**b. Medical treatment**

Fibrinolytic agents, such as rt-PA, urokinase and streptokinase, have been used in recent decades to lyse intraluminal thrombi, to restore device patency and to avoid catheter removal. Intraluminal installation of fibrinolytic agents is still considered the safest and most effective therapy for the treatment of IVAD intraluminal thrombotic occlusions. These agents are associated with some complications e.g. bleeding, hypersensitivity reactions, arrhythmias, hypotension, fever, nausea or vomiting and the attending physician is advised to make note of this at the time when a decision is made.

#### **c. Recombinant tissue-plasminogen activator (rt-PA)**

Alteplase is the most popular and effective rt-PA used in the treatment of thrombotic occlusions. It is a serine protease that activates plasminogen to plasmin in the cleavage of thrombus-bound fibrin. In adult patients, 2 mg alteplase in 2 mL sterile water may be injected into the occluded catheter. Restoration of function is assessed 30–120 minutes later and if function is not restored, a second attempt with the same dose is performed (141-142). In 64-86% of patients successful treatment was achieved after a single dose, and two doses achieved 81–94% success. In addition, alteplase has the advantages of a low incidence of allergic reactions (< 0.02%) and no documented reports of sustained antibody formation after administration (134). Although small dose alteplase is so far not commercially available, large dose alteplase can be split into unit doses and cryopreserved at –20°C for 30 days (141). Reconstruction to small dose aliquots makes this a cost-effective treatment without compromising safety and efficacy (141-142). However, the production of a singledose rt-PA vial is still needed, not only for small institutions but also as a convenient, economically sound and safe agent for oncologic patients.

### **d. Urokinase**

In 1999, the FDA reported on microorganism contamination of urokinase and issued a warning about variations in quality control during manufacture, recommending that urokinase be restricted to specific patients in whom the physician has judged urokinase to be critical to the clinical situation (143).

#### **e. Streptokinase**

Although streptokinase can resolve occlusions without hemorrhagic side effects or coagulation changes. Its use is fraud with some difficulties: allergic reactions and the induction of antibody formation, fever and shivering in 1–4% and anaphylactic reactions 0.1% of patients these risks/issues led to the restriction of its usage (141,144). The producers

## **2.5.6 Radiation**

Pathophysiology and Clinical Aspects of 84 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

more significant in acute occlusions than in CVT, which is always detected after a period of time i.e. chronic organized thrombosis. Although some studies mentioned their usage,

Surgical explantation of the device should be considered after fibrinolytics have failed or therapy has been terminated because of its minor severity and the high success rate of

Fibrinolytic agents, such as rt-PA, urokinase and streptokinase, have been used in recent decades to lyse intraluminal thrombi, to restore device patency and to avoid catheter removal. Intraluminal installation of fibrinolytic agents is still considered the safest and most effective therapy for the treatment of IVAD intraluminal thrombotic occlusions. These agents are associated with some complications e.g. bleeding, hypersensitivity reactions, arrhythmias, hypotension, fever, nausea or vomiting and the attending physician is advised

Alteplase is the most popular and effective rt-PA used in the treatment of thrombotic occlusions. It is a serine protease that activates plasminogen to plasmin in the cleavage of thrombus-bound fibrin. In adult patients, 2 mg alteplase in 2 mL sterile water may be injected into the occluded catheter. Restoration of function is assessed 30–120 minutes later and if function is not restored, a second attempt with the same dose is performed (141-142). In 64-86% of patients successful treatment was achieved after a single dose, and two doses achieved 81–94% success. In addition, alteplase has the advantages of a low incidence of allergic reactions (< 0.02%) and no documented reports of sustained antibody formation after administration (134). Although small dose alteplase is so far not commercially available, large dose alteplase can be split into unit doses and cryopreserved at –20°C for 30 days (141). Reconstruction to small dose aliquots makes this a cost-effective treatment without compromising safety and efficacy (141-142). However, the production of a singledose rt-PA vial is still needed, not only for small institutions but also as a convenient,

In 1999, the FDA reported on microorganism contamination of urokinase and issued a warning about variations in quality control during manufacture, recommending that urokinase be restricted to specific patients in whom the physician has judged urokinase to

Although streptokinase can resolve occlusions without hemorrhagic side effects or coagulation changes. Its use is fraud with some difficulties: allergic reactions and the induction of antibody formation, fever and shivering in 1–4% and anaphylactic reactions 0.1% of patients these risks/issues led to the restriction of its usage (141,144). The producers

antithrombotic agents are still the first choice (134,138).

to make note of this at the time when a decision is made. **c. Recombinant tissue-plasminogen activator (rt-PA)** 

economically sound and safe agent for oncologic patients.

be critical to the clinical situation (143).

• **Intraluminal thrombotic occlusion** 

**a. Surgical management** 

**b. Medical treatment** 

**d. Urokinase** 

**e. Streptokinase** 

medical treatment (134,139-140).

