Approach

Evaluation of VTE risk, as well as consideration of bleeding risk and any contraindications to pharmacologic VTE prophylaxis, should be undertaken in all patients prior to the administration of VTE prophylaxis. VTE prophylaxis entails pharmacologic and nonpharmacologic measures to diminish the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Knowledge translation of guidelines into clinical practice is a significant challenge. Overall, only 40% to 50% of medical patients admitted to the hospital receive adequate thromboprophylaxis. Adherence to guidelines is higher in surgical patients but remains limited.[74][75] Developing thromboprophylaxis guidelines in each hospital to guide clinicians is strongly recommended. Moreover, methods such as computer-based decision systems and preprinted orders, whereby physicians are confronted with decision making for each individual patient, have been shown to be most effective in optimizing adherence to thromboprophylaxis guidelines.[76][77] Periodic audits by pharmacists or other health professionals reinforce the consistent use of VTE prophylaxis.[78]

Dissemination of information through networks such as the Canadian-based Safer Health Care Now network also contributes to global awareness of the importance of VTE in the hospital setting.[79][80]

For information on VTE prophylaxis in patients with COVID-19, see Coronavirus disease 2019 (COVID-19) (Management approach).

Types of prophylaxis measures (pharmacologic and nonpharmacologic)

Pharmacologic thromboprophylaxis

Pharmacologic agents should be considered the mainstay of VTE prophylaxis, together with early ambulation. Three pharmacologic agents have been approved for some time: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and the selective anti-Xa inhibitor fondaparinux. [ Cochrane Clinical Answers logo ] [Evidence A]​ The vitamin K antagonist warfarin is a reasonable alternative, but it requires frequent monitoring and is associated with an increased risk of bleeding. The use of aspirin alone for thromboprophylaxis is controversial.[49] In one multicenter randomized controlled trial, extended prophylaxis for 28 days with aspirin was noninferior to, and as safe as, dalteparin for the prevention of VTE after total hip replacement surgery in patients who all initially received dalteparin for 10 days.[81]

Other oral agents, such as direct thrombin inhibitors (dabigatran) and anti-Xa inhibitors (rivaroxaban, apixaban), collectively known as direct oral anticoagulants (DOACs), can be used for thromboprophylaxis in hip and knee replacement surgery, but not in hip fracture surgery.[49][68][82][83][84][85]​​​​[Evidence A]​ In the US, dabigatran has been approved for thromboprophylaxis in patients who have undergone hip replacement, but not knee replacement, surgery. Unlike warfarin, DOACs require no monitoring when used as prophylactic agents. Dabigatran must not be used in patients with mechanical prosthetic valves, either in a prophylactic or in a therapeutic setting, due to its association with a higher risk of thromboembolic events and excess bleeding compared with warfarin.[86]

Rivaroxaban and apixaban have also been studied for thromboprophylaxis in medical patients. The MAGELLAN trial, a phase 3 trial comparing rivaroxaban versus enoxaparin in medical patients, showed that rivaroxaban was noninferior to enoxaparin with regard to the primary efficacy endpoint, but that bleeding was significantly increased.[87] Bleeding was also an issue in the ADOPT trial (apixaban vs. enoxaparin) and in the MARINER trial (rivaroxaban vs. placebo in extended prophylaxis) in medical patients.[88][89]​ Therefore, extended thromboprophylaxis for medical patients with these agents is not recommended.

Other characteristics of DOACs include twice daily dosing for apixaban versus once daily dosing for dabigatran and rivaroxaban. Dabigatran is not recommended in patients with a creatinine clearance (CrCl) <30 mL/minute, especially if it is co-administered with a P-glycoprotein inhibitor. Rivaroxaban is also not recommended in patients with a CrCl <30 mL/minute, and apixaban should be used with caution in these patients. All DOACs are started postoperatively as indicated in the individual product monographs. LMWH can be started preoperatively or postoperatively, but the authors recommend that LMWH be started after surgery because of concerns about the risk of bleeding into the joint following orthopedic surgery.

