Venous Thromboembolism

3.0 ANCC Contact Hours AACN Category A

Syllabus

At the conclusion of this activity, the learner will be able to

  1. Review the pathophysiology of venous thromboembolism (VTE).
  2. Recall the risk factors, signs, and symptoms of VTE.
  3. Evaluate the process of diagnosing VTE.
  4. Assess the various prevention and treatment modalities of VTE.

Venous thromboembolism (VTE) includes two pathologies: deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE affects between 300,000 and 600,000 people a year in the United States (American Heart Association [AHA], 2017). The incidence is between 0.7 and 1.4 per 1,000 person years with an annual cost of $13.5-27.2 billion in the United States. The hospitalized mortality rate secondary to PEs has decreased in the United States from 1999-2008 to 30%, despite an increase in hospitalizations during that same time due to advancements in imaging technology (Tritschler, Kraaijpoel, LeGal & Wells, 2018). PEs are responsible for roughly 10% of all hospital deaths in the United States (Prisco, Cenci, Silvestri, Emmi & Ciucciarelli, 2014). According to the National Institutes of Health (NIH), VTEs are caused by slower blood flow, damaged blood vessel lining, increased estrogen, or a change in the makeup of the blood which allows it to clot easier (U.S. Department of Health and Human Services [USDHHS], n.d.). DVT is a blood clot in a deep vein which more commonly occurs in the lower extremities but occasionally in the upper extremities and elsewhere (AHA, 2017). According to the Centers for Disease Control and Prevention (CDC) DVTs can also lead to complications such as postthrombotic syndrome (PTS), which is the presence of pain, swelling, discoloration/hyperpigmentation, scaling or ulcers after the acute phase of a DVT (USDHHS, 2019). This is related to decreased blood flow, increased inflammation, and damage to the blood vessels at the site of the DVT and can lead to prolonged or even permanent disability long after the DVT itself has resolved (USDHHS, n.d.). 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. DVTs found in the thigh are more likely to cause PEs as compared to 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 the obstructed blood flow. This can lead to heart failure and symptoms such as difficulty breathing, swelling, fatigue, palpitations and hemoptysis (coughing up blood) (USDHHS, n.d.).

Risk Factors, Signs, and Symptoms

Risk factors for the development of a VTE include:

  • Oral contraceptive use or other oral estrogen therapy such as hormone replacement therapy (HRT)
  • Pregnancy (pregnant and postpartum women have 5x the average risk)
  • Older age (risk increases at the age of 40, then doubles every ten years)
  • Obese or overweight
  • Cancer
  • Lupus
  • Thicker blood related to polycythemia vera
  • Thrombophilia, which is excessive blood clotting/clotting disorder
  • Spinal cord injury
  • Pelvic/hip/long bone fracture or multi-trauma
  • Personal or family history of VTE
  • Major surgery in the last 3 months (joint replacement, arterial bypass, neurosurgery, abdominal)
  • Prolonged immobility or hospitalization (AHA, 2017)

The CDC also includes the presence of a catheter in a central vein or chronic medical conditions such as heart disease, lung disease, and inflammatory bowel disorders in the list of risk factors for a VTE (USDHHS, 2019). In addition, the NIH also notes an increased risk for VTE amongst patients with varicose veins, sickle cell disease, and those of African American ethnicity. They note an increased risk in women of childbearing years, but after menopause a decreased risk exists for women as compared to that of men (USDHHS, n.d.). 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 certain cases if left untreated (Nisio, Wichers, & Middeldorp, 2018). Protective factors include maintaining a healthy weight, staying well hydrated, using compression stockings, and staying active/maintaining a healthy level of regular movement (AHA, 2017). 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 (AHA, 2017; USDHHS, n.d.) Signs and symptoms of a PE may include shortness of breath (SOB), tachypnea, chest pain (worse with deep inhalation), tachycardia, light-headedness/loss of consciousness, irregular heart rate, hemoptysis, hypotension, anxiety/feeling of impending doom, and sweating (AHA, 2017; USDHHS, 2019; USDHHS, n.d.).

