Risk Factors for Venous Thromboembolism and Duration of Anticoagulation Therapy

An adequate regimen for prophylaxis of venous thromboembolism (VTE) requires indentifi cation of reversible and irreversible risk factors. Recent data confi rm that the greatest number of pulmonary emboli (PE) occur in non-surgical patients. VTE also develops in many surgical patients upon hospital discharge. These fi ndings emphasize the need for adequate VTE prophylaxis in infl ammatory diseases, acute medical illness, and other conditions, as well as the need to optimize anticoagulant regimens after surgery. Establishing VTE risk factors, identifying acquired or inherited thrombophylias and occult or previously undiagnosed malignancy will help design an adequate anticoagulant regimen as secondary VTE prophylaxis for surgical and other patients. Follow up measures should include D-dimer values, ultrasonographic assessment of residual venous thrombosis and echocardiographic parameters, along with other relevant clinical data to assess the risk of VTE reoccurrence. These procedures will ensure the optimal duration of individually tailored anticoagulant therapy, with special attention to comorbidities and tendency to hemorrhage.

Venous thromboembolism (VTE) is the third leading vascular cause of mortality after myocardial infarction and cerebrovascular insult. 1 It is the most preventable disorder.Thus improving measures to prevent VTE remains a top clinical priority. 2Over two-thirds of all symptomatic VTE occur in patients that were not subjected to surgical procedures. 3It was reported that 47-76% of all clinical VTE events after hip and knee surgery occur after hospital discharge, and it is recommended to extend VTE prophylaxis in such patients. 3,4though venous thromboembolism is often present in surgical patients during the postoperative period, 70-80% of fatal pulmonary emboli (PE) develop in nonsurgical hospital patients.In 40% of such cases, an age factor is associated with other risk factors, such as previous VTE, malignancy, cerebrovascular accident, heart failure, chronic obstructive pulmonary disease, sepsis and immobilization or confi nement to bed. 5 The incidence of venous thrombo-embolism increases with age, ranging between 1/10,000 per year in younger patients and 5-6/1,000 per year in people over 80 years. 5An increase in VTE-related morbidity correlates with a number of associated comorbidities, such as infl ammatory conditions, elevated acute-phase reactants and reduced anticoagulant proteins. 5evention and treatment of VTE requires key decisions for further management.These include determining the duration of anticoagulant treatment, selection of measures to prevent recurrent venous thromboembolism and VTE sequelae (pulmonary hypertension, post-thrombophlebitic syndrome) as well as appropriate diagnostic screening for thrombophilia and occult malignancy, along with defi ning reversible and irreversible risk factors for VTE. 6A number of authors give priority to establishing optimal anticoagulant treatment over detecting possible congenital thrombophilic states that indicate clinical risk factors for VTE. 6K 616.14-005

Classifi cation of risk factors for VTE
The various classifi cations and categorizations of risk factors for VTE are a mainstay for tailoring the optimal treatment of VTE patients to their individual characteristics. 7r example, Kaatz's categorization of VTE is particularly useful: VTE provoked by risk factors, cancer-related, idiopathic, thrombophilia-related and recurrent VTE. 7Another classifi cation is based on the strength of risk factors for VTE: strong risk factors for VTE with odds ratio > 10 include trauma or fracture, major orthopedic surgery, oncology surgery; moderate risk factors with odds ratio 2-9 include non-oncology surgery, use of oral contraceptives and hormone replacement therapy, pregnancy and puerperium, hypercoagulability state and previous VTE; weak risk factors with odds ratio <2 include advanced age, bed confi nement for longer than three days, imobility on long trips, metabolic syndrome and air pollution. 8The life-style or disease-associated risk factors for arterial and venous thromboembolism include obesity, diabetes mellitus, hypertension and smoking, 8 with special consideration given to the impact of dyslipidemia on VTE occurence.(Commonly known VTE risk factors [4][5][6][7][8][9][10] are presented in Table 1.) Risk factors for VTE often overlap with those for coronary heart disease (smoking, obesity, high consumption of red meat instead of a healthier diet of fi sh, fruit and vegetables, psychosocial stress, hypertension).The JUPITER study (Justifi cation for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) provides a convincing example of how risk factors for arterial and venous thromboembolism converge.Results of that study showed a reduction in VTE by 43% in the group treated with rosu-vastatin (20 mg daily) compared to the control (untreated) group. 9uer and Previtali 8,10 group the VTE risk factors into acquired (including antiphospholipid syndrome, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, infl ammatory bowel disease, Wegener granulomatosis, paresis/paralysis of lower extremities, etc.), inherited (defi ciencies of antithrombin, proteins C and S, factor V Leiden and prothrombin G20210A mutations, disfi brinogenemias) and mixed risk factors (hyper-homocysteinemia, resistance to activated protein C in the absence of factor V Leiden mutation, increased activity of factors VIII, IX, XI, thrombin-activated fi brinolysis inhibitor (TAFI), reduction of tissue factor pathway inhibitor (TFPI), and fi brinolytic activity).
