Karen A Valentine, MD, PhD
Russell D Hull, MBBS, MSc
Lawrence LK Leung, MD
Stephen A Landaw, MD, PhD
INTRODUCTION — This topic will review the general principles underlying the therapeutic use and monitoring of unfractionated and low molecular weight (LMW) heparins [1,2]. Specific uses of these heparin preparations in the treatment and/or prevention of thromboembolic disease are discussed separately. (See “Treatment of acute pulmonary embolism” and “Low molecular weight heparin for venous thromboembolic disease” and “Treatment of lower extremity deep vein thrombosis” and “Prevention of venous thromboembolic disease in surgical patients” and “Prevention of venous thromboembolic disease in medical patients”.)
The use of heparin and LMW heparin in patients with acute myocardial infarction or stroke is discussed separately. (See “Anticoagulant therapy in acute ST elevation myocardial infarction” and “Anticoagulant therapy in unstable angina and acute non-ST elevation myocardial infarction” and “Antithrombotic treatment of acute ischemic stroke”.)
USE OF HEPARIN
MECHANISM OF ACTION — Heparin is an indirect thrombin inhibitor which complexes with antithrombin (AT, formerly known as AT III), converting this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa [1,3]. AT has two active functional sites: the reactive center, Arg393-Ser394; and the heparin binding site located at its amino terminus . The binding of AT to heparin is mediated by a unique pentasaccharide sequence that is randomly distributed along the heparin chains [1,5].
The binding of heparin to the heparin binding site on AT produces a conformational change in AT, accelerating the inactivating function of AT 1000- to 4000-fold [4,6]. Inactivation of thrombin, but not factor Xa, requires the formation of a ternary complex in which heparin binds to both AT and to a binding site on thrombin (figure 1) . This complex forms only on pentasaccharide-containing chains at least 18 saccharide units long; such long units are present in most chains of unfractionated heparin, are less commonly present in the low molecular weight (LMW) heparins, and are not present in fondaparinux. Accordingly, LMW heparins and fondaparinux have less antithrombin activity than does unfractionated heparin [8,9].
Less important actions of heparin include direct binding to platelets and, at high concentrations, binding to heparin cofactor II (AT is heparin cofactor I). Heparin does not cross the placenta, making it safer to use in pregnancy than warfarin. (See “Anticoagulation during pregnancy”.)
Limitations — Heparin has a number of limitations, including a narrow therapeutic window of adequate anticoagulation without bleeding, and a highly variable dose-response relation requiring laboratory monitoring. The variable anticoagulant response is due in part to differences in bioavailability of subcutaneous heparin and to competitive occupation of binding sites by plasma proteins (other than AT and coagulation factors), by proteins secreted by platelets (platelet factor 4), and by endothelial cells [1,10]. Some of these heparin-binding proteins are acute phase reactants, thus reducing the effectiveness of heparin in acutely ill patients.
The variable response to treatment with unfractionated heparin was illustrated in results of the ExTRACT TIMI 25 study, in which 6055 patients with ST-segment elevation myocardial infarction received unfractionated heparin along with a fibrin-specific thrombolytic agent . Despite close adherence to recommended heparin dosing according to the American College of Cardiology/American Heart Association weight-based nomogram, only 34 percent of initial aPTTs were therapeutic (ie, 1.5 to 2.0 times control), 13 percent were markedly low (<1.25 times control), and 16 percent were markedly high (≥2.75 times control). (See “Anticoagulant therapy in acute ST elevation myocardial infarction”, section on ‘Unfractionated heparin’.)
Another limitation to the use of heparin is a reduced ability to inactivate thrombin bound to fibrin as well as factor Xa bound to activated platelets within a thrombus . As a result, a thrombus may continue to grow during heparin therapy or clotting may be reactivated after heparin has been discontinued.
Heparin induced thrombocytopenia — Thrombocytopenia following the use of heparin (heparin-induced thrombocytopenia, HIT) is a potentially fatal complication that may be associated with thrombosis (HITT). This subject is discussed separately. (See “Heparin-induced thrombocytopenia”.)
Heparin monitoring — The anticoagulant response to a standard dose of unfractionated heparin varies widely among patients. Further, there is insufficient information in the literature to modify the initial dose according to estimates of the patient’s “wet” versus “dry” weight or rapidly changing weight. This makes it necessary to monitor the response in each patient, using the activated partial thromboplastin time (aPTT) or heparin levels (see below), or the activated clotting time in the case of the high doses of heparin as used in interventional cardiology, and to titrate the dose to the individual patient [13,14]. Such measurements should be made prior to heparin therapy, four to six hours after initiation, and four to six hours after any dosage change. (See “Clinical use of coagulation tests”, section on ‘Activated partial thromboplastin time’ and “Clinical use of coagulation tests”, section on ‘Activated whole blood clotting time’.)
The dosing of heparin in the obese subject is discussed separately. (See “Management of the critically ill obese patient”, section on ‘Anticoagulants’.)
In patients with venous thromboembolism, the critical therapeutic level of heparin (as measured by the aPTT) to be reached within the first 24 hours is 1.5 times the mean of the control value or the upper limit of the normal aPTT range. This level of anticoagulation generally corresponds to a heparin blood level of 0.2 to 0.4 units/mL by the protamine sulfate titration assay and 0.3 to 0.7 units/mL by an amidolytic antifactor Xa assay [1,15,16].
The importance of achieving this therapeutic range within 24 hours according to the aPTT is discussed separately. Failure to promptly achieve a therapeutic aPTT level in patients with VTE treated with unfractionated heparin has been associated with a statistically significant and clinically important increase in the risk of subsequent recurrent thromboembolism. (See “Treatment of lower extremity deep vein thrombosis”, section on ‘Unfractionated heparin’.)
As will be described below in the nomograms for heparin therapy, the generally accepted value of the aPTT that should be reached for maintenance heparin therapy is 1.5 to 2.5 times the mean of the control value or the upper limit of the normal aPTT range. There is, however, a wide variability in the aPTT and heparin blood levels with different reagents and even with different batches of the same reagent [17,18]. As a result, it is vital for each laboratory to establish the minimal therapeutic level of heparin, as measured by the aPTT, that will provide a heparin blood level of at least 0.2 units/mL by the protamine titration assay for each batch of thromboplastin reagent being used; this is particularly important when switching to a reagent provided by a different manufacturer.
Effect of the change in heparin potency — Unfractionated heparin (UFH) products manufactured in the United States after October 8, 2009 will be 10 percent less potent because of the use of a new United States Pharmacopeia (USP) reference standard, which will lessen the potential of contamination and calibrate the new material relative to the international standard issued by the World Health Organization FDA Safety Alert. However, the USP has