Heparin and LMW heparin: Dosing and adverse effects

INTRODUCTION — Heparins, including unfractionated heparin and a variety of low molecular weight (LMW) heparin products, are used extensively as anticoagulants. This topic will review the general principles underlying the therapeutic use of unfractionated and LMW heparins including dosing, monitoring, and reversal of anticoagulation, as well as danaparoid (not available in the United States).

Use of unfractionated heparin during cardiac surgery and cardiopulmonary bypass, including reversal with protamine sulfate, is discussed separately. (See "Blood management and anticoagulation for cardiopulmonary bypass" and "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass".)

The use of other anticoagulants, including vitamin K antagonists (VKAs), direct thrombin inhibitors, direct factor Xa inhibitors, and fondaparinux, are presented separately.

●VKAs – (See "Warfarin and other VKAs: Dosing and adverse effects".)

●Direct thrombin and factor Xa inhibitors – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

●Fondaparinux – (See "Fondaparinux: Dosing and adverse effects".)

INDICATIONS AND CONTRAINDICATIONS — The indications for heparin and the choice among heparin products in specific clinical settings and in specific populations are discussed separately:

●Coronavirus disease 2019 (COVID-19) – (See "COVID-19: Hypercoagulability".)

●Venous thromboembolism (VTE) prophylaxis – (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

●Deep vein thrombosis (DVT) – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

●Pulmonary embolism (PE) – (See "Venous thromboembolism: Initiation of anticoagulation".)

●Myocardial infarction (MI) – (See "Acute ST-elevation myocardial infarction: Management of anticoagulation".)

●Acute coronary syndrome (ACS) – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes".)

●Stroke or transient ischemic attack (TIA) – (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

●Children and adolescents – (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

●Neonates – (See "Neonatal thrombosis: Management and outcome".)

●Pregnancy – (See "Use of anticoagulants during pregnancy and postpartum".)

●Neuraxial anesthesia – (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

●Perioperative – (See "Perioperative management of patients receiving anticoagulants".)

Possible contraindications to anticoagulation are listed in the table (table 1); however, this list is not intended to substitute for the judgment of the treating clinician, who should weigh the risks and benefits for the individual patient.

MECHANISMS OF ACTION — Heparin is an endogenously produced, linear polysaccharide that consists of repeating units of pyranosyluronic acid and glucosamine residues [1,2]. Endogenous heparin and heparin-binding proteins have a variety of anticoagulant, anti-inflammatory, and possibly antiangiogenic effects, which are incompletely understood [3-8].

The form of heparin used clinically as an anticoagulant is isolated from porcine (pig) or bovine (cow) intestines [9]. It has a mixture of different-length polysaccharides, with a mean size of approximately 45 saccharide units, corresponding to a mean molecular weight of approximately 15,000 daltons (range 3000 to 30,000 daltons). Low molecular weight (LMW) heparins are derived via enzymatic or chemical depolymerization of unfractionated heparin, resulting in a product with a mean length of approximately 15 saccharide units and a mean molecular weight of approximately 4000 to 5000 daltons (range 2000 to 9000 daltons) [10-14]. Fondaparinux, which consists of the minimal AT-binding region of heparin, contains five saccharide units (ie, pentasaccharide) and has an approximate molecular weight of 1700 daltons.

Heparins act indirectly by binding to antithrombin (AT, formerly called AT III, also known as heparin cofactor I) rather than by binding directly to coagulation factors (figure 1). Binding of heparin to AT is mediated by a unique pentasaccharide sequence in heparin that is randomly distributed along the heparin chains [10,15]. The binding site for heparins on AT is located at the AT amino terminus [16]. Binding of heparin to this site on AT induces a conformational change in AT, which converts AT from a slow to a rapid inactivator of coagulation factors (eg, thrombin [factor IIa], factor Xa) (figure 2). The enhancement of AT anticoagulant activity by heparins is on the order of 1000- to 4000-fold [16,17].

Both unfractionated and LMW heparins efficiently inactivate factor Xa via AT. However, unfractionated heparin is a much more efficient inactivator of thrombin because thrombin inactivation requires the formation of a ternary complex between heparin, AT, and thrombin, and this ternary complex can form only when heparin chains are at least 18 saccharide units long (figure 2) [18]. These 18-saccharide-long units are present to a much smaller extent in LMW heparins and are absent from fondaparinux. Thus, unfractionated heparin, LMW heparin, and fondaparinux all inactivate factor Xa, but unfractionated heparin also inhibits thrombin [11,19]. Fondaparinux appears to have nearly pure anti-factor Xa activity.

PHARMACOLOGY

●Unfractionated heparin – Heparin is metabolized in the reticuloendothelial system and the liver, and it is excreted in the urine. Kidney function does not affect elimination at therapeutic doses, although elimination by the kidneys may play a role at very high doses. However, dose adjustment is not used in patients with chronic kidney disease or kidney failure. (See 'Initial dosing' below.)

The onset of heparin action when administered intravenously is instantaneous; plasma levels following subcutaneous administration peak at two to four hours, with considerable individual variation. The metabolism of heparin is complex and dose-dependent, with a half-life of approximately 45 minutes to one hour [9].

Variable bioavailability of unfractionated heparin is due in part to competitive occupation of binding sites by proteins other than antithrombin (AT) and coagulation factors, including plasma proteins, proteins secreted by platelets (eg, platelet factor 4), and proteins secreted by endothelial cells [10,20]. Some of these heparin-binding proteins are acute phase reactants that may be increased substantially in acutely ill patients.

●Low molecular weight (LMW) heparins – LMW heparins are metabolized in the liver and excreted by the kidney. Clearance by the kidneys contributes approximately 10 to 40 percent. Patients with impaired kidney function may have reduced clearance of LMW heparins, with marginally increased plasma levels in individuals with mild to moderate chronic kidney disease. Individuals with creatinine clearance <30 mL/min have a significantly increased plasma level (eg, by approximately 65 percent) and generally require dose adjustment or use of an alternative agent such as unfractionated heparin. (See 'LMW heparin standard dosing' below.)

LMW heparin levels peak at approximately three to five hours after subcutaneous administration and at approximately two hours after intravenous administration [21]. When administered subcutaneously (the most common route of administration), the half-life of LMW heparins ranges from three to seven hours if kidney function is normal. Steady state levels are reached on approximately day two to three of therapy.

Unfractionated heparin and LMW heparin do not cross the placenta; however, multiple dose vials may contain benzyl alcohol, which does cross the placenta and may cause fetal harm. Thus, individuals who are pregnant should use preservative-free preparations [9]. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Preservative-free vials'.)

Unfractionated heparin and LMW heparin can be used in breastfeeding because they do not accumulate in breast milk. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Breastfeeding'.)

UNFRACTIONATED HEPARIN

Advantages and limitations — Heparin has a number of potentially advantageous attributes. These include:

●Rapid onset and offset of action, allowing for more flexibility in dose titration or discontinuation when needed (eg, for select surgical procedures or bleeding)

●Ability to monitor using the activated partial thromboplastin time (aPTT), anti-factor Xa activity, or activated clotting time (ACT), which are widely available

●Lack of substantial elimination by the kidneys, allowing use in kidney failure or chronic kidney disease

●Extensive clinical experience

●Ability to fully and rapidly reverse activity using protamine sulfate

●Intravenous or subcutaneous route of administration

Heparin also has a number of limitations:

●Short half-life, typically necessitating administration via continuous infusion for therapeutic levels of anticoagulation (although it may be administered by the subcutaneous route for acute venous thromboembolism [VTE]) [22]

●Highly variable dose-response relationship, necessitating frequent laboratory monitoring

●Achieving and maintaining therapeutic levels (based on the aPTT or anti-factor Xa activity) is often challenging

●No oral formulation

●Potential complications including heparin-induced thrombocytopenia (HIT), skin reactions, and osteoporosis with long-term use

●Reduced ability to inactivate thrombin bound to fibrin or factor Xa bound to activated platelets within a thrombus, resulting in the potential for thrombus extension during heparin therapy [23]

●Potentially increased risk of hemorrhagic complications compared with other parenteral anticoagulants such as LMW heparin [24]

The variable response to unfractionated heparin was illustrated in the Enoxaparin and Thrombolysis in Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction (ExTRACT TIMI) 25 trial, which compared the low molecular weight (LMW) heparin enoxaparin versus unfractionated heparin in the treatment of patients with myocardial infarction [25]. The 6055 patients randomly assigned to receive unfractionated heparin had dosing according to an American College of Cardiology/American Heart Association weight-based nomogram with centrally monitored aPTTs. This central monitoring demonstrated that only 34 percent of initial aPTTs were in the therapeutic range; 13 percent were markedly low (<1.25 times control); and 16 percent were markedly high (≥2.75 times control).

