secured and documented.

and outcome of discussion of the case at the tumor board.

recommendation which is being adapted/summarized hereunder:

thrombohemorrhagic event into a major one.

supplementation after careful evaluation.

prognosis.

baseline assessment.

the neurologist.

**5-Fluorouracil** 

L-Asparaginase converts L-Asparagine to L-aspartic acid and, thereby, reduces levels of L-Asparagine, an essential amino acid for protein synthesis and as a result, leukemic cell growth is inhibited. However, the production of multiple plasma proteins by the liver including haemostatic factors, is also reduced and hence causing marked disruption of the haemostatic mechanism: prolongation of PT and aPTT, reduced fibrinogen level, reduced levels of protein C and protein S, Antithrombin III (AT) , plasminogen, factor IX and factor XII. On the other hand, ASNase causes increased procoagulant factors V, VIII (54-56). In addition, to the profound effects of the drug on the pro- and anticoagulant molecules, ASNase has also been shown to increase levels of immunomodulin a marker of vascular injury (66).

The simultaneous effects of ASNase on both procoagulant and thrombolytic proteins increase the risk of both bleeding and thrombosis, the latter being the main challenge.

The incidence of ASNase – associated VTE complications is age-dependent, 3-5% in children (67, 31) whereas the incidence reported from Dana-Farber Cancer Institute (1991-2008) in adult patients (≥ 30 years) was 34% and 42% (68). Less intensive ASNase regimen in adult patients have reported lower rates of thrombotic complications (69). Limited reports and data on a small number of patients treated with pegASNase –related DVT may be less frequent than those treated with after E. Coli ASNase (70-74). In UKALL 2003, Children with DVT were routinely retreated with pegASNase and concurrent heparin prophylaxis without recurrence of thrombosis (75). The confounding factors for VTE during ASNase therapy are presence of indwelling catheter, oral contraception, prednisolone and inherited thrombophilia (76).

The majority of clinically important thrombotic events were those related to venous catheters and those in the central nervous system. The majority of catheter-associated thrombosis (CAT) are asymptomatic and the majority, in both children and adults, occur during induction (68).

In the randomized trial of native ASNase versus pegASNase (74), the incidence of cerebral venous sinus thrombosis (CVST) of 2-3% in children was reported. In children ≥ 10 years, initial WBC > 50x109 /L at diagnosis may predict higher risk for CVST (77). The GIMEMA study on adult ALL patients protocol, including E. Coli ASNase in the induction phase, CNS thrombotic events was 3% (77).

### **Prevention and Management of ASNase induced thrombosis**

Primary Prevention: In children and adolescents prophylaxis is rarely undertaken and there has been few reports that the use of AT concentrate may decrease the incidence of thrombosis (78-79)

In a historically controlled study of adult patients, Mitchell et al (78) reported that the incidence of VTE was lower in a cohort of patients who received prophylactic AT concentrate but the study did not establish efficacy. A retrospective comparison of cohort of patients at two centers in Canada who had prophylaxis against CNS thrombosis with fresh frozen plasma and cryoprecipitate did not develop CVST (80).

Most paediatric oncology centers do not perform the coagulation screening tests or perform AT levels routinely. If prophylaxis is deemed appropriate for a particular patient, it is best applied during induction phase of therapy when the majority of VTE events take place.

Pathophysiology and Clinical Aspects of 78 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

L-Asparaginase converts L-Asparagine to L-aspartic acid and, thereby, reduces levels of L-Asparagine, an essential amino acid for protein synthesis and as a result, leukemic cell growth is inhibited. However, the production of multiple plasma proteins by the liver including haemostatic factors, is also reduced and hence causing marked disruption of the haemostatic mechanism: prolongation of PT and aPTT, reduced fibrinogen level, reduced levels of protein C and protein S, Antithrombin III (AT) , plasminogen, factor IX and factor XII. On the other hand, ASNase causes increased procoagulant factors V, VIII (54-56). In addition, to the profound effects of the drug on the pro- and anticoagulant molecules, ASNase has also been

The simultaneous effects of ASNase on both procoagulant and thrombolytic proteins increase the risk of both bleeding and thrombosis, the latter being the main challenge.

The incidence of ASNase – associated VTE complications is age-dependent, 3-5% in children (67, 31) whereas the incidence reported from Dana-Farber Cancer Institute (1991-2008) in adult patients (≥ 30 years) was 34% and 42% (68). Less intensive ASNase regimen in adult patients have reported lower rates of thrombotic complications (69). Limited reports and data on a small number of patients treated with pegASNase –related DVT may be less frequent than those treated with after E. Coli ASNase (70-74). In UKALL 2003, Children with DVT were routinely retreated with pegASNase and concurrent heparin prophylaxis without recurrence of thrombosis (75). The confounding factors for VTE during ASNase therapy are presence of indwelling catheter, oral contraception, prednisolone and inherited

The majority of clinically important thrombotic events were those related to venous catheters and those in the central nervous system. The majority of catheter-associated thrombosis (CAT) are asymptomatic and the majority, in both children and adults, occur

In the randomized trial of native ASNase versus pegASNase (74), the incidence of cerebral venous sinus thrombosis (CVST) of 2-3% in children was reported. In children ≥ 10 years, initial WBC > 50x109 /L at diagnosis may predict higher risk for CVST (77). The GIMEMA study on adult ALL patients protocol, including E. Coli ASNase in the induction phase, CNS

