See ((Deep vein thrombosis))
End product of imbalance of procoagulant, anticoagulant and fibrinolytic factors.
Arterial thrombosis seen mainly in myocardial infarction and ischemic stroke, but can involve other locations.
Almost universally superimposed on blood vessel wall disease.
Thrombosis second leading cause of death among patients with malignant disease.
Arterial thrombosis usually related to chronic process of slowly increasing severity of atherosclerosis.
Venous thrombosis is usually a sudden process which does not follow a build up of disease but a reaction to an acute short lasting risk.
Arterial thrombosis chronic disease with acute symptoms and venous thrombosis is an acute process with chronic symptoms.
Risk increased 2.5-fold during pregnancy and 20-fold in the puerperium.
Optimal duration of oral anticoagulants remains a matter of debate.
In the absence of prophylactic treatment the incidence of DVT on the tenth day after surgery is approximately 15% with a risk of pulmonary embolism close to 0.5%.
Highest risks associated with orthopedic surgery and neurosurgery.
Risk 30-50% with hip and knee surgery.
The incidence of venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism are 30-100 percent higher in black Americans than white Americans.
High risk surgery associated total hip or knee replacement even in the presence of anticoagulant therapy are associated with symptomatic venous thrombosis in 1-3% of cases.
Risk associated with abdominal, gynecological and urologic surgery up to 30%.
Generally the larger the surgical intervention the greater the risk of thromboembolism, but in orthopedic surgery even minor interventions such associated arthroscopy can increase risk.
Trauma associated with increased risk of 50-60% of patients with head trauma, spinal injury, pelvic, femoral and tibial fractures and such patients require anticoagulant prophylaxis.
All circumstances that lead to immobility such as paralysis, bed confinement, casts, and prolonged travel associated with increased risk.
Increased with long-haul flying and duration of flights, and with all modes of travel for patients with factor V Leiden, obese individuals and users of oral contraceptives.
Immobilization interferes with calf musculature pumping blood upstream through the veins.
Immobilization in the sitting position increased risk of thromboembolism than in other positions.
Risk increases by approximately 2 fold in the presence of diabetes.
Reduced GFR associated with increased venous thromboembolism risk in the general population.
Annual cumulative incidence of recurrence ranges from 4% to 17%.
Estimates of 5-year cumulative incidence of recurrent events are around 25%.
Extended bed rest in women with premature labor or preterm rupture of the membranes associated with significant increase in risk of thromboembolism.
Long-haul flights of 8 hours or more double the risk of calf muscle thrombosis.
Thrombolytic therapy in acute myocardial infarction saves 30 lives for every 1000 patients treated.
Oral contraceptives associated with an increase in procoagulants Factors VII, IX, X, fibrinogen, thrombin generation, activated protein C resistance.
Oral contraceptives associated with decreases in Antithrombin, protein S, fibrinolysis inhibitor, alpha-2-plasmin.
Prothrombotic findings in patients with hormonal replacement therapy include decreased levels of antithrombin, protein C and S.
Elderly patients with acute venous thromboembolism have a substantial long-term mortality rate, approximately 21%, and several factors including age, diabetes, cancer, polypharmacy, no physical activity, systolic hyportension, anemia, an elevated troponin, elevated C reactive protein and elevated D dimer are associated with increased risk of long term mortality.
Venous clots form on the surface of intact vascular endothelium because of a combination of changes in the blood vessel wall, blood flow disturbances and thrombogenic factors in the blood.
VTE results from the interaction of an environmental and constitutional predisposing risk factors, which can be inherited or acquired.
These factors include non-modifiable factors: older age, thrombophilias, family history of VTE, and potentially temporary factors such as major trauma or surgery, recent long plane or car trips, cancer, estrogen containing oral contraceptives, pregnancy, and post partum status.
Smoking is not associated with higher rates of VTE.
Comprises deep vein thrombosis and pulmonary embolism.
There are approximately 900,000 cases reported every year.
About 100,000 patients die every year of VTE-related complications.
The third leading vascular disease after myocardial infarction and stroke.
Occurs in about 1 to 4 per 1000 adults annually.