The Diagnosis of VTE

The diagnosis of VTE starts with obtaining a comprehensive history of present illness (including any recent surgery or prolonged immobility due to trauma or illness), past medical history (including any cancer), current medications, family history (USDHHS, n.d.). According to the recommendations from the American Society of Hematology (ASH), 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 the presence of a VTE with a validated clinical prediction tool (Boka, 2018; Lim et al., 2018). The 2015 ACP guidelines state this should be done with the Modified Wells (Canadian PE) score or the Revised Geneva score to establish risk. The Modified Wells is reportedly better to be utilized in pregnant patients and younger patients without comorbidities or a history of VTE. It assigns points for the following characteristics:

  • Previous history of VTE (1.5 points)
  • HR over 100 bpm (1.5 points)
  • Recent surgery or immobility within the last 30 days (1.5 points)
  • Clinical signs of DVT (3 points)
  • Alternative diagnosis less likely than PE (3 points)
  • Hemoptysis (1 point)
  • Active cancer treatment or recent history in the last 6 months (1 point)

A score of 0-1 points indicates a low risk, 2-6 points indicates intermediate risk, and a score of 6 or above indicates high risk of VTE presence. The Revised Geneva score has been reported to be 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). The Revised Geneva score assigns points for:

  • Age over 65 (1 point)
  • Previous history of VTE (3 points)
  • Surgery under general anesthesia or fracture of the lower extremities in the last month (2 points)
  • Active malignancy or cured within the last year (2 points)
  • Unilateral lower extremity pain (3 points)
  • Hemoptysis (2 points)
  • Elevated heart rate: 75-94 bpm (3 points) or 95 or higher (5 points)
  • Unilateral lower extremity edema and pain with deep venous palpation (4 points)

A score of 0-3 indicates a low risk, 4-10 points indicates an intermediate risk, and a score of 11 or above indicates a high risk of VTE. They also indicate that provider clinical judgment or Gestalt should factor into this decision as well (Boka, 2018). Emergency departments (EDs) in the United States are considered a setting with a relatively low prevalence of VTE, especially as 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, 2018). This validated scale developed by Kline in 2004 assesses risk of PE based on eight criteria:

  • Age over 50
  • Pulse over 100 bpm
  • Oxygen saturation over 95%
  • No unilateral lower extremity swelling
  • No hemoptysis
  • No history of trauma or surgery in the previous 28 days
  • No prior history of VTE
  • No exogenous estrogen use

If the patient meets all eight of the above criteria, the patient can be safely discharged from the hospital or ED without any further testing recommended (Freund et al., 2015). The false negative rate (the presence of PE despite a negative result on the screen) with this test is less than 1%, a sensitivity of 97% and a specificity of 22%. The YEARS diagnostic algorithm is being developed but has not yet been validated for use in clinical practice (Tritschler et al., 2018). If the PTP is intermediate or low but the patient does not meet all eight PERC criteria, further testing with a high-sensitivity D-dimer is then recommended (Boka, 2018; Lim et al., 2018). A D-dimer tests the amount of the substance released into the bloodstream when fibrin proteins in a blood clot dissolve (USDHHS, n.d.) A result on the D-dimer of 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, 2018). ASH guidelines warn against a high rate of false positive results with D-dimer testing, especially in certain patient populations such as post-surgical or pregnant patients (Lim et al., 2018).

If a DVT is suspected, the D-dimer should be followed up with a lower extremity ultrasound (US) in low-risk patients (Lim et al., 2018). Ultrasounds use sound waves to create pictures of blood flowing inside veins with the ability to compress the veins during the test to determine if the veins react normally or appear stiff secondary to the presence of blood clots (USDHHS, n.d.). In patients with intermediate or high PTP, the D-dimer may be bypassed and the US done instead. The ASH also recommends repeating the US if the initial US is negative, the PTP is high, and no alternative diagnosis can be found (Lim et al., 2018). In many medical centers, a compressive US does not offer 24 hour availability but if necessary can be done by an ED physician in less than 15 minutes with a sensitivity of 96% and a specificity of 97%. If the US is negative, and a DVT not ruled out, another alternative is to perform magnetic resonance venography, which is especially helpful in obese or pregnant patients but is not yet validated for routine clinical use (Bates et al., 2018; Tritschler et al., 2018)