Patients heterozygous for factor V Leiden have a three times higher risk for an initial VTE while homozygous individuals carry a 15-20-fold increased risk. 9Goldhaber considers the combination of homozygous factor V Leiden mutation, double heterozygotes for factor V Leiden and prothrombin G20210A mutation, defi ciencies of proteins C, S and antithrombin as well as antiphospholipid syndrome to be a particularly ominous setting for thrombophilia. 9though estrogens in the form of oral contraceptives or postmenopausal hormone therapy are well-known risk factors for VTE, it is interesting to note that the third-generation progestins, dezogestrol and gestodene also rank among risk factors for VTE. 9 In order to optimize an anticoagulation regimen for patients with VTE, one should establish the importance of their specifi c VTE risk factors by distribution into these Surgery, trauma (major or lower limb trauma) Long-term anticoagulant therapy is strongly recommended for patients with persistent nonreversibile risk factors, such as homozygous mutation of factor V Leiden, double heterozygotes for factor V Leiden and prothrombin G20210A mutations, protein C/S defi ciency, antiphospholipid antibodies. 11Interruption of anticoagulant therapy constitutes a greater risk for recurrent VTE in patients with previous proximal deep vein thrombosis (DVT) compared with the distal lower limb DVT. 12 Agnelli classifi es risk factors for VTE as transient (surgery, trauma, immobilization) or persistent (cancer and paralysis), but considers those individuals with idiopathic and spontaneous VTE to have no identifi ed risk factors for thrombosis.Numerous studies identifed male gender as a risk factor for recurrent VTE [relative risk (RR) 1,6; 95% confi dence interval (CI) 1,2-2,0]. 13The observation that the risk of fatal pulmonary embolism is two-three times greater after an episode of PE than after a DVT episode is also of clinical relevance. 13assifi cation based on risk for recurrent VTE Prandoni 14 defi nes several groups of risk factors for recurrent VTE: 1) persistent acquired risk factors (active malignancy, especially with metastasis and treated with chemotherapy, patients with chronic nonsurgical diseases who are immobilized for long periods of time), 2) major transient risk factors (previous surgery or trauma), 3) minor transient risk factors (minor trauma, long-haul fl ights, estrogen therapy, pregnancy and puerperium), 4) spontaneous VTE, 5) congenital thrombophilias (with special emphasis on the defi ciencies of proteins C and S and antithrombin, increase of factors VIII and IX, hyper-homocysteinemia).Although recent studies associating recurrent VTE with homozygous factor V Leiden and prothrombin 20210 remain controversial, it is indisputable that patients on one-year anticoagulation therapy regimens have a lower percentage of recurrent VTE than those on conventional three-month anticoagulation regimens.Lowering homocysteine levels with vitamin B12 supplementation does not reduce the risk of recurrent VTE.Prophylaxis of VTE in pregnancy must not be discontinued before the end of the puerperium (6 weeks after childbirth).
