ACUTE VENOUS THROMBOEMBOLISM:
PROPHYLAXIS

     Autopsy continues to verify that venous thromboembolism (VTE), subcategorized as deep venous thrombosis (DVT) and pulmonary embolism (PE), too often goes undetected and even unsuspected. With an estimated 250,000 new cases of deep venous thrombosis per year 50,000 - 100,000 cases of pulmonary embolism per year, up to 10% of all hospital deaths in this country are attributed to pulmonary embolism; and chronic venous insufficiency afflicts many thousands of those who have had deep venous thrombosis.
     Diagnosis is made difficult by a number of factors. Since many thrombi incompletely obstruct the involved veins, deep venous thrombosis is frequently asymptomatic, with less than 30% of victims showing symptoms of pain, swelling and Homan's sign. Collateral vasculature will generally compensate to further mask the obstruction. Pulmonary emboli can be similarly difficult to diagnose because 80% occur without clear clinical symptoms. Death comes within 30 minutes of the occurrence of two thirds of lethal pulmonary emboli; but the risk factors for pulmonary embolism exist for an average of four to five weeks after hospital discharge.
     The necessity of recognizing the risk factors and taking appropriate prophylactic action is highlighted by the fact that such therapy is perpetually underutilized. Recent analyses of hospital practices have shown that prophylaxis is employed in 44% of high-risk cases, even in teaching hospitals; and patients in non-teaching hospitals fared far worse at only 19%. The simple triad of risk factors for developing venous thrombosis (Virchow’s triad) includes stasis, venous endothelial injury, and hypercoagulability. Venous valves, where blood tends to stagnate during periods of immobilization are a primary concern. Thus, any hospitalized patient suddenly immobilized to lesser or greater degree by surgery, trauma, paralysis, or simply by being confined to bed may be a candidate for prophylaxis, depending on the assessment of other risk factors. Though detection via duplex ultrasonography is possible, screening has proven less than cost-effective, leaving prophylaxis the best option by far.
     Graduated compression stockings (GCS), intermittent sequential pneumatic compression devices (ISCD), pneumatic foot pumps (booties), and inferior vena caval filters are all viable mechanical means of thromboembolic prophylaxis; and they may be employed with or without pharmacological methods, depending on assessed risks. Currently, low-dose (unfractionated) heparin (LDH), the low molecular weight heparins (LMWH), and warfarin comprise the pharmacological arsenal.
     Adjusted-dose heparin (ADH) using unfractionated heparin subcutaneously depends on dosing based on PTT adjustment to 1.5 times normal prior to administering the next dose, usually at six to eight-hour intervals. It has been effective for deep venous thrombosis prophylaxis, especially in orthopedic procedures; but constant dosage adjustments and lab monitoring make it impractical with the availability of low molecular weight heparin. Dextran has also been used in deep venous thrombosis prophylaxis for general surgical patients; but required continuous infusion, cost, and volume expansion properties make it an impractical choice for most applications. Aspirin is not currently felt to be an effective agent for deep venous thrombosis prophylaxis.

Risks and Prophylaxis for Different Patient Groups
     In general, the risk of venous thrombosis is increased with advancing age, with previous medical history of venous thrombosis, and with familial history of venous thrombosis. Among general surgery patients without prophylactic measures, deep venous thrombosis can be expected 19% of the time; while among those patients with a prior history of venous thrombosis, deep venous thrombosis can be expected fully 50% of the time. The percentages are higher for total knee replacement. Trauma to the pelvis (including hip fracture) and lower extremities increase the chances of mortality from pulmonary embolism. Emboli from upper extremities are less common and usually attributable to central venous catheters or trauma, when a cause can be identified. 
     Malignant disease, especially of the lung, stomach, pancreas, breast, and genitourinary tract, carries a high risk of deep venous thrombosis, with confinement to bed contributing further to risks in this group. Oral contraceptives, especially third-generation agents containing a progestogen like gestodene or desogestrel, should be prescribed with an evaluation of existing venous thrombosis risk factors in mind.
     Pulmonary embolism is the leading cause of maternal mortality following live birth in this country, with deep venous thrombosis and pulmonary embolism equally common in the antepartum and postpartum periods. Parity, obesity, bedrest, caesarean section, previous venous thrombosis, increased venous capacitance, IVC compression, and possibly increased clotting factors all increase the risks of deep venous thrombosis, pulmonary embolism, and complications therefrom. Though little prophylaxis data during pregnancy exists, pregnant patients with previous history of venous thrombosis should receive LDH 7500 units SC every 12 hours for the first 36 weeks of pregnancy, then 10,000 units every 12 hours until delivery.
     Inherited risk factors (coagulopathies) can also confer different degrees of risk. Patients with factor V Leiden (activated protein C resistance), protein C or protein S deficiency, antithrombin III deficiency, dysfibringenemia, or plasminogen disorders may or may not remain free of thromboembolic disease until other risk factors are imposed.

