About this course:
This course discusses venous thromboembolism (VTE), including the condition’s definition and incidence in the US. In addition, this course reviews the pathophysiology, various risk factors, and clinical manifestations of VTEs. Finally, this course reviews the process of diagnosis, various prevention and treatment modalities, and complications associated with VTE treatment.
This course discusses venous thromboembolism (VTE), including the condition’s definition and incidence in the US. In addition, this course reviews the pathophysiology, various risk factors, and clinical manifestations of VTEs. Finally, this course reviews the process of diagnosis, various prevention and treatment modalities, and complications associated with VTE treatment.
After this activity, learners will be prepared to:
Define types of VTE such as deep vein thrombosis and pulmonary embolism
Describe the incidence and pathophysiology of VTEs
Identify various risk factors and clinical manifestations of VTEs
Discuss the process of diagnosing VTEs
Describe the various prevention and treatment modalities for VTE, including complications associated with treatment
Venous thromboembolism (VTE) refers to blood clots that start in a vein and encompass two pathologies: deep vein thrombosis (DVT) and pulmonary embolism (PE). VTEs are caused by slower blood flow, damaged blood vessel lining, increased estrogen, or a change in the makeup of the blood that facilitates clotting. When a blood clot occurs due to surgery, hospitalization, or another healthcare treatment or procedure, it is known as healthcare-associated venous thromboembolism (HA-VTE). According to the American Heart Association (AHA, 2017c), VTEs are the third leading vascular diagnosis after heart attacks and strokes, affecting 300,000 to 600,000 people a year in the US. The Centers for Disease Control and Prevention (CDC, 2020a) estimate that the incidence of VTEs could be as high as 900,000 people each year, equating to 1 to 2 cases per 1,000 people, as many cases go undiagnosed. The associated healthcare costs are $10 billion or more annually in the US. The CDC also estimates that 60,000 to 100,000 Americans die each year from a VTE, with 10% to 30% dying within a month of diagnosis. Sudden death occurs in approximately 25% of people who have a PE. Not only is there a high risk for mortality related to VTEs, but also an estimated one-third to one-half of patients diagnosed with a DVT will have long-term complications (i.e., post-thrombotic syndrome [PTS]), including pain, swelling, discoloration, and scaling in the affected limb. In addition, approximately 33% of people with a VTE will have a recurrence within 10 years of diagnosis. Although there are many risk factors for VTEs, about 5% to 8% of Americans have a genetic risk factor (i.e., inherited thrombophilia; CDC, 2020a, 2020b, 2020c; National Heart, Lung, and Blood Institute [NHLBI], n.d.).
The body requires adequate perfusion to ensure oxygenation and nourishment of tissues, which depend on a properly functioning cardiovascular system. Adequate blood flow throughout the body depends on the sufficient circulating blood volume and the efficiency of the heart to pump that blood through blood vessels. Patent, intact, and responsive blood vessels are necessary to deliver oxygen to the tissues and remove metabolic wastes. Arteries are thick-walled structures that carry blood from the heart to the tissues, while veins are less muscular, thin-walled structures that carry blood back to the heart. The walls of arteries and veins have three layers, including the intima, media, and adventitia. The thinner, less muscular walls of the veins allow the vessels to distend more than arteries, which permits large volumes of blood to remain in the veins under low pressure (i.e., approximately 75% of the total blood volume remains in the veins). The sympathetic nervous system stimulates the veins to constrict, which reduces venous blood volume and increases the volume of blood circulating throughout the body. Within the extremities, skeletal muscle contraction creates a pumping action to facilitate blood flow back to the heart. Since the veins in the lower extremities carry blood against the force of gravity, they are equipped with valves that prevent blood from seeping backward. Arteries can become obstructed or damaged due to atherosclerotic plaques, chemical or mechanical trauma, thromboembolism, vasospastic disorders, infections or inflammatory processes, and congenital malformations. Arterial occlusion can occur suddenly or gradually over time. A sudden occlusion can lead to profound and often irreversible tissue ischemia and death, while a gradual occlusion poses a lower risk of significant damage. When a gradual occlusion occurs, collateral circulation can develop, allowing the tissues to adapt to decreased blood flow (Hinkle & Cheever, 2018).
Venous blood flow disorders can result from thromboembolism obstructing the vein, incompetent venous valves, or a reduction in the effectiveness of the pumping action of the muscles. Since venous disorders reduce blood flow and venous stasis, this can lead to coagulation defects, edema, tissue breakdown, and increased susceptibility to infection. A decreased venous blood flow will increase venous pressure and hydrostatic capillary pressure. As a result, fluid will move out of the capillaries and into the interstitial spaces, resulting in edema. Edematous tissues are more susceptible to injury, breakdown, and infection since they cannot receive adequate nutrition from the blood. A DVT is a blood clot in a deep vein that more commonly occurs in the lower extremities but occasionally appears in the upper extremities and elsewhere (see Figure 1). If the clot breaks free from the wall of the vein and travels to the lungs, it causes a PE, partially or completely blocking the blood flow to the lungs (see Figures 2 and 3). DVTs found in the thigh are more likely to cause PEs than those found in the lower leg or elsewhere. PEs can lead to pulmonary hypertension, an increase in the blood pressure in the vessels leading to the lungs due to obstructed blood flow. Pulmonary hypertension can lead to heart failure and symptoms such as difficulty breathing, swelling, fatigue, palpitations, and hemoptysis (coughing up blood; Hinkle & Cheeve
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Venous thrombosis can happen in any vein but most commonly occurs in the veins of the lower extremities. The formation of a thrombus frequently accompanies phlebitis (i.e., inflammation of the vein walls). DVTs in the upper extremity occur about 2% of the time, but the incidence may be as high as 65% in patients with central venous cannulation or upper extremity compression. When an upper extremity DVT does develop, it usually involves multiple venous segments, with the subclavian most affected. Other risk factors for upper extremity DVTs include internal trauma to the vein from the presence of an IV, pacemaker leads, chemotherapy ports, dialysis catheters, or parenteral nutrition lines. Another mechanism for upper extremity DVTs is repetitive motion or effort thrombus formation (i.e., Paget-Schroetter syndrome). Effort thrombosis results when repetitive motion irritates the vessel wall, causing inflammation and subsequent thrombus. Construction workers, competitive swimmers, tennis players, baseball players, and weightlifters are examples of individuals who engage in repetitive motion activities that can cause effort thrombosis (HInkle & Cheever, 2018).