Annual event rate of venous thromboembolism has increased and remains high suggesting that the current prevention and treatment strategies are less than optimal.
The socioeconomic effect of venous thromboembolism is estimated with an annual cost ranging from 13.5 billion to 27.2 billion in the US.
Incidence increases sharply with age, 27 cases for 100,000 person-years of persons to 40 years to 410 cases in those age 65 or above.
Patients age 65 years or more comprise more than 60% of venous thromboembolism cases occurring in the community.
The incidence of VTE is underestimated, as studies of thousands of patients undergoing CT Chest have found unexpected pulmonary embolism with the mean incidence of 2.6%.
Of all venous thromboembolism cases occurring in the community, approximately 50% or related to current or recent hospitalization for surgery or medical illness.
The morbidity and mortality of VTE is high: about 10% of hospital deaths are associated with PE and nearly 1/3 of all DTE patients have a recurrence within 10 years of the initial event.
Rate of first venous thromboembolism is 1-2 events per 1000 patient years, and is observed mostly in patients older than 55 years.
Incidence of a VTE in industrial countries is 0.5-2 cases per 1000 person-years.
VTE has an estimated annual incidence of 0.1% to 0.27% and affects up to 5% of the population during their lifetime.
Patients with VTE are at increased risk for development of subsequent arterial ischemic events, such as myocardial infarction or stroke.
Affects 700,000 persons annually in North America.
Approximately 1% of hospital admissions are for the VTE.
Approximately 14% of overall VTE hospitalizations are for DVT and PE.
CDC analysis for years 2007-2009 estimated annual hospitalizations of 547,596 for VTE in the US, for indivuals over the age of 18 years.
Hospitalization rates for patients with VTE substantially higher among adults with advanced age.
The third most common cause of vascular death after myocardial infarction and stroke.
Atherogenic factors such as smoking, hypertension and hyperlipidemia do not affect the risk of thrombosis.
Estimated to be about 900,000 events a year in the U.S.
Majority of deaths from VTE occurring in individuals who are untreated, and for whom the diagnosis is made after death, or are not diagnosed but are attributed to another ideology, such as cardiac arrhythmia or myocardial infarction.
Approximately 2/3 of cases of VTE are associated with a hospitalization within the previous 90 days.
Incidence increases significantly after age 60.
Elderly patients with acute venous thromboembolism have a substantial long-term mortality rate, approximately 21%, and several factors including age, diabetes, cancer, polypharmacy, no physical activity, systolic hypertension, anemia, an elevated troponin, elevated C reactive protein and elevated D dimer are associated with increased risk of long term mortality.
Elderly patients with acute venous thromboembolism have a substantial long term mortality of about 21%.
Most elderly patients with venous thromboembolism die of cancer, pulmonary embolism, infection, and bleeding (Faller N).
Metastatic disease at the time of cancer diagnosis is the strongest predictor of venous thromboembolism.
Brain metastasis are less strongly associated with the thromboembolism: approximately 10% with lung cancer and lower with melanomas, renal cell cancer, breast cancer or colorectal cancer.
Neurosurgery is an established risk factor for VTE.
Infection has been associated with venous thrombo embolism, and could account for a substantial burden of incidental recurring veous thromboembolism, currently labeled as idiopathic.
Risk is increased among glucocorticoid users (Johannesdottir SA et al).
Patients who receive perioperative RBC transfusions have significantly increased odds of developing VTE in the 30-day postoperative period.
Incidence rates increase from one per 10,000 annually among persons less than 40 years of age to nearly 1% annually among individuals 80 years or older.
More than one third of cases occur in individuals older than 60 years of age.
Almost one fifth of all new events are associated with an active cancer.
Approximately 10% of patients die within 28 days of developing such an event.
Patients experience a risk of recurrence of approximately 30% during the first 8 years after the initial episode.
Recurrent venous thromboembolism is largely preventable if patients receive extended duration anticoagulation therapy.
Patients prescribed extended duration oral anticoagulation therapy beyond 90 days after hospitalization for VTE apixaban compared with warfarin beyond 90 days was significantly associated with the modestly lowered rate of hospitalization for recurrent VTE but no significant difference in rate of hospitalization for major bleeding.
