1. Vascular disorders associated with thrombus formation and thromboembolism account for more illness and deaths than any other category of human disease (e.g., myocardial infarction, stroke, pulmonary embolus, chronic coronary ischemia, peripheral vascular disease, etc.).

   A thrombus is a clot - a solid mass composed of platelets, fibrin and entrapped red blood cells that forms in the vascular system. By definition, a thrombus is attached to vascular endothelium (or to the endocardial lining of the heart). A thromboembolus is a fragment of a thrombus that detaches and is carried downstream to occlude a smaller vessel.

   Thrombosis can occur in the arterial tree, the heart, or within the venous system. Common locations for arterial thrombi include the cerebral, coronary, mesenteric, and renal arteries. A thrombus on the wall of a heart chamber (ventricle or atria) is referred to as mural thrombus. In the venous circulation, thrombi most commonly form in the large, deep veins of the pelvis and lower extremities (deep venous thrombosis ).

2. Three pathophysiologic mechanisms are involved in thrombus formation: (1) blood vessel (endothelial) injury, (2) alterations in normal blood flow, or (3) hypercoagulability of blood.
   1. Endothelial injury - Endothelial injury exposes platelets and plasma coagulation factors to subendothelial collagen and tissue factor thereby activating primary and secondary hemostasis. This process is aided by the loss of coagulation inhibitors normally associated with intact endothelium (see below).

   2. Alteration to normal blood flow - Normal laminar blood flow keeps platelets in the center of the blood stream and away from the vessel wall where they can be activated by contact with the endothelium. Normal blood flow also dilutes and/or carries away any thrombin or fibrin that may form inadvertently in the circulation. Abnormal slowing of blood flow (stasis), or turbulence in the circulation, can bring platelets into contact with the endothelium leading to the activation of primary hemostasis. Turbulent blood flow and hypertension generate shearing forces near branching points or constrictions in vessels that can lead to endothelial cells injury.

      Altered blood flow occurs in dilated vessels (aneurysms, venous varicosities, compression of pelvic veins during pregnancy, etc.), and in regions of constricted or turbulent blood flow (vessel stenosis, valvular heart diseases, atherosclerotic plaques in arteries, etc.). The noncontractile myocardium of a myocardial infarction can produce pockets of stasis in the ventricles promoting the formation of mural thrombi. Similarly, thrombi can form in a dilated or fibrillating atrium.

      Although less common, hyperviscosity of the blood associated with polycythemia vera, sickle cell disease, and multiple myeloma may also alter blood flow and contribute to thrombus formation.

   3. Increased coagulability of blood
      • The coagulation system, which is responsible for the formation of fibrin clots, probably functions at a low level of activity in the normal circulation generating minute amounts of thrombin and fibrin. In this "idling" state it can respond to injury by rapidly generating a clot at the site of vessel damage. At the same time, inappropriate activation of coagulation within intact blood vessels is normally held in check by mechanisms associated with intact endothelium - mechanisms that inhibit platelet activation, suppress fibrin production, and protect us from the formation of intravascular clots (thrombosis). Thus, normal hemostasis is a balance between those factors that promote clot formation when injury occurs, and those factors that prevent inappropriate clot formation.

        

        Elements of the body's normal "anti-thrombotic" mechanisms include:

        • Prostacyclin and nitric oxide (produced by endothelial cells) inhibit intravascular platelet aggregation.

        • Heparin-like molecules on the surface of endothelial cells combine with the plasma protein Antithrombin III (AT-III) to inactivate thrombin, factors Xa and IXa, and most other coagulation factors.

        • Another cell surface molecule, Thrombomodulin, binds thrombin so that it cannot convert fibrinogen to fibrin.

        • The thrombomodulin-thrombin complex also activates two other naturally occuring anticoagulants, Protein C and Protein S, which are responsible for degrading activated factors V and VIII.

        • Tissue Factor Pathway Inhibitor (TFPI) is a plasma lipoprotein that inactivates Tissue Factor:Factor VII complex and blocks the activation of the extrinsic coagulation pathway.

        • Endothelial cells secrete tissue plasminogen activator (tPA) which activates the fibrinolytic system to degrade fibrin.