A venous thrombus forms when platelets aggregate and attach to the vein wall. The thrombus has a tail-like appendage containing fibrin and white and red blood cells. Successive layers of the thrombus can form and propagate in the direction of blood flow. The propagating thrombus is dangerous because parts can break off (i.e., emboli) and travel to the pulmonary blood vessels, causing a PE (see Figure 2). Fragmentation of the thrombus can occur spontaneously as it naturally dissolves. Elevated venous pressure can also lead to fragmentation, specifically when engaging in muscular activity after prolonged inactivity. When a DVT occurs, recannulation (i.e., reestablishment of the lumen of the vessel) typically results. PTS is more likely to develop when recannulation does not occur within 6 months of the DVT formation (Hinkle & Cheever, 2018).
Risk Factors for VTE
Although the exact cause remains unclear, three factors may play a significant role in the development of VTEs. Collectively, these factors are known as Virchow’s triad and include endothelial damage, venous stasis, and altered coagulation (i.e., inherited or acquired). A risk factor for thrombosis can be identified in over 80% of patients with VTE, many of which have several contributing factors. Endothelial damage (i.e., damage to the intimal lining of the blood vessel) creates a site for a blood clot to form. This damage can occur from trauma (e.g., fractures or dislocations), surgery, pacing wires, central venous or dialysis catheters, local vein damage (e.g., diseases of the vein or chemical irritation from intravenous [IV] medications or solutions), or repetitive motion injuries. Venous stasis occurs when blood pools in the lower extremities. Venous stasis can result from reduced blood flow from conditions such as heart failure or shock. Medications that cause dilation of the veins can also provoke venous stasis. Other risk factors for venous stasis include conditions that decrease skeletal muscle contraction (e.g., immobility, paralysis, or anesthesia), obesity, history of varicosities, prolonged travel, and age (over 65 years old; Bauer & Lip, 2021; Hinkle & Cheever, 2018).
The third significant risk factor for VTEs is altered coagulation, and this commonly affects patients whose anticoagulant medications (e.g., warfarin [Coumadin]) have been abruptly stopped. Other common reasons for hypercoagulability include elevated C-reactive protein (CRP) levels, oral contraceptive use or other oral estrogen therapy (e.g., hormone replacement therapy), and several blood dyscrasias (with prevalence varying by ethnicity). For example, antithrombin III deficiency, protein C deficiency, and protein S deficiency are found primarily in patients of Southeast Asian descent. Factor V Leiden and prothrombin G20210A mutation are more common in Caucasians, while elevated factor VIII concentrations affect more African Americans. These inherited forms of hypercoagulability are rare. Acquired hypercoagulability is far more common, and causes include medications (e.g., testosterone, glucocorticoids, antidepressants, oral contraceptives, estrogen replacement), rheumatologic disease (e.g., lupus), polycythemia vera, and sick cell anemia. Pregnancy is another risk factor for thrombus formation due to increased clotting factors that may remain elevated for more than 6 weeks postpartum. In addition, pregnancy decreases venous flow by 50% due to hormonally decreased venous capacity and reduced venous outflow due to compression from the uterus (Ashorobi & Ameer, 2021; Bauer & Lip, 2021; Hinkle & Cheever, 2018). The presence of the following factors increases the risk of a VTE in pregnancy:
a genetic predisposition to or family history of VTE
older maternal age
other illnesses during pregnancy (e.g., cancer, infection, or pre-eclampsia; AHA, 2017a)
The AHA also includes chronic medical conditions such as heart disease, lung disease, and inflammatory bowel disorders in the list of risk factors for a VTE. All cancers increase the risk for VTE; however, the risk rises if the cancer is widespread; if it includes the lung, brain, lymph nodes, gynecologic system (e.g., ovarian, or uterine), or gastrointestinal tract (e.g., pancreas or stomach); or if the patient is receiving chemotherapy or surgery. In addition, a lower extremity superficial thrombophlebitis (ST), which consists of a blood clot in a more superficially located vein causing swelling and/or pain, can also progress to a VTE in some instances if left untreated. Protective factors include maintaining a healthy weight, staying well hydrated, using compression stockings, and staying active/maintaining a healthy level of regular movement (AHA, 2017a, 2017c; CDC, 2020c; NHLBI, n.d.; Nisio et al., 2018).
The clinical manifestations of a VTE will vary depending on the location and severity of the thrombus. Signs and symptoms of a DVT include lower extremity pain (which the patient may describe as an ache or cramping), tenderness, swelling, warmth, or redness. In addition, the patient may exhibit a decreased range of motion, an inability to ambulate, or pain that radiates (e.g., from the thigh into the groin). Signs and symptoms of a PE may include shortness of breath (SOB), tachypnea, chest pain (worsening with deep inhalation), tachycardia, light-headedness/loss of consciousness, an irregular heart rate (HR), hemoptysis, hypotension, anxiety/feeling of impending doom, coughing with or without blood, and sweating (AHA, 2017b; Ashorobi & Ameer, 2021; CDC, 2020c; NHLBI, n.d.).