Patients with signifi cant transient risk factors should be treated for three months, but the duration of treatment could be less (six weeks) if thrombosis is localized to veins in the lower legs.Patients with minor transient risk factors require treatment tailored to the degree of hemorrhagic risk for each individual. 15Indefi nite anticoagulant treatment is recommended for patients with multiple episodes of VTE.This might include an implanted vena cava fi lter if anticoagulants are contraindicated as well as for individuals with antiphospholipid syndrome. 14ble 1 lists the most important risk factors for recurrence of VTE upon anticoagulant therapy discontinuation. 15Prospective studies in patients with VTE indicate a greater risk of recurrent VTE in patients who have high levels of D-dimer a month after termination of anticoagulant therapy. 13Identifi cation of these patients by D-dimer monitoring can single out those at greatest risk and help to prevent recurrent VTE. 14 In the PREVENT trial (Prevention of Recurrent Venous Thromboembolism), one group of patients with spontaneous VTE received anticoagulant (warfarin) therapy for six months, but measurement of D-dimer for seven weeks following warfarin withdrawal showed that those with increased D-dimer levels had a twofold higher recurrence rate.However, a meta-analysis of 1888 patients with spontaneous VTE suggests that the problem is not that simple.That study reported that 3.5% of patients have an annual risk for recurrent VTE despite normal D-dimer levels measured upon discontinuation of anticoagulant therapy. 15In a separate meta-analysis of idiopathic VTE studies, the recurrence rate was 7.2% for patients who had normal Ddimer values measured one month after discontinuation of anticoagulant therapy.Some reports suggest that elevation of D-dimer one or two months after therapy is associated with signifi cant risk of spontaneous recurrent thrombosis [hazard ratio 2.0, 95% confi dence interval (CI) 1.01 to 3.9]. 16The risk of recurrent VTE is 10% per year in men who have had spontaneous VTE with elevated D-dimer, whereas the risk of spontaneous VTE, or VTE caused by defi ned factors with negative D-dimer, in women is about 2%.Consequently, the benefi t of long-term anticoagulant therapy in these women remains vague. 16cording to Agnelli, the main predictors of recurrent thromboembolism are D-dimer levels and the presence of residual thrombosis. 13The hazard ratio for recurrent VTE was 2.4 in patients with persistent residual thrombosis (shown by venous ultrasonography) compared with those who had vein recanalization. 13The same author notes that recurrent VTE can be as high as 29% in patients positive for anti-cardiolipin antibodies after a fi rst episode of VTE compared with 14% of those without the antibodies (p <0.01).The PREVENT study established the effi cacy of prolonged anticoagulant therapy in patients with factor V Leiden and prothrombin G20210A mutations by showing that the annual incidence of recurrent VTE was reduced from 8.6% to 2.2% per year. 13e Vienna Prediction Model for Recurent VTE identifi es the risk of recurrent VTE in relation to sex, clinical presentation and laboratory values of D-dimer. 14,17[19][20][21][22][23][24][25][26][27] Duration of anticoagulant therapy for secondary prophylaxis depends upon the category of VTE According to Goldhaber, 9 the recommended duration of anticoagulant therapy for a fi rst attack of PE and/or DVT related to an identifi ed risk factor for VTE (surgery, trauma, oral contraceptives, pregnancy, hormone replacement therapy) is from three to six months with a target International Normalized Ratio (INR) 2-3.For patients with a fi rst episode of upper limb DVT or isolated lower leg DVT with identifi ed risk factors, a three-month course of anticoagulant therapy with an INR of 2-3 is advised.For a second attack of VTE provoked by an identifi ed risk factor, most clinicians recommend doubling the duration of anticoagulant therapy; a few of them favor so-called lifelong anticoagulation therapy, or indefi nite treatment.The ACCP (American College of Chest Physicians), NCCN (National Comprehensive Cancer Network) and ASCO (American Society of Clinical Oncology) reached a consensus that patients with malignancies should be treated with low-molecular-weight heparin (LMWH) during the fi rst from three to six months and then indefi nite anticoagulation therapy (vitamin K antagonists or LMWH).Table 3 shows the recommended duration of anticoagulant therapy for secondary prophylaxis of VTE 15 Aggressive use of anticoagulant therapy after the fi rst six months of treatment remains debatable.Many physicians continue the standard anticoagulant regimen with a target INR 2-3, whereas others consider a low-intensity anticoagulant regimen with a target INR 1.5-2 to be effective and safe. 15Three studies achieved a 90% risk reduction in patients with standard anticoagulation therapy and a target INR of 2.5 (range 2-3) with the extended regimen, while a low-dose regimen (INR 1.5-2) resulted in 60% risk reduction. 16Any decision on anticoagulant therapy cessation in individual patients should take into account that the annual incidence of major bleeding in patients on long-term anticoagulant therapy is 1.5-2%, and that case fatality rate or frequency of major bleeding episodes with fatal outcome is greater than the frequency of recurrent VTE.Consequently, for certain patients with high hemorrhagic risk, unconventional oral anticoagulant therapy with a target INR 1.5 to 2 should be considered. 