Challenges of maintaining an aPTT in the therapeutic range have also been seen in additional real-world studies, which have demonstrated an aPTT outside the therapeutic range in 60 to 70 percent of measurements despite close monitoring and dose titration [26-28].

Dosing and monitoring

Baseline testing (unfractionated heparin) — Baseline assessment prior to heparin administration generally includes the following:

●Thorough history for underlying bleeding disorders and/or recent trauma or surgery.

●Complete blood count (CBC) to obtain a baseline hemoglobin level and platelet count.

●Coagulation studies including prothrombin time (PT) and aPTT to verify that the patient does not have an underlying coagulopathy or laboratory abnormality (such as a lupus anticoagulant, which may prolong the aPTT) that would interfere with standard heparin monitoring.

●In some cases, a baseline anti-factor Xa level may be used [29]. (See 'Special scenarios' below.)

Checking liver function tests (transaminases) may be appropriate in many patients because heparins can cause an asymptomatic elevation of transaminases in some individuals; evidence that transaminases were normal prior to starting heparin and increased mildly following heparin initiation suggests that the heparin is the likely explanation and no further/more aggressive evaluation is needed. However, more marked changes in transaminases may require additional evaluation.

Serum creatinine level is not required because heparin dosing is not affected by kidney function.

Initial dosing — Unfractionated heparin for intravenous or subcutaneous use is available in a variety of concentrations. The United States Joint Commission's National Patient Safety Goal 03.05.01 calls for hospitals to use commercially available premixed products whenever possible to minimize risk for medication errors [30]. (See 'Medication errors' below.)

Heparin is not intended for intramuscular use and cannot be given orally.

●Therapeutic (full-dose) heparin – After baseline testing (eg, aPTT, PT) has been performed, therapeutic (full-dose) anticoagulation with heparin is administered intravenously as an initial bolus followed by a continuous infusion, or as an infusion without a bolus, depending on bleeding risks and the rapidity with which therapeutic anticoagulation is needed. For patients with acute VTE, nomogram-based dosing has been demonstrated to improve the rapidity of establishing an anticoagulant effect and to reduce the risk of recurrent VTE, compared with practices in which the clinician estimated the initial dosing without using a nomogram [31]. (See "Venous thromboembolism: Initiation of anticoagulation", section on 'Unfractionated heparin' and "Venous thromboembolism: Initiation of anticoagulation".)

Nomograms may be based on the aPTT or anti-factor Xa activity and either weight based (eg, initial bolus, 80 units/kg; followed by 18 units/kg/hour) (table 2) or non-weight based (table 3). Existing guidelines offer no preference of one strategy over another, but they do emphasize the need for adequate dosing. For example, the 2012 American College of Chest Physicians (ACCP) Guidelines suggest either a weight-based approach, a non-weight-based, or a fixed-dose approach (eg, initial bolus of 5000 units followed by an infusion of ≥1300 units per hour) that ensures at least 32,000 units/day of unfractionated heparin [10,32-35].

The advantages of dosing based on patient weight are especially important for individuals with a large VTE (eg, massive pulmonary embolism), whereas initial dosing with an upper limit or dose cap (rather than weight-based dosing) may be more appropriate in individuals with a higher-than-average risk of bleeding.

Weight-based heparin nomograms generally use low-intensity or high-intensity dosing strategies. Low-intensity dosing is often used for individuals with a higher-than-average risk of bleeding, for whom the potential concern about supratherapeutic levels is greater and for whom omission of the bolus dose and/or a lower initial infusion dose may be appropriate. Examples include recent (eg, within two weeks) thrombotic stroke, surgery, or bleeding; or comorbidities that increase bleeding risk such as uremia, coagulopathy, concomitant antiplatelet agents, or thrombocytopenia [34]. For individuals with obesity or other factors expected to reduce heparin bioavailability, individuals for whom the urgency of anticoagulation is greater, or those known to require higher doses in the past, higher-intensity dosing nomograms may be indicated.

Dosing in other settings is discussed in separate topic reviews:

•Pregnancy – (See "Use of anticoagulants during pregnancy and postpartum".)

•Acute coronary syndrome – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes".)

•Acute myocardial infarction – (See "Acute ST-elevation myocardial infarction: Management of anticoagulation".)

•Children – (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

•Neonates – (See "Neonatal thrombosis: Management and outcome".)

Although intravenous dosing of unfractionated heparin is preferred for most circumstances in which a therapeutic anticoagulant effect is desired, weight-based subcutaneous dosing without monitoring was shown to be equally effective and safe when compared with intravenous heparin in one randomized trial among patients with acute VTE [22]. However, this trial was closed prematurely due to low accrual, and additional direct comparisons between these approaches are not available.

●Prophylactic (lower dose) heparin – Prophylactic-dose heparin is generally administered as a subcutaneous injection, given two or three times daily. A typical dose for patients undergoing general surgery is 5000 units subcutaneously two hours preoperatively and then every 8 or 12 hours postoperatively (ie, either three times daily or twice daily, respectively). Additional details are presented separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Low-dose unfractionated heparin'.)

For therapeutic dosing, the greater efficacy of nomograms over clinician-estimated doses was illustrated in a review of seven trials involving 849 patients undergoing initial therapy for VTE [31]. The likelihood of a therapeutic aPTT within the first 24 hours was greater in those who received nomogram-based dosing than those whose dosing was not guided by a nomogram (odds ratio [OR] 3.6, 95% CI 2.6-4.9). The frequency of VTE recurrence was also lower in patients who received nomogram-based dosing (OR 0.3, 95% CI 0.1-0.8), highlighting the clinical significance of the findings. Bleeding events were similar.

The clinical relevance of rapid achievement of a therapeutic aPTT has been well established in randomized trials. As an example, analysis of three consecutive randomized trials for VTE therapy found that individuals who exceeded the therapeutic aPTT threshold within the first 24 hours had a 4 to 6 percent rate of VTE recurrence, compared with a 23 percent recurrence risk in those who did not exceed the therapeutic aPTT threshold within the first 24 hours. The authors presume that rapid achievement of therapeutic anti-factor Xa levels would have similar benefits, but this has not been directly demonstrated [36].

Laboratory monitoring and dose titration (unfractionated heparin) — Once an initial dose has been administered, therapeutic (full-dose) heparin administration is monitored using a combination of clinical assessment and laboratory testing (table 2). The infusion rate is adjusted based on results of laboratory testing (eg, aPTT or anti-factor Xa activity).

A persistent clinical controversy is whether the aPTT or anti-factor Xa activity (or both) is superior for heparin monitoring. There is no evidence to support using one over the other (or using both) for routine monitoring [37]; one retrospective study that compared outcomes in over 5000 individuals monitored with one or the other method did not find any clinically meaningful differences [37,38]. Thus, clinicians should use whichever test is available. Both assays should not be used simultaneously, and it is not advisable to alternate between the tests, as they are rarely concordant [39]. Availability of (and turnaround time for) anti-factor Xa activity measurements validated for heparin dosing varies by institution, and institutional protocols should be observed. If both an aPTT and anti-factor Xa test are available, the choice between them (pending further evidence) may be based on cost, convenience, and clinician familiarity. There may be certain exceptions, such as a baseline prolonged aPTT, as discussed below.

For most indications, the aPTT or anti-factor Xa activity is measured approximately four to six hours after heparin initiation to allow attainment of steady-state plasma heparin concentrations. An aPTT of 1.5 to 2.5 times the mean of the control value or upper limit of the normal range has conventionally been widely accepted for maintenance therapy based on an early study among acute VTE patients [40]. However, it is now recognized that with changes to reagents and instrumentation over time, use of this target range may lead to suboptimal anticoagulation, and an aPTT range that correlates with anti-factor Xa activity of 0.3 to 0.7 units/mL should be used [35,41].