Nonpharmacologic thromboprophylaxis

Nonpharmacologic agents include graduated compression stockings (GCS) and intermittent pneumatic compression (IPC) devices.[90] IPC devices significantly decrease the rate of DVT versus placebo, but they are not as effective as pharmacologic agents; on a background of pharmacologic prophylaxis, however, they do provide some benefit.[3]​​[91][92] [ Cochrane Clinical Answers logo ] [Evidence B]​​​ Therefore, IPC devices and GCS should be used alone only if pharmacologic agents are contraindicated. Once the contraindication has resolved, the patient should receive pharmacologic prophylaxis. IPC devices can also be added to pharmacologic agents in selected high-risk patients, such as those with cancer having a major surgery. GCS are generally safe to use, with relatively few complications. However, the nonadherence rate has been reported to be 30% to 65%. Commonly cited reasons include pain, discomfort, difficulty putting on the stockings, perceived ineffectiveness, excessive heat, skin irritation, cost, and appearance.[93] Mobile compressive devices have shown interesting results since they can be comfortably worn while the patient is walking and the time of use is recorded by the device.[94][95] [ Cochrane Clinical Answers logo ]

Medical patients

Thromboprophylaxis is generally recommended for most hospitalized medical patients, except for patients who are at low risk for VTE. The use of risk assessment models has been suggested to estimate baseline risks for patients at low and high risk for VTE. One of the risk assessment models suggested by the American College of Chest Physicians (ACCP) is the Padua Prediction Score.[51]​ The American Society of Hematology (ASH) also endorses an individualized approach to medical inpatient thromboprophylaxis and highlights the use of the two most extensively studied risk scores: the Padua score and the database-derived IMPROVE score.[83][96]​ Both scores have been externally validated, but have not undergone extensive impact analyses to show that their use leads to a reduction in adverse clinical outcomes. Nonetheless, the assessment of all hospitalized medical patients for risk of VTE is important so that appropriate thromboprophylaxis can be provided. 

If the patient is admitted due to pulmonary or cardiovascular decompensation, or acute infectious, rheumatic, or inflammatory conditions, and is immobilized due to a medical illness, with one or more additional VTE risk factors, thromboprophylaxis with LMWH or fondaparinux is preferred over UFH, until either full mobility is restored or the patient is discharged from the hospital.[83][Evidence C]​​ While ASH guidelines do not recommend DOACs for thromboprophylaxis, rivaroxaban is now approved by the US Food and Drug Administration for VTE prevention in acutely ill hospitalized medical patients; however, data from clinical trials found increased bleeding risk with DOACs, and the current authors do not recommend their use.[87] In a study that compared apixaban with enoxaparin in medically ill patients, the extended course of apixaban (30 days) was not superior to a shorter course of enoxaparin and was associated with significantly more bleeding. Similarly, an extended course of rivaroxaban for 45 days after discharge from the hospital did not result in a decrease in VTE or death by PE.[88][89]​​ Extended use of thromboprophylaxis in medically ill patients beyond the period of hospitalization or patient immobilization is not currently recommended.[51][83][97][98][99][100][101]​​​ Certain subgroups of medical patients, such as acutely ill patients with recently reduced mobility, might benefit from extended thromboprophylaxis, but further studies are needed.[102][103]

Medical patients (intensive care unit, cancer [ambulatory])

Patients in the ICU

Most critical care patients should receive thromboprophylaxis and UFH or LMWH is generally recommended. No agent has been clearly shown superior in terms of efficacy or bleeding.[104] In the PROTECT trial, where 3675 critical care patients were randomly assigned to receive prophylactic dalteparin versus UFH, dalteparin was not superior to UFH in preventing thrombosis.[104] There are no data on fondaparinux or DOACs in this population. ASH guidelines suggest using LMWH over UFH due to a lower incidence of heparin-induced thrombocytopenia (HIT) with LMWH.[83][Evidence B]