      • Thrombosis can occur if changes in blood composition makes the blood "hypercoagulable" - i.e., if the normal balance between coagulation and anti-thrombotic mechanisms shifts in favor of clot formation. Hypercoagulable states may be inherited or acquired.
        • The inherited hypercoagulability states are also known as inherited thrombophilias. They are the result of genetic mutations that produce deficiencies or defects in coagulation inhibitors. (See venous thrombosis and thromboembolism below.)

        • There are several forms of acquired hypercoagulability:
          • Use of estrogen and progesterone agents (oral contraceptives, hormone replacement therapy) promotes thrombosis by decreasing coagulation inhibitors anti-thrombin III, Protein C and Protein S.

          • Pregnancy (See venous thrombosis and thromboembolism below.)

          • Many cancers generate pro-coagulants such as tissue factor, or enzymes that activate plasma coagulation factors such as Factor X.

          • Abnormally high numbers of platelets (thrombocytosis) also increase the risk for thrombosis - especially in the arterial tree. (E.g., polycythemia vera, essential thrombocytosis, CML.)

          • About one out of four adults with nephrotic syndrome will have a thromboembolic event during the course of their illness. The hypercoagulability of nephrotic syndrome is due to multiple abnormalities in the coagulation and anticoagulation systems (elevated plasma fibrinogen and other coagulation factors, decreased anti-thrombin III, and impaired fibrinolysis).

          • Elevated levels of the amino acid homocysteine is associated with an increased risk for arterial and venous thrombosis. This may be inherited (rare) or acquired (common). Acquired hyperhomocysteinemia has been associated with advancing age, renal failure, hypothyroidism, and certain medications that interfere with folate metabolism. In many cases of hyperhomocysteinemia, the underlying cause is never determined. The mechanism by which hyperhomocysteinemia causes hypercoagulability is not fully understood. One important feature of hyperhomocysteinemia is that it frequently responds to treatment with folic acid and vitamin B12.

          • An important auto-immune cause for thrombosis risk is the antiphospholipid syndrome. High levels of autoantibodies directed against phospholipids (lupus anticoagulant, anti-cardiolipin antibodies) induce a hypercoagulable state. The exact mechanism by which this occurs is unclear. About 40% of all cases of antiphospholipid syndrome are associated with systemic lupus erythematosus and other auto-immune rheumatologic disorders. The remaining cases occur in otherwise healthy individuals, are secondary to certain viral infections (e.g., HIV), or are induced by medications.

            In spite of its name, lupus "anticoagulant" does not cause clinical bleeding in patients; however, it does prolong the PTT in the laboratory. This makes the PTT a useful screening test for lupus anticoagulant.

          • Elevated Coagulation Factor Levels - Elevated plasma levels of Factors VII, VIII, IX, X, XI, Von Willebrand Factor, or fibrinogen increase the risk for thromboembolism. This situation occurs most commonly in diseases associated with chronic inflammation. Plasma coagulation factors are also increased during pregnancy and with the nephrotic syndrome. Elevated plasma levels of coagulation factors may occasionally be inherited.

      • Arterial vs Venous Thrombosis: Thrombosis can occur in arteries or veins. However the pathogenesis and complications of arterial and venous thrombosis differ:
        • Arterial thrombosis most commonly results from endothelial injury and platelet activation - particularly endothelial injury caused by atherosclerosis (see below). Inherited hypercoagulability rarely plays a role. Complications of arterial thrombosis or arterial embolization involve vessel occlusion and ischemic injury or infarction to organs (MI, stroke, etc.).

        • Venous thrombosis is most commonly associated with altered blood flow (especially venous stasis) or hypercoagulability states. Platelets play only a minor role. Thromboembolization - especially pulmonary emboli - is the most significant consequence of venous thrombosis.

        • Hyperhomocysteinemia and the antiphospholipid syndromes are risk factors for both arterial as well as venous thrombosis.