Table of Clinical VENOUS THROMBOSIS Risk Factors
Age over 40 Obesity
Oral contraceptive therapy Pregnancy
Prior venous thrombosis
Familial history venous thrombosis
Prior major trauma or surgery
Hip fracture
Bedrest/immobilization
Paralysis
Venous stasis/Varicose veins
Myocardial infarction/Stroke
Congestive Heart Failure
Cancer
Paroxysmal nocturnal hemoglobinuria
Antiphospholipid antibody syndrome (lupus anticoagulant)
Inherited coagulopathies

Prophylactic Pharmacology
     Unfractionated heparin is a complex of saccharide polymers with molecular weights between 3 and 30,000; and it has been in use since the 1930s derived from porcine or bovine sources. Its anticoagulant effects depend upon a specific pentasaccharide sequence present in only 30% of the molecules in the conglomerate, which interacts with antithrombin III (AT-III) and the serine proteases involved in the clotting process, factors IIa, IXa, Xa, and XIa. Fibrinolytic effects and platelet inhibitory effects are produced by other polymers in the conglomerate.
     Consistent bioavailability of heparin may be difficult to achieve due to its strong affinity for other proteins, necessitating frequent laboratory monitoring of PTT. A dose of 5,000 units of unfractionated heparin given subcutaneously every eight to twelve hours for prophylaxis rarely produces full anticoagulation and thus little risk of bleeding. Most of the dose is bound by endothelium and simply reinforces endogenous heparin activity. It is essential to administer enough heparin, as failure to achieve adequate anticoagulation at 24 hours is the strongest predictor of repeat thrombosis.
     An initial drip rate of 1400 units per hour should follow a bolus of 5,000 units or even 10,000 units for pulmonary embolism or larger thrombi; and aPTT is checked six hours after the bolus. With therapeutic range between 60 and 90 seconds (1.8 to 2.8 times control), an aPTT reading above that range may only reflect the bolus. Reducing the infusion rate at that point may fail to achieve therapeutic effect. The following nomogram is a good guide for adjusting flow.

Heparin Nomogram: Initial infusion rate = 1400 units/hr

      Bleeding with heparin therapy is also a function of relevant risk factors: Age over 60, aspirin or NSAID usage, liver disease or other severe illness like cardiovascular disease or cancer. Patients with such risk factors can be expected to bleed in about 20% of the cases, while those without bleed only 1% of the time. Though a close correlation exists between underdosing with heparin and recurrent thrombisis, the correlation does not exist between supratherapeutic aPTT and bleeding.
     Heparin can also cause thrombocytopenia, a drop in platelet count below 150,000/mm3 that becomes apparent between days 3 and 15 of therapy. It is mediated by activation of platelets by heparin-dependent IgG antibodies and requires platelet aggregation studies for assessment and cessation of all heparin – drips, flushes, and heparin-coated lines.
      Low Molecular Weight Heparins contain only the polymers required for antithrombin III activation, producing greater specific antithrombotic activity, less antiplatelet activity, and improved anti-Xa activity. Compared to unfractionated heparin, the low molecular weight heparin products exhibit comparable or greater efficacy and safety, and better bioavailability. They can be administered subcutaneously and dosed only once or twice daily with longer half-lives, require no lab monitoring, result in less phlebotomy, afford earlier ambulation, and facilitate home therapy in some circumstances. Their dose response is more predictable; they are protein-bound to a lesser extent; and they have greater bioavailability.
     Ardeparin therapy should be begun in the evening of the day of surgery or the morning after, to be continued until the patient is ambulatory or up to two weeks. Dalteparin therapy should begin one to two hours before surgery with daily doses for five to ten days. In high-risk patients, another 2,500 units can be given twelve hours after the first; or the initial dose may be 5,000 units. Subsequent daily doses can also be 5,000 units.    
     Enoxaparin therapy should be initiated 12 to 24 hours after surgery and continued for 7 to 10 days. It has been approved for home use following total hip replacement in a single daily dose of 40mg for up to three weeks. Therapy for abdominal surgery should begin two hours before surgery and continue for 7 to 10 days.