Diagnosis of VTE
An accurate diagnosis is critical due to the morbidity and mortality associated with missed diagnoses and complications of DVT and PE. VTE diagnosis starts with obtaining a comprehensive history of the present illness (i.e., any recent surgery or prolonged immobility due to trauma or illness), past medical history (including any cancer), current medications, and family history. According to the recommendations from the American Society of Hematology (ASH), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP), the diagnostic algorithm for VTE should begin by assessing the patient’s pretest probability (PTP) of VTE with a validated clinical prediction tool. The 2015 ACP guidelines state that risk should be established with the Modified Wells (Canadian PE) score or the Revised Geneva score. The Modified Wells performs better for pregnant patients and younger patients without comorbidities or a history of VTE (Boka, 2020; Lim et al., 2018). The Modified Wells assigns points for the following characteristics:
previous history of VTE
HR over 100 bpm
recent surgery or immobility within the last 30 days
clinical signs of DVT
alternative diagnosis less likely than PE
active cancer treatment or recent history in the last 6 months
The Revised Geneva score is reportedly less accurate than the Modified Wells due to a roughly 8% rate of VTE found within the low-risk group of patients (score of 0; Boka, 2020). The Revised Geneva score assigns points for the following:
age over 65
previous history of VTE
surgery under general anesthesia or fracture of the lower extremities in the last month
active malignancy or remission within the last year
unilateral lower extremity pain
HR of 75-94 bpm or 95 or higher
unilateral lower extremity edema and pain with deep venous palpation (Boka, 2020)
In both scales, a lower score indicates a lower risk (Boka, 2020; Lim et al., 2018).
Emergency departments (EDs) in the US are considered a setting with a relatively low VTE prevalence, especially compared to European EDs (Tritschler et al., 2018). If the score indicates a low PTP, the Pulmonary Embolism Rule-Out Criteria (PERC) is recommended (Boka, 2020). This validated scale developed by Kline in 2004 assesses the risk of PE based on eight criteria:
age over 50
pulse over 100 bpm
oxygen saturation over 95%
no unilateral lower extremity swelling
no history of trauma or surgery in the previous 28 days
no prior history of VTE
no exogenous estrogen use (Boka, 2020)
If the patient meets all 8 of these criteria, the patient can be safely discharged from the hospital or ED without any further testing recommended. The false-negative rate (the presence of PE despite a negative result on the screen) with this test is less than 1%, with a sensitivity of 97% and a specificity of 22%. If the PTP is intermediate or low, but the patient does not meet all 8 PERC criteria, further testing with a high-sensitivity D-dimer is recommended. A D-dimer test measures the amount of D-dimer released into the bloodstream when fibrin proteins in a blood clot dissolve. A result over 500 ng/mL is considered positive for the presence of VTE in patients under the age of 50, while a score of age x 10 ng/mL should be used as an age-adjusted cut-off for all patients over the age of 50 (Boka, 2020). ASH guidelines warn against a high rate of false-positive results with D-dimer testing, especially in certain populations such as post-surgical or pregnant patients (Boka, 2020; Lim et al., 2018; Tritschler et al., 2018).
If a DVT is suspected, the D-dimer should be followed by a lower extremity ultrasound (US) for low-risk patients. Ultrasounds use sound waves to create pictures of blood flow inside the veins. Technicians also can compress the veins during the test to determine if the veins react normally or appear stiff secondary to the presence of blood clots. The D-dimer may be bypassed in patients with intermediate or high PTP who underwent US instead. The ASH also recommends repeating the US if it was initially negative, the PTP is high, and no alternative diagnosis can be found. Many medical centers do not offer 24-hour departmental availability to perform a compressive US. If necessary, the test can be done by an ED physician in under 15 minutes with a sensitivity of 96% and a specificity of 97%. If the US is negative and a DVT is not ruled out, another alternative is to perform magnetic resonance venography, which is especially helpful for obese or pregnant patients but is not yet validated for routine clinical use (Bates et al., 2018; Lim et al., 2018; Tritschler et al., 2018)
For patients with a suspected PE and a low or intermediate PTP, the ASH recommends a ventilation-perfusion (V/Q) scan instead of computed tomography pulmonary angiography (CTPA) due to a lower level of radiation exposure. This reduced radiation exposure is especially important for pregnant patients. A planar lung V/Q scan is a 2-stage radionuclide imaging test that requires the inhalation of radioisotope gas prior to the ventilation portion of the scan, followed by injection of radioisotope albumin intravenously for the perfusion portion to be completed. This test assesses the gas exchange and blood flow within the lungs and surrounding vasculature. CTPA utilizes CT technology and the injection of intravenous contrast dye to visualize the lungs and possibly the lower extremities to assess for any blood clots. It is contraindicated in patients with a contrast dye allergy or severe renal impairment. CTPA has better accuracy than planar V/Q scans and is widely available and easy to perform. The downsides of CTPA include exposure to ionizing radiation at high levels and the need for an intravenous contrast medium. If a patient’s PTP is assessed as high risk, or if the D-dimer result is elevated, the ASH guidelines and the 2015 ACP guidelines recommend advanced imaging with CTPA. V/Q scintigraphy/single-photon emission CT (SPECT) is a reasonable second choice if CTPA is contraindicated or if CTPA results are negative, but suspicion remains high. V/Q SPECT has a similar sensitivity and specificity to CTPA, reduces the patient’s radiation exposure, and eliminates the need for contrast. Unfortunately, its safety and efficacy are not yet validated for routine clinical use. Magnetic resonance imaging (MRI) scans can also be used to eliminate exposure to radiation and contrast but have significantly lower accuracy. MRI is inconclusive in up to 19% of suspected PE cases (Bates et al., 2018; Boka, 2020; Lim et al., 2018; NHLBI, n.d.; Tritschler et al., 2018).