14rsistent dysfunction or right ventricular enlargement after acute PE, residual DVT, non-recanalised DVT (confi rmed by venous ultrasonography), low HDL, male sex and body overweight are considered risk factors for recurrent VTE.In contrast, the fi nding of a persistent thrombus on chest computed tomography (CT) has no predictive value for the recurrence of pulmonary emboli (PE) since about half of PE appear as persistent defects in chest CT recordings six months after the initial event. 9,15Also, most thrombophilias do not increase the risk of recurrent VTE. 15 Clus-tered data from 10 studies (3104 patients enrolled with a fi rst episode of VTE) indicate an odds ratio for recurrent VTE to 1.72 (95% CI 1.27 to 2.31) in those with prothrombin mutation G20210A and a ratio of 1.41 (95% CI 1.14 to 1.75) with factor V Leiden mutation. 13Meta-analyses indicate that the incidence of recurrent VTE is higher immediately after discontinuation of anticoagulant therapy, but it tends to decrease over time.In addition, the onset of recurrent VTE nine months after discontinuation of anticoagulation therapy does not depend on the prior therapy duration. 13

Recommended duration of primary prophylaxis anticoagulant therapy depends upon VTE category
Based on offi cial recommendations, primary prevention of VTE depends upon the type of previous surgery.In addition to selecting the appropriate type of thromboprophylaxis (mechanical, medication, or combined) and the type and dose of anticoagulant agents, it is necessary to consider the duration of treatment and to tailor it to the specifi c requirements of a particular surgical procedure.This would apply as well for protection against VTE in nonsurgical ("medical") patients, too.The National Institute for Health and Clinical Excellence (NICE) clinical recommendations (2010) advise thromboprophylaxis over a period of 28-35 days for patients with elective hip surgery or hip fractures and 10-14 days for patients with elective knee surgery, while major surgery for abdominal or pelvic malignancy requires thromboprophylaxis for 28 days from the day of the intervention. 4,28 merican College of Chest Physicians (ACCP) guidelines recommend continuing thromboprophylaxis up to 28 days, continuing after hospital discharge for those with malignancies and for other high-risk patients after general or gynecological surgery. 28romboprophylaxis is advisable for individuals with reduced mobility, such as those who have had general, gynecologic, urologic, thoracic surgery, coronary artery bypass graft or bariatric surgery as well as those with major trauma or spinal cord injury.It should be continued until the patient has regained mobility, usually about fi ve -seven days. 28ere there is lower limb immobilization in a cast, the physician should prescribe the appropriate thromboprophylaxis after evaluating the risk and benefi t in each patient. 28ACCP (2008) recommends thromboprophylaxis for acutely ill patients admitted to the hospital due to congestive heart failure, severe respiratory diseases, and for those who are "bedridden" or who have additional risk factors for VTE, such as: active malignancy, previous VTE, sepsis, acute neurologic disease or infl ammatory bowel disease. 28he ACCP also advises tailoring thromboprophylaxis according to the type of cancer surgery and bedridden patients. 28The ACCP guidelines from the CHEST 2008 do not recommend pharmacotherapy for prevention of thrombosis caused by venous catheters or as routine thromboprophylaxis in patients receiving hormone or chemotherapy; similarly, thromboprophylaxis is not recommended as a means of increasing survival rates in patients with malignancies. 28romboprophylaxis should be initiated as soon as possible for patients with burns and additional risk factors for VTE (one or more of the following: advanced age, morbid obesity, extensive burns, particularly in lower extremities, concomitant lower extremity injuries, the use of femoral venous catheters and prolonged immobility).For travellers on long-haul fl ights for more than eight hours (even over 4-6 hours), the ACCP emphasizes the importance of general measures, such as maintaining adequate hydration, avoidance of tight clothing around the waist and lower extremities and exercising the lower-leg muscles.If these travelers have additional risk factors for VTE, they should also wear lower-leg elastic stockings that provide 15-30 mm Hg pressure at the level of ankle.31] Thromboprophylaxis is recommended for pregnant women and those who gave birth in the last six weeks (without surgery).This is particularly important if they have one or more of the following risk factors presented in Table 4.Because of the high incidence of arterial cardiovascular events in patients with previous spontaneous VTE antiplatelet agents should be considered as part of the regime for long-term secondary prevention of VTE. 13 In addition, to prevent VTE, other general, non-pharmacological measures can be used, such as weight reduction, prevention of dehydration, and mechanical means (elastic stockings, compression devices such as intermittent pneumatic compression or foot pumps). 14Temporary anticoagulant therapy should be considered in a setting of infl ammation, immobilization, estrogen therapy etc.A number of studies indicate that up to 40% of patients with previous VTE develop recurrent VTE.It should be noted that recurrent VTE occurs more frequently in those with spontaneous VTE than in patients with clearly defi ned risk factors. 14e decision to terminate anticoagulation therapy requires individual assessment of each patient, including their Ddimer values and ultrasound fi ndings in lower limb veins.