Arterial Thrombosis and Atherosclerosis

1. Atherosclerosis is a condition that affects the large and medium sized arteries of almost every human (especially in societies where cholesterol-rich foods are abundant). Atherosclerosis is characterized by a fibrous thickening in the arterial wall called an atheroma (or "fibro-fatty plaque"). Atheromas narrow the lumen of arteries and weaken the vessel wall. Atherosclerosis begins in childhood and slowly progresses throughout life. Typically, it produces symptomatic clinical disease during the fifth and sixth decades of life.

   

   1. What is an atheroma? - The atheromatous plaque is a raised lesion within the intima of arteries composed of a core of cholesterol, necrotic cellular debris, and inflammatory cells. This is covered by a "cap" of smooth muscle cells and collagen fibers.

   2. How do atheromas develop? - The exact pathogenesis of atherosclerosis is still being debated. However, current theories stress the following events:
      • Endothelial Injury - Chronic endothelial injury is the initial step in the development of atherosclerosis. Hemodynamic stresses such as turbulence at points of narrowing and branching in the arterial tree are the earliest and most significant cause of endothelial injury. This probably explains why atheromas are not uniformly distributed within the arterial system. Instead, they tend to occur most frequently in the abdominal and thoracic aortas, the coronary arteries, the internal carotid arteries, the iliac and popliteal arteries, and the circle of Willis. Other postulated causes of direct endothelial injury include high levels of cholesterol, toxins from cigarette smoke, and perhaps even infectious agents and immune-mediated injury.

      • Cholesterol - In addition to being directly toxic to endothelium, cholesterol (as low density lipoprotein - LDL) readily diffuses across injured endothelium and accumulates within the intima of arteries where it undergoes oxidation by free radicals. Evidence of lipid accumulation in vessel walls is seen early in childhood as smooth, barely visible raised areas on the intimal surface of the aorta and other large arteries called "fatty streaks". It is believed that most atheromatous disease develop from these fatty streaks.

        
        

        Lipid Metabolism and Atherosclerosis... Because cholesterol, triglycerides, and other lipids are nonpolar and insoluble, they require a special transport system in the circulation. This is accomplished by surrounding lipid molecules with a protein shell producing lipoproteins which are soluble in body fluids The major lipoproteins include chylomicrons, very-low density lipoproteins (VLDL), low-density lipoproteins (LDL), and High-density lipoproteins (HDL). Chylomicrons transport dietary triglycerides and cholesterol from the intestine to the liver, and carry triglycerides to adipose tissue and muscle. (Triglycerides are an important source of energy for muscle and many other tissues.) VLDL transports cholesterol and triglycerides that have been synthesized in the liver to muscle and adipose tissues. After triglycerides are removed from VLDL, the molecule is converted into cholesterol rich LDL. LDL binds to LDL receptors found on many cells in the body (including endothelium) and delivers cholesterol to various tissues. (Keep in mind that cholesterol is used as a substrate for a number of biologically important molecules such as steroids, as well as being a component of normal plasma membranes.) HDL is a cholesterol scavenger. It removes excess cholesterol from tissues, gets re-converted to LDL, and returns cholesterol to the liver where it is excreted in bile. Laboratory Measurement of Cholesterol Total Cholesterol = HDL + LDL + VLDL. Most laboratories measure total cholesterol and HDL directly. A total cholesterol < 200 mg/dl (or lower) is considered desirable. VLDL = Triglyceride/5 (as long as triglycerides <400 mg/dl). LDL = Total Cholesterol - HDL - VLDL. LDL levels >160 mg/dl are associated with a significantly increased risk for atherosclerotic coronary artery disease. HDL levels <35 mg/dl are associated with increased coronary artery disease risk. HDL >60 mg/dl is associated with a reduced risk. The ratio between total cholesterol and HDL also predicts coronary heart disease risk (Total Cholesterol/HDL). A ratio less than 4.5 is considered desirable. A ratio of 5 = standard risk. A ratio of 10 is associated with a doubling of risk. A ratio of 20 triples the risk.

        
        

      • Smooth Muscle Proliferation - Platelets that adhere to the injured endothelium begin secreting the cytokine Platelet Derived Growth Factor (PDGF) which stimulates smooth muscle cells in the media of affected arteries to proliferate and invade the intima. Smooth muscle cells then synthesize and secrete collagen which is deposited within the atheroma.

