Glossary of Risk Factors

Here you will find a glossary of venous thromboembolism risk factor terms. All of the risk factors in the Clinical Risk Factor Assessment are contained in this section. Click here to go to the Risk Assessment Form.

ACUTE SPINAL CORD INJURY
Definition:
Neurologic findings in spinal cord injury reflect the functional level of cord transection with motor paralysis and total anesthesia developing below the level of damage.
Effect:
Spinal cord injury causes a state of flaccid paralysis, which leads to prolonged immobilization and venous stasis in the lower extremities.
References: 65,76,95

AGE
Effect:
With advancing age, there is an increase in the level of activated coagulation peptides and a decrease in the activity of the fibrinolytic system. After 40 years of age, the risk of developing a deep vein thrombosis (DVT) increases with advancing age with a sharp increase in risk beginning during the fifth decade of life. One study showed a dramatic increase in DVT rate from six percent in patients under 40 years to seventy percent in patients older than 75 years.
References: 1,2,3,22,77,78,94,95,96

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS)
Definition:
Antiphospholipid antibody syndrome (APS) is a disorder involving venous or arterial thrombosis. Patients often manifest recurrent miscarriages, stillborn births, or toxemia of pregancy. Thrombocytopenia may also be seen in some patients. Antiphospholipid antibodies (e.g., Anticardiolipin antibodies (aCLs), such as IgG or IgM, are directed against negatively charged cell membrane phospholipids and are present in approximately one-third of patients with systemic lupus erythematosus (SLE).
Effect:
Antiphospholipid antibodies predispose toward acute arterial and venous thrombosis in young adults by altering normal endothelial functions. In pregnant women with SLE, aCLs may cause fetal death after the first trimester or premature birth due to placental thrombosis, infarction, or insufficiency.
Detection:
The most sensitive test for antiphospholipid antibodies is the anticardiolipin antibody immunoenzymatic assay. Lupus anticoagulants are seen in these settings. They are identified by their capacity to prolong the phospholipid-dependent coagulation tests i.e. aPTT. Although this clotting test is prolonged, the patient exhibits a severe antithrombotic tendency.
References: 38,46,64,69,70,95

ANTITHROMBIN III (AT III) DEFICIENCY
Definition:
AT III is a glycoprotein that inhibits the activation of serine proteases (Factors XIa, Xa, IXa, and thrombin) by forming a 1:1 complex that is resistant to dissociation. In AT III deficiency, a genetic defect leads to a decrease in function of AT III.
Effect:
A deficiency in AT III leads to a relative increase in clotting factors XI, X, and IX and therefore a state of hypercoagulability, which may manifest itself as a venous thrombotic event. In addition, heparin's anticoagulation effect is diminished since heparin is a cofactor of AT III.
Detection:
Functional assays measure the ability of AT III to inhibit thrombin or Factor Xa in the absence or presence of heparin. Immunologic assays for AT III are also readily available. Clinical evidence of this defect may be an apparent resistance to heparin.
References: 24,26,31,94,95

CENTRAL VENOUS ACCESS (CVA)
Definition:
Indwelling catheter placement in the central venous system that is most commonly used for the administration of chemotherapy in cancer patients.
Effect:
The development of a fibrin sleeve thrombosis and eddy flow formation around the area of insertion of the catheter creates stasis and predisposes veins to DVT formation. In addition, prolonged use of a catheter predisposes to infection and sepsis, which increases the risk of catheter-related thrombogenesis. Furthermore, the presence of cancer in many patients with CVA leads to an increased risk of DVT (see malignancy below). Finally, venous thrombi may arise around these catheters and can break off to produce pulmonary emboli.
References: 20,40,41,94,95

CONGESTIVE HEART FAILURE (CHF)
Definition:
Congestive heart failure is a condition where the systemic cardiac output is reduced, leading to increased venous pressure, pulmonary congestion, and peripheral edema.
Effect:
CHF can lead to passive congestion particularly in the liver and peripheral venous tree. This may result in venous stasis and dilation of the pelvic and leg veins. Since the venous tree is easily overdistended with blood, cracks in the endothelium can occur to initiate thrombosis.
References: 1,20,79,95