Prevention of VTE
An estimated 50% of hospitalized medical patients are at risk of developing a VTE, and thromboprophylaxis (VTE prophylaxis) is critical to prevent VTEs. Healthcare professionals (HCPs) should be aware that thromboprophylaxis does not eliminate the risk of VTEs, making diligent assessments essential to reducing morbidity and mortality. VTE prophylaxis can be defined as primary or secondary: primary is preferred over secondary prophylaxis due to its efficacy and cost-effectiveness. Primary prophylaxis consists of pharmacologic (e.g., low molecular weight heparin [LMWH], unfractionated heparin [UFH], fondaparinux [Arixtra], direct oral anticoagulants [DOACs]) or mechanical methods (e.g., compression stockings, intermittent pneumatic compression [IPCs] devices). In contrast, secondary prevention involves the early detection and treatment of subclinical venous thrombosis. Secondary prevention is done by screening medical patients with objective methods that are sensitive to detecting the presence of a VTE (e.g., venous ultrasound, MRI venography, contrast venography). This approach is not commonly used due to the limited established efficacy of these screening methods. Secondary prevention may be used during pregnancy or when primary prevention is contraindicated (Pai & Douketis, 2021a).
Thrombosis and Bleeding Risk Assessment
Before initiating VTE prophylaxis, HCPs should assess each patient for the risk of thrombosis and bleeding. The risk of VTE depends on the circumstances of the acute illness and the presence of risk factors. Therefore, HCPs should complete a history and physical examination for all patients admitted to the hospital. Medical patients with a single risk factor are considered at risk for a VTE. Some of the most common risk factors for medical patients include acute respiratory failure, sepsis, known thrombophilia, previous VTE, age older than 60 years, elevated D-dimer, heart failure, inflammatory bowel disease, and prolonged immobility (i.e., for longer than 3 days). Patients with active cancer, lower limb paralysis (e.g., from a stroke), or critical illness are considered high risk. When pharmacologic VTE prophylaxis is indicated, HCPs should assess the risk of bleeding for all patients. Validated tools for assessing bleeding risk are lacking or require further evaluation (Pai & Douketis, 2021a).
Long-distance travel is associated with a small risk for VTE, with the greatest risk developing in the 2 weeks after travel. For individuals traveling long distances (i.e., more than 4 hours), the AHA recommends doing seated ankle/calf exercises, getting up to walk around every 2-4 hours, and staying hydrated (AHA, 2017c). The ASH does not recommend compression stockings or aspirin (ASA) for individuals without increased risk. For individuals with increased risk, the ASH recommends the use of compression stockings, LMWH, or ASA during long-distance travel. Compression stockings and LMWH are the preferred VTE prophylaxis for these individuals. For patients who cannot use compression stockings or LMWH (e.g., aversion to anticoagulants), ASA is recommended versus no prophylaxis (Pai & Douketis, 2021a; Schunemann et al., 2018).
Acutely or Critically Ill Medical Patients
The ASH estimates that approximately 50% of all VTEs occur due to current or recent hospitalization for an acute medical illness or surgery. Hospital-acquired VTEs are preventable using anticoagulants and mechanical devices (e.g., compression stockings and IPC devices). Pharmacological prophylaxis is preferred for acute medical patients admitted to the hospital with an increased VTE risk and acceptable bleeding risk. LMWH or fondaparinux (Arixtra) is preferred over UFH or DOACs due to its once-daily dosing regimen and reduced rate of complications. LMWHs, such as enoxaparin (Lovenox) and dalteparin (Fragmin), are subcutaneous medications that inhibit thrombin and factor Xa. These recommendations also apply to critically ill medical patients with acceptable bleeding risk. The ASH recommends mechanical prophylaxis (e.g., sequential compression device, foot pumps, etc.) instead of pharmaceutical prophylaxis for acute medical patients admitted to hospitals with an increased risk of bleeding. For acutely and critically ill medical patients who do not receive pharmacological VTE prophylaxis (e.g., patient refusal), the ASH recommends mechanical prophylaxis versus no prophylaxis. Treatment with both pharmacological and mechanical prophylaxis is not recommended for acutely or critically ill medical patients (Pai & Douketis, 2021a; Schunemann et al., 2018).
Suggested LMWH prophylactic dosing for VTE prevention among medical patients:
enoxaparin (Lovenox) 40 mg subcutaneously once daily
dalteparin (Fragmin) 5000 units subcutaneously once daily
tinzaparin (Innohep) 4500 anti-Xa subcutaneously (Pai & Douketis, 2021a)
The platelet counts should be checked regularly (i.e., on days 5 and 9) for all patients receiving LMWH to detect potential heparin-induced thrombocytopenia (HIT). For patients with a creatinine clearance of less than 30 mL/min, tinzaparin (Innohep), dalteparin (Fragmin), or a reduced dose of enoxaparin (Lovenox) should be used. Other pharmacologic VTE prophylactic dosing is as follows (Pai & Douketis, 2021a):
UFH is dosed at 5000 units subcutaneously 2 to 3 times daily. Like LMWH, the platelet count should be monitored routinely (i.e., on days 5 and 9) to detect HIT.
Fondaparinux (Arixtra) is typically dosed at 2.5 mg subcutaneously once daily
DOAC dosing for rivaroxaban (Xarelto) is 10 mg orally once daily, Although
ASA has been shown to reduce the risk of arterial thrombosis, there is little evidence supporting the use of ASA to prevent VTEs. Similarly, warfarin (Coumadin) initiation is not recommended for VTE prevention due to its delayed (i.e., 36 to 72 hours) therapeutic anticoagulation effect (Pai & Douketis, 2021a).
Chronically Ill Medical Patients
The ASH guidelines recommend inpatient-only VTE prophylaxis versus inpatient plus extended outpatient prophylaxis for acutely or critically ill medical patients. However, this recommendation does not apply to patients previously on a DOAC for another indication. For chronic medical inpatients residing in skilled nursing facilities, the guidelines recommend that these individuals should not be given prophylactic treatment for VTE (Pai & Douketis, 2021a; Schunemann et al., 2018).