Unlike the international normalized ratio (INR) for the PT, there is no standard against which to normalize aPTT or anti-factor Xa values. Thus, values from different laboratories cannot be compared directly, and each laboratory must independently determine the normal values and therapeutic ranges for heparin that will provide a sufficient blood heparin level (0.2 to 0.4 units/mL by the protamine titration assay or 0.3 to 0.7 units/mL by chromogenic anti-factor Xa assay) for each batch of thromboplastin reagent (for the aPTT) or anti-factor Xa assay used [42,43]. (See "Clinical use of coagulation tests", section on 'Activated partial thromboplastin time (aPTT)' and "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

Exceptions to the use of the aPTT or anti-factor Xa activity for monitoring therapeutic dose heparin may include the following:

●Baseline prolonged aPTT – Some individuals with a baseline prolongation of the aPTT (eg, due to a lupus anticoagulant) may require alternative testing such as the anti-factor Xa activity. (See 'Prolonged baseline aPTT' below.)

●Interventional cardiology and vascular procedures – Patients receiving very high doses of heparin during interventional cardiology or cardiac surgical procedures (eg, percutaneous coronary interventions or coronary artery bypass graft surgery) or vascular procedures requiring cross-clamping of major arteries may have monitoring using the activated clotting time (ACT). (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Management of anticoagulation".)

●Direct factor Xa inhibitor therapy – The anti-factor Xa assay may not be a viable heparin monitoring approach in patients who have recently taken a direct oral factor Xa inhibitor such as apixaban, edoxaban, or rivaroxaban [29,44]. (See 'Special scenarios' below.)

Additional monitoring generally is not required, especially because most individuals receive heparin for a relatively short period of time (eg, during an acute hospitalization). The hemoglobin level should be checked if there is any concern about bleeding. Routine platelet count monitoring for HIT is described in the following section (see 'Platelet count monitoring' below); the platelet count also should be checked if there is any concern about bleeding or thrombosis.

Prophylactic dose unfractionated heparin does not require monitoring of anticoagulant effect or dose titration.

Platelet count monitoring — Platelet count monitoring is used to identify the rare but potentially life-threatening complication of heparin-induced thrombocytopenia (HIT). Approaches to monitoring have been described in the 2018 The American Society of Hematology (ASH) Guidelines based on the type of heparin, clinical setting, and estimated risk of HIT [45]. Estimated risks in different patient populations are summarized in the table (table 4) and a suggested approach is outlined briefly below; however, this should not supersede clinical judgment or institutional guidelines. If there is concern about HIT, platelet counts may be monitored more frequently.

●Recent heparin exposure – Patients who have received unfractionated heparin in the past 100 days and who are starting treatment with unfractionated heparin or LMW heparin are at risk for developing accelerated HIT (also called rapid-onset HIT). For these patients, a baseline platelet count and a repeat platelet count within 24 to 48 hours is recommended. Subsequent monitoring depends on the clinical setting and heparin product as outlined in the following points.

●Postoperative patient; unfractionated heparin – Postoperative patients receiving unfractionated heparin have the greatest risk of HIT, which may be >1 percent. For these patients, platelet count is monitored every other day from day 4 to day 14 or until heparin is stopped, whichever occurs first.

●Postoperative patient; LMW heparin or unfractionated heparin catheter flushes only – Postoperative patients receiving prophylactic dose LMW heparin, or postoperative patients receiving unfractionated heparin as vascular catheter flushes only, have a risk of HIT of approximately 0.1 to 1 percent. For these patients, platelet count may be monitored every two to three days from day 4 to day 14 or until heparin is stopped, whichever occurs first.

●Medical/obstetric patient; prophylactic dose unfractionated heparin, or LMW heparin following unfractionated heparin – Medical or obstetric patients receiving prophylactic dose unfractionated heparin, or medical/obstetric patients receiving LMW heparin following treatment with unfractionated heparin, have a risk of HIT of approximately 0.1 to 1 percent. For these patients, platelet count may be monitored every two to three days from day 4 to day 14 or until heparin is stopped, whichever occurs first.

While platelet count monitoring is an option for obstetric patients, the benefit is highly uncertain in individuals who have been receiving LMW heparin throughout the pregnancy without incident. UpToDate contributors generally do not routinely monitor platelet counts in these individuals. Details are presented separately. (See "Use of anticoagulants during pregnancy and postpartum".)

●Medical/obstetric patient; LMW heparin – Medical/obstetrical patients who are receiving only LMW heparin have a risk of HIT of <0.1 percent. For these patients, routine monitoring generally is not necessary.

●Medical patient, unfractionated heparin catheter flushes only – Medical patients who are receiving unfractionated heparin as vascular catheter flushes only have a risk of HIT of <0.1 percent. For these patients, routine monitoring generally is not necessary.

This monitoring approach only applies to detection of HIT and should not supersede measurement of platelet counts for other clinical reasons.

Evaluation of thrombocytopenia and diagnosis of HIT in patients receiving unfractionated or LMW heparin is discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Special scenarios

Recent oral factor Xa inhibitor use — A patient who has recently used an oral factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) may have detectable anti-factor Xa activity before intravenous unfractionated heparin is initiated.

If such a patient requires a switch to intravenous unfractionated heparin, use of the heparin-calibrated anti-factor Xa assay to monitor heparin will not be feasible until the effect of the oral factor Xa inhibitor subsides, which may be longer than the time estimated by the pharmacokinetic half-life [44]. Both the prior oral factor Xa inhibitor and the newly introduced unfractionated heparin will contribute to the total anti-factor Xa activity, and this may lead to downward titration and underdosing of unfractionated heparin in the first few days of unfractionated heparin therapy [29].

Best approaches to circumvent the problem of monitoring a heparin infusion during the transition from an oral factor Xa inhibitor are not yet known. Whenever possible, it is preferable to switch to a nonmonitored anticoagulant such as LMW heparin (initiated at the time the next dose of the oral factor Xa inhibitor would be due) to avoid this issue. (See 'Transitioning between anticoagulants' below.)

For patients suspected or confirmed to have recently taken an oral factor Xa inhibitor and who must be switched to an unfractionated heparin infusion, a baseline anti-factor Xa activity level should be drawn. If a DOAC-calibrated assay is used, it is reasonable to initiate intravenous heparin once the plasma level is <30 ng/mL [46]. If a standard unfractionated heparin/LMW heparin-calibrated anti-factor Xa assay is used, it may be reasonable to initiate intravenous unfractionated heparin when the anti-factor Xa activity is below the upper end of the target range for heparin (<0.7 units/mL), although this has not been formally studied. An alternative suggestion is use of an aPTT-based unfractionated heparin protocol/nomogram for the first few days until the oral factor Xa inhibitor-associated impact on the anti-factor Xa assay has resolved [29,47,48]. However, this approach does not account for the residual anticoagulant effect of the oral factor Xa inhibitor during the initial period of heparinization, and close monitoring for bleeding is essential.

Recent LMW heparin use — For patients recently on a parenteral factor Xa inhibitor such as LMW heparin, it is important to know if the hospital laboratory uses a hybrid assay for unfractionated and LMW heparin that is calibrated to both anticoagulants. If so, switching between these agents does not pose a monitoring issue. If each of these anti-Xa assays is calibrated to a separate heparin product, then the unfractionated heparin infusion should not be initiated until the LMW heparin assay result is below the therapeutic range to avoid overanticoagulation.

Prolonged baseline aPTT — Patients with a prolonged aPTT at baseline cannot have reliable heparin monitoring using the aPTT. When possible, the cause of the prolonged aPTT should be investigated prior to initiating anticoagulant therapy. (See "Clinical use of coagulation tests", section on 'Causes of prolonged aPTT'.)

●If the patient has a compromised coagulation system (eg, liver disease, disseminated intravascular coagulation [DIC]), it may be possible to improve hemostasis by treating the underlying condition; the appropriateness of heparin must be determined on a case-by-case basis.