In patients with a suspected PE and a low or intermediate PTP, the ASH recommends a ventilation-perfusion (V/Q) scan in lieu of a computed tomography pulmonary angiography (CTPA) due to a lower level of radiation exposure (Lim et al., 2018). This reduced radiation exposure is especially important in pregnant patients (Bates et al., 2018). A planar lung V/Q scan is a two-stage radionuclide imaging test which requires the inhalation of radio-isotope 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. A CTPA utilizes CT technology and the injection of intravenous contrast dye to image the lungs and possibly the lower extremities to assess for any blood clots. It is contraindicated if the patient has a contrast dye allergy or severe renal impairment (USDHHS, n.d.). CTPA is a test known to have better accuracy than planar V/Q scans as well as being widely available and easy to perform. The downsides of CTPAs include exposure to ionizing radiation at high levels and the need for intravenous contrast medium (Tritschler et al., 2018). If the patient’s PTP is assessed as high risk, or if the D-dimer result is elevated, the ASH guidelines and the 2015 ACP guidelines then recommend advanced imaging with a CTPA. V/Q scintigraphy/single-photon emission CT is a reasonable second choice if CTPA is contraindicated or if CTPA results are negative but suspicion remains high (Boka, 2018; Lim et al., 2018). V/Q scintigraphy/single-photon emission CT has a similar sensitivity and specificity to CTPA, reduces the radiation exposure for the patient, and eliminates the need for contrast. Unfortunately, its safety and efficacy is not yet validated for routine clinical use. Magnetic resonance imaging (MRI) scans can also be used, as it eliminates the exposure to radiation and contrast, but has a significantly lower accuracy. MRI is inconclusive in up to 19% of cases of suspected PE (Tritschler et al., 2018).

Prevention and Treatment of VTE

 Prevention techniques for VTE are sometimes as simple as moving. In patients traveling for eight hours or longer, the AHA recommends doing seated ankle/calf exercises, getting up to walk around every two-four hours, and stay hydrated (AHA, 2017). The ASH recommends no compression stockings or aspirin (ASA) in patients without increased risk. In patients with increased risk (defined as a recent history of surgery, prior history of VTE, within six weeks postpartum, a current active malignancy, or the presence of two or more risk factors such as hormone replacement therapy, obesity, and pregnancy) the ASH recommends the use of compression stockings, low molecular weight heparin (LMWH) or ASA during long distance travel. Chronic medical inpatients residing in skilled nursing facilities should not be given prophylactic treatment for VTE. The ASH recommends mechanical prophylaxis (sequential compression device, foot pumps, etc.) in lieu of pharmaceutical prophylaxis in acute medical patients admitted to hospitals with an increased risk for bleeding. Pharmacological prophylaxis is preferred in acute medical patients admitted to the hospital with increased VTE risk and acceptable bleeding risk. LMWH is preferred over unfractionated heparin (UFH) or direct oral anticoagulants (DOACs) secondary to its once daily dosing regimen and reduced rate of complications. LMWHs, such as enoxaparin (Lovenox) and dalteparin (Fragmin), are subcutaneous medications that work by inhibiting thrombin and factor Xa. Treatment with both pharmacological and mechanical prophylaxis is not recommended. ASH also does not recommend prophylaxis for outpatients with minor risk factors such as prolonged immobility, injury, illness, or infection (Schunemann et al., 2018). European guidelines recommend that patients undergoing total hip and knee arthroplasty surgery (THA/TKA) receive LMWH, fondaparinux (Arixtra), or a new DOAC. They recommend LMWH or fondaparinux (Arixtra) at prophylactic dosages for femoral neck fractures (FNF), increased thromboembolic risk, or trauma involving the pelvis, acetabulum or knee. Heparin is not recommended in orthopaedic patients secondary to its shorter half-life and increased risk of thrombocytopenia (reduced platelet count). Fondaparinux (Arixtra) has been shown to be more effective than LMWH in most studies but with an increased risk of bleeding. It works as a synthetic selective factor Xa inhibitor. DOACS, including dabigatran (Pradaxa), rivaroxaban (Xarelto), or apixaban (Eliquis), have no scientific evidence for their use in FNF or greater than two weeks after TKA. They also found limited evidence regarding their use in fragile patients with low body weight and renal insufficiency. Dabigatran (Pradaxa) is an oral reversible thrombin inhibitor that has been shown to be non-inferior to LMWH in terms of both effectiveness and safety. Rivaroxaban (Xarelto) is an oral factor Xa inhibitor that has been shown in studies to have greater efficacy than LMWH and a similar safety profile. Apixaban (Eliquis) is an oral factor Xa inhibitor that has been shown in studies to be safer than LMWH with similar efficacy. If using LMWH, prophylaxis should be given for a minimum of 10 days and up to a total of 35 days in patients that have undergone THA, TKA, and/or FNF. In FNF patients, LMWH can be dosed 12 hours before or after surgery or fondaparinux (Arixtra) can be used at least 6 hours after surgery. In THA/TKA patients, LMWH can be given before or after surgery, but fondaparinux (Arixtra) and DOACs are only approved for use after surgery. Prophylaxis is not recommended for elective spine surgery except in prolonged complex cases or in patients with a high risk of VTE. They recommend post-operative start of prophylaxis in other non-arthroscopic elective orthopedic surgeries. In orthopedic trauma patients there are certain positions in the operating room that increase the patient’s risk for VTE, such as lying prone and any forced twisting or traction applied to a limb. Absolute contraindications to pharmaceutical prophylaxis include active bleeding or an untreated congenital coagulopathy (hemophilia, severe von Willebrand disease). These patients should receive mechanical prophylaxis only. High-risk patients with an increased risk of bleeding who can be given pharmacological prophylaxis with caution and extensive patient education and counseling include:

  • Personal or family history of hemorrhage
  • Acquired coagulopathy (hepatic insufficiency with abnormal coagulation studies)
  • Prothrombin Time/International Normalized Ratio (PT/INR) >1.5
  • Activated partial thromboplastin time (aPTT) >1.25
  • Thrombocytopenia (platelet [PLT] <50,000/mL)
  • Severe renal failure (Creatinine clearance [CC] < 30 ml/min)
  • Cerebral metastases or angioma
  • A recent stroke (within 24 hours)
  • Gastrointestinal, genitourinary, or ocular hemorrhage in the last two weeks
  • Medications (nonsteroidal anti-inflammatory drugs, antiplatelet drugs)
  • Severe hypertension (BP > 230/120)
  • Acute infection (endocarditis) (Prisco et al., 2014)

Because a superficial thrombophlebitis can progress to a VTE, many believe they should be treated to avoid progression. Currently fondaparinux (Arixtra), dosed prophylactically at 2.5 mg/day subcutaneously for 45 days, has the most clear and concise evidence regarding efficacy and safety versus placebo (Nisio et al., 2018). The ASH recommends antepartum prophylaxis with the standard dose of LMWH in 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 that was related to a hormonal risk factor or unprovoked who are not currently on long-term anticoagulation treatment. They recommend postpartum prophylaxis with the standard or intermediate dose of LMWH in women with antithrombin deficiency and a family history of VTE, homozygous for factor V Leiden or prothrombin genetic mutation, combined thrombophilia, a protein C or S deficiency, or a personal history of VTE. No prophylaxis is recommended in pregnant women with no or just one clinical risk factor for VTE. In women undergoing assistive reproductive treatment who develop severe ovarian hyperstimulation syndrome, the ASH recommends antithrombotic prophylaxis (Bates et al., 2018).

Once a VTE has been diagnosed, there are numerous options available for treatment. Benefits of treatment include prevention of clot extension, a PE, recurrent VTE, hemodynamic collapse and even death. VTEs are generally categorized as provoked (related to a specific known risk factor) or unprovoked. Surgical patients who develop VTE post-operatively are considered low risk (<1% after one year, 3% after five years) for recurrence. Patients with VTE not related to surgery but instead related to pregnancy, prolonged immobility, or exogenous estrogen therapy are considered intermediate risk for recurrence (5% after one year, 15% after five years). Both low and intermediate risk patients can be treated with anticoagulant medication for a period of three months. For high risk patients (those with unprovoked or cancer-related VTE) their risk for recurrence is high. Cancer patients have a 15% recurrence rate and should be treated until cured or at least 6 months. Patients with unprovoked VTE have a 10% risk of recurrence after one year and 30% after five years. They should be treated indefinitely if their bleeding risk is low-intermediate or for 3-6 months if they are high-risk for bleeding, especially in men who are at twice the risk for recurrence as compared to women. In general, the 2016 American College of Chest Physicians (ACCP) and 2017 European Society of Cardiology (ESC) guidelines recommend the use of DOACs over other medications as they have been proven to be non-inferior in terms of efficacy with an improved safety profile based on a reduced risk of major bleeding as compared to vitamin K antagonist (VKA) such as warfarin (Coumadin). They also carry the added advantage of a rapid onset of action and a predictable pharmacokinetic profile which negates the need for monitoring and dose adjustments. If using dabigatran (Pradaxa) or edoxaban (Savaysa, an oral factor Xa inhibitor), they recommend using LMWH for at least five days first, whereas with rivaroxaban (Xarelto) and apixaban (Eliquis) antecedent LMWH is not necessary. DOACs should be avoided in patients with concomitant medications that are potent p-glycoprotein inhibitors or cytochrome P450 3A4 inhibitors or inducers. This includes azole antimycotics like ketoconazole, several protease inhibitors used for HIV, and antiepileptics such as phenytoin and carbamazepine. VKAs are still recommended by the AACP/ESC for patients with severe renal impairment. If VKAs are chosen, the recommendation is to use a parenteral anticoagulant treatment first, and then initiate warfarin (Coumadin) with a 10 mg dose on days 1 and 2 followed by dosing based on INR results from day 3 (Tritschler et al., 2018).