      • Macrophage Activation - Monocytes adhere to injured endothelium and migrate into the intima. Within the intima, monocytes are transformed into macrophages which actively engulf oxidized cholesterol forming "foam cells". As foam cells accumulate, they die and release cholesterol crystals into the core of the developing atheroma. Activated macrophages also produce cytokines which probably contribute to smooth muscle proliferation within the atheroma.

      • The Complicated Lesion - As the atheromatous plaque evolves and enlarges, it may undergo changes that help contribute to the development of clinical disease - the so called "complicated" atheromatous lesion.
        • Calcifications may develop within the atheroma making it brittle.

        • The friable atheroma may rupture, or its surface may ulcerate, exposing its core to platelets and plasma coagulation factors which are activated and produce a thrombus or thromboembolus.

        • Rupture of the fibrous cap may lead to hemorrhaging into the plaque causing it to suddenly expand and abruptly narrow the lumen of an artery. This is particularly a problem in coronary arteries.

        • An atheroma expanding within the wall of a large artery may weaken the vessel and lead to aneurysmal dilation of the artery.

   3. What are the risk factors for atherosclerosis? - Table I summarizes risk factors that have been identified in epidemiologic studies as being associated with atherosclerosis. Note that some atherosclerosis risk factors (advancing age, male sex, and a positive family history) are not subject to therapeutic intervention or prevention strategies. However, other risk factors such as smoking, hypertension, hyperlipidemia, and diabetes can potentially be modified to reduce the incidence of atherosclerotic disease or slow its progression.

      
      

      TABLE I Risk Factors for Atherosclerosis Non-modifiable Age - The incidence of atherosclerotic complications increase with advancing age. For example the incidence of myocardial infarction increases by a factor of 5 between the ages of 40 and 60. Gender - Men are more prone to atherosclerotic disease than women. This difference diminishes after menopause, however. Family history - Atherosclerotic disease sometimes clusters in certain families. Polygenetic factors are believed to be responsible. Potentially Modifiable Hyperlipidemia - A major risk for atherosclerosis. Elevated levels of cholesterol (especially LDL cholesterol) is a greater risk than elevated levels of triglycerides. Hyperlipidemia may be related to diet and/or inherited defects in lipid metabolism. Inherited hyperlipidemias probably contribute to the increased risk seen in some families. Hypertension - Probably increases hemodynamic stress on endothelium. The incidence of atherosclerosis rises steadily as the systolic and/or diastolic blood pressure rises above normal range (140/90). Cigarette smoking - Probably contributes to endothelial injury. The death rate for ischemic heart disease increases by 200% when more than one pack of cigarettes are smoked for several years. Diabetes mellitus - Induces hypercholesterolemia. Other - Several other factors have been implicated in atherosclerosis. However, their pathophysiologic mechanisms have yet to be identified, or they are difficult to accurately quantify in patients. These factors include obesity, physical activity, emotional stress, postmenopausal estrogen deficiency, high carbohydrate intake, alcohol, and certain bacterial toxins. High levels of the amino acid homocysteine is toxic to endothelial cells and is known to contribute to atherosclerosis.

      
      

   4. What are the clinical consequences of atherosclerosis?
      • Chronic Ischemia - As atheromas slowly grow, they progressively narrow the lumen of an artery and gradually reduce blood supply to those tissues supplied by the artery. Chronic ischemia can lead to atrophy of an organ as is seen in renal artery stenosis. Chronic ischemia of the coronary arteries is responsible for the syndromes of angina pectoris and sudden cardiac death. Narrowing of the iliac, femoral or popliteal arteries leads to syndromes of peripheral vascular disease such as intermittent claudication.

      • Thrombosis and acute vascular occlusion - Acute arterial occlusion by thrombosis on, or hemorrhage into, an atherosclerotic plaque leads to an abrupt decrease in blood flow through the affected vessel and causes ischemic injury to those tissues supplied by the vessel. (Myocardial infarction, stroke, mesenteric infarction, or gangrene in lower extremities.