Hospitalized cancer patients

Hospitalized cancer patients should receive thromboprophylaxis.[51][61]​​​[62][105]​​​​​​ The American Society for Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend prophylactic LMWH, UFH, or fondaparinux in this population.[61][62]​ ASH and European Society of Medical Oncology (ESMO) guidelines suggest using LMWH.[60][105]​​​​​

Ambulatory cancer patients receiving chemotherapy

Thromboprophylaxis is generally not recommended for low-risk ambulatory cancer patients receiving chemotherapy.[51][60]​​​[61][62][105]​​​ However, ASCO, the International Initiative on Thrombosis and Cancer, ASH, and ESMO guidelines recommend offering thromboprophylaxis with apixaban, rivaroxaban, or LMWH to high-risk outpatients with cancer (Khorana score ≥2 prior to starting a new systemic chemotherapy regimen) provided there are no significant risk factors for bleeding and no drug interactions.[60][62][63][105]​​​​​ In the AVERT trial, apixaban demonstrated efficacy in preventing thromboembolic events in patients with cancer undergoing chemotherapy and intermediate to high thrombotic risk (Khorana score ≥2).[64] However, major bleeding was significantly increased in this study, particularly in patients with gynecologic and gastrointestinal cancer. In the CASSINI trial, rivaroxaban did not reduce the incidence of thromboembolic disease and death compared with placebo in ambulatory high-risk cancer patients.[65] In recent years, a number of meta-analyses have shown that primary prophylaxis lowers the risk of VTE for ambulatory cancer patients but also increases the risk of bleeding.[106][107][108]​​​​[109]​​[110]​​ ​

ACCP guidelines suggest prophylactic dose LMWH or low-dose UFH in outpatients with solid tumors who have additional risk factors for VTE and are at low risk of bleeding.[51]​ Additional risk factors include previous VTE, immobilization, hormonal therapy, angiogenesis inhibitors, and thalidomide or lenalidomide therapy.​[51]​ Evidence for this suggestion is weak and further trials are needed to clarify this question.​

Central venous catheters increase the risk of upper extremity thrombosis in patients with cancer. One Cochrane review noted that the evidence was inconclusive as to the benefit of LMWH or vitamin K antagonists for prevention of catheter-associated thrombosis.[111] Routine prophylaxis for catheter-related thrombosis is not recommended.​[51][60]​​​

Patients with multiple myeloma are at particularly increased risk of VTE as a result of treatments (thalidomide-, lenalidomide-, and pomalidomide-containing regimens; dexamethasone; erythropoietin), and also other factors, such as characteristics of the malignancy.[60] The highest risk for VTE is in the first 6 months following diagnosis.[112]​ Use of VTE prophylaxis in these patients is guided using risk stratification scores, such as IMPEDE or SAVED.[112]​​[113][114]​​​​​ Both scores require future validation. Generally, guidelines recommend aspirin in low-risk patients and prophylaxis-dose LMWH, warfarin, or low-dose direct oral anticoagulants (rivaroxaban or apixaban) in high-risk patients. Specific recommendations from different organizations are as follows:

  • ASCO recommends aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients​​​.[62]

  • The 2008 International Myeloma Working Group guidelines recommend aspirin in low-risk patients with one VTE risk factor and LMWH or​ warfarin in high-risk patients with two or more risk factors.[25]

  • ​The NCCN recommends aspirin for low-risk patients and LMWH, warfarin, rivaroxaban, apixaban, or fondaparinux for high-risk patients.[112]

  • ESMO recommends aspirin for low-risk patients, with LMWH for high-risk patients, or rivaroxaban or apixaban as an alternative.[60]

  • ASH suggests using either prophylactic LMWH, low-dose aspirin, or a low-dose vitamin K antagonist (warfarin) for patients receiving thalidomide, lenalidomide, or pomalidomide.[105]