Non-Orthopedic Surgical Patients
VTE is common in the postoperative setting, with over 50% of these patients at moderate risk for VTE. Non-orthopedic surgeries involve the skin and soft tissues of the trunk and extremities or surgery involving the abdomen, head, neck, chest, or pelvic organs. Like acutely ill medical patients, HCPs should assess the risk for thrombosis and bleeding. For surgical patients, the risk of VTE depends not just on patient factors but also on the type of procedure (Anderson et al., 2019; Pai & Douketis, 2021b).
The ASH (2019) sets specific guidelines for the prevention of VTE in surgical patients. For patients undergoing major non-orthopedic surgery, the ASH recommends using pharmacological or mechanical prophylaxis depending on the risk of VTE, the risk of bleeding, and the type of surgical procedure. For patients who receive pharmacologic prophylaxis (LMWH or UFH), a combined approach with pharmacological and mechanical prophylaxis is recommended, especially for patients with a high risk of VTE. The ASH recommends that mechanical prophylaxis should be given to patients who do not receive pharmacologic prophylaxis. When mechanical prophylaxis is used for non-orthopedic surgical patients, the ASH recommends IPC devices over compression stockings. For patients with a high risk for bleeding, mechanical prophylaxis with IPC is recommended. In the 2019 guidelines, the ASH panel also recommended avoiding inferior vena cava (IVC) filters for VTE prophylaxis (Anderson et al., 2019; Pai & Douketis, 2021b).
Orthopedic Surgical Patients
The VTE risk among orthopedic surgical patients is highest among all types of surgery. The risk of VTE and bleeding in orthopedic surgical patients can vary depending on patient-related risk factors and the type of procedure (i.e., elective or emergent, major or minor); therefore, the preferred VTE prophylaxis method should be determined on an individual basis. Like non-orthopedic surgical patients, HCPs should assess the risk of thrombosis and bleeding for orthopedic surgical patients. Orthopedic surgeries considered low risk for VTE include foot and ankle fractures, arthroscopy, and shoulder and elbow surgery. In contrast, hip and knee arthroplasty, pelvic surgery, hip fracture surgery, and multiple fracture surgery are considered high risk for VTE. Procedural factors that can impact VTE risk include the type of anesthesia, the extent and length of surgery, and the likelihood of postoperative immobility. Patient-related factors include the same risk factors identified for non-orthopedic surgery. Additional patient-related risk factors specific to orthopedic surgery include poor ambulation prior to surgery, age older than 75 years old, obesity, and cardiovascular disease. Next, HCPs should assess bleeding risk according to Individual risk factors (Anderson et al., 2019; Pai & Douketis, 2020).
According to the ASH, patients undergoing total hip arthroplasty (THA), total knee arthroplasty (TKA), and hip fracture surgery should receive pharmacological VTE prophylaxis. For patients at low risk of bleeding, pharmacological prophylaxis is recommended for up to 10 to 14 days. The initial pharmacologic agent of choice for THA/TKA patients is LMWH or a DOAC (rivaroxaban [Xarelto] or apixaban [Eliquis] are preferred over dabigatran [Pradaxa] or edoxaban [Lixiana]). Mechanical prophylaxis can be combined with pharmacologic agents for orthopedic surgery patients, although limited evidence supports the added benefit of mechanical prophylaxis (Anderson et al., 2019; Pai & Douketis, 2020).
LMWH has been considered the gold standard for pharmacologic VTE prophylaxis for other major orthopedic surgery patients. Studies have shown that LMWH is more effective than UHF or warfarin (Coumadin) for VTE prevention but less effective than fondaparinux (Arixtra). The bleeding risk among these agents is similar, except that fondaparinux (Arixtra) has a higher incidence of hemorrhage. Studies have also shown that DOACs, specifically rivaroxaban (Xarelto) and apixaban (Eliquis), have similar safety and efficacy profiles as LMWH. The efficacy of ASA is unclear in the initial postoperative period, but clinical evidence does support using ASA for extended prophylaxis (i.e., beyond 5 days; Anderson et al., 2019; Pai & Douketis, 2020).
Mechanical prophylactic VTE methods should be used for patients deemed high risk for bleeding when pharmacologic prophylaxis is contraindicated. Mechanical prophylactic methods for this population include IPC devices, compression stockings, and venous foot pumps (VFPs). IPC devices are the preferred mechanical method of VTE prophylaxis based on the available data. The ASH does not recommend the use of IVC filters for VTE prophylaxis. Research has shown that mechanical methods can reduce the risk of asymptomatic VTE by 50% compared to placebo; however, these methods are less effective than LMWH or warfarin (Coumadin). Therefore, if the risk of bleeding decreases, patients should be switched to a pharmacologic agent. Another disadvantage of IPC device use is poor compliance, with under 50% of patients using this approach properly (Anderson et al., 2019; Pai & Douketis, 2020).
Because superficial thrombophlebitis can progress to VTE, many providers believe these cases should be treated to avoid progression. Currently, fondaparinux (Arixtra), dosed prophylactically at 2.5 mg/day subcutaneously for 45 days, has the clearest and most concise evidence for efficacy and safety versus placebo. For patients who refuse or cannot take parenteral anticoagulation, rivaroxaban (Xarelto) 10 mg daily is recommended (Nisio et al., 2018; Stevens et al., 2021).
The ASH recommends antepartum prophylaxis with the standard dose of LMWH for women with antithrombin deficiency and a family history of VTE, a homozygous mutation for factor V Leiden, combined thrombophilia, or a personal history of VTE related to a hormonal risk factor or unprovoked who are not currently on long-term anticoagulation treatment. They recommend postpartum prophylaxis with a standard or intermediate dose of LMWH for women with antithrombin deficiency and a family history of VTE, women who are homozygous for factor V Leiden or prothrombin genetic mutation, women with combined thrombophilia, women with a protein C or S deficiency, or women with a personal history of VTE. No prophylaxis is recommended for pregnant women with no or a single clinical risk factor for VTE. The ASH recommends antithrombotic prophylaxis for women undergoing assistive reproductive treatment who develop severe ovarian hyperstimulation syndrome (Bates et al., 2018).