●If the aPTT is prolonged due to a lupus anticoagulant or a medication such as oritavancin that interferes with in vitro aPTT test results by phospholipid binding, options for monitoring unfractionated heparin therapy include the following:

•Monitor unfractionated heparin dosing by using an anti-factor Xa activity assay or a specific heparin assay. In general, these are not affected by the presence of a lupus anticoagulant.

•Use an aPTT test that is not sensitive to the presence of a lupus anticoagulant. The laboratory should be consulted to determine which of these alternative assays is available. Since aPTT assays vary greatly in their sensitivity to heparin, if a different aPTT assay is employed it should be calibrated so that the targeted therapeutic range in seconds corresponds to established ranges for unfractionated heparin by protamine titration (0.2 to 0.4 units/mL) or anti-Xa activity (0.3 to 0.7 units/mL).

Alternatively, another anticoagulant such as subcutaneous LMW heparin may be used. Routine monitoring of LMW heparin is not generally required. However, if monitoring is used, it is important to note that the therapeutic range for anti-factor Xa activity differs for LMW heparin.

Heparin resistance/antithrombin deficiency — The phenomenon of heparin resistance is poorly understood and generally refers to a requirement for unusually large doses of heparin in order to achieve an aPTT (or activated clotting time [ACT]) in the therapeutic range (eg, >35,000 units of heparin per 24 hours, excluding initial bolus doses, or an infusion rate of >400 units/hour in patients undergoing coronary artery bypass surgery) [49,50]. In a series of 200 consecutive patients undergoing coronary revascularization, 53 had heparin resistance (26 percent) [51]. Predictors of heparin resistance included a baseline antithrombin (AT) activity level ≤60 percent, platelet count >300,000/microL, age ≥65 years, and prior heparin therapy. In another series of 500 consecutive patients undergoing coronary revascularization from the same authors, heparin resistance was observed in 104 (21 percent) [52]. The likelihood of heparin resistance was inversely proportional to the baseline AT value. Additional details of the clinical presentation and diagnosis of antithrombin deficiency are presented separately. (See "Antithrombin deficiency".)

Additional causes of heparin resistance include increased heparin clearance, increased levels of heparin-binding proteins, elevations of fibrinogen and factor VIII levels, and certain medications (eg, aprotinin) [10,49,53].

We use anti-factor Xa activity testing for patients whose heparin dose requirement is much greater than expected based on aPTT testing [10,35,54]. This practice is based on results of a trial that randomly assigned 131 individuals with heparin resistance to have their heparin dosage adjusted based on anti-factor Xa activity (target, 0.35 to 0.67 international units/mL) or based on the aPTT (target, 60 to 80 seconds), both of which were equivalent to a heparin level of 0.2 to 0.4 units/mL by protamine titration [55]. The risks of recurrent VTE and bleeding were similar in the two treatment arms, although the dose of heparin required was significantly lower in those being monitored by anti-factor Xa activity.

Clinicians should be cautious about interpreting AT activity levels on samples drawn from patients who have been receiving heparin because heparin treatment will reduce AT activity. However, if a patient is found to have AT deficiency, administration of AT concentrates can potentiate the heparin effect and reduce total heparin usage [56,57]. Whether administration of AT concentrates in this setting reduces thrombosis risk or increases bleeding risk (or both) is not known. The use of AT concentrate to improve heparin dosing as well as to reduce the risk of recurrent thromboembolism in patients with AT deficiency is discussed separately. (See "Antithrombin deficiency", section on 'Management'.)

Pregnancy/neonates/children — Some heparin solutions contain the preservative benzyl alcohol, which undergoes oxidation to benzoic acid and then conjugation in the liver before being eliminated. This metabolic pathway is not well developed in infants, and benzyl alcohol has been associated with serious adverse events such as metabolic acidosis and even death in pediatric patients. Preservative-free solutions should be used during pregnancy and in neonates and infants.

Dosing in these populations is presented separately. (See "Neonatal thrombosis: Management and outcome" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Use of anticoagulants during pregnancy and postpartum".)

LMW HEPARIN

Advantages and limitations — The low molecular weight (LMW) heparins have a number of advantages over unfractionated heparin [12]:

●Greater bioavailability than unfractionated heparin

●Extensive clinical experience with subcutaneous administration, often facilitating outpatient treatment

●Longer duration of the anticoagulant effect, permitting administration only once or twice daily and administration in the outpatient setting

●Better correlation between dose and anticoagulant response, permitting administration of a fixed dose without laboratory monitoring

●Lower risk of heparin-induced thrombocytopenia (see "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Incidence and risk factors')

●Lower incidence of osteoporosis (see "Drugs that affect bone metabolism", section on 'Low molecular weight heparin')

The relative ease of administration compared with unfractionated heparin and the lack of placental passage make LMW heparin the anticoagulant of choice during pregnancy. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Choice of anticoagulant'.)

Potential disadvantages of LMW heparin compared with unfractionated heparin include:

●Slightly delayed onset of action (eg, 20 to 30 minutes, rather than instantaneous for unfractionated heparin by intravenous bolus)

●Longer duration of action, making it more difficult to rapidly halt the anticoagulant effect

●Less easily inactivated with protamine sulfate

●Prolonged half-life in patients with kidney failure, especially with enoxaparin

●In rare instances where monitoring may be indicated, anti-factor Xa activity testing with a rapid turnaround time may be less widely available

Available products — Commercially available LMW heparins are derived from unfractionated heparin by various processes (eg, nitrous acid, alkaline, or enzymatic depolymerization) and differ from one another both chemically and pharmacokinetically [12,14]. Variations in molecular weights of the various LMW heparin preparations also result in different ratios of factor Xa versus thrombin inhibition (see 'Mechanisms of action' above), although the clinical significance of these differences is unclear [10].

Available LMW products include the following:

●Enoxaparin – Enoxaparin (Lovenox) is a LMW heparin with 100 units of anti-factor Xa activity per mg.

●Dalteparin – Dalteparin (Fragmin) is a LMW heparin with approximately 156 units of anti-factor Xa activity per mg.

●Tinzaparin – Tinzaparin (Innohep) is a LMW heparin with 70 to 120 units of anti-factor Xa activity per mg.

●Nadroparin – Nadroparin (Fraxiparine) is a LMW heparin with various formulations that have differing anti-factor Xa activity.

There have been very few studies comparing clinical outcomes with different LMW heparin products. Thus, the doses of the different LMW heparins are not necessarily interchangeable.

Dosing and monitoring

Baseline testing (LMW heparin) — Baseline testing prior to LMW heparin administration generally includes the following:

●Thorough history for underlying bleeding disorders and/or recent trauma or surgery

●Complete blood count (CBC), to obtain a baseline hemoglobin level and platelet count

●Coagulation studies including prothrombin time (PT) and partial thromboplastin time (aPTT), to verify that the patient does not have an underlying coagulopathy

●Serum creatinine

Checking liver function tests (transaminases) may be appropriate in many patients because heparins can cause an asymptomatic elevation of transaminases in some individuals; evidence that transaminases were normal prior to starting heparin and increased mildly following heparin initiation suggest that the heparin is the likely explanation and no further/more aggressive evaluation is needed. However, more marked changes in transaminases may require additional evaluation.

LMW heparin standard dosing — LMW heparins are typically administered subcutaneously in fixed or weight-based dosing without monitoring, and no laboratory assessment of the LMW heparin anticoagulant effect has been correlated with clinical endpoints. LMW heparin products can also be administered intravenously (eg, in acute myocardial infarction). LMW heparins are not administered intramuscularly. A 2017 Cochrane review identified four trials that compared injection site pain with rapid versus slow subcutaneous injection (10 versus 30 seconds, respectively) and found a possible role for the slower injection rate in reducing pain, but the quality of the evidence was low [58].

Recommended dosing for different clinical indications is presented in separate topic reviews on the individual clinical settings.

●Liver disease – Dose adjustment generally is not needed in patients with isolated liver disease.

●Pregnancy – Dose adjustment may be appropriate during pregnancy as weight increases. This subject is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Administration during pregnancy'.)

●Children and neonates – Dosing is presented separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Low molecular weight heparin' and "Neonatal thrombosis: Management and outcome", section on 'Low molecular weight heparin'.)