DISORDERS OF PLASMINOGEN & PLASMIN ACTIVATION
Definition:
There are two main disorders: (1) 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor (PAI-1) gene causes decreased plasminogen activation; and (2) congenital plasminogen deficiencies. Some patients will exhibit high PAI-1 levels post-operatively, which are also seen in some patients with cancer.
Effect:
Either reduced fibrinolytic capacity due to increased (PAI-1) activity or decreased levels of plasminogen can lead to a relative state of hypercoagulability.
Detection:
Levels of plasminogen and PAI-1 can be detected through enzyme-linked immunosorbent assay (ELISA) methods and immunohistochemistry (IHC). Both tests provide information on the amount of protein expressed in tissue samples.
References: 67,68,80,81,94,95

DYSFIBRINOGENEMIA
Definition:
A point mutation in the fibrinogen gene that leads to the production of a qualitatively abnormal and functionally defective protein. DVT is observed in 10% of patients with dysfibrinogenemia.
Effect:
Tentative mechanisms for increased thrombotic risk include fibrin resistance to plasmin proteolysis, the presence of fibrinogen that is not susceptible to normal fibrinolytic mechanisms, defective thrombin binding, enhanced platelet aggregation, increased blood viscosity, and alteration of clotting architecture.
Detection:
Tests include thrombin time, reptilase time and functional versus non-functional based assays of fibrinogen concentration.
References: 24,26,31,66,94,95

ELECTIVE MAJOR LOWER EXTREMITY ARTHROPLASTY
Background:
Despite prophylaxis, the incidence of venographically detected DVT after total hip replacement (THR) and total knee replacement (TKR) surgery remain high, at approximately 15% and 30% respectively. In fact, DVT remains the most common reason for emergency readmission following THR surgery.
Effect:
The total hip replacement surgery involves dislocation of the hip from the socket, which can produce kinking of the femoral vein. This may result in endothelial damage that that can be a precursor for deep vein thrombosis. The head of the femur is then sawed off producing further trauma and intravascular contamination that can create a hypercoaguable state. This state is intensified by driving the surgical stem down the center of the bone marrow in the femur. This direct trauma to the vasculature, along with the length of surgery, general anesthesia, and post-operative immobilization, lead to a period of highly increased risk of DVT. TKR surgery is accompanied by lower extremity tourniquet use, which can cause ischemia and venous stasis along with direct trauma to the vascular system. This leads to an increased risk of DVT formation, and emboli released into the venous system after tourniquet release may travel directly to the lungs of patients (i.e., pulmonary emboli). It should be pointed out that many THR and TKR patients are elderly patients with additional risk factors for DVT formation.
References: 53,57,58,82,95

FACTOR V LEIDEN / ACTIVATED PROTEIN C RESISTANCE
Definition:
This is a single point defect in the gene coding for coagulation factor V which results in a form of Factor Va that is resistant to degradation by activated protein C (i.e., activated protein C resistance (APC –R)). This genetic mutation, Factor V Leiden, is the most common cause of thrombophilia, and is found in 4-6% of the U.S. population and 20-40% of patients with an episode of confirmed DVT.
Effect:
In patients with this defect, the abnormal Factor V molecule is resistant to degestion from protein C. This alters the clotting sequence to produce a hypercoagulable state, which may be associated with a three to six-fold increase in the risk for primary or recurrent DVT. In patients with transient risk factors such as surgery or trauma, a Factor V Leiden defect can increase the risk of thrombosis eighty-fold.
Detection:
A plasma-based test is performed to measure the activated partial thromboplastin time in the presence and absence of protein C; results are expressed as a ratio of these values.
References: 27,28,31,95

HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)
Definition:
An immune response to heparin is stimulated by a complex of heparin with platelet factor 4 (PF4) and it is clinically manifested by the development of thrombocytopenia and thrombosis. Thrombotic complications develop in about 29% of hospitalized patients who develop HIT, and primary thrombotic events are more commonly venous than arterial.
Effect:
Autoantibodies to complexes containing heparin and PF4 cause platelet adhesion and aggregation that can lead to massive systemic clotting in both the venous and arterial vasculature.
Detection:
IgG and IgM antibodies specific for complexes containing heparin and PF4 can be detected using an enzyme-linked immunosorbent assay (ELISA). HIT can also be identified by a heparin-induced platelet aggregation test.
References: 72,73,95

HIP, PELVIC, OR PROXIMAL FEMUR FRACTURE
Background:
Patients with trauma to the pelvic area sufficient enough to cause fracture of the pelvis or proximal femur have an incidence of DVT equal to 35-40%.
Effect:
A hip or proximal femur fracture can cause trauma and compression to the femoral vein, leading to a site of hypercoagulability as well as lower extremity immobilization, venous stasis, and edema. The repair of these fractures may involve a simple pinning together of the bones or require a more elaborate surgical procedure that can approach a THR in complexity.
References: 54,55,56,95