Treatment of VTE
Once a VTE has been diagnosed, numerous options are available for treatment. Benefits of treatment include preventing clot extension, a PE, recurrent VTE, hemodynamic collapse, and even death. VTEs are generally categorized as provoked (i.e., related to a specific known risk factor) or unprovoked. Surgical patients who develop VTE postoperatively are considered low risk (less than 1% after a year, 3% after 5 years) for recurrence. Patients with VTE not related to surgery but instead related to pregnancy, prolonged immobility, or exogenous estrogen therapy have an intermediate risk for recurrence (5% after a year, 15% after 5 years). Both low- and intermediate-risk patients can be treated with anticoagulant medication for 3 months. For high-risk patients (those with unprovoked or cancer-related VTE), the risk of recurrence is high. Cancer patients should be treated until remission or for at least 6 months. Patients with unprovoked VTE should be treated indefinitely if their bleeding risk is low to intermediate or for 3-6 months if they have a high risk for bleeding, especially for men who have twice the risk of recurrence compared to women (Stevens et al., 2021; Tritschler et al., 2018).
In symptomatic, isolated distal DVT cases without severe symptoms, the 2021 ACCP update of the 2016 guidelines recommends serial ultrasound surveillance (i.e., 2 weeks) for an extension to the proximal veins over anticoagulation for low-risk patients. Anticoagulation is recommended over serial imaging for acute isolated distal DVT of the leg with severe symptoms or risk factors for an extension. If thrombus extension occurs in patients receiving serial imaging, anticoagulation should be initiated (Kearon et al., 2016; Steven et al., 2021; Tritschler et al., 2018).
Nonpharmacological and Procedural Treatment Options
Compression stockings are recommended only for symptomatic relief of swelling and discomfort. Catheter-directed thrombolysis should be performed in cases of threatened limb loss. A combination of thrombolysis and an anticoagulant compared to anticoagulants alone reduced the risk of PTS by one-third but had no significant effect on the risk of PE, recurrent DVT, or death; the thrombolysis group also had an increased risk of bleeding. Inferior vena cava (IVC) filters are only recommended for patients with an absolute contraindication to pharmacological anticoagulation and proximal DVT or PE (Tritschler et al., 2018).
The 2018 ASH guidelines do not specify which medication is preferred for VTE treatment but instead give guidelines regarding the groups of medications available. All patients on anticoagulants should receive additional supplementary patient education. The ASH recommends against the use of a daily lottery to improve medication adherence, as evidence has not shown them to be effective. Instead, the ASH recommends ensuring access to providers across the care continuum, including team-based care, and reducing barriers to obtaining medications, such as costs. In addition, the ASH recommends using health information technology to improve communication and medication adherence (Witt et al., 2018)
In general, the 2016 American College of Chest Physicians (ACCP) guidelines and the 2019 European Society of Cardiology (ESC) guidelines recommend the use of DOACs over other medications as they are non-inferior in terms of efficacy with an improved safety profile based on a reduced risk of major bleeding as compared to a vitamin K antagonist (VKA) such as warfarin (Coumadin). They also carry the advantage of a rapid onset of action and a predictable pharmacokinetic profile, which negates the need for monitoring and dose adjustments. For dabigatran (Pradaxa) or edoxaban (Savaysa, an oral factor Xa inhibitor), they recommend using LMWH for at least 5 days first; with rivaroxaban (Xarelto) and apixaban (Eliquis), antecedent LMWH is not necessary (Kearon et al., 2016; Konstantinides & Meyer, 2019; Steven et al., 2021; Tritschler et al., 2018; Witt et al., 2018).
For patients on a VKA, the guidelines suggest home point-of-care INR testing (patient self-testing or PST) and self-adjusting of dose (patient self-management or PSM) for competent and capable patients. INR testing should be done every 4 weeks or fewer after initiation and dose adjustments and every 6-12 weeks when dosing is stable. They suggest using an anticoagulant management service (AMS) in a specialized clinic over a primary care clinic when available. For patients on a VKA with a low to moderate risk of recurrent VTE who require a planned invasive procedure, no perioperative bridging with UFH or LMWH is recommended (Kearon et al., 2016; Konstantinides & Meyer, 2019; Steven et al., 2021; Tritschler et al., 2018; Witt et al., 2018).
As previously mentioned, VKAs are still recommended by the ACCP/ESC for patients with severe renal impairment (Kearon et al., 2016; Konstantinides & Meyer, 2019; Steven et al., 2021; Tritschler et al., 2018; Witt et al., 2018)
Ante and Postpartum Patients
VTE complicates approximately 1.2 of every 1,000 deliveries in the United States. LMWH is recommended for the treatment of acute VTE or superficial vein thrombosis for pregnant patients over UFH, according to the ASH. As with other patients, the ASH does not recommend monitoring of anti-factor Xa for dosing. Catheter-directed thrombolysis is not recommended for pregnant patients for acute lower extremity DVTs. If a patient is on LMWH at a therapeutic dose, the ASH suggests stopping the anticoagulant medication prior to scheduled delivery. They suggest this is unnecessary for women on the lower prophylactic dose of LMWH. Avoid the use of DOACs for breastfeeding mothers and opt for UFH, LMWH, VKA, or fondaparinux (Arixtra; Bates et al., 2018).