      • Thromboembolus - A thrombus formed over an atherosclerotic plaque may detach and be carried downstream causing acute arterial occlusion and tissue/organ infarction (TIA, embolic stroke, etc.).

      • Aneurysm formation - Atherosclerotic lesions may extend into the media of large arteries leading to weakening of arterial walls and aneurysm formation. This is particularly a problem in the abdominal aorta.

2. In addition to atherosclerosis, other mechanisms for arterial thrombosis and thromboembolism include:
   1. Bacterial endocarditis
      
   2. Rheumatic heart disease and autoimmune vasculitis
      
   3. Atrial fibrillation
      
   4. Aortic aneurysms
      
   5. Sickle cell disease
      
   6. Prosthetic heart valves

Venous Thrombosis and Thromboembolism

1. The annual incidence of venous thrombosis in the U.S. is 1 to 3 individuals per 1000 per year. Venous thrombosis typically develops in the large veins of the pelvis and lower extremities (deep venous thrombosis - DVT). Other less common locations for venous thrombosis include cerebral, hepatic, retinal, mesenteric, or axillary veins.

   1. What is the clinical presentation for deep venous thrombosis? - The most common presentation for DVT is unilateral leg edema - typically with redness and warmth in the affected extremity. Pain and calf tenderness may also be seen; however, many patients with DVT may present without these symptoms. The most reliable way to diagnose DVT is by venous ultrasonography.

      
      

   2. What happens to a thrombus after it forms in a vein?
      • The fibrinolytic system may completely degrade the clot allowing normal blood flow to return ("resolution").

      • The thrombus may "propagate" - accumulate more fibrin and platelets and grow along the course of the vessel. This is particularly a problem in the lower extremities where thrombosis of a calf vein (low risk for pulmonary embolus) propagates proximally into the larger veins of the thigh and pelvis (high risk for pulmonary embolus).

      • The most dangerous consequence of deep venous thrombosis is fragmentation of the thrombus with embolization into the pulmonary artery via the vena cava and right side of the heart (pulmonary embolus). Occlusion of small pulmonary arterioles leads to segmental pulmonary infarction. Occlusion of the main pulmonary artery by a large thromboembolus can cause acute right sided heart failure, cardiovascular collapse, and sudden death. The most common clinical manifestation of pulmonary embolus is sudden dyspnea and tachypnea. Occasionally, a pulmonary embolus is accompanied by pleuritic chest pain, cough and hemoptysis. Large pulmonary emboli may present with a clinical picture resembling acute coronary syndrome. Death from pulmonary emboli occurs in approximately 2% of all patients with DVT's.

      • The thrombus may become fibrotic and become incorporated into the wall of the blood vessel ("organization"). This leads to a permanent reduction in blood flow and the clinical picture of chronic venous insufficiency or post phlebitic syndrome (leg pain and swelling with hyperpigmentation of the skin and occasionally ulceration). In some cases new blood vessels may grow into the fibrotic thrombus and establish partial blood flow ("recanalization") and symptoms of venous insufficiency.

      
      

   3. What are the risk factors for deep venous thrombosis? - Most DVT's occur in situations associated with venous stasis, vein injury, and/or hypercoagulability. The majority of DVT's and pulmonary emboli appear to result from the interaction between some inherited predisposition for clot formation and acquired factors that trigger coagulation.
      • Acquired risk factors
        • Age - The incidence of venous thrombosis increases with advancing age. Venous thrombosis is very unusual in children but occurs in as many as 1% of the elderly (compared to 1 in 1000 younger adults).

        • Immobilization - Paralysis, prolonged bed rest, wearing a plaster cast, and even long airplane flights are associated with venous stasis and DVT's.

        • Surgery and Trauma - Major surgery is an important risk factor for venous thrombosis - especially abdominal, gynecologic, urologic, and orthopedic surgery. Orthopedic surgery involving the hip and knee is associated with a venous thrombosis rate of 30-50%. Venous thrombosis is also common in patients with head trauma, spinal injury, pelvic fracture, femoral fracture, and tibial fracture.

        • Oral Contraceptives - Even low dose estrogen preparations and hormone replacement therapy in menopausal women have a 2-4 fold increased risk for venous thrombosis.