One systematic review found that aspirin may not be adequate thromboprophylaxis for patients with multiple myeloma receiving lenalidomide plus high-dose dexamethasone.[115] A Cochrane review found that the currently available evidence on the comparative effects of aspirin, vitamin K antagonist (warfarin), LMWH, or direct oral anticoagulants on all‐cause mortality, symptomatic deep vein thrombosis, or bleeding events in patients with multiple myeloma is inconclusive.​[116]

Surgical patients

The ACCP suggests two risk assessment models that take into consideration patient- and procedure-specific risk factors to estimate baseline risk factors of surgical patients:[3]​

  • The Rogers score: stratifies patients from very low (<7 points), to low (7-10 points), to moderate risk (>10 points) for VTE. Somewhat cumbersome to use and has not been externally validated.

  • The Caprini score: categorizes patients as being at very low (0 points), low (1-2 points), moderate (2-3 points), or high risk (≥5 points) for VTE. Relatively easy-to-use and has been validated in a sample of general, vascular, and urologic surgery patients.[3]

General, gynecologic, urologic, gastrointestinal, and vascular surgery:

Pharmacologic thromboprophylaxis is not indicated if the patient is at low risk for VTE (Caprini score 1-2; or Rogers score 7-10), but mechanical prophylaxis (preferably with IPC) is recommended.[3]​ In consensus guidelines, GCS are usually recommended in low-risk patients.[66]​ However, prophylaxis with UFH or LMWH plus mechanical prophylaxis is recommended for high-risk patients (e.g., major surgery or the patient has additional VTE risk factor(s)).[3]​​[68][Evidence B]​​​​​​​ The current authors recommend the addition of IPC rather than GCS to pharmacologic thromboprophylaxis in patients undergoing elective surgery considered at moderate to high risk of VTE. In the GAPS study, the use of pharmacologic thromboprophylaxis alone was found noninferior to the combination of pharmacologic thromboprophylaxis and GCS for the prevention of VTE.[117] Of note, the UK National Institute for Health and Care Excellence (NICE) guidelines recommend the addition of LMWH or fondaparinux for at least 7 days in patients undergoing abdominal surgery in whom the risk of VTE outweighs the risk of bleeding.[52][Evidence C]​​​​​ For high-risk major abdominal or pelvic surgery including cancer patients, thromboprophylaxis with UFH or LMWH with extended prophylaxis up to 4 weeks after surgery can be considered, as well as adding IPC devices or GCS.[3][30]​​​[52][63][66][105][118]​​​​​​​​ No prophylaxis is recommended after an elective abortion; however, an increased risk of venous thrombosis has been documented.[67]

Thoracic surgery:

Most thoracic surgery patients are considered to be at least at moderate risk for VTE and thromboprophylaxis should be routinely used.[3]​ Mechanical prophylaxis (preferably IPC; GCS is an alternative) is recommended for most patients undergoing thoracic surgery and should be started on admission and stopped when the patients ambulate.[52] For patients at moderate or high risk for VTE who are not at high risk for major bleeding, guidelines recommend the addition of pharmacologic prophylaxis with UFH, LMWH, or dalteparin for a minimum of 7 days.[3][52]​​ For patients who are at high risk for major bleeding, mechanical prophylaxis alone, preferably with IPC, should be used. Once bleeding risk diminishes, pharmacologic prophylaxis should be initiated.[3]​

Cardiac surgery:

Most patients undergoing cardiac surgery (including coronary artery bypass graft [CABG]) are considered at moderate risk for VTE and at high risk for major bleeding complications. The ACCP recommends mechanical prophylaxis for patients with an uncomplicated postoperative course and suggests adding UFH or LMWH in patients with a prolonged hospital course with one or more nonhemorrhagic surgical complications.[3]​ ASH guidelines suggest considering LMWH or UFH for patients undergoing cardiac surgery when there is a higher baseline risk for VTE.[68][Evidence C]​​​​​​​ UK NICE guidelines recommend considering the addition of LMWH to mechanical prophylaxis for at least 7 days in patients who are not receiving other anticoagulation therapy.[52][Evidence C]​​​​​​ Fondaparinux should be used second-line if LMWH is contraindicated.