VTE affects children at a rate of 0.07-0.14 per 10,000 children, but among hospitalized patients, this rate increases to 58 per 10,000. The ASH suggests that asymptomatic VTE should not be treated but encourages treatment with LMWH or VKA for symptomatic cases. Treatment is recommended for a maximum of 3 months for cases of DVT or provoked PE or for 6-12 months in the case of unprovoked PE. Thrombolysis is suggested for PE with hemodynamic instability followed by anticoagulant therapy, but not in cases of DVT or sub-massive PE. Thrombolysis may also be indicated for pediatric patients with life-threatening renal vein thrombosis. Thrombectomy is not recommended for pediatric patients, and neither are IVC filters. Treatment with anticoagulant medication is recommended for children with right atrial thrombosis, renal vein thrombosis, portal vein thrombosis (with occlusive thrombus, post-liver transplant, or idiopathic), or cerebral sinovenous thrombosis. No anticoagulation is recommended for children with portal vein thrombosis with nonocclusive thrombus or portal hypertension. For children with congenital purpura fulminans related to homozygous protein C deficiency, the ASH recommends protein C replacement with or without liver transplantation. Antithrombin replacement treatment is not recommended for pediatric patients unless they fail to respond to standard anticoagulation medication and their antithrombin levels are low when tested. Central venous access devices do not have to be removed until after treatment has been initiated if they are still functioning and required for treatment purposes (Monagle et al., 2018).
Cancer patients who develop VTE have an especially high risk of recurrence and bleeding complications. Cancer patients have a 15% VTE recurrence rate and should be treated until remission or for at least 6 months. The 2021 ACCP update recommends that, for patients with an acute VTE (cancer-associated thrombosis), an oral Xa inhibitor (e.g., apixaban [Eliquis], edoxaban [Savaysa], rivaroxaban [Xarelto]) should be initiated over LMWH for the treatment phases of therapy. Edoxaban (Savaysa) and rivaroxaban (Xarelto) have a higher risk for major GI bleeding than LMWH for patients with cancer-associated thrombosis and gastrointestinal malignancy. Therefore, apixaban (Eliquis) or LMWH is preferred for these patients (Stevens et al., 2021).
Patients with unprovoked episodes of VTE (no identifiable risk factor or trigger present at the time of diagnosis) and low to moderate bleeding risk should receive long-term treatment to prevent a recurrence. Patients with unprovoked VTE have a 10% risk of recurrence after a year and 30% after 5 years. For women, who have a lower risk of recurrence than men, serial D-dimer testing may be acceptable, and for patients with increased bleeding risk or other contraindications to anticoagulant medications. Another option for adult women with an unprovoked VTE is to calculate their risk of recurrence using the Hyperpigmentation, Edema, Redness, D-dimer, Obesity, Older age 2 (HERDOO2) score. Originally developed in 2008, this score attempts to identify the low-risk group of women who may be safe to discontinue anticoagulant therapy after the acute treatment phase for a single unprovoked VTE. The patient receives 1 point for each of the following risk factors:
signs/symptoms of PTS in either lower extremity (hyperpigmentation, redness, or edema)
D-dimer over 249 µg/L while taking an anticoagulant for at least 6 months
BMI over 29
age older than 64
If a patient has a score of 0-1, they are considered at low risk for VTE recurrence according to the HERDOO2 developers, and discontinuation of the anticoagulant medication could be considered. If a patient’s score is 2 or above, medication should be continued. The 2016 ACCP, the 2021 ACCP update, and 2019 ESC guidelines recommend treatment with a DOAC for patients without cancer instead of a VKA or ASA. DOACs have equivalent effectiveness and a reduced risk of bleeding compared to VKAs and superior effectiveness compared to ASA. DOACs are typically more expensive than VKAs, and there is no evidence for their use for patients with significant renal impairment (CC < 30 mL/min), antiphospholipid syndrome, HIT, or a VTE in an unusual site (e.g., the splanchnic vein). For patients with unprovoked VTEs, offering extended-phase anticoagulation (i.e., 6 months or indefinite) is recommended. The 2021 ACCP update recommends extended-phase anticoagulation with a DOAC, or VKA, for patients who cannot receive a DOAC. A reduced dose of apixaban (Eliquis) or rivaroxaban (Xarelto) is recommended over full doses for extended-phase anticoagulation (Kearon et al., 2016; Konstantinides et al., 2019; Steven et al., 2021; Tritschler et al., 2018).
Systemic thrombolysis is currently the initial treatment of choice for patients with acute massive or high-risk PE (with hemodynamic compromise or instability such as a systolic blood pressure < 90), according to the 2016 ACCP, 2021 ACCP update, and 2019 ESC guidelines. This treatment carries an increased risk of major bleeding, including intracranial hemorrhage, and is not recommended for intermediate-risk patients. In a recent study, intravenous heparin combined with systemic thrombolysis reduced the risk of recurrent PE but increased the risk of major bleeding when compared with intravenous heparin alone. Therefore, this treatment is only recommended by the ASH for patients with life-threatening hemodynamic instability, especially pregnant patients with VTE (Bates et al., 2018; Kearon et al., 2016; Konstantinides et al., 2019; Steven et al., 2021; Tritschler et al., 2018).
Management of Complications
As with most medications and medical treatments, complications may arise with the use of anticoagulant medications. For anticoagulant therapy, the primary potential complication is bleeding. The ASH has some general guidelines regarding the management of this complication. For patients on a VKA, complications may begin with an unsafe/highly elevated INR (> 4.5), leading to dangerous bleeding. For patients with an INR 4.5-10 without any clinically relevant bleeding, they suggest stopping the medication but do not recommend administering vitamin K. In the case of life-threatening bleeding, they recommend administering 4-factor prothrombin complex concentrate (PCCS) with vitamin K as opposed to fresh frozen plasma and vitamin K (Tritschler et al., 2018; Witt et al., 2018).