Low Molecular Weight Heparins

Warfarin
     Inhibiting the vitamin K-dependent gamma-carboxylation of factors II, VII, and X, full anticoagulant effect (reduction in prothrombin and factor X) generally takes several days. Heparin therapy should be continued for at least 24 hours after reaching target prothrombin times to compensate for this lag time.

Medical Patients
     When medical patients are at risk of deep venous thrombosis, 5,000 units of subcutaneous heparin every 8 to 12 hours is usually sufficient for prophylaxis, though mechanical prophylactic measures can take its place when contraindicated. Patients at very high risk might benefit from employing both measures. The risk of deep venous thrombosis in this group is 4% for all patients, 20% for patients with heart failure or pneumonia, and up to 80% for patients with stroke.

General Surgery
     Non-orthopedic surgical patients are categorized according to level of risk, with low-risk patients being less than forty years old with no other risk factors of venous thrombosis and undergoing uncomplicated minor surgery of less than 30 minutes in duration. They generally require no prophylactic measures. Medium-risk patients are older than forty with no other risk factors undergoing major surgery of more than 30 minutes in duration. One of the following measures should be employed: Elastic stockings, heparin at 5,000 units every 12 hours, or intermittent pneumatic compression devices (IPC).
     High-risk patients are older than forty with other risk factors of venous thrombosis and undergoing major surgery. Heparin at 5,000 units every 8 hours, a low molecular weight heparin, or IPC is appropriate prophylaxis. Very-high-risk patients are the same as high-risk patients with a history of venous thrombosis, cancer, hip fracture, orthopedic surgery, spinal cord injury, or stroke. Low molecular weight heparin therapy, warfarin therapy, a combination of IPC with heparin or LMWH, or adjusted-dose heparin therapy is recommended.

Knee Surgery
     These patients have a 60% risk of deep venous thrombosis in a calf vein with a relatively low risk of pulmonary embolism except in bilateral surgery. Ardeparin at 50 units/kg every 12 hours produces predictably good results in unilateral surgery, but bilateral patients may require adjusted-dose heparin or warfarin therapy.

Elective Hip Surgery (Hip Replacement)
     With a 50% risk of deep venous thrombosis, 11% risk of pulmonary embolism, and 2% risk of fatal pulmonary embolism, this is a high-risk situation requiring enoxaparin at 30mg every 12 hours, though warfarin and adjusted-dose heparin are also effective. Pneumatic booties are considered less effective; and therapy should be continued for three to four weeks in high-risk patients, since many deep venous thromboses occur after the first post-op week.

Hip Fracture
     The risk of deep venous thrombosis here is 80%, 20% for pulmonary embolism, and 7% for fatal pulmonary embolism; and about 10% of these patients have had prior deep venous thrombosis. Adjusted-dose heparin or a low molecular weight heparin is most appropriate for this very high-risk group.

Orthopedic Surgery With Other Risk Factors
     This very high risk is prophylaxed with pneumatic booties and either adjusted-dose heparin or a LMWH. The booties are continued for a month post-op in combination with warfarin therapy.