        • Pregnancy - Venous thrombosis occurs in about 1 out of every 1500 pregnancies (this risk is 5 times greater than would be expected in non-pregnant women). The risk for thromboembolic disease during pregnancy is multifactorial:
          • Normal pregnancy is accompanied by a hypercoagulable state. Coagulation factors and fibrinogen levels are increased. Protein S levels are decreased. Fibrinolytic activity is markedly reduced.
            
          • Compression of the inferior vena cava and iliac veins by the pregnant uterus produces venous obstruction and stasis.
            
          • Local damage to pelvic veins may occur during vaginal and Caesarean delivery.

          Thromboembolic risk is even higher with preeclampsia (and other obstetric emergencies), Caesarean section, and during the post-partum period.

        • Active Malignancy - Venous thrombosis is a frequent complication of cancer. This results from either increased production of procoagulants by malignant cells, obstruction of veins (and stasis) by growing tumors, or immobility in very ill cancer patients. Vessel injury caused by radiation therapy or chemotherapy also contributes to the risk for venous thrombosis in the cancer patient.

        • Other - Hyperviscosity due to polycythemia vera or multiple myeloma increases thromboembolic risk. Nephrotic syndrome, obesity, inflammatory bowel disease, and cardiomyopathy - all are poorly understood risk factors for venous thromboembolus. As noted above, hyperhomocysteinemia and antiphospholipid syndrome are also associated with an increased risk for venous thromboembolic disease.

        
        

        Relative Risk of Venous Thromboembolic Disease
        Thromboembolic Risk Factor	Relative Risk
        Factor V Leiden (heterozygous) Factor V Leiden (homozygous) Factor V Leiden homozygous) + OCP's Prothrombin Gene Mutation (heterozygous) Prothrombin Gene Mutation (homozygous) Protein C Deficiency (heterozygous) Protein C Deficiency (homozygous) Protein S Deficiency (heterozygous) Protein S Deficiency (homozygous) Antithrombin III Deficiency (heterozygous) Antithrombin III Deficiency (homozygous) Hyperhomocysteinemia Antiphospholipid syndrome	5-7 x Normal 80 x Normal >100 3 x Normal ?? 7 x Normal Severe thrombosis at birth 6 x Normal Severe thrombosis at birth 5 x Normal Probably lethal before birth 2-4 x Normal 10 x Normal

        
        

      • Inherited risk factors (Inherited Thrombophilia) - Qualitative defects or quantitative deficiencies of any anti-thrombotic protein predisposes individuals to thrombosis. The overall lifetime risk for venous thromboembolism with an inherited thrombophilia is about 50%. Additionally, women with inherited thrombophilias are more likely to develop venous thromboemboli while taking oral contraceptives, and are more likely to have miscarriages and stillbirths.
        • Antithrombin III, Protein C, and Protein S Deficiency - These substances are important components of the body's natural anticoagulation system which balances the process of clot formation. Protein C, and its co-factor Protein S, are important for degrading activated coagulation factors V and VIII. Antithrombin inactivates thrombin and activated factors X, IX, XI, and XII. Deficiencies in any of these proteins causes hypercoagulability.

          Antithrombin III, Protein C, and Protein S deficiency were the first genetic causes of venous thrombosis to be recognized. However, they are rare. Together, these three disorders occur in less than 1% of the U.S. population overall.

        • Factor V Leiden - This is the most common form of inherited thrombophilia occurring in about 5% of caucasians and in up to 60% of patients with recurrent venous thromboembolic disease. This disorder is due to a mutation in Factor V which makes it resistant to degradation by Protein C. This condition is also called Activated Protein C Resistance.

        • Prothrombin Gene Mutation - Prothrombin G20210A is a mutation in the prothrombin gene that produces higher than normal levels of prothrombin in the blood.

        • Other - Inherited defects in fibrinolysis or the presence of abnormal fibrinogens (dysfibrinoginemia) are very rare causes of venous thrombosis.