For patients on a DOAC, the ASH recommends against measuring their effect during the management of heavy bleeding. If these patients develop life-threatening bleeding, the ASH recommends stopping the anticoagulant medication and administering 4-factor PCCS or coagulation factor Xa (recombinant), inactivated-zhzo (andexanet alpha or Andexxa) if on rivaroxaban (Xarelto), edoxaban (Savaysa), or apixaban (Eliquis). In contrast, the ACCP/ESC guidelines state that andexanet alpha (Andexxa) should be used to reverse apixaban (Eliquis) or rivaroxaban (Xarelto) in cases of life-threatening bleeding but does not mention its use for patients taking edoxaban (Savaysa). For most mild-to-moderate bleeding cases that are not life-threatening, the ACCP/ESC guidelines recommend simply stopping the medication and supportive care due to their short half-life. Patients on dabigatran (Pradaxa) who develop life-threatening bleeding should stop the medication and receive the reversal agent idarucizumab (Praxbind). The guidelines suggest restarting oral anticoagulants within 90 days of major bleeding for patients with a moderate to high risk of recurrent VTE and a low to moderate risk of recurrent bleeding. For patients on UFH or LMWH who develop life-threatening bleeding, the ASH recommends stopping the anticoagulant and administering protamine (Tritschler et al., 2018; Witt et al., 2018).
Outside of bleeding, a potential complication of using UFH and, to a lesser degree, LMWH or fondaparinux (Arixtra) is the development of HIT. This syndrome is a prothrombotic adverse drug reaction mediated by IgG antibodies that target PLT factor 4 and heparin complexes. The ASH defines the following patients as low risk for developing HIT: medical or obstetric patients or patients following minor surgeries or trauma on LMWH or fondaparinux (Arixtra). Patients on LMWH or fondaparinux (Arixtra) following major surgery or trauma or medical/obstetric patients on UFH are considered at intermediate risk for HIT. Patients on UFH after major surgery or trauma are defined as high risk for the development of HIT. Patients at low risk for HIT require no PLT monitoring. For intermediate- or high-risk patients, the ASH recommends monitoring PLT on day 0 if the patient has a history of heparin use in the last 30 days or day 4 if there has been no recent heparin use. After this, the ASH recommends checking PLT every 2–3 days thereafter (intermediate risk) or every other day (high risk). The 4T score assesses a patient’s PTP of HIT. A score of 0-3 indicates low risk, 4-5 indicates intermediate risk, and 6-8 indicates high risk for HIT. Points are assigned for the degree of thrombocytopenia, the timing of thrombocytopenia, the presence of thrombosis, and the presence of an alternative cause of thrombocytopenia (Cuker et al., 2018). See details of the 4T score as follows:
0 points if PLT reduced < 30% or nadir < 10,000/mL
1 point if PLT reduced 30-50% or nadir 10-19,999/mL
2 points if PLT reduced > 50% and nadir > 20,000/mL
Timing of thrombocytopenia
0 points if within 4 days of heparin initiation without recent heparin exposure
1 point if timing unclear, > 10 days, or within 1 day with heparin exposure in the last 30-100 days
2 points if between days 5-10 or within 1 day with heparin exposure in the last 30 days
Presence of thrombosis
0 points if no thrombosis
1 point if suspected thrombosis, progressive or recurrent thrombosis, or erythematous skin lesions
2 points if newly confirmed thrombosis, skin necrosis, or acute systemic reaction after intravenous UFH bolus
Alternative cause of thrombocytopenia
0 points if definite alternative diagnosis present
1 point if possible alternative diagnosis present
2 points if no apparent alternative diagnosis is present (Cuker et al., 2018)
Immunoassays and/or functional assays are typically used to confirm a diagnosis of HIT. In acute HIT (when the diagnosis has been confirmed, but PLT remains low), heparin is contraindicated. An alternative anticoagulant should be started, such as argatroban (Acova, a direct thrombin inhibitor given intravenously with a shorter duration that should be avoided for patients with hepatic dysfunction), bivalirudin (Angiomax, another direct thrombin inhibitor given intravenously), fondaparinux (Arixtra), or a DOAC. VKAs are not recommended until a patient’s PLT count has recovered to over 150,000/mL. IVC filters are not recommended, and antiplatelet medication is unnecessary unless a patient also has coronary artery disease, a cardiac stent, or some other indication for antiplatelet medication. Platelet infusion is only recommended for actively bleeding or high-risk patients. For patients who require dialysis during acute HIT, the ASH recommends using argatroban (Acova) or bivalirudin (Angiomax) to prevent thrombosis of the circuitry (Cuker et al., 2018).
The ASH suggests a bilateral lower extremity US to screen for lower extremity thrombosis and an upper extremity US for patients with a central venous catheter in place. For patients with isolated HIT and no associated DVT, anticoagulants should be continued until the PLT count recovers but not for longer than 3 months. During those 3 months, the ASH recommends that patients wear an emergency alert bracelet warning medical providers of their recent history of HIT. In the case of life or limb-threatening thrombosis, the ASH recommends a parenteral medication instead of an oral option (Cuker et al., 2018).
Subacute HIT A refers to the period when the patient's PLT count has recovered, but immunoassays remain positive. During this period, the ASH recommends treatment with a DOAC instead of a VKA. Subacute HIT B refers to the period when a patient’s functional assay has returned to normal, but the immunoassay remains positive for HIT. Remote HIT refers to the period following HIT when all lab values have returned to normal. The ASH recommends waiting until the Subacute B or remote stage before proceeding for patients who require cardiovascular surgery. According to the ASH, patients requiring percutaneous coronary intervention should receive bivalirudin (Angiomax) as the anticoagulant of choice. For patients with a remote history of HIT who require VTE treatment, UFH and LMWH are not recommended; argatroban (Acova), fondaparinux (Arixtra), or a DOAC is a safer option. For patients requiring dialysis during subacute or remote HIT, regional citrate is recommended by the ASH to prevent thrombosis of the circuitry (Cuker et al., 2018).
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