1. 
   

   Which hospitalized patients are at risk for venous thromboembolism?

   
   
2. 
   

   Who is at increased risk for complications from thromboprophylaxis?

   
   
3. 
   

   How do you make sure that thromboprophylaxis is prescribed to all patients who should get it?

Many patients have an increased baseline propensity for thrombosis due to underlying hypercoagulable states, the majority of which are acquired. An acute insult may then result in hospitalization, which usually further increases the risk due to immobilization, procedures including central venous catheter placement or pacemaker, and/or administration of certain drugs. The main question in most patient groups detailed below is whether they can expect a net benefit from pharmacologic thromboprophylaxis, mainly low-molecular-weight heparins (LMWHs). Ideally, one has to balance the risk and consequences of venous thromboembolism (VTE) with the risk of bleeding and other complications of anticoagulants in every patient, while also taking the values and preferences of that patient into consideration. To facilitate this balancing process, institutions and national and international organizations have developed guidelines for the use of thromboprophylaxis. The use of these guidelines and local protocols has greatly improved patient outcomes, mainly by increasing the use of pharmacologic thromboprophylaxis in patients at risk for VTE. The authors strongly advise the development and implementation of a local protocol.

Deficiencies of Natural Inhibitors of Coagulation

Less than 1% of the general population has a congenital deficiency of one of the natural inhibitors of coagulation: antithrombin, protein C, and protein S. These deficiencies are associated with a high lifetime risk of VTE (60–70% in a recent study) and with a high risk of recurrence after a first event (50% after 10 years). A limitation to these data is that they are derived from highly selected families, which might have led to an overestimation of risk. No population-based data are available.

Acquired protein C deficiency may be seen with disseminated intravascular coagulation (DIC), extensive deep vein thrombosis (DVT), severe liver disease, infection, malignancy, acute respiratory distress syndrome (ARDS), the hemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP), and following L-asparaginase therapy. Although levels of protein C may decrease postoperatively, the significance is unknown. Acquired protein S deficiency may be seen with DIC and severe liver disease. Total and free protein S decrease steadily during pregnancy, with the lowest levels at term. Acquired antithrombin deficiency may be seen due to decreased synthesis (liver disease, following L-asparaginase therapy), malnutrition, or consumptive states (acute thrombosis, DIC, malignancy, pre-eclampsia). Most patients, however, will have normal antithrombin levels within 24 hours of initiation of heparin therapy. A clue to antithrombin deficiency may be inadequate or failure of activated partial thromboplastin time (PTT) to prolong during intravenous heparin therapy. Because protein C and protein S are vitamin K–dependent factors, warfarin-induced skin necrosis may occur with these deficiencies.

Patients with a known deficiency, primarily of antithrombin but to some extent also protein C and protein S, have a strong indication for pharmacologic thromboprophylaxis in any situation that increases the risk of thrombosis, including lower-limb immobilization, pregnancy, and bed rest as a medical patient. Given the high risk of recurrence, long-term anticoagulation should be considered in these patients after the first episode of VTE, especially if it was unprovoked (ie, not associated with a transient major risk factor for VTE, such as major surgery or trauma).

The utility of testing for a deficiency of a natural inhibitor is strongly debated, mainly because of its low prevalence. Testing in the context of thromboprophylaxis is not indicated. Even in patients who present with DVT, the prevalence of these deficiencies is so low that testing is rarely cost effective. Most centers limit thrombophilia testing to those patients who are young, who have recurrent VTE, or who have a strong family history.

Common Thrombophilic Mutations

Heterozygous factor V Leiden (causing resistance to degradation by activated protein C) and prothrombin mutation occur in 5% and 2% to 3%, respectively, of the Caucasian population and rarely in other races. The lifetime risk of VTE associated with these mutations is 5% to 10% in unselected populations. While the risk of a first VTE is increased, these mutations hardly increase the risk of recurrence after a first event. Testing for factor V Leiden and prothrombin mutation is not recommended in routine clinical practice, as their (heterozygous) presence does not influence the indication for, or intensity of, thromboprophylaxis or the duration of treatment for VTE.

Elevated Levels of Factor VIII

Increased levels of coagulation factor VIII are a mild risk factor for VTE. As with heterozygous factor V Leiden and prothrombin mutation, routine testing for high factor VIII in patients who present with VTE is not useful. A previously documented high level of factor VIII does not influence the indication or intensity of thromboprophylaxis.

However, evidence is accumulating that high levels of factor VIII and D-dimers in patients one month after discontinuation of anticoagulation for VTE might predict a high risk of recurrence of VTE. It is not yet common clinical practice to tailor duration of anticoagulation according to these tests, but trials are ongoing.

Homocysteinemia and Homocystinuria

Deficiency of folic acid or vitamin B12 accounts for approximately two-thirds of patients with elevated plasma homocysteine levels. This condition becomes more prevalent with increasing age, end-stage renal disease, and in pregnancy, and has been associated with occlusive arterial disease and with VTE, often at unusual sites (thrombosis in the central, cerebral, or splanchnic veins). Certain mutations that result in a high homocysteine level have only been weakly associated with VTE, and lowering of the level with vitamin supplementation has not been shown to be effective in reducing the risk of thromboembolism.

Homocystinuria, an autosomal recessive disease resulting from cystathionine beta-synthase deficiency, is associated with a tenfold or greater increase in homocysteine levels and has a prevalence of four per million. Approximately 20% of affected patients suffer from arterial and venous thromboembolism.

Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is defined as a combination of laboratory evidence (ie, presence of lupus anticoagulant or antibodies against cardiolipin or β2-glycoprotein I) and clinical manifestations (ie, at least one thrombotic event or obstetric complications). Thromboembolic events are more often venous than arterial and often involve unusual locations. The strongest laboratory association with thromboembolism is for lupus anticoagulant, followed by β2-glycoprotein I antibodies, and then cardiolipin antibodies; combined serologic abnormalities result in even stronger associations. When the APS is secondary to systemic lupus erythematosus, the presence of lupus anticoagulant or antibodies against cardiolipin increases the risk of VTE sixfold and twofold, respectively.

Primary prophylaxis with anticoagulation in APS should be provided for high-risk situations (surgery, trauma, puerperium), whereas aspirin is suggested for prophylaxis during pregnancy.

After a VTE event, secondary prophylaxis should be with the same intensity (warfarin with a target international normalized ratio (INR) of 2.0–3.0) as for other VTE. The duration of anticoagulation needs to be assessed after three to six months, taking into account whether the event was unprovoked, the presence of multiple serologic abnormalities, the serologic titer, compliance, and patient preferences. The risk of recurrence, including fatal events, is increased and some patients may experience recurrence in spite of anticoagulant therapy. This may be due to falsely prolonged coagulation times, and a switch from warfarin to long-term LMWH, or to monitoring warfarin with a coagulation factor X method, is then helpful. Patients with APS and arterial events should receive aspirin since there is no evidence that warfarin is more effective. Pregnancy loss in APS is most typical in patients with systemic lupus or with previous pregnancy complications. For these patients, heparin (unfractionated or LMWH) in combination with aspirin provides the highest success rate regarding live births.

The catastrophic APS (cAPS, Asherson syndrome) is characterized by microthrombi, anemia with schistocytes, and thrombocytopenia and is often triggered by an infection. The clinical course is rapid with multiorgan failure (usually pulmonary, cardiac and renal) and about 50% mortality, but this occurs only in 1% of patients with APS. Treatment with a combination of intravenous heparin, high-dose corticosteroids, and plasma exchange results in the highest rate of recovery (78%). The addition of intravenous immunoglobulin does not seem to improve the prognosis. The survivors may sometimes develop additional APS manifestations, but relapse of cAPS is very unusual.

Medically ill patients have a moderately increased risk of VTE, depending on their conditions, age, and treatments. In addition to potentially preventable mortality due to pulmonary embolism, VTE in medically ill patients prolongs hospitalization and increases costs. A growing body of evidence shows that thromboprophylaxis is underused in this patient group.

Pharmacologic prophylaxis is recommended for all patients admitted with congestive heart failure, severe respiratory disease, and those in intensive care unless there is an increased risk of bleeding. Hospitalized patients who have no contraindications should be prescribed pharmacologic prophylaxis if they have additional risk factors for VTE, including previous VTE, known thrombophilic states pregnancy (discussed later), inflammatory diseases, or malignancy. In case of recent, current, or high risk of bleeding, compression therapy of the legs should be used.

The elderly have a higher risk of VTE but also a higher risk of bleeding. Clinicians tend to overestimate the risk of bleeding and to underestimate the risk (and consequences) of VTE, thus withholding thromboprophylaxis from patients who are likely to benefit. However, older patients are more likely than younger patients to have renal dysfunction, which increases the bleeding risk with any anticoagulant. In patients with a creatinine clearance less than 30 ml/min, unfractionated heparin or vitamin K antagonists might be preferred over LMWH.

Sickle cell disease is associated with hypercoagulability through activation of both plasma coagulation and platelets. Ischemic stroke, pulmonary hypertension, avascular joint necrosis, and leg ulcers are viewed as thrombotic complications. The hypothesis that antiplatelet agents, warfarin, and heparin can prevent vasoocclusive events and subsequent complications has been tested, but studies were small and results not conclusive. Therefore, maintenance antithrombotic therapy is not routinely given. Patients who are hospitalized with a sickle cell crisis should be given thromboprophylaxis to prevent VTE.

Patients with the nephrotic syndrome have an increased risk of renal vein thrombosis, deep vein thrombosis, and pulmonary embolism. This is probably mediated by imbalances between pro- and antithrombotic factors. Estimates of the absolute risk vary from 2% to 40% of patients during their course of disease, with higher incidences in older studies. Randomized studies to guide prophylactic anticoagulant treatment in these patients have not been performed. Clinical practice is to consider vitamin K antagonists in patients with serum albumin below 2.0 to 2.5 g/dL (20 to 25 g/L) who do not have an increased risk of bleeding, especially when other risk factors including previous VTE, positive family history, and high body mass index are present.

The risk of VTE and need for adequate thromboprophylaxis in postoperative patients is well established. Early ambulation is sufficient in low-risk patients who undergo minor or laparoscopic or arthroscopic procedures, and mechanical prophylaxis can be used in patients with increased risk of bleeding, but all others should receive pharmacologic prophylaxis. This includes patients who undergo major general, orthopedic, gynecologic, urologic, and thoracic surgery. A prophylactic dose of LMWH is adequate for most patients, with fondaparinux as an alternative, and subcutaneous unfractionated heparin for patients with renal dysfunction. In most patients, thromboprophylaxis is given until discharge. For very high-risk patients (for example, major surgery for malignancy in a patient with previous VTE), thromboprophylaxis should be continued for about a month after surgery.