The risk of recurrence of venous thromboembolism is highest for patients with cancer related disease, closely followed by patients with unprovoked venous thromboembolism.
Guidelines recommend a minimum of three months of anticoagulation for patients experiencing a VTE, with the decision to use longer duration of anticoagulation based on the balance between the competing risks of recurrent venous thromboembolism and clinically relevant bleeding.
Among patients experiencing an unprovoked venous thromboembolism, the risk of recurring thrombosis is approximately 10% in the first year and about 30% in the first five years after anticoagulation therapy is stopped.
Patients with provoking risk factors not related to a major surgery or trauma have an elevated risk of recurrent venous thromboembolism after anticoagulation discontinuation, at a rate of 5% in the first year and 15% at five years.
In patients experiencing a provoked venous thromboembolism and treated with rivaroxaban for three months compared to a group with continued rivaroxaban, there was in associated 44% lower risk of recurrent venous thromboembolism.
Most common site occurs at valve pockets.
Compared with men shorter than 5 feet and men taller than 6 feet have a 65% increase risk of VTE.
Compared to women shorter than 5feet and women taller than 6 feet have a 69% higher risk VTE (BENGT Z).
Thrombosis dependent on tissue factor (TF) expression by neutrophils, hematopoietic cell derived tissue factor microparticles, and blood vessel wall tissue factor.
Unprovoked venous thromboembolism, it is also termed idiopathic VTE, refers to the absence of transient-triggering risk factors or an active underlying disease associated with thrombosis.
After a minimum of three months of warfarin therapy unprovoked VTE is associated with an annual recurrence rate of 10% in each of the first two years, and drops to 3% annual recurrence after, and late recurrence rate at four years is approximately 25%.
Unprovoked venous thromboembolism is a chronic process and continuation of warfarin therapy for three months is greater than 90% effective in preventing recurrences.
Treating unprovoked VTE with warfarin beyond three months does not reduce recurrence risk once the drug is discontinued.
A first unprovoked venous thrombotic event with the antiphospholipid antibody syndrome should be treated with anticoagulation indefinitely.
When warfarin is discontinued after treatment for unprovoked venous thromboembolism, there is a catch up affect, such that by 2 years the risk of recurrence in patients treated for 3 months is similar to patients treated for 12 months: Therefore some suggest a lifelong warfarin therapy for unprovoked thromboembolism.
Aspirin reduces the risk of recurrence when given to patients with unprovoked venous thromboembolism who have discontinued anticoagulant therapy, with no increase in the risk of major bleeding(Becattini Celia).
Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism (ASPIRE Investigators)
Patients with a first episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued.
Long-term treatment with a vitamin K antagonists are very effective in preventing a recurrence of venous thromboembolism while treatment continues, but has not been shown to improve survival, is associated with an increased risk of bleeding, and is inconvenient.
Many patients who have had a first episode of unprovoked venous thromboembolism discontinue anticoagulant therapy after 3 to 6 months despite recommendations to prolong therapy.
Low-dose aspirin is a simple, inexpensive, and widely available treatment that is effective for the prevention of arterial vascular events and for the primary prevention of venous thromboembolism in high-risk surgical patients.
Aspirin may also be effective in preventing a recurrence of venous thromboembolism after a first event.
The objective of our study was to evaluate the efficacy of low-dose aspirin, as compared with placebo, in preventing a recurrence of venous thromboembolism in patients who had completed initial anticoagulation with warfarin after a first unprovoked episode of venous thromboembolism.
The Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study was a double-blind, randomized, placebo-controlled study of the use of low-dose aspirin in patients who had had a first-ever unprovoked venous thromboembolism and who had completed initial anticoagulation therapy: Random assignment of patients who had completed anticoagulation therapy to aspirin, at a dose of 100 mg daily, or placebo for a minimum of 2 years: Recurrent venous thromboembolism occurred in 73 of 411 patients (18%) assigned to placebo and 57 of 411 (14%) assigned to aspirin, a rate of 6.5% per year vs. 4.8% per year, respectively.