HISTORY OF DVT/PE
Effect:
A vein may never be the same after an initial episode of DVT and is therefore a place of origin for future DVT. The formation of a clot results in vein scarring, valvular destruction and muscle pump deterioration that in turn leads to blood stasis and a decrease in fibrinolytic activity.
Detection:
Signs of prior DVT include limb edema (swelling) and skin changes (mottling, cyanosis).
References: 1,32,94,95

HORMONE REPLACEMENT THERAPY
Definition:
Hormone replacement therapy is the administration of exogenous estrogen or estrogen/progesterone preparations in post-menopausal women. In women, ERT (estrogen only) increases the risk of DVT two-fold. Administration of these hormones in patients with thrombophilic defects such as Factor V Leiden or Prothrombin 20210A can produce an enormous increase in the incidence of venous thromboembolism.
Effect:
ERT use can lead to changes in the body's hemostatic balance including an increase in coagulation factors FII, FX, FVII, FIX, FVIII, fibrinogen, von Willebrand's factor and a decrease in total and free protein S, antithrombin III, and fibrinolytic activity. These changes in the coagulation system are reversible with removal of the ERT.
References: 1,17,18,19,20,24,71,83,94,95

HOMOCYSTEINEMIA
Definition:
Homocysteinemia is defined as an excess of homocysteine, an amino acid intermediate in the methionine metabolism pathway in the blood, and is most commonly caused by genetic defects, vitamin deficiency (folic acid, B6, B12), or renal failure.
Effect:
The occurrence of homocysteinemia indicates that excess homocysteine is being exported into the blood, which limits intracellular toxicity and leaves the vascular endothelium exposed to the damaging effects of excess homocysteine (e.g., increased oxidant stress). Thrombosis may begin in an area where this vascular endothelium has been damaged. Damage to vascular endothelium contributes to stroke, myocardial infarction, and venous thromboembolism and is the major cause of morbidity and mortality in patients with homocysteinemia.
Detection:
Plasma level of homocysteine.
References: 25,38,39,42,43,44,45,60,61,95

HYPERVISCOSITY SYNDROME
Definition:
An increased concentration of the constituents of whole blood including fibrinogen, antibodies, and other proteins (e.g., Waldenstrom's macroglobulinemia).
Effect:
The increased resistance to blood flow leads to venous stasis and an increased risk of DVT.
References: 74,75,95

IMMOBILIZING PLASTER CAST
Background:
The incidence of phlebographically confirmed DVT after plaster-cast immobilization of the lower extremity has been reported to be somewhere between 4 and 30 %.
Effect:
Long bone casting leads to blood flow reduction and stasis due to immobilization. In addition, trauma to the vasculature can cause activation of the coagulation cascade due to release of tissue thromboplastin. The lack of normal muscle contractions that normally occur during walking can contribute to the venous stasis.
References: 33,34,35,84,95

INFLAMMATORY BOWEL DISEASE (IBD)
Definition:
IBD is the classification given to ulcerative colitis and Crohn's disease, which are chronic diseases of unknown etiology characterized by inflammation of the intestinal tract.
Effect:
Open ulcers in the bowel are a means for toxic substances to be absorbed into the bloodstream (the equivalent of an intravenous injection of feces). In addition, in patients with IBD there are increased levels of fibrinogen, factor VII, and platelet activity and a decrease in the levels of AT III and alpha-2 macroglobulin.
References: 1,14,32,94

LAPAROSCOPIC SURGERY (>45 MINUTES)
Definition:
Laparoscopic cholecystectomies and upper abdominal laparoscopic surgery.
Effect:
The pneumoperitoneum created during laparoscopic surgery results in intraabdominal pressure that exceeds the pressure of venous blood return from the legs. This factor, along with general anesthesia and the reverse Trendelenburg position, can lead to venous stasis in the legs and an increased risk of DVT formation.
References: 49,51,52,95

LUPUS ANTICOAGULANT
Definition:
Lupus is an inherited immune hyperactivity disorder characterized by anti-nuclear antibodies (ANA). The lupus anticoagulant is an IgG or IgM antiphospholipid antibody that attacks the phospholipid portion of platelet and endothelial cell membranes.
Effect:
The exact mechanisms of thrombosis formation are still unknown, but are thought to involve inhibition of AT III and plasminogen to plasmin conversion, platelet damage leading to increased adhesiveness, thrombomodulin inhibition causing decreased protein C activity, and vascular damage caused by the vasculitis commonly present in lupus patients.
Detection:
The lupus anticoagulant antibody (LA) prolongs phospholipid-dependent in vitro clotting assays such as the aPTT and dilute Russell viper venom time. Note: Lupus anticoagulant increases PTT while paradoxically causing hypercoagulability.
References: 24,26,46,94,95