In the case of a symptomatic isolated distal DVT, the 2016 ACCP guidelines recommend serial ultrasound surveillance for extension to the proximal veins in low-risk patients. A meta-analysis of patients with distal DVT showed potential benefit of decreased rate of recurrence amongst patients treated with anticoagulants but this was based on limited evidence. The only double-blind randomized clinical trial showed that six weeks of LMWH was not superior to placebo in low-risk patients regarding proximal extension of the clot, development of a contralateral DVT, or development of a symptomatic PE. The LMWH group also had an increased risk of bleeding. Compression stockings are recommended only for symptomatic relief of swelling and discomfort. Catheter-directed thrombolysis is recommended in cases on threatened limb loss. The combination of thrombolysis and anticoagulant was compared to anticoagulants alone and was found to reduce the risk of PTS by ⅓ but had no significant effect on the risk of PE, recurrent DVT, or death. The thrombolysis group also had an increased risk of bleeding. The recent ATTRACT trial compared thrombolysis to anticoagulants and found the thrombolysis group had an increased risk of major bleeding in the first 10 days and equivalent rates of PTS at 24 months, VTE recurrence, and mortality when compared with the medication group. Inferior vena cava (IVC) filters are only recommended in patients with an absolute contraindication to pharmacological anticoagulation and proximal DVT or PE. Their use has become controversial secondary to increased mortality rate in the first 30 days following placement. A recent trial comparing IVC filter with anticoagulants versus anticoagulants alone found no reduction in recurrent PE or death at three to six months in the combination treatment group (Tritschler et al., 2018).

The 2018 ASH guidelines do not specify which medication is preferred for the treatment of VTE, but instead give guidelines regarding the use of the various different groups of medications available. All patients on anticoagulants should receive additional supplementary patient education. To improve medication adherence, the ASH recommends against the use of a daily lottery, electronic reminder system or visual medication schedule to improve adherence. Similar to the guidelines referenced above, for patients on inhibitors or inducers of P-glycoprotein or cytochrome p450 the ASH recommends the use of VKA or LMWH in lieu of DOACs to avoid drug interactions. For patients with mild renal impairment (CC > 49 mL/min), they recommend monitoring renal function every 6-12 months. For those with moderate renal impairment (CC 30-50 mL/min) they should be monitored every three months. For patients on a VKA, they suggest home point-of-care INR testing (patient self-testing or PST) and self-adjusting of dose (patient self-management or PSM) in competent and capable patients. INR testing should be done every four weeks or less after initiation or dose adjustments, 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. In those patients on a VKA with a low to moderate risk of recurrent VTE that require a planned invasive procedure, no perioperative bridging with UFH or LMWH is recommended. If transitioning a patient from a DOAC to a VKA, the ASH recommends the provider continue to administer the DOAC until the INR becomes therapeutic in lieu of administering a bridge medication. In those patients on LMWH, the ASH recommends dosing based on body weight in obese patients rather than on anti-factor Xa concentration monitoring. For those patients on LMWH with severe renal dysfunction (CC < 30 mL/min), they recommend adjusting the dose based on the package insert instructions rather than on anti-factor Xa concentration monitoring. In patients on a DOAC with a planned invasive procedure, the ASH suggests that lab testing prior to the procedure for DOAC effect is unnecessary (Witt 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 systolic blood pressure <90) according to the 2016 ACCP and 2014 ESC guidelines. This treatment carries an increased risk for major bleeding, including intracranial hemorrhage, and is thus not recommended in intermediate risk patients. In a recent study, intravenous heparin combined with systemic thrombolysis resulted in a reduction in the risk of recurrent PE but an increase in the risk of major bleeding when compared with intravenous heparin alone (Tritschler et al., 2018). This treatment is only recommended by the ASH in patients with life-threatening hemodynamic instability, especially in pregnant patients with VTE (Bates et al., 2018).