●Older adults – In general, older adults should be treated with standard weight-adjusted doses of LMW heparin. Standard dosing in older adults weighing <45 kg may result in an increased incidence of bleeding [59]. (See 'Dosing at extremes of body weight' below.)

Dosing at extremes of body weight — Optimal dosing of LMW heparin in extremes of weight is unknown.

●Low body weight – A cross-sectional pharmacokinetic study of patients ≤55 kg receiving standard dose enoxaparin 40 mg once daily for primary VTE prevention showed a significant inverse relationship between body weight and anti-factor Xa levels, with 85 percent of patients ≤45 kg and 61 percent of patients ≤55 kg having an anti-factor Xa level exceeding 0.5 units/mL (the upper end of an expected prophylactic range). Thus, it may be reasonable to decrease the dose of LMW heparin for primary VTE prevention in low-weight patients (≤55 kg or body mass index [BMI] <18 kg/m²) [59]. For therapeutic-intensity anticoagulation with LMW heparin in low-weight patients, we follow standard dosing using total body weight as described in US Food and Drug Administration labeling, with close monitoring for bleeding.

●High body weight/high BMI – Data are sparse on optimal dosing for LMW heparin in individuals with a high BMI. It is unclear whether prophylactic dosing should be fixed-dose or weight-based and whether therapeutic dosing should be adjusted or the dose capped. Information from various sources is summarized in the table (table 5).

•VTE prophylaxis – The 2012 American College of Chest Physicians (ACCP) Guidelines suggest weight-based prophylactic dosing is preferable to fixed dosing for patients with a high BMI [35]. The ASH 2018 and 2019 Guidelines for VTE prevention in medical and surgical patients do not provide specific recommendations on whether to use weight-based or fixed dosing in these individuals [60,61]. A meta-analysis from 2021 evaluated data from studies using fixed versus weight-based dosing of LMW and unfractionated heparin for thromboprophylaxis and found efficacy and safety were similar regardless of the dosing approach [62]. Compared with fixed dosing, weight-based dosing did not lead to a statistically significant difference in the rate of VTE recurrence (odds ratio [OR] 1.03, 95% CI 0.79-1.35) or bleeding (OR 0.84, 95% CI 0.65-1.08). A 2018 literature review suggested that use of increased fixed doses of enoxaparin (40 mg every 12 hours for BMI ≥40 kg/m², 60 mg every 12 hours for BMI ≥50 kg/m²), or weight-based prophylaxis dosing of enoxaparin (0.5 mg/kg once or twice daily) are reasonable options [63]. Many experts and institutional protocols use weight-based dosing, and the best approach remains to be determined. In light of the limited body of evidence, these data are reassuring in suggesting that both approaches show similar low bleeding rates.

•VTE treatment – Studies of therapeutic intensity LMW heparin have not been sufficiently powered to evaluate thrombosis and bleeding rates in individuals with high BMI and are mainly focused on pharmacokinetic assessment of anti-factor Xa levels. Some of these studies suggest that high BMI correlates with either low or high anti-factor Xa levels, but the clinical relevance of anti-factor Xa levels is unclear [63]. Some experts have suggested a dose reduction or dose capping of LMW heparin in individuals with high BMI to minimize supratherapeutic anti-factor Xa levels and complications [64]. Until better data are available, we agree with the ASH 2018 Guideline, which suggests dosing based on actual body weight rather than capped or reduced dosing in individuals with high BMI [65].

Anti-factor Xa levels are not routinely used, as there are no established target ranges or validated dosing adjustment nomograms to guide therapy. However, judicious measurement may be reasonable in selected situations such as an adverse event. If anti-factor Xa monitoring is indicated, the anti-factor Xa activity level should be drawn three to five hours after a dose and only after the patient has had at least two doses and is at steady state. Close clinical monitoring for signs and symptoms of complications such as bleeding or thrombosis is recommended, particularly in those with weight >150 kg or BMI >40 kg/m².

Dosing in CKD — LMW heparins are primarily excreted by the kidneys; their biological half-life may be prolonged in patients with kidney failure [35]. Uremia may also contribute to increased bleeding risk. As a result, most trials have excluded patients with creatinine clearance (CrCl) ≤30 mL/min.

In a systematic review and meta-analysis of studies that evaluated bleeding risk in individuals with chronic kidney disease (CKD) who were receiving a LMW heparin, patients with a CrCl ≤30 mL/min receiving LMW heparin were more likely to have bleeding than those with a CrCl >30 mL/min, (odds ratio [OR] 2.25, 95% CI 1.19-4.27) [66]. Individuals with CrCl ≤30 mL/min who were receiving enoxaparin at therapeutic doses had higher levels of anti-factor Xa activity compared with individuals without CKD or those who had dose adjustments based on kidney function or anti-factor Xa activity, although anti-factor Xa activity measurements in patients on LMW heparin have not been correlated with clinical events.

In contrast, tinzaparin and dalteparin do not appear to bioaccumulate in individuals with this degree of CKD, although less rigorous evidence is available for these products [66,67].

Options for management depend on the degree of CKD and the available LMW heparin.

●For those with a CrCl ≤30 mL/min, use of unfractionated heparin avoids the problems associated with impaired clearance of LMW heparin by the kidneys.

●If LMW heparin is used in an individual with chronic kidney disease, dose-reduction and/or adjustment based on anti-factor Xa levels (see 'Laboratory monitoring/measurement (LMW heparins)' below) may be appropriate, especially for enoxaparin (table 6) [35,68-77]. Enoxaparin dose reduction based on anti-factor Xa activity or kidney function appears to reduce the risk of bleeding [66,67]. Information in the prescribing information should be consulted for each product, and information from one LMW heparin product should not be extrapolated to a different LMW heparin.

Laboratory monitoring/measurement (LMW heparins) — In general, monitoring of LMW heparin anti-factor Xa activity is not recommended due to lack of established therapeutic ranges [65]. If anti-factor Xa testing is used, it should be noted that expected on-therapy ranges differ depending on the treatment schedule (once versus twice daily) and the preparation and assay used. Thus, institutional guidelines for the specific LMW heparin and clinical setting should be followed [10]. Dose reduction may be considered if the anti-factor Xa activity four hours after subcutaneous injection is excessive. The therapeutic range for full-dose (treatment-dose) enoxaparin dosed twice daily is generally 0.5 to 1 anti-factor Xa units/mL four to six hours following injection. Additional information regarding this testing and issues that may affect inter-institutional variability among tests are discussed separately. (See "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

Of note, the aPTT may be prolonged by (but is relatively insensitive to) LMW heparin effect and thus is not appropriate for monitoring.

Additional testing and monitoring include the following:

●Platelet count monitoring is appropriate for some patients receiving LMW heparin due to the potential risk of heparin induced thrombocytopenia (HIT) (table 4), although this risk is very low (see 'Platelet count monitoring' above). A platelet count also should be checked if there is any concern about bleeding or thrombosis.

●Routine monitoring of the hemoglobin level generally is not needed; however, hemoglobin level should be checked if there is any concern about bleeding.

●Periodic bone density testing (eg, annually) is appropriate for individuals receiving long-term therapy with a LMW heparin.

DANAPAROID — Danaparoid is a low molecular weight heparinoid (ie, a heparan derivative), consisting of a mixture of heparan sulfate (83 percent), dermatan sulfate, and chondroitin sulfate [78,79]. Its anticoagulant effect is mediated by inhibition of thrombin via a combination of antithrombin (AT; heparin cofactor I) and heparin cofactor II, plus undefined endothelial cellular mechanisms.

Danaparoid is available in Canada, Japan, Europe, and Australia [80]. It is not available in the United States due to a shortage in supply from the manufacturer. (See "Danaparoid (United States: Not available): Drug information".)

FONDAPARINUX — Fondaparinux is a synthetic pentasaccharide with a structure based on the minimal antithrombin (AT) binding region of heparins. Therapeutic use of fondaparinux is discussed in detail separately. (See "Fondaparinux: Dosing and adverse effects".)