MAJOR SURGERY
Definition:
A major operative procedure greater than 45 minutes under general anesthesia. Background: Without recommended prophylaxis, patients subjected to major abdominal surgery have an incidence of DVT equal to approximately 30%.
Effect:
Major abdominal operative procedures may be associated with the release of clotting factors from tissue trauma. Operative and post-operative interventions can lead to immobilization, venous stasis and coagulation cascade alterations.
References: 1,2,9,37,93,94,95

MALIGNANCY
Background:
Thrombotic complications are especially prevalent in patients with mucin-secreting adenocarcinomas, brain tumors, and hematological malignancies.
Effect:
The etiology of thrombosis in malignancy is multifactorial and mechanisms include the release of procoagulants by tumor cells that cause coagulation dissemination, impaired fibrinolytic activity, activation of blood clotting factors (V, VIII, IX, X) and abnormal platelet-vessel interactions. In addition, chemotherapeutic agents and cancer cells can injure endothelial cells directly, and indwelling central venous catheters used to deliver chemotherapy can increase the risk of developing DVT (see central venous access). Note: A two-way clinical association links DVT and cancer since DVT may be the presenting feature of an occult cancer and patients with clinically overt cancer have a high risk of developing a DVT.
References: 1,7,20,23,9,62,63,94,95

MINOR SURGERY
Definition:
An operative procedure lasting less than 45 minutes that is performed under local or spinal anesthesia.
Effect:
Minor surgical procedures may be associated with the release of clotting factors from tissue trauma and venous stasis from post-operative immobilization.
References: 93,94,95

MULTIPLE TRAUMA
Definition:
DVT has been reported to occur in 20-40% of high-risk trauma patients without recommended prophylaxis.
Effect:
Trauma can predispose patients to multiple risk factors including immobilization, major surgery, central venous access and infection depending on the severity of the trauma. In addition, any trauma to the vascular system can lead to sites of hypercoagulability within the vessels since injury to the endothelium is accompanied by a loss of protective molecules and an expression of adhesive molecules. Furthermore, damaged endothelium enhances procoagulant activities and secretes von Willebrand's factor to increase platelet adhesion and aggregation.
References: 1,10,88,95

MYELOPROLIFERATIVE DISORDERS (MPDs)
Definition:
Four diseases are commonly grouped together as myeloproliferative disorders (MPDs): polycythemia vera, myelofibrosis, thrombocythemia, and chronic myelogenous leukemia.
Effect:
The chronic MPDs are characterized by a high incidence of thromboembolic complications due to hyperviscosity of blood and an inappropriate level of platelet activation, including elevated levels of platelet-specific proteins, increased thromboxane A2 generation and an over-expression of activation-dependent epitopes on platelet surfaces. In addition, an increased hematocrit has been clearly associated with thrombosis.
References: 59,89,95

MYOCARDIAL INFARCTION (MI)
Definition:
MI refers to irreversible necrosis of myocardium usually resulting from thrombosis in a major coronary artery, sudden progression of atherosclerotic changes, or prolonged constriction of the arteries.
Effect:
MI can lead to increased activation of the coagulation system, immobilization, and venous stasis (see CHF above). In addition, MI is a reflection of underlying systemic artherothrombotic disease.
References: 1,15,20,21,95

OBESITY
Definition:
A body mass index (BMI) (weight [kg]/height [m]2) of between 30 and 40.
Effect:
Different studies have concluded that obesity is a risk factor for DVT since it can cause increased immobility and is associated with reduced fibrinolytic activity. Obesity works in concert with other risk factors for venous disease such as pregnancy, surgery, and estrogen treatment to increase the risk of developing a DVT. In addition, obesity is associated with such conditions as congestive heart failure, myocardial infarction, and elevated levels of free fatty acids and cholesterol in the blood stream.
References: 1,11,12,37,90,94,95