Neurosurgery:

Patients undergoing neurosurgery (such as resection of meningioma) are a special population because of the bleeding risk and potential serious consequences of bleeding. Routine mechanical thromboprophylaxis with IPC devices is recommended.[3]​​[52][66]​​​​​[68][Evidence C]​​​ In patients at low risk of major bleeding, UFH or LMWH should be used alongside IPC devices if not contraindicated.[3]​​[52][66]​​​​​[68][Evidence C][Evidence C]

High-risk groups include trauma patients, orthopedic surgery patients, and patients with acute spinal cord injury. Trauma patients should routinely receive prophylaxis with UFH, LMWH, and/or mechanical methods, preferably IPC, until discharge, unless contraindicated.[3]​​[66]​ In surgery for acute spinal cord injury, prophylaxis with UFH or LMWH is started after surgery and continued for 3 months or until the patient is fully ambulatory.[3]​ IPC devices are used if pharmacologic prophylaxis is contraindicated or preferably in association with UFH or LMWH in these high-risk groups.[3]​​[52][66]​​​​​

Spinal surgery:

Routine thromboprophylaxis with IPC devices is recommended for patients undergoing elective spinal surgery.[3][52][66]​​ If additional VTE risk factors are present, a combination of pharmacologic methods (LMWH or UFH) with IPC devices can be used once adequate hemostasis is established and the risk of bleeding decreases.[3]

Orthopedic surgery:

Patients undergoing orthopedic surgery are an extremely high-risk population.[69][70]​​​​

Elective total hip arthroplasty (THA) and total knee arthroplasty (TKA)

​Society guidelines all agree that some form of prophylaxis is necessary; however, there is no consensus on choice of agent or duration, although all recommend the use of mechanical prophylaxis with IPC. Pharmacologic prophylaxis should be used first-line; however, mechanical prophylaxis as a sole therapy is only recommended if pharmacologic prophylaxis is contraindicated.[49][52][66]​​

  • The 2012 ACCP guidelines recommend the use of one of the following for a minimum of 10-14 days (ideally extended in the outpatient period to 35 days) for both total hip and knee arthroplasty procedures: LMWH (the preferred option), aspirin, fondaparinux, apixaban, dabigatran, UFH, warfarin, aspirin, and/or an IPC device. In patients who receive LMWH, prophylaxis should be started at least 12 hours preoperatively or postoperatively. Dual prophylaxis with an antithrombotic agent and IPC device should be used during the hospital stay. In patients who are at increased risk for bleeding, an IPC device or no prophylaxis is favored over pharmacologic prophylaxis. For patients who decline injections or an IPC device, apixaban or dabigatran (or, if these are unavailable, rivaroxaban or adjusted-dose vitamin K antagonist) can be used.[49]

  • The 2019 ASH guidelines recommend using aspirin or anticoagulants for a minimum of 3 weeks. When anticoagulants are used, DOACs are preferred over LWMH, which is preferred over warfarin or UFH. Any of the DOACs approved for use are acceptable, as they have not been directly compared head-to-head in clinical trials.[68]

  • The 2018 UK NICE guidelines recommend offering prophylaxis for patients whose risk of VTE outweighs the risk of bleeding. For hip replacement, first-line options are: LMWH for 10 days followed by aspirin for 28 days, LMWH for 28 days, or rivaroxaban for 35 days. If none of these options are possible, apixaban or dabigatran can be used. For knee replacement, first-line options are: LMWH for 14 days, aspirin for 14 days, or rivaroxaban for 14 days. If none of these options is possible, apixaban or dabigatran can be used.[52]