Primary Prevention: In children and adolescents prophylaxis is rarely undertaken and there has been few reports that the use of AT concentrate may decrease the incidence of

In a historically controlled study of adult patients, Mitchell et al (78) reported that the incidence of VTE was lower in a cohort of patients who received prophylactic AT concentrate but the study did not establish efficacy. A retrospective comparison of cohort of patients at two centers in Canada who had prophylaxis against CNS thrombosis with fresh

Most paediatric oncology centers do not perform the coagulation screening tests or perform AT levels routinely. If prophylaxis is deemed appropriate for a particular patient, it is best applied during induction phase of therapy when the majority of VTE events take place.

shown to increase levels of immunomodulin a marker of vascular injury (66).

thrombophilia (76).

during induction (68).

thrombosis (78-79)

thrombotic events was 3% (77).

**Prevention and Management of ASNase induced thrombosis** 

frozen plasma and cryoprecipitate did not develop CVST (80).

For intracranial thrombohemorrhagic complications, the use of AT concentrates and/or cryoprecipitates to replace both AT and fibrinogen, respectively, is a reasonable approach. In case of unavailability of AT, fresh frozen plasma (FFP) at a dose of 20 ml/kg can raise the AT level by approximately 20%. However, FFP may also replenish asparagine and, thereby, counteract the anti-leukemic effect of ASNase. There is no clear indication from the literature about whether further administration of ASNase should be stopped in adults after a thrombotic event while on therapy. In children, ASNase is continued under cover of low-molecular-weight heparin. Patients with thrombotic events after ASNase have been successfully re-challenged with ASNase without recurrence of thrombosis (75). In the Dana-Farber Cancer Institute review (63) confirms that, after venous thromboembolic events, asparaginase can be restarted after demonstrating clot stabilization or improvement by imaging with close monitoring of anticoagulation. Therefore, a history of venous thromboernbolic events does not seem to adversely impact prognosis.

The expert panel, Wendy Stock et al (81) in their excellent article published in Leukemia and Lymphoma, 2011 detailed the management of ASNase associated VTE and put down the recommendation which is being adapted/summarized hereunder:


#### **5-Fluorouracil**

This synthetic pyrimidine analogue is an important chemotherapeutic agent for treatment of various solid tumors. The incidence of VTE in patients treated for colorectal cancer with this

Venous Thromboembolism in Cancer Patients 81

Dusenbery et al (101) in a study of patients receiving rHuEpo along with chemotherapy and radiation therapy for cervical carcinoma, reported that 2 of 20 patients had DVT during therapy, and 2 other patients had DVT 9 days and 10 days after radiation therapy and rHuEpo were discontinued. Although it was a small sample, the rate of 20% in that study is similar to the rate found in by Ted Wun et al (102). The combination of chemotherapy and radiation may lead to a more vigorous inflammatory response that may predispose patients

In a recent Cochrane meta-analysis of 35 trials representing almost 7000 patients, epoetin or darbepoetin treatment was associated with a significantly increased risk for thromboembolic

Erythropoietin may contribute synergistically to thrombosis in cancer patients through several mechanisms. (a) Increasing red cell mass leading to increasing whole blood viscosity, (b) Erythropoietin therapy results in reticulocytosis, the metabolically active young red blood cells. Elegant studies have demonstrated that metabolically active red blood cells augment platelet reactivity in vitro (104-108) (c) rHuEpo is synergistic with the platelet growth factor, thrombopoietin, for platelet activation in vitro (109-110) at concentrations that can be achieved pharmacologically in vivo. (d) Erythropoietin has been associated with increased platelet reactivity and evidence of endothelial activation when administered to healthy male volunteers (111) (e) In vitro data have demonstrated receptormediated endothelial cell activation in response to rHuEpo and that extracellular matrix produced by the activated endothelial cells enhanced platelet aggregation and recent evidence suggests that platelet-red cell interactions can play a role in venous thrombosis

The role of prophylactic myeloid growth factors: granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) in increasing risk of

Is a well-known risk factor for development of VTE in patients without cancer. Underlying cancer increases the risk of surgery-related VTE by two-fold. Some studies have demonstrated that longer time in the operating room, longer time under anesthesia, and need for surgical re-exploration is associated with increased risk of VTE in cancer patients (37, 115-116). A study analyzing the effect of surgery in patients with glioma revealed that patients who underwent major neurosurgery or brain biopsy were 70% more likely to

The use of CVC has improved the management of patients with cancer as they simplified the administration of chemotherapy, parental nutrition, antibiotics and other supportive intravenous therapy. However, the CVCs are associated with complications including a significant risk of catheter-associated thrombosis (CAT). The risk of VTE associated with hospitalization has increased over the last decade a time associated with increased use of medical thromboprophylaxis. The incidence of symptomatic catheter-related DVT in adult

to thrombosis in the background of other predisposing factors.

cancer-associated thrombosis is unclear (113-114).

**2.5.5 Indwelling central venous catheters (CVC)** 

events (103).

(112).

**2.5.4 Surgery** 

develop VTE within 3 months.

drug has been reported at 15-17%. During 5-FU infusion, there is a reduction of protein C and an increase level of fibrinopeptide through the action of thrombin (83-84).