TRANSITIONING BETWEEN ANTICOAGULANTS

●Underlying indication – In most cases, specific recommendations about transitioning between anticoagulants depend on the underlying indication for anticoagulation. As examples, many patients initiating an oral anticoagulant for uncomplicated nonvalvular atrial fibrillation do not require overlapping heparin therapy. Conversely, patients being treated with a VKA for a mechanical heart valve or recent pulmonary embolism require careful overlapping of heparin and the VKA during the transition.

Discussion of the issues specific to each clinical scenario are presented separately:

•Prosthetic heart valve – (See "Antithrombotic therapy for mechanical heart valves".)

•Atrial fibrillation – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

•Deep vein thrombosis – (See "Venous thromboembolism: Initiation of anticoagulation".)

•Pulmonary embolism – (See "Venous thromboembolism: Initiation of anticoagulation".)

•Surgical procedures – (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.)

•Endoscopic procedures – (See "Management of anticoagulants in patients undergoing endoscopic procedures".)

●Heparin to a VKA – When it is important to overlap a heparin product with a VKA, a general rule to follow is to co-administer the two anticoagulants until the effect of the VKA is established. For warfarin, this generally entails four to five days of overlap and at least 24 hours of a therapeutic international normalized ratio (INR).

●VKA to heparin – Transitioning from a VKA to heparin typically occurs when a patient is admitted to the hospital for a surgical procedure, although it is not always necessary to switch to heparin, and in selected cases bleeding is less if the VKA is continued, as discussed separately. If a switch is indicated, the unfractionated heparin infusion should generally be initiated once the INR is <2. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.)

●Heparin to any DOAC – For direct-acting oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, edoxaban), the maximal anticoagulant effect occurs two to three hours after the first dose. Intravenous unfractionated heparin can be stopped when the first dose of the DOAC is taken. For a patient transitioning from low molecular weight (LMW) heparin to a DOAC, the DOAC should be given within zero to two hours before the time the next dose of the LMW heparin would have been due [81,82].

●Oral factor Xa inhibitor to heparin – The optimal strategy for transitioning from an oral factor Xa inhibitor (apixaban, rivaroxaban, edoxaban) to heparin has not been determined.

It is important to follow institutional protocols and to be aware that oral factor Xa inhibitors can interfere with anti-factor Xa activity monitoring of unfractionated heparin [83,84]. In one study of patients recently on an oral factor Xa inhibitor that compared outcomes at one institution that used the activated partial thromboplastin time (aPTT) to monitor unfractionated heparin and another institution that used anti-factor Xa activity, nonmajor bleeding was slightly lower with the anti-factor Xa monitoring (8 versus 15 percent), but death, major bleeding, and thrombosis were not statistically different [84].

Transitioning from one oral anticoagulant to another oral anticoagulant is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

BLEEDING

Bleeding risk — Bleeding risk is increased with unfractionated or low molecular weight (LMW) heparin therapy as is the case with all anticoagulants.

Specific risk estimates depend on patient factors (eg, age, comorbidities, underlying indication for anticoagulation), heparin dose, activated partial thromboplastin time (aPTT) level, and the use of other antithrombotic therapies (eg, antiplatelet agents). Bleeding risk also is increased in patients with trauma and/or invasive procedures. Product information for LMW products includes a Boxed Warning for an increased risk of spinal or epidural hematoma in patients undergoing neuraxial procedures. Patients undergoing neuraxial or any elective procedures in which concerns about bleeding risk outweigh concerns about thromboembolic risk should ensure that the heparin has been discontinued for an appropriate duration of time to allow the anticoagulant effect to resolve. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication" and "Perioperative management of patients receiving anticoagulants".)

The increase in bleeding risk when heparin is combined with a nonsteroidal antiinflammatory drug (NSAID) or aspirin was demonstrated in a prospective analysis of 8246 patients in a trial that compared enoxaparin with a factor Xa inhibitor for the treatment of venous thromboembolism [85]. The rate of major bleeding in patients receiving an anticoagulant plus an NSAID (enoxaparin or rivaroxaban at therapeutic dose) was 6.5 per 100 patient-years, compared with 2.0 per 100 patient-years in those receiving an anticoagulant with no NSAID exposure. Major bleeding in anticoagulant-treated patients receiving concomitant aspirin occurred with an event rate of 4.8 per 100 patient-years, compared with 2.2 per 100 patient-years without aspirin use (hazard ratio 1.50, 95% CI 0.86-2.62). Gastrointestinal bleeds accounted for only 30 of 231 clinically relevant bleeds (13 percent); the rest were distributed among multiple sites.

The correlation of heparin-associated bleeding with the aPTT is weak [86]. This was demonstrated in a review of 416 patients treated with heparin, in which hemorrhagic complications occurred in 5.5 percent and were more closely related to underlying clinical risk factors rather than an aPTT elevation above the therapeutic range [87]. Patients at particular risk are those who have had recent surgery or trauma, or who have other clinical factors that predispose to bleeding such as chronic kidney disease, peptic ulcer, occult malignancy, liver disease, hemostatic defects, age >65 years, female sex, or underlying anemia [34,86-88]. A similar lack of correlation between anti-factor Xa levels and bleeding was shown in registry data of 803 consecutive patients with acute coronary syndrome treated with therapeutic enoxaparin [89]. Anti-factor Xa activity was not predictive of 30-day major bleeding. People with lower anti-Xa activity levels had nearly three- to fourfold higher bleeding rates than people with levels within or above the expected on-therapy range. Significant confounding precludes drawing any meaningful conclusions from these observational data.

Reversal — The management of bleeding in a patient receiving heparin depends upon the location and severity of bleeding, the underlying thromboembolic risk, and the current aPTT (for heparin) or anti-factor Xa activity (for LMW heparin). As an example, a patient with minor skin bleeding in the setting of a mechanical heart valve (high thromboembolic risk) and a therapeutic aPTT may continue heparin therapy, whereas a patient with major intracerebral bleeding in the setting of a venous thromboembolism several months prior who is receiving heparin bridging perioperatively may require immediate heparin discontinuation and reversal with protamine sulfate. Clinician judgment and early involvement of the appropriate consulting specialists is advised.

Urgent reversal (protamine) — The need for urgent or emergent heparin reversal is individualized according to the site and severity of bleeding and the degree of anticoagulation. If reversal is required, heparin is discontinued and protamine sulfate is administered at a dose calculated based on the dose of heparin administered and the elapsed time since the last heparin dose. Protamine sulfate should ideally be administered by slow intravenous infusion; the infusion rate should not exceed 5 mg/minute, and the total dose should not exceed 50 mg in any 10-minute period in order to avoid potential adverse effects such as hypotension, anaphylactoid-like reactions, or cardiac collapse [90-93]. Excessive doses of protamine should be avoided due to known anticoagulant effect (platelet impairment and reduced thrombin generation). Higher doses may be used in cardiopulmonary bypass, and close monitoring is essential. (See "Protamine: Administration and management of adverse reactions during cardiovascular procedures".)

●Unfractionated heparin – Full neutralization of heparin effect is achieved with a dose of 1 mg protamine sulfate/100 units of heparin. Because of the relatively short half-life of intravenously administered heparin (approximately 30 to 60 minutes), the dose of protamine sulfate is calculated by estimating the amount of heparin remaining in the plasma at the time that reversal is required. If this information is not immediately available, administration of a single dose of 25 to 50 mg can be given and the aPTT or anti-factor Xa activity rechecked, as well as clinical response of the patient.

If heparin had been given by subcutaneous injection, repeated small doses of protamine may be required because of prolonged heparin absorption from the various subcutaneous sites.

●LMW heparin – Unlike its efficacy with unfractionated heparin, protamine does not completely abolish the anti-factor Xa activity of LMW heparins, but it may neutralize the higher molecular weight fractions of heparin, which are thought to be most responsible for bleeding [94]. For patients who experience bleeding while receiving LMW heparin, protamine sulfate may be used at the following doses [10,90,95,96]:

•Enoxaparin administered in the previous eight hours: 1 mg protamine per 1 mg of enoxaparin.

•Enoxaparin administered more than eight hours ago, or if it has been deemed that a second dose of protamine is warranted: 0.5 mg protamine per 1 mg of enoxaparin.