The rates of all bleeding episodes did not differ significantly between the study groups.
The analysis of net clinical benefit, defined as a reduction in the rate of the composite of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause, showed that aspirin was associated with a reduction of 33% in that composite outcome, with an event rate of 9.0% per year in the placebo group as compared with 6.0% per year in the aspirin group.
Results of the ASPIRE trial did not show a significant reduction in the primary outcome of recurrent venous thromboembolism with aspirin as compared with placebo in patients who had had a first unprovoked venous thromboembolism, it did show that aspirin reduced the secondary composite outcome of major vascular events by 34% without increasing bleeding and resulted in a significant net clinical benefit.
The estimated reduction of 26% in the rate of recurrence of venous thromboembolism with aspirin is consistent with results from the recently reported WARFASA study,14 which showed a reduction of 42% in the rate of recurrence of venous thromboembolism.
The combined results of the WARFASA and ASPIRE trials show a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.
For patients who discontinue anticoagulation, the risk of a late recurrence of venous thromboembolism after a first unprovoked event remains high: approximately 10% in the first year and 30% after 10 years.
Recurrent venous thromboembolism is associated with a case fatality rate of 5 to 10% and a risk of post-thrombotic syndrome that is increased by a factor of 6.
In this context, aspirin, although substantially less effective than warfarin, provides an attractive alternative because it is simple and inexpensive and its safety profile is well documented.
Patients who have had a first unprovoked event of venous thromboembolism appear to be at greater risk for arterial thrombosis and cardiovascular death,and an added appeal of aspirin is that it has been associated with an overall reduction in the risk of major thrombotic events (arterial and venous) and cardiovascular death.
The ASPIRE study suggests that for every 1000 patients treated for 1 year, aspirin can be expected to be associated with 17 fewer episodes of recurrent venous thromboembolism and 28 fewer major thrombotic events, at the cost of 5 nonfatal bleeding episodes.
Unprovoked thrombotic events with factor V Leiden or prothrombin G20210A mutation are not significantly associated with increased risk of recurrent VTE among heterozygotes, and such events do not merit long-term anticoagulation after a first event:risks of recurrent events are 2.12 for factor V Leiden and 1.45 for prothrombin G20210 mutation.
Among individuals with a first episode of proximal DVT or pulmonary embolus associated with a transient risk factor, such as trauma, pregnancy, surgery, and oral contraceptive use, the risk of recurrent DVT following discontinuation of warfarin is under 5% in the first year and remains low for subsequent years: the risk of major bleeding. When treating with warfarin beyond three months is 2-6% year and outweighs the benefit of prolonged therapy in these patients
Can occur in other veins such as the upper extremities, liver, cerebral sinus, retina and mesentery.
Chronic sequelae of DVT, ((postthrombotic syndrome)), can be disabling in up to 20% of patients.
Long-term complications include post phlebotic syndrome from DVT in up to 40% of patients and chronic thromboembolic pulmonary hypertension after pulmonary embolism in 1-4% of cases.
Prior to anticoagulant therapy, untreated VTE was often fatal in up to 30% of cases.
Up to half of patients who survive an episode of venous thromboembolism may develop a post-thrombotic syndrome.
Case fatality of DVT mainly die to pulmonary embolism ranges from 1 in young patients and 10% in older individuals with the highest rate in those with underlying malignancy.
Occurs less frequently among Asians and Hispanics than among Caucasians and African-Americans.
Risk is higher in older age, blacks compared to whites, and in obese individuals.
Compared with white individuals, blacks generally have higher levels of plasma biomarkers associated with Venous thromboembolism: D-dimer, factor VIII, factor IX. and a higher prevalence of many medical conditions leading to provoked venous thromboembolism.
Explained as a multicausal disease in which genetic or environmental conditions coincide to produce thromboses.
Of traditional cardiovascular risk factors only obesity and advancing age are consistently demonstrated to be independent risk factors for VTE.
Waist circumference of greater than 100 cm is associated with VTE.
Statin use significantly reduces the rates of Venus thromboembolism recurrence, and should be considered as adjuvant therapy in the prevention of blood clots (Stewart L).
