**8.4 Prothrombin G20210 polymorphism**

Prothrombin (Factor II) is a zymogen synthesized in the liver and dependent on vitamin K. When prothrombin is activated, it forms thrombin (Factor IIa). A single mutation where adenine is substituted for guanine occurs at the 20210 position. The mechanism for increased thrombotic risk is not well understood, but individuals with this genetic variant have supranormal levels of prothrombin. The mutation is inherited as an autosomal dominant trait and is associated with both arterial and venous thrombosis.

Clinically, patients may present with deep venous thrombosis of the lower extremity, cerebral venous thrombosis, as well as arterial thrombosis. The risk of thrombosis increases in the presence of other genetic coagulation defects and with acquired risk factors.88,84

#### **8.5 Hyperhomocysteinemia**

8 Deep Vein Thrombosis

Antithrombin deficiency is associated with lower extremity venous thrombosis as well as mesenteric venous thrombosis. The most common presentation in those with antithrombin

Protein C is a vitamin K dependent anticoagulant protein that, once activated by thrombin, will inactivate factors Va and VIIIa, thereby inhibiting the generation of thrombin.83 Additionally, activated protein C stimulates the release of t-PA. It is produced in the liver and is the dominant endogenous anticoagulant with an eight-hour half-life. Protein C deficiency has a prevalence of 1 in 200–300 with more than 150 mutations and an autosomal

Protein S is also a vitamin K dependent anticoagulant protein that is a cofactor to activated protein C. The actions of protein S are regulated by complement C4b binding protein and only the free form of protein S serves as an activated protein C cofactor.85 Additionally, protein S appears to have independent anticoagulant function by directly inhibiting procoagulant enzyme complexes.84,86 The prevalence of protein S defi ciency is about 1 : 500

Clinically, protein C and S deficiencies are essentially identical. With homozygous protein C and S defi ciencies, infants typically will succumb to purpura fulminans, a state of unrestricted clotting and fi brinolysis. In heterozygotes, venous thromboses may occur at an early age especially in the lower extremity.87 Thrombosis may also occur in mesenteric,

Factor V is a glycoprotein synthesized in the liver. With Factor V Leiden, a point mutation occurs when arginine is substituted by glutamine at position 506. This point mutation causes the activated Factor V to be resistant to inactivation by activated protein C thus causing a

Clinically, patients may present with deep venous thrombosis in the lower extremities, or

Prothrombin (Factor II) is a zymogen synthesized in the liver and dependent on vitamin K. When prothrombin is activated, it forms thrombin (Factor IIa). A single mutation where adenine is substituted for guanine occurs at the 20210 position. The mechanism for increased thrombotic risk is not well understood, but individuals with this genetic variant have supranormal levels of prothrombin. The mutation is inherited as an autosomal

Clinically, patients may present with deep venous thrombosis of the lower extremity, cerebral venous thrombosis, as well as arterial thrombosis. The risk of thrombosis increases

in the presence of other genetic coagulation defects and with acquired risk factors.88,84

less commonly in the portal vein, cerebral vein, or superfi cial venous system.

dominant trait and is associated with both arterial and venous thrombosis.

**8.3 Factor V Leiden mutation and activated protein C resistance** 

deficiency is deep venous thrombosis with or without pulmonary embolism.82

**8.2 Protein C and protein S deficiency** 

with an autosomal dominant inheritance.

**8.4 Prothrombin G20210 polymorphism** 

dominant inheritance.83,84

renal, and cerebral veins.

procoagulant state.

Homocysteine is an amino acid formed during the metabolism of methionine and may be elevated secondary to inherited defects in two enzymes that are part of the conversion of homocysteine to cysteine. The two enzymes involved are N5,N10–methylene tetrahydrofolate reductase (MTHFR) or cystathionine beta-synthase. Hyperhomocysteinemia has been shown to increase the risk of atherosclerosis, atherothrombosis, and venous thrombosis. Elevated plasma homocysteine levels cause various dysfunctions of endothelial cells leading to a prothrombotic state.

Hypercoagulable syndromes include inherited and acquired thrombophilias. The former is discussed in detail in the article by Weitz in this issue. The latter includes the antiphospholipid syndrome, heparin-induced thrombocytopenia, acquired dysfibrinogenemia, myeloproliferative disorders, and malignancy. Myeloproliferative disorders and malignancy are described elsewhere in this article. Regarding the antiphospholipid syndrome, antiphospholipid antibodies are associated with both arterial and venous thrombosis.89 The most commonly detected subgroups of antiphospholipid antibodies are lupus anticoagulant antibodies, anticardiolipin antibodies and anti-b2 glycoprotein I antibodies.90 DVT, the most common manifestation of the antiphospholipid syndrome, occurs in 29% to 55% of patients with the syndrome, and about half of these patients have pulmonary emboli.91,92 The risk of heparin-associated thrombocytopenia is more duration related than dose related. Heparin-associated thrombocytopenia occurs more frequently with unfractionated heparin when used for an extended duration than with LMWH used for an extended duration.93 When used for prophylaxis, there was a higher prevalence of heparin-associated thrombocytopenia inthose receiving unfractionated heparin (1.6%, 57 of 3463) than in those receiving LMWH (0.6%, 23 of 3714).93 However, treatment resulted in only a small difference in the prevalence of heparinassociated thrombocytopenia comparing unfractionated heparin (0.9%, 22 of 2321) with LMWH (0.6%, 18 of 3126).93 Acquired dysfibrinogenemia occurs most often in patients with severe liver disease.94 The impairment of the fibrinogen is a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule.94