•Dalteparin, tinzaparin, or nadroparin: 1 mg protamine per 100 anti-factor Xa units of LMW heparin.

Protamine is a protein derived from fish sperm and it carries a small but potential risk of anaphylaxis in individuals who have previously been exposed, including diabetic patients who have received protamine-containing insulin (eg, NPH, PZI), and individuals with fish allergy (protamine is derived from fish). However, unless such an allergy is known, the benefits of protamine administration to manage bleeding are likely to outweigh this potential risk. The product information carries a Boxed Warning regarding the risks of hypotension, cardiovascular collapse, non-cardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension for patients who have previously received protamine sulfate or other protamine-containing drugs. Thrombocytopenia following protamine administration has also been reported [97]. Patients receiving protamine should be monitored closely, and access to therapies for anaphylaxis should be available.

General measures that should be taken in any patient with anticoagulant-associated severe bleeding are presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Major bleeding'.)

Elective procedure/minor bleeding — If less urgent reversal of heparin is needed (eg, elective procedure, minor bleeding), heparin discontinuation may be sufficient. The effect of heparin is expected to be largely eliminated after five half-lives (approximately four to five hours for unfractionated heparin, and approximately 24 hours for LMW heparin [half-life of LMW heparin is highly dependent on kidney function]) (see 'Pharmacology' above). When appropriate, the aPTT or anti-factor Xa activity level can be monitored to confirm the resolution of unfractionated heparin effect, and anti-factor Xa activity can be measured to evaluate the presence of residual LMW heparin.

Guidance for dosing around the time of surgery and/or neuraxial anesthesia is presented separately. (See "Perioperative management of patients receiving anticoagulants" and "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Guidelines for timing of neuraxial anesthesia procedures'.)

Alternative means of reducing thromboembolic risk (eg, mechanical thromboprophylaxis, insertion of an inferior vena cava filter) in patients with active anticoagulant-associated bleeding who are no longer receiving an anticoagulant are also presented separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis' and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Selecting thromboprophylaxis' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter'.)

OTHER COMPLICATIONS — Most heparin-related complications can be seen with either unfractionated or low molecular weight (LMW) heparin. As a general rule, complications are greater with unfractionated heparins compared with LMW products. However, in many cases, underlying patient factors may make a greater contribution to risk than the specific product.

Medication errors — Importantly, heparin sodium for injection should not be used to flush catheter locks or intravenous ports because the solutions intended for intravenous heparin therapy are significantly more concentrated than the solutions used for catheter flushes. Fatal medication errors have occurred due to the mistaken substitution of one heparin formulation for another. Limiting the number of available heparin products and concentrations will reduce risk for errors [30].

Heparin-induced thrombocytopenia (HIT) — Heparin-induced thrombocytopenia (HIT) is a rare and potentially fatal complication of heparin exposure in which heparin-induced anti-platelet antibodies can cause thrombocytopenia and an increased risk of venous and arterial thrombosis. HIT can occur with any heparin exposure (any product, any dose) but is more frequently seen with unfractionated heparin compared with LMW heparin (see 'Platelet count monitoring' above). The pathogenesis, likelihood, clinical manifestations, evaluation of the pretest probability (eg, using the 4 Ts score (calculator 1)), laboratory diagnosis, and treatment of HIT, as well as the possibility of brief use of heparin in patients with a prior diagnosis of HIT who are undergoing cardiopulmonary bypass, are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

Nonimmune (heparin-associated) thrombocytopenia — In contrast to HIT, which is rare and life threatening, mild thrombocytopenia is common with administration of unfractionated heparin. A typical finding is a mild, transient drop in the platelet count (eg, to approximately 100,000/microL) within the first two days of heparin exposure. The mechanism is not well understood but is not associated with platelet activation or increased thrombosis risk. Patients generally have an otherwise low pretest probability of HIT (eg, low 4 Ts score) and are managed expectantly without any change in heparin administration. The mild thrombocytopenia typically resolves, either with continuation or with discontinuation of heparin.

Skin necrosis and local allergic reactions — Heparin can cause allergic and nonallergic skin lesions. The incidence of skin lesions is highly dependent on the route of administration. Thus, LMW heparins, which are administered subcutaneously, carry a higher risk of local skin reactions, and unfractionated heparin carries a lower risk of skin reactions overall, but the associated skin lesions are more concerning for a systemic complication such as skin necrosis associated with HIT.

In a prospective study of 320 consecutive patients receiving subcutaneous heparin (LMW heparin in more than 90 percent), 24 (7.5 percent) developed skin lesions [98]. Delayed-type hypersensitivity (DTH) reactions were identified as the cause in all 24. Lesions were mostly either eczematous or pruritic erythematous plaques; necrosis was not seen. Thrombocytopenia was noted in only 1 of the 24 patients. Significant risk factors for the development of such non-necrotic lesions were a body mass index >25, female sex, and a treatment duration >9 days. A subsequent report of 87 consecutive patients with heparin-induced (85 due to LMW heparin) skin lesions from the same investigators indicated that all lesions were caused by delayed-type IV-hypersensitivity reactions, rather than microvascular thrombosis [99].

Provided HIT is not suspected (eg, provided the platelet count has not decreased and/or the 4T s score indicates a low probability for HIT), switching to another LMW heparin product is reasonable, although cross-reactivity between LMW heparin preparations has been described [100]. In one report, all of the four patients who had developed DTH reactions to a LMW heparin were able to take the related product fondaparinux without a cutaneous reaction [101].

The most important distinction is between skin necrosis associated with HIT and a localized allergic reaction, which is based on the presence of other clinical findings (eg, thrombocytopenia, thrombosis, systemic reactions). Rarer lesions include pustulosis, calcinosis cutis, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE, intertriginous drug eruption, baboon syndrome) [102]. (See "Drug eruptions", section on 'Classic drug reaction patterns' and "Drug eruptions", section on 'Heparin'.)

Skin necrosis is another well-described but rare complication of treatment with unfractionated heparin or LMW heparin. The reported frequency with unfractionated heparin is 0.2 percent; with LMW heparin there are only a few case reports [103]. Affected patients develop heparin-dependent antibodies but most do not have thrombocytopenia. The lesions that will eventually progress to obvious skin necrosis may initially appear similar to those of localized allergic reactions. However, in contrast to allergic reactions, skin necrosis typically is nonpruritic. Although skin necrosis is not always accompanied by HIT, the possibility of HIT should be addressed. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Evaluation'.)

DTH reactions can occur with unfractionated heparin or LMW heparin. These usually present as erythematous, pruritic plaques at the site of injection [102]. They often occur within the first two weeks of heparin administration but have been reported months after initiation. Histology of skin biopsy is useful for confirming the diagnosis. Three to 10 percent of cases progress to a generalized allergic skin reaction [102]. (See "Drug hypersensitivity: Classification and clinical features", section on 'Type IV reactions' and "Drug allergy: Pathogenesis", section on 'Type IV (T cell-mediated)'.)

Systemic allergic reactions — Systemic reactions to heparin are very rare. These reactions may include immediate hypersensitivity reactions, toxic epidermal necrolysis, and hypereosinophilia. Systemic allergic reactions can be manifested by fever, generalized urticaria, skin lesions, dyspnea, and hyper- or hypotension. Immediate hypersensitivity reactions can be either IgE-mediated or non-IgE-mediated [104]. Clinical symptoms can include generalized or localized urticaria. Anaphylaxis has been reported, although these reactions are rare [104-106]. (See "Pathophysiology of anaphylaxis", section on 'Nonimmunologic anaphylaxis' and "Drug hypersensitivity: Classification and clinical features", section on 'Type I reactions'.)

Systemic allergic reactions can also be seen in the setting of HIT, an antibody-mediated phenomenon that confers a high risk of thrombosis. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Anaphylaxis'.)

Management of systemic allergic reactions depends on the severity of the reaction. (See "Anaphylaxis: Emergency treatment".)