Obesity is strongly associated with the risk of DVT in men and women.
Obesity is an independent predictor of pulmonary embolus.
Elevated triglycerides and low levels of high-density lipoprotein increase the risk of venous thromboembolism.
Elevated HDL levels may protect against venous thromboembolism.
Elevated serum triglyceride levels in postmenopausal women associated with a doubling of the risk of VTE (Doggen CJ et al).
Increased lipoprotein (a) associated with it increased risk of venous thromboembolism.
A positive association exists between DVT and or pulmonary embolism and diabetes, hypertension and smoking (Petrauskiene V et al).
In a study of 19,293 individuals, a higher incidence of VTE associated with obesity and diabetes but not hypertension at eight years of follow-up (Tsai AW et al).
Risk for patients with thrombophilia increases with age, particularly after the age of 60 years.
More than 60% of surgical patients and greater than 40% of medical patients are a risk for venous thromboembolism.
Thromboembolism in patients with nephrotic syndrome can arise from increased platelet activation and aggregation, loss of anticoagulant proteins, decreased fibrinolytic system activity and associated problems such as the antiphospholipid syndrome.
The annual incidence of venous thromboembolism is approximately 1% in the nephrotic syndrome.
The risk of thromboembolism in the nephrotic syndrome is more closely linked with hypoalbuminemia then to proteinuria.
In the nephrotic syndrome the risk of venous thromboembolism increases by a factor of 2 for each decrease of 1gm per d/L in the albumin level.
Patients with rheumatoid arthritis are at increased risk of venous thromboembolism, and that the risk increases shortly after the diagnosis of rheumatoid arthritis and remains elevated during the first decade (Holmqvist ME et al).
Venous thrombosis occur equally in men and women, with possible higher rates among younger women and older men.
Strongly age depended with it being very uncommon in childhood, 1 in 100,000 per year, and up to 1% per year in old age.
Postmenopausal hormone estrogens, with or without progestins, and estrogen modulators such as tamoxifen and raloxifene are associated with a 2-3 fold increased risk.
Presence of factor V Leiden increases the risk of thromboembolism associated with estrogen use to approximately 15 fold.
Approximately 10% of patients with VTE have antiphospholipid antibodies.
In a California study the annual incidence of venous thromboembolism: 23 per 100,000 among Caucasians, 29 per 100,000 among African-Americans, 14 per 100,000 among Hispanics and 6 per 100,000 among Asians.
Risk in pediatric population is 1 per 100,000 per year.
3-month mortality of 17.5% in patients with newly diagnosed venous thromboembolic disease.
The third most common cardiovascular disorder.
Total hip or knee arthroplasty are the procedures with the highest risk of venous thromboembolism.
Risk increased in persons with previous venous thromboembolism, recent surgical procedures, immobilization, fracture of a lower extremity and inherited coagulation disorders.
High plasma levels of factor VIII is and strong risk factor for recurrent thromboembolism.
The third most common cause of in-hospital deaths in trauma patients.
Orthopedic patients constitute 8.6% of all patients who develop hospital associated VTE. (Goldhaber).
Incidence of venous thromboembolism among pregnant or postpartum women ranges from 9 to 65 per 100,000 woman years for pulmonary embolism and deep vein thrombosis during pregnancy and from 70 to 180 per 100,000 woman years for pulmonary embolism and deep vein thrombosis during the puerperium.
All forms of cancer predispose to thromboembolic disease, but adenocarcinoma is the most commonly recognized.
The prognosis of patients with VTE and cancer is grave with 1-year survival about 12% compared to 36% in similar cancer patients without VTE.
Incidence in patients with cancer about 15% with range 3.8-30.7%.
20-50% of patients with metastatic cancer have thromboses at postmortem evaluation.
Second most common cause of death in hospitalized cancer patients.
Cancer patients have a 3-4 times greater risk of recurrent VTE during anticoagulation therapy than do patients without cancer.
Factors associated with increased risk of recurrent VTE in cancer patients include development of new metastatic lesions, recurrent neutropenic episodes and history of previous VTE and the extent of the malignancy.
Associated with antiangiogenic agents.