For cancer patients who develop VTE, they are at an especially high risk of recurrence as well as bleeding complications. The 2016 ACCP and 2017 ESC guidelines recommend subcutaneous LMWH as a first choice for these patients for a period of six months or more. The Hokusai trial compared edoxaban (Savaysa) and the LMWH dalteparin (Fragmin) and showed that edoxaban was slightly better in terms of recurrent VTE (7.9% versus 11.3%) but with slightly more major bleeding (6.9% versus 4%). Similarly, the SELECT-D trial compared rivaroxaban (Xarelto) and dalteparin (Fragmin) found a reduced rate of recurrent VTE (4% versus 11%) with rivaroxaban but a slightly increased rate of major bleeding (6% versus 4%). The recommendation in 2018 from the International Society on Thrombosis and Hemostasis was to treat with edoxaban (Savaysa) or rivaroxaban (Xarelto) in those patients with a reduced risk of bleeding and no existing drug interactions. Note that the cost of these DOACs is typically 10% of the cost of dalteparin or similar, which may cost roughly $3,500/month (Tritschler et al., 2018).

For those patients with unprovoked episodes of VTE (no identifiable risk factor or trigger present at the time of diagnosis) and low to moderate bleeding risk, long term treatment is recommended to prevent recurrence. For women, who have a lower risk of recurrence than men, serial D-dimer testing may be acceptable as well in 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 >249 µg/L while taking an anticoagulant for at least 6 months
  • BMI > 29
  • Age > 64

If the patient has a score of 0-1, they are considered low risk for VTE recurrence according to the HERDOO2 developers and discontinuation of anticoagulant medication could be considered. If the patient’s score is 2 or above, medication should be continued. The 2016 ACCP and 2017 ESC guidelines recommend treatment with a DOAC in those patients without cancer as opposed to a VKA or ASA. DOACs have been shown to have equivalent effectiveness and reduced risk of bleeding when compared to VKAs, and superior effectiveness when compared to ASA. A prophylactic dose of apixaban (Eliquis) or rivaroxaban (Xarelto) has been shown to be as effective as therapeutic dosing with reduced risk of bleeding for extended treatment. DOACs are typically more expensive than VKAs, and there is no evidence for their use in patients with significant renal impairment (CC < 30ml/min), antiphospholipid syndrome, heparin-induced thrombocytopenia (HIT), or a VTE in an unusual site (such as the splanchnic vein) (Tritschler et al., 2018).

VTE complicates approximately 1.2 of every 1,000 deliveries in the United States. LMWH is recommended for treatment of acute VTE or superficial vein thrombosis in pregnant patients over UFH according to the ASH. As in other patients, the ASH does not recommend monitoring of anti-factor Xa for dosing. Catheter-directed thrombolysis is not recommended in pregnant patients for acute lower extremity DVTs. If on LMWH at therapeutic dose, the ASH suggests stopping the anticoagulant medication prior to a scheduled delivery. They suggest this is not necessary for women on the lower prophylactic dose of LMWH. They recommend against the use of DOACs in breastfeeding mothers, but instead recommend 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 in hospitalized patients that rate increases to 58 per 10,000. The ASH suggests that asymptomatic VTE not be treated but suggest treatment with LMWH or VKA for symptomatic cases. Treatment is recommended for three months or less for cases of DVT or provoked PE, or for 6-12 months in the case of unprovoked PE. Thrombolysis is suggested in cases of PE with hemodynamic instability followed by anticoagulant therapy, but not in cases of DVT or submassive PE. Thrombolysis may also be indicated in pediatric patients with life-threatening renal vein thrombosis. Thrombectomy is not recommended in pediatric patients, nor 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. In 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 in pediatric patients unless they fail to respond to standard anticoagulation medication and their levels of antithrombin are low when tested. Central venous access devices do not have to be removed until after treatment has been initiated if still functioning and required for treatment purposes (Monagle 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 management of these complications. In patients on VKA, this may present as an unsafe/highly elevated INR (>4.5) which may lead to dangerous bleeding. For patients with an INR 4.5-10 without any clinically relevant bleeding, they suggest stopping the medication but do not suggest 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. For those patients on a DOAC, the ASH recommends against measuring their effect during 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) (Witt et al., 2018). By contrast, the ACCP/ESC guidelines state that andexanet alpha (Andexxa) should be used to reverse apixaban (Eliquis) or rivaroxaban (Xarelto) in the case of life-threatening bleeding but does not mention its use in patients taking edoxaban (Savaysa). In most cases of mild-to-moderate bleeding that is not life-threatening, the ACCP/ESC guidelines recommend simply stopping the medication and supportive care due to their short half-life (Tritschler et al., 2018). In patients on dabigatran (Pradaxa) who develop life-threatening bleeding, the ASH and ACCP/ESC guidelines suggest stopping the medication and administering the reversal agent idarucizumab (Praxbind) (Tritschler et al., 2018; Witt et al., 2018). They suggest restarting oral anticoagulants within 90 days of major bleeding in patients with moderate to high risk of recurrent VTE and 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 (Witt et al., 2018).