When an alternative anticoagulant is needed, a chemically unrelated product such as bivalirudin, argatroban, a direct oral anticoagulant, or fondaparinux may be substituted [107]. The choice of product depends on the specific circumstances including indication, clinical setting, comorbidities such as chronic kidney disease, and available options. (See "Fondaparinux: Dosing and adverse effects" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Systemic allergic reactions were responsible for alerting clinicians to a large-scale heparin contamination event during late 2007 that has since been resolved. These serious reactions in late 2007 lead to an urgent recall of some heparin preparations. Adverse events included allergic or hypersensitivity-type reactions (eg, hypotension, dyspnea, nausea, vomiting, diarrhea, abdominal pain), at least 81 reports of death, and an increase in the incidence of HIT [108-111]. The suspect heparin products originated in China and were available in at least 12 countries. Subsequently, screening procedures were developed to identify oversulfated chondroitin sulfate (OSCS) and other highly sulfated polysaccharide contaminants thought to be responsible for these reactions. Unfractionated heparin available in the United States is considered safe from this contamination. LMW heparin, which undergoes an additional fragmentation process, has not been associated with chondroitin sulfate contamination.

Hyperkalemia — Hyperkalemia is a rare but possible complication of heparin therapy. It rarely requires intervention but could be more serious in rare settings such as chronic kidney disease. Some series suggest the risk is lower with LMW heparin; others have not observed this difference [112,113]. The mechanism is due to a toxic effect on adrenal cells that produce aldosterone, leading to hypoaldosteronism (type 4 renal tubular acidosis). This complication is discussed separately. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Heparin and low-molecular-weight heparin'.)

Osteoporosis — Osteoporosis has been reported in patients receiving unfractionated heparin for more than six months, although the absolute risk is unknown [9,10,114]. Demineralization can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible. (See "Drugs that affect bone metabolism", section on 'Heparin'.)

Interference with thrombophilia testing — Most thrombophilia testing can be performed during heparin therapy, if indicated (table 7). Exceptions include the following:

●Antithrombin deficiency – Use of heparin reduces antithrombin levels by approximately 30 percent; thus, accurate testing for antithrombin deficiency cannot be performed during heparin therapy. (See "Antithrombin deficiency", section on 'Timing of testing'.)

●Lupus anticoagulant – Testing for a lupus anticoagulant (LA) often cannot be performed accurately during heparin therapy because the assay is based on a modified activated partial thromboplastin time (aPTT), which is prolonged by heparin; LMW heparin can also interfere with testing, especially at high doses [115]. Some laboratories add heparinase to the assay, allowing LA testing, but this practice is not universal.

In contrast, serologic tests for antiphospholipid antibodies (anti-cardiolipin and anti-beta-2 glycoprotein I) can be performed, because these tests are immunoassays that are unaffected by heparin. This issue is discussed in more detail separately. (See "Diagnosis of antiphospholipid syndrome", section on 'Patients on an anticoagulant'.)

Importantly, these caveats for thrombophilia testing should not be interpreted to imply that thrombophilia testing is performed routinely prior to, during, or after heparin therapy. In most cases, heparin management is not altered by the results of thrombophilia testing, and inappropriate thrombophilia testing may lead to adverse outcomes without any accompanying benefit. Appropriate indications for thrombophilia testing are presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Overview of the evaluation of stroke", section on 'Blood tests'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Deep vein thrombosis (blood clot in the leg) (The Basics)" and "Patient education: Pulmonary embolism (blood clot in the lung) (The Basics)" and "Patient education: Factor V Leiden (The Basics)")

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Pulmonary embolism (Beyond the Basics)" and "Patient education: Antiphospholipid syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Biology of heparins – Heparin is an indirect inhibitor of thrombin (factor IIa) and factor Xa that dramatically enhances the ability of antithrombin to inactivate these factors; low molecular weight (LMW) heparins efficiently inactivate factor Xa via antithrombin (figure 2 and figure 1). (See 'Mechanisms of action' above.)

●Baseline assessment – A thorough bleeding history should be obtained prior to administration of unfractionated heparin or LMW heparin. Baseline testing generally includes coagulation prothrombin time (PT), activated partial thromboplastin time (aPTT), and a complete blood count (CBC) with platelet count. For LMW heparin, serum creatinine is also measured. Many patients will benefit from baseline measurement of transaminases because mild transaminase elevations can occur with heparins, and this information may obviate the need for more extensive testing. (See 'Baseline testing (unfractionated heparin)' above and 'Baseline testing (LMW heparin)' above.)

●Heparin dosing – Unfractionated heparin generally is administered intravenously as an initial bolus followed by a continuous infusion using a nomogram. Subsequent dose adjustments are made based on aPTT or anti-factor Xa activity values (table 2). (See 'Unfractionated heparin' above.)

●Monitoring platelet counts – Platelet count monitoring is done in individuals at risk for heparin-induced thrombocytopenia (HIT), the most feared complication of heparin; the risk of HIT in different populations is summarized in the table (table 4). Monitoring is discussed above. (See 'Platelet count monitoring' above.)

●aPTT test interference

•Individuals with a prolonged baseline aPTT (eg, due to a lupus anticoagulant) and individuals who require significantly higher than average doses of heparin based on aPTT values may be best monitored by using an anti-factor Xa activity assay. (See 'Prolonged baseline aPTT' above and 'Heparin resistance/antithrombin deficiency' above.)

•Anticoagulant effect from an oral factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) or LMW heparin will complicate the measurement of unfractionated heparin effect in the plasma.

●AT deficiency – Individuals requiring unusually large doses of heparin may have antithrombin (AT) deficiency, although this condition is extremely rare. Administration of AT concentrates may be appropriate in some cases. (See 'Heparin resistance/antithrombin deficiency' above and "Antithrombin deficiency".)

●LMW heparin dosing – LMW heparin typically is administered subcutaneously in fixed or weight-based dosing without monitoring. Several LMW heparin products are available. (See 'LMW heparin' above.)

•Some patient groups may require special dosing of LMW heparin (older age, high body mass index [BMI], chronic kidney disease [CKD] (table 6), pregnancy).

•A properly timed anti-factor Xa activity measurement may be used in selected situations in which there is a benefit from confirming that the expected anticoagulant effect has been achieved. (See 'Laboratory monitoring/measurement (LMW heparins)' above.)

•Some patients receiving LMW heparin require platelet count monitoring for HIT (table 4). (See 'Platelet count monitoring' above.)

•Transitioning between heparin and other anticoagulants depends on the clinical scenario. (See 'Transitioning between anticoagulants' above.)

●Bleeding – Bleeding risk is increased with unfractionated or LMW heparin. Management of bleeding in a patient receiving heparin depends upon the location and severity of bleeding, the thromboembolic risk, and the aPTT or anti-factor Xa activity. If urgent reversal is required, protamine sulfate is administered by slow intravenous infusion (ideally not to exceed 5 mg/min or 50 mg in any 10-minute period). Full neutralization is achieved with a dose of 1 mg protamine sulfate/100 units of unfractionated heparin. Protamine sulfate does not fully neutralize LMW heparins, but clinical bleeding may be reduced. Protamine sulfate carries risks of anaphylaxis in some patients. (See 'Bleeding' above.)

●Other complications – Other complications besides bleeding and HIT include cutaneous reactions, systemic allergic reactions, and hyperkalemia. Osteoporosis typically is of concern with long-term administration of unfractionated heparin. Some thrombophilia testing cannot be performed while the patient is receiving heparin (table 7); however, this should not be interpreted to mean that thrombophilia testing is routinely indicated. (See 'Other complications' above.)

●Indications – Indications for heparin and/or LMW heparin are discussed separately:

•Coronavirus disease 2019 (COVID-19) – (See "COVID-19: Hypercoagulability".)

•Venous thromboembolism (VTE) prophylaxis – (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

•Deep vein thrombosis (DVT) – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

•Pulmonary embolism (PE) – (See "Venous thromboembolism: Initiation of anticoagulation".)

•Myocardial infarction – (See "Acute ST-elevation myocardial infarction: Management of anticoagulation".)

•Acute coronary syndrome – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes".)

•Stroke or transient ischemic attack (TIA) – (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

•Children and adolescents – (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

•Pregnancy – (See "Use of anticoagulants during pregnancy and postpartum".)

•Neuraxial anesthesia – (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

•Perioperative – (See "Perioperative management of patients receiving anticoagulants".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karen A Valentine, MD, PhD, who contributed to earlier versions of this topic review.