Factors contributing to risk of venous thromboembolism in cancer patients include type and stage, procoagulant effect of cancer cells, age, surgery, mobility, and type and intensity of therapy.
The highest risk of developing thromboembolism in cancer patients is related to major surgery with 50% incidence postoperatively in the absence of prophylaxis management.
Venous thromboembolism is an important complication in hospitalized patients: if thrombo prophylaxis is not administered deep vein thrombosis, with potential for pulmonary embolism, will develop in 10 to 20% of medical patients and in 40 to 60% of patients undergoing major orthopedic surgery (Geerts WH et al).
VTE prophylaxis in acutely ill medical patients is done primarily with low molecular weight heparin which is preferred over heparin or direct oral anticoagulants.
Guidelines recommended against extending drug prophylaxis with direct oral anticoagulants after discharge given lack of reduction in mortality or symptomatic DVT, and only a very small reduction in PE .
In an autopsy study of 6833 hospitalized patients, 81% of fatal pulmonary emboli occurred in nonsurgical patients (Alikhan R et al).
Complicates cancer of virtually all organ systems with similar frequency.
Patients with idiopathic venous-thromboembolic disease have a 10-20% chance of developing cancer over a 2-year period of observation.
Documented in 22-45% of patients operated on for brain malignancies.
Patients with active cancer and those in remission have an increased risk of venous thromboembolism.
Most frequent complication of cancer and the second most common cause of death in patients with overt malignant disease.
Cancer patients have a six-fold greater risk of venous thromboembolism than do patients with other medical illnesses.
Cancer patients undergoing surgical procedures have a 2-3 fold greater risk of venous thromboembolism than other cancer patients in the absence of surgery.
Optimal duration of anticoagulant management is controversial.
6 or months of treatment with anticoagulation for patients at higher risk may be warranted, but beyond that there is a relatively modest incremental risk reduction.
Recurrence rate following the index event reaches a lower plateau at about 9 months later independent of the duration of anticoagulants.
For patients who stop anticoagulation therapy before stabilization of an active thrombus are prone to propagation and embolization.
When anticoagulation is stopped during the first four weeks of treatment, the risk of recurrent VTE is 0.3% to 1.3% per day, dropping to 0.03% to 0.2% per day over the next four-twelve weeks.
Anticoagulation can safely be discontinued after three months of therapy, particularly if the thrombotic event occurred in the setting of a reversible precipitant.
Third of cases are pulmonary embolisms with a 30 day mortality of 12% and two-thirds are deep vein thromboses with a 30 day mortality of 6%.
For prevention dalteparin, enoxaparin, and tinzaparin administered once daily subcutaneously, unfractionated heparin 5000 units three times daily, fondaparinux 2.5 mg subcutaneously daily.
In a randomized double-blind noninferiority study patients with acute venous thromboembolism who had received initially heparin were randomized to receive Edoxaban 60 mg daily or 30 mg daily or to receive warfarin: patients received the study drugs for 3 to 12 months and Edoxaban was not inferior to standard care and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism including severe pulmonary embolus (Hokusai-VTE Investigators).
Objective of initial treatment is prevention of DVT extension or prevention of pulmonary embolus occurrence or reoccurrence and relief of acute symptoms while preventing hemodynamic collapse or death.
Options for initial management of VTE include immediate treatment with direct oral anticoagulant, initial parenteral and anticoagulation followed by direct oral anticoagulation, or initial parenteral anticoagulation overlapped with warfarin for at least five days until the INR is more than 2.0 on two occasions 24 hour apps rt.
When diagnostic testing for VTE is delayed empirical administration of therapeutic doses of low molecular weight heparin is indicated.
The use of low molecular weight dalteparin for VTE prophylaxis among critically ill medical surgical patients was more effective and had similar or lower costs than the use of UFH: lower rates of pulmonary embolus and heparin induced thrombocytopenia accounted for lower overall use of resources with low molecular weight heparin (Fowler RA et al).
Retrievable inferior vena cava filter insertion is reserved for patients with proximal DVT and contraindications to anticoagulation or those with pulmonary embolus despite therapeutic anticoagulation.