There are limited data on the effect of isolated radiation modality on risk of cancer-associated thrombosis. However, the combination of chemotherapy and radiation could lead to a more vigorous inflammatory response that may predispose patients to thrombosis in the setting of other predisposing factors. In a study of patients receiving rHuEpo along with chemotherapy and radiation therapy for cervical carcinoma, Dusenbery et al (101) 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 remarkably close to the rate found by other investigators. Large, randomized studies of combined chemotherapy and radiation therapy in patients with carcinoma of the cervix did not report on the rate of venous thrombosis (145-148).

#### **2.5.7 Hormonal therapy: Tamoxifen and exemestane**

Tamoxifen was discovered by pharmaceutical company Imperial Chemical Industries (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still widely referred to by its generic name "tamoxifen."

Tamoxifen binds to estrogen receptors but produces both estrogenic and antiestrogenic effects. It reduces circulating insulin-like growth factor-1, inhibits angiogenesis, and induces apoptosis (149)

Tamoxifen is highly beneficial as adjuvant therapy for breast cancer, and more recently, its effectiveness has been demonstrated for prevention of breast cancer in high-risk women. (150-151)

The most frequent side effect in patients treated with tamoxifen versus placebo was a doubling of the rate of DVT and PE: 118 versus 62 cases and a similar increase in superficial phlebitis (68 versus 30 cases) (152) A systematic review of adjuvant hormonal therapy for breast cancer estimated that women treated with 5 years of tamoxifen have a 1.5-7.1 fold increased risk of VTE compared to women treated with placebo or on observation only. (153)

As to the evaluation of women who are about to initiate tamoxifen to prevent the development of breast cancer, the question raised is cost: benefit ratio of tamoxifen therapy if the patient have risk factors for DVT or PE. On the basis of the solid data favoring tamoxifen, the prevention of breast cancer should take priority over the risk of venous thromboembolism. If the risk of developing DVT is high, it is reasonable to go for concomitant anticoagulation with Coumadin (INR 2-3) for the planned treatment period with tamoxifen.

However VTE risk may become less problematic in breast cancer patients as the thirdgeneration oral aromatase inhibitors, such as the irreversible steroidal inactivator

Venous Thromboembolism in Cancer Patients 87

In another publication, Piccioli et al (161) reported that patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. In their study, apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3–36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of

Rickles et al (162) stated that while migratory thrombophlebitis is a clear indicator of an underlying neoplasm, the risk of cancer in patients with the more typical form of VTE has been the subject of intense debate over recent years. The authors concluded that, the costeffectiveness of aggressive screening for cancer in patients with VTE remains questionable. Nordström, M et al (163) conducted a prospective study of 366 patients in Malmo, Sweden, who had treatment after positive results on venography reported an overall incidence of deep venous thrombosis of 159 per 100 000 inhabitants per year. At the time of diagnosis of deep venous thrombosis, 71 patients (19%) had a known cancer and a further 19 (5%) developed cancer within the following year. Eight of the cancers were obvious at the time of

To date, there is very little evidence that routine cancer screening is indicated or costeffective in patients with unprovoked thrombosis. Nonetheless, it is prudent to perform a comprehensive history and physical exam and check basic blood work with relevant tumor markers, as deemed appropriate, in patients with unprovoked thrombosis because about

At our institutions, when performing pulmonary artery CTA and CTV for unprovoked VTE, our radiologist analyzes all information produced by the imaging examination. An attentive analysis of the entire thoracic and abdominal structures on all pulmonary artery CTA and CTV examinations is routine. Careful evaluation is also made in hospitalized patients in whom thromboembolic disease is discovered incidentally. In such patients, pulmonary artery CTA and CTV is considered a cancer screening procedure with an increased likelihood of finding an occult malignancy. When the CTV examination begins at the level of the diaphragm instead of below the level of the iliac crest, it permits the detection of venous thrombosis and serves as a simultaneous screening for possible underlying malignant

90% of occult cancers can be detected using this conservative approach (164-165).

**4. The use of biomarkers for risk assessment for VTE in cancer patients** 

Despite the well documented association of cancer with increased risk of thrombosis, clinical studies have not consistently demonstrated improved outcomes with

the 102 control patients [absolute difference, 1.9% (95% CI,) 5.5–10.9)].

diagnosis of the deep venous thrombosis and 11 were occult.

disease.

exemestane, are being used in place of tamoxifen for long-term prophylaxis after initial therapy of breast cancer. Exemestane is the generic name for the brand-name drug Aromasin and works by binding irreversibly to the body's aromastase enzyme, which is responsible for producing estrogen. Many breast cancer cells depend on estrogen to grow and multiply quickly. Once the aromatase inhibitor binds to the aromastase enzyme, the bound aromatase enzyme can no longer produce estrogen. This drug caused lack of estrogen "starves" estrogen- dependent breast cancer cells, preventing them from multiplying. Coombes et al, in a trial in which 4742 breast cancer patients were randomized to continue tamoxifen or to switch to exemestane. Those receiving exemestane experienced improvement in disease-free survival (154-155) The adjusted hazard ratio was 0.67 (95% CI 0.56 to 0.82, P<0.001) and the rate of thromboembolic events was almost halved in those receiving exemestane as compared with tamoxifen (1.3% versus 2.4%, p=0.007).