A balanced approach takes into account the risk of hemorrhage. 14The choice of an anticoagulant regime must include assessment of the risk of venous thrombosis caused by heparin-induced thrombocytopenia type II while selecting an adequate non-heparin anticoagulant. 15-17, 28, 32-37nagement of bleeding associated with oral anticoagulants Because the use of any anticoagulant (old and new) may be complicated by the potential of bleeding, the clearance mechanisms, and the half-life of each of these agents one should understand in order to plan strategy for rapid reversal. 38Options for reversing anticoagulation include: (1) withholding anticoagulation therapy (observation); (2) administering a specifi c reversal agent (e.g.oral or intravenous vitamin K if the bleed-related to a vitamin K antagonist); and (3) administering supplemental clottingfactor substitutes (e.g.fresh frozen plasma or prothrombin complex concentrates).However, appropriate supportive and symptomatic treatment is also needed (e.g.mechanical compression or surgical intervention).
Dabigatran and rivaroxaban have relatively short halflives (dabigatran 12-17h, rivaroxaban 7-11h), in majority of patients with minor or mechanically controlled bleeding, observation and supportive care is the preferred strategy.
In the event of a bleed or the need to take a patient emergently to surgery, there are pharmacodynamic parameters that can be measured to determine the approximate level of anticoagulation.For example, fordabig atran monitoring includes following: ecarin clotting time (ECT), thrombin time (TT) and activated partial thromboplastin time (aPTT), which, being relatively insensitive especially at high plasma concentrations, is not suitable for precise quantifi cation of anticoagulant effect.Anticoagulation reversal agent for dabigatran is recombinant factor VIIa (rF-VIIa).

Epilogue
Anticoagulation is a common intervention in the prevention and treatment of thrombosis in multiple clinical settings.Its duration, both in primary and in secondary prevention, depends upon the risk for recurrent VTE as well as the risk for bleeding and present comorbidities. 7Therefore, determining the length and type of an anticoagulant regimen must be guided by achieving the proper balance between the benefi t of therapy and the risk of hemorrhage. 13ew oral anticoagulants (direct thrombin inhibitor and factor Xa inhibitors) may present simpler and safer treatment and prevention of VTE.Their immediate onset of anticoagulant effect, convenient administration, and lack of needed regular anticoagulation monitoring are of interest both for the patients and medical profesionals.Dabigatran is the fi rst oral thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fi brillation and one or more risk factors for stroke.Dabigatran has also been approved in several countries for the prevention of venous thrombosis in patients undergoing total knee or hip replacement.The RE-NOVATE study on the prevention of venous thromboembolism (VTE) after hip arthroplasty and RE-MODEL study on VTE prophylaxis after knee arthroplasty showed non-inferiority of dabigatran compared with enoxaparin adminstered in European doses of 40 mg daily, while the RE-MOBILISE study after hip arthroplasty confi rmed dabigratan inferiority compared with enoxaparin at the North American dose of 30 mg twice daily.However, in the treatment and prevention of VTE, more data should be accumulated to show their ultimate place in therapy.
disease Enlargement or dyskinesia of right heart ventricle After the termination of anticoagulant therapy Male gender Body overweight Signs and symptoms of PE before DVT Low levels of HDL Absence of recanalization of lower limbs veins on ultrasound scan