#### **9. Heart failure**

Congestive heart failure (CHF) is considered amajor risk factor for VTE.13,41,61,95,96 Among patients with established CHF, those with lower ejection fractions had a higher risk of thromboembolic event.97,98 However, some investigators did not evaluate CHF among the risk factors for VTE.99 The reported frequency of PE in patients with heart failure has ranged widely from 0.9% to 39% of patients. 13,97,98,100,101 The reported frequency of DVT in patients with CHF also ranged widely from 10% to 59%.13,41,61 The largest investigation was from the National Hospital Discharge Survey.102 Among 58,873,000 patients hospitalized with heart failure in short-stay hospitals from 1979 to 2003, 1.63% had VTE (relative risk 5 1.47).102 The relative risk for VTE was highest in patients less than 40 years old (relative risk 5 6.91). Some showed the lower the ejection fraction, the greater the risk of VTE.103 Among 755,807 adults older than 20 years with heart failure who died from 1980 to 1998, PE was listed as the cause of death in 20,387 (2.7%).104 Assuming that the accuracy of death certificates was only 26.7%,105 the rate of death from PE in these patients may have been as high as 10.1%.

Risk Factors of Deep Vein Thrombosis 11

Spinal cord injuries with paralysis result in an immobile state with retardation of the blood flow caused by the relaxation of muscle and the atony of blood vessels. It is not surprising that spinal cord injuries are frequently complicated by the development of venous thrombosis, which is inevitably linked to hospitalization, immobilization, vein wall damage, stasis, and hypercoagulability. Deep vein thrombosis and pulmonary emboli remain the major complications in spinal cord injuries below the C2 through T12 vertebrae associated with motor complete or motor nonfunctional paralysis. 113,114,115,116,117,118,119 Two surprising findings set spinal cord injury apart from other risk factors for venous thrombosis: incidence of leg DVT and pulmonary embolism in spinal cord injury is three times higher than in the

Patients with stroke are at particular risk of developing DVT and PE because of limb paralysis, prolonged bed rest, and increased prothrombotic activity.120 Among 14,109,000 patients with ischemic stroke hospitalized in short-stay hospitals from 1979 to 2003, VTE was diagnosed in 165,000 (1.17%).121 Among 1,606,000 patients with hemorrhagic stroke,

Among patients with ischemic stroke who died from 1980 to 1998, PE was the listed cause of death in 11,101 of 2,000,963 (0.55%).122 Based on an assumed sensitivity of death certificates for fatal PE of 26.7% to 37.2%,105,123 the corrected rate of fatal PE was 1.5% to 2.1%. Death rates from PE among patients with ischemic stroke decreased from 1980 to 1998, suggesting

Cancer is a major risk factor of venous thromboembolism (VTE) 124,125 as defined by deepvein thrombosis (DVT) – including central venous catheter (CVC) related thrombosis – or

In studies looking at pooled groups of patients with different types of malignancy, the rate of VTE is consistently highest in patients with cancer of the pancreas, stomach, brain,

Both large retrospective studies by Stein et al and Chew et al based on discharge claims databases reported the highest rates of VTE in patients with pancreatic cancer (4.3% and 5.3%, respectively). Patients with stomach cancer had the second and third highest risk of developing VTE in these studies 128,132. In patients with testicular and lung cancer, those with metastases to the liver and brain were shown to have higher rates of VTE compared with patients with other sites of metastases 133,134. The rates of VTE for specific types of

Multiple studies have shown an increased risk of VTE in patients with advanced-stage cancer. In a retrospective study of over 500 000 patients from the California Cancer Registry, patients with metastatic cancer stage were twice as likely to have developed VTE in the year

pulmonaryembolism (PE), which occur in 4 to 20% of cancer patients 126,127.

general population.

**12. Cancer** 

**12.1 Cancer-related factors** 

kidney, uterus, lung or ovary 128,129,130,131.

cancer have been reported in many studies.

**12.1.1 Site of cancer** 

**12.1.2 Cancer stage** 

the incidence of VTE was higher (1.93%).

effective use of antithrombotic prophylaxis.

Therefore, the estimated death rate from PE in patients who died with heart failure was 3% to 10%. CHF seems to be a stronger risk factor in women. Dries and colleagues97 reported a higher proportion of PE in women (24%) compared with men (14%). We too showed a higher relative risk of PE and of DVT in women with CHF than in men.102 Although these data seemcompelling, multivariate logistic analysis failed to identify CHF as an independent risk factor for DVT or PE.43 However, it was a risk factor for postmortem VTE that was not a cause of death.43 In one study of pediatric patients with dilated cardiomyopathy awaiting transplant the incidence of pulmonary embolism was 13.9% 106.

Heart failure is the second most common risk factor for VTE in hospitalized patients, as shown in ENDORSE.107