Outside of bleeding, a potential complication of the use of 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 complexes of PLT factor 4 and heparin. The ASH defines the following patients as low risk for development of 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 intermediate risk for HIT. Patients on UFH after major surgery or trauma are defined as high risk for development of HIT. In patients at low risk for HIT, no PLT monitoring is required. In 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 no recent heparin use. After this, the ASH recommends checking PLT every two to three days thereafter if intermediate risk, or every other day if at high risk for development of HIT. The 4T score assesses a patient’s pretest probability of HIT. A score of 0-3 indicates low risk, 4-5 indicates intermediate risk, and a score of 6-8 indicates high risk for HIT. Points are assigned for degree of thrombocytopenia, the timing of the thrombocytopenia, the presence of thrombosis, and the presence of an alternative cause for the thrombocytopenia (Cuker et al., 2018). See details of the 4T Score below:

  1. Thrombocytopenia severity
    • 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
  2. 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 last 30-100 days
    • 2 points if between days 5-10 or within 1 day with heparin exposure in last 30 days
  3. Presence of thrombosis
    • 0 points if no thrombosis
    • 1 point if suspected thrombosis, progressive or recurrent thrombosis, or erythematous skin lesions
    • 2 points if new confirmed thrombosis, skin necrosis, or acute systemic reaction after intravenous UFH bolus
  4. Alternative cause of thrombocytopenia present
    • 0 points if definite alternative diagnosis present
    • 1 point if possible alternative diagnosis present
    • 2 points if no apparent alternative diagnosis present (Cuker et al., 2018)

Immunoassays and/or functional assays are typically used to confirm a diagnosis of HIT. In acute HIT (diagnosis has been confirmed, PLT remains low), heparin is contraindicated and an alternative anticoagulant should be started such as argatroban (a direct thrombin inhibitor given intravenously with a shorter duration that should be avoided in patients with hepatic dysfunction), bivalirudin (Angiomax, another direct thrombin inhibitor given intravenously), fondaparinux (Arixtra), or a DOAC. In the case of life or limb-threatening thrombosis, the ASH recommends a parenteral medication in lieu of an oral option. VKAs are not recommended until the PLT count has recovered to > 150,000/mL. IVC filters are not recommended, and antiplatelet medication is not necessary unless the patient also has coronary artery disease, a cardiac stent or some other indication for antiplatelet medication. Platelet infusion is only recommended in actively bleeding or high-risk patients. The ASH suggests a bilateral lower extremity US to screen for lower extremity thrombosis, as well as an upper extremity US in patients with central venous catheter(s) in place. In patients with isolated HIT with no associated DVT, anticoagulants should be continued until the PLT count recovers but not greater than three months. During those three months, the ASH recommends that patients wear an emergency alert bracelet warning medical providers of their recent history of HIT. In patients who require dialysis during acute HIT, the ASH recommends use of argatroban or bivalirudin (Angiomax) to prevent thrombosis of the circuitry. Subacute A HIT refers to the period of time when the patients PLT count has recovered but immunoassays remain positive. During this period, the ASH recommends treatment with a DOAC in lieu of a VKA. Subacute B HIT 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. In patients who require cardiovascular surgery, ASH recommends waiting until Subacute B or remote stage before proceeding. In patients requiring percutaneous coronary intervention, bivalirudin (Angiomax) is the anticoagulant of choice according to the ASH. In patients with a remote history of HIT who require VTE treatment, UFH and LMWH are not recommended, but rather argatroban, fondaparinux (Arixtra) or a DOAC are safer options. In 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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