DOACs have varying degrees of approval worldwide. Based on four randomized trials, dabigatran has been approved in Europe, Canada, and Australia for thromboprophylaxis after THA and TKA.[119][120][121]​​​​​[122]​ In the US, dabigatran has been approved by the Food and Drug Administration in patients who have undergone THA only.[123]​ Rivaroxaban and apixaban have been approved in the US and Europe for thromboprophylaxis after both THA and TKA.[123] The RECORD (REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) series of phase 3 studies of rivaroxaban showed a significant decrease in total VTE without an increase in bleeding compared with enoxaparin for TKA and THA.[124][125][126][127]​​​​ The evidence for apixaban was based on the ADVANCE-2 and ADVANCE-3 trials.[128][129]​​​​ 

One randomized controlled trial found that in the prevention of symptomatic VTE after THA or TKA, extended prophylaxis with aspirin was not significantly different from rivaroxaban in patients who had already received 5 days of rivaroxaban.[130]​ Another study, however, found that in patients undergoing hip or knee arthroplasty for osteoarthritis, use of aspirin resulted in a significantly higher rate of symptomatic VTE within 90 days compared with enoxaparin.[131]

Hip fracture surgery:

For hip fracture surgery, LMWH, fondaparinux, low-dose UFH, warfarin, aspirin, or an IPC device are recommended for prophylaxis, with preference for LMWH. DOACs should not be used.[49][66]​​​​​​[68][Evidence C][Evidence C]​​​​​​​ Again, society guidelines all agree that some form of prophylaxis is necessary; however, there is no consensus on choice of agent or duration​​​​: 

  • ACCP guidelines recommend one of the following for a minimum of 10-14 days: LMWH, aspirin, fondaparinux, UFH, vitamin K antagonist.[49]

  • ASH guidelines advise LMWH or UFH for a minimum of 3 weeks.[68]

  • UK NICE guidelines recommend offering VTE prophylaxis for a month if the risk of VTE outweighs the risk of bleeding. Options are: LMWH, starting 6-12 hours after surgery; or fondaparinux, starting 6 hours after surgery, providing there is low risk of bleeding. If surgery is delayed beyond the day after admission, preoperative VTE prophylaxis should be considered. For LMWH, the last dose should be given no less than 12 hours before surgery; for fondaparinux sodium this is extended to 24 hours. If surgery for hip fracture is delayed, LMWH or UFH should be given at least 12 hours before the surgery.[52]

Lower leg fractures:

Thromboprophylaxis for lower-extremity fractures of the tibia, fibula, or ankle is generally not recommended but can be considered if there are additional risk factors for VTE.[49][66]​​​​​​ One study compared the efficacy of aspirin with enoxaparin in patients who had an extremity fracture (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture.[132] Aspirin was non-inferior to LMWH for the primary outcome of death from any cause at 90 days. DVT occurred in 2.51% of patients in the aspirin group and in 1.71% of patients in the LMWH group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31), while the​​ incidence of PE (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups. This study is limited in its generalizability given an extremely heterogeneous patient population. Moreover, although the death rate did not differ between groups, the higher rate of DVT in the aspirin group may be meaningful to patients and physicians.

Arthroscopic surgery:

The incidence of proximal DVT is very low after arthroscopic surgery, regardless of receiving prophylaxis. Thromboprophylaxis after arthroscopic surgery cannot currently be recommended.[49][71][72] [ Cochrane Clinical Answers logo ] ​​ UK NICE guidelines advise that while VTE prophylaxis is generally not needed for people undergoing arthroscopic knee surgery, LMWH (started 6-12 hours after surgery and continued for 14 days) should be considered if total anesthesia time is more than 90 minutes or the person's risk of VTE outweighs their risk of bleeding.[52]

Bariatric surgery:

Bariatric surgery patients are probably a high-risk population also, although data are more limited. Thromboprophylaxis with LMWH, fondaparinux, or UFH is recommended, with the possible addition of mechanical devices.[3]​​ [ Cochrane Clinical Answers logo ] [Evidence A]​​​​ Higher doses of LMWH and UFH may be required in obese patients.[3]​ UK NICE guidelines recommend mechanical VTE prophylaxis for all patients undergoing bariatric surgery, with the addition of LMWH or fondaparinux for at least 7 days in patients whose risk of VTE outweighs their risk of bleeding.[52] A Cochrane review found that mechanical combined with pharmacologic prophylaxis, compared to mechanical prophylaxis alone, started 12 hours before bariatric surgery, may reduce the incidence of VTE. However, the evidence was of low certainty and the authors could not assess the effect of this intervention on the incidence of major bleeding, PE, death, or adverse events. The authors concluded that there is a need for high-quality, large randomized controlled trials to determine the best way to prevent VTE in this patient group.​[133]

Special situations (kidney disease, obesity, pregnancy, HIT)

Kidney disease:

LMWH, fondaparinux, rivaroxaban, apixaban, and dabigatran are eliminated through the kidney and must be used with caution in patients with chronic kidney disease.[57][58]​ Few data are available on the use of LMWH with reduced CrCl (<30 mL/minute) because these patients have been excluded from randomized controlled trials. Three options are suggested if LMWH is to be used in these patients: use UFH; reduce the dose of LMWH according to the manufacturer's instructions; or measure anti-Xa levels.[3]​ Because no level of anti-Xa has been shown to be effective and safe for prophylactic doses of LMWH, we do not recommend routine anti-Xa level monitoring. The dose of enoxaparin can be reduced according to the manufacturer's instructions. Preliminary data show that bioaccumulation of anti-Xa activity may vary with different LMWH molecules.[134] For example, among patients with a CrCl <30 mL/minute, two studies showed no bioaccumulation of anti-Xa activity with prophylactic doses of dalteparin.[135][136]​ Further studies will need to clarify whether a particular LMWH is safer in patients with chronic kidney disease. Fondaparinux is contraindicated in patients with severe renal insufficiency (CrCl <30 mL/minute). Dabigatran is not recommended in patients with a CrCl <30 mL/minute, especially if it is co-administered with a P-glycoprotein inhibitor. Rivaroxaban is also not recommended in patients with a CrCl <30 mL/minute. Apixaban should be used with caution in patients with a CrCl <30 mL/minute.

Obesity:

It has been suggested that weight-based dosing of LMWH might be preferable to fixed-dosing for obese patients (body mass index >30 kg/m²).[137] However, one meta-analysis concluded that for hospitalized obese patients, weight-adjusted heparin dosing was not associated with a decreased risk of VTE compared with fixed-dose heparin.[138]​ Further studies are required to elucidate this question. Dose can be adjusted empirically for patients <50 kg who are at risk of bleeding, but guidelines do not address this issue.[3]

Pregnancy:

For pregnant women requiring thromboprophylaxis, UFH and LMWH are safe because they do not cross the placenta. The ACCP guidelines recommend the prophylactic use of LMWH over UFH for pregnant patients.​[139]​ Pharmacologic VTE prophylaxis should not be used while women are in active labour.[52]​ UK NICE guidelines recommend dual prophylaxis with LMWH and mechanical prophylaxis (IPC is first-line; if this is contraindicated, GCS can be used) for pregnant women, or women who gave birth or had a miscarriage or termination of pregnancy, in the past 6 weeks and who are likely to be immobilized, or have significantly reduced mobility relative to normal, for 3 or more days after surgery (including cesarean section). This should be continued until the woman no longer has significantly reduced mobility relative to normal or until discharge from hospital.[52]​ Insufficient data are available on fondaparinux, rivaroxaban, or dabigatran to approve their use in pregnancy.

Past history of heparin-induced thrombocytopenia (HIT):

A past history of HIT is an important contraindication to UFH or LMWH. Even if serum antiplatelet factor 4 antibodies are not detectable, avoiding UFH or LMWH for thromboprophylaxis is advisable if alternative agents are available.[56] Consultation with a thrombosis specialist is warranted to determine the best treatment option, as these agents have a long half-life and no antidote.

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