      
      

   4. What are the clinical consequences of venous thrombosis and thromboembolism?
      • Pulmonary embolus

      • Pulmonary hypertension

      • Post phlebitic syndrome and chronic venous insufficiency

      
      

   5. Which patients should be referred for a workup to rule out an inherited thrombophilia? - Most patients with DVT's have an obvious provocative risk factor present such as surgery, immobilization, cancer, etc. These patients are usually treated with a 3-6 month course of anticoagulation and do not require laboratory evaluation for thrombophilia.

      However, individuals with an inherited hypercoagulable disorder may require long-term anticoagulation. Because of that, patients presenting with any of the following features should probably be referred to a hematologist for evaluation to rule out thrombophilia:

      • A strong family history of arterial or venous thrombosis.

      • Personal history or family history of recurrent venous or arterial thrombosis.

      • Venous thrombosis in unusual sites (mesenteric veins, hepatic veins, dural venous sinuses, veins of the neck or upper extremities).

      • Initial arterial or venous thrombosis occurring before the age of 45-50 years - especially if no provocative risk factor is evident.

      • Women with thrombosis associated with oral contraceptives or pregnancy.

   
   

   Anticoagulation therapy for venous thromboembolic disease: Patients diagnosed with DVT or pulmonary embolus are usually treated with anticoagulation therapy. Treatment is typically divided into several phases: (1) Initial therapy, (2) Subacute therapy, and for some patients (3) Long-term anticoagulation: Initial anticoagulation therapy Indication: All patients. Medication: Heparin (IV or SC UFH* or SC LMWH**). One common dosage schedule for UFH involves an initial IV bolus dose of 5,000 U followed by 1,280 U/hr Duration: 4-7 days. Patient Monitoring: IV UFH is monitored by the PTT every 4-6 hours (target PTT 1.5-2.5 x normal). Factor Xa assay or plasma heparin levels can also be used for monitoring therapy. LMWH dose is weight based. LMWH has a more predictable dose-response and does not require laboratory monitoring. The PTT is not a sensitive test for monitoring the anticoagulation effects of LMWH. Subacute anticoagulation therapy Indication: All patients Medication: Oral Warfarin*** (Coumadin) begun 1-2 days after starting heparin or when PTT is prolonged >1.5 times normal. Heparin should be continued for a minimum of four days after Warfarin is started. Warfarin dose is individualized based on INR. Initial dose usually 2-5 mg/day p.o. Once-daily dosing of LMWH is also effective for subacute therapy. Duration: Up to 3-6 months. Patient Monitoring: INR in target range of 2.0-3.0. LMWH is dosed based on patient weight and does not require laboratory monitoring. Long-term anticoagulation therapy Indication: - Patients with an inherited thrombophilia, recurrent thrombosis, or ongoing thrombotic risk factors Medication: Oral Warfarin (coumadin). Once daily dosing of LMWH is being investigated as an alternate chronic anticoagulation therapy. Duration: Greater than six months. Patient Monitoring: INR if Warfarin therapy is used (target range 1.5-2.0 - greater for high risk patients). *   UFH = Unfractionated heparin **   LMWH = Low Molecular Weight Heparin ***   Warfarin is contraindicated during pregnancy. The drug crosses the placenta and can cause fetal hemorrhage. Warfarin has also been associated with fetal malformations. Heparin is the preferred anticoagulant for venous thromboemboli during pregnancy.

   
   

   Not all emboli are thromboemboli. Other types of clinically significant emboli include: Air embolism - Introduction of large amounts of air (usually greater than 100 ml) into the circulation can physically obstruct blood flow. This can impair blood return to the right side of the heart, or impair circulation to the lungs or brain. Air embolism most commonly occurs in the setting of neck wounds, thoracentesis, punctures of large veins, and with hemodialysis. Air embolism is also part of the clinical picture of decompression sickness seen in deep sea divers. Amniotic fluid embolism - This disorder occurs during labor when amniotic fluid and fetal cells enter the maternal circulation through open uterine veins. Because amniotic fluid is highly thrombogenic, pulmonary emboli or even DIC can result from amniotic emboli. Fat (bone marrow) embolism - Fractures of long bones, sternum, or ribs may release hematopoietic cells and fat into the circulation. Embolization to lungs or brain may occur.