ORAL CONTRACEPTIVES (OCs)
Definition:
Oral contraceptives (OCs) are estrogen or estrogen/progesterone preparations that prevent ovulation in women by decreasing in vivo levels of leutinizing hormone (LH) and follicle stimulating hormone (FSH) by a negative-feedback mechanism. In women, OCs increase the risk of DVT three to four-fold.
Effect:
The use of oral contraceptives can lead to changes in the body's hemostatic balance, including an increase in coagulation factors FII, FX, FVII, FIX, FVIII, fibrinogen, von Willebrand's factor and a decrease in total and free protein S, antithrombin III, and fibrinolytic activity. In young women, most thrombotic events can be attributed to the use of OCs. These changes in the coagulation system are reversible with removal of the OCs.
References: 1,17,18,19,20,24,71,94,95

PATIENTS CONFINED TO BED >72 HOURS
Definition:
The reduction or elimination of body motion by mechanical means or strict bed confinement for greater than 72 hours.
Effect:
Immobilization causes venous stasis, venous dilation, slowing of blood flow, increased blood viscosity, and activation of coagulation factors that are prevented from being diluted and cleared by normal blood flow.
References: 1,3,4,5,685,86,87,94,95

PREGNANCY
Background:
The risk of DVT increases five-fold in patients who are pregnant or less than one month post-partum over non-pregnant women. The greatest risk of DVT occurs during the third trimester of pregnancy.
Effect:
Coagulation factors increase and fibrinolysis activity decreases in pregnant women since there is a reduction in fibrinolytic activity during pregnancy, including significantly reduced levels of protein S and elevated levels of Factors VII, VIII, IX, X, and fibrinogen due to increased levels of natural hormones.
References: 1,13,21,26,94,95

PROTEIN C DEFICIENCY
Definition:
Protein C, a vitamin K-dependent protein, is activated by thrombin to a serine protease that inactivates Factors Va and VIIIa in the clotting cascade. Activated protein C also stimulates fibrinolysis by neutralizing a major inhibitor of tissue plasminogen activator.
Effect:
A deficiency in protein C leads to a state of hypercoagulability due to the fact that Factors V and VIII are not inactivated and fibrinolysis is not stimulated. The first thromboembolic event usually occurs in the mid-teens to early twenties, and at least 25% of the patients will have had at least one VTE by the age of 50.
Detection:
Immunologic assays for total protein C.
References: 24,26,31,94,95

PROTEIN S DEFICIENCY
Definition:
Protein S, a vitamin K-dependent protein, is a cofactor for the anticoagulant activity of activated protein C, and it therefore enhances the inactivation of factors Va and VIIIa while stimulating fibrinolysis.
Effect:
A deficiency in protein S leads to a state of hypercoagulability due to the fact that factors V and VIII are not inactivated, thrombin generation is not inhibited and fibrinolysis is not stimulated.
Detection:
Immunologic assay for total protein S is reliable and available.
References: 24,26,31,94,95

PROTHROMBIN 20210A
Definition:
Prothrombin (Factor II) is a phospholipid binding protein with procoagulant properties. A genetic defect in the gene for prothrombin termed the prothrombin 20210A allele has recently been identified in association with an increased risk of DVT.
Effect:
This defect is associated with an elevated plasma level of prothrombin and therefore a state of hypercoagulability.
Detection:
Amplification of DNA by polymerase chain reaction (PCR).
References: 48,50,95

SEPSIS / INFECTION
Definition:
A toxic condition resulting from the spread of bacteria or their products from a local focus of infection into the blood stream.
Effect:
The presence of foreign proteins, damaged cells, organisms, or toxins in the blood can cause activation of the complement cascade and a state of hypercoagulability. In addition, there is an elevation in platelet number and a lowering of AT III levels in the blood.
References: 1,37,95

STROKE
Definition:
An ischemic stroke is caused by either embolic or thrombotic occlusion of a major artery in the neck or head that supplies the central nervous system.
Effect:
A major stroke can be associated with prolonged immobilization and bed confinement that can lead to venous stasis and an increased risk of DVT. One study showed that leg paralysis due to a stroke had a fifty-three percent DVT rate while limbs with normal mobility had a seven percent DVT rate.
References: 1,16,20,91,94,95

VARICOSE VEINS
Definition:
Varicose veins are distended, tortuous, superficial veins with incompetent valves resulting from congenital conditions, thrombophlebitis, or conditions that cause increased venous pressure.
Effect:
The increased venous pressure and incompetent pumping mechanisms of varicose veins can lead to a state of chronic venous insufficiency and venous stasis. In addition, varicose veins can cause symptoms that mimic DVT (pain, edema, skin changes).
References: 1,8,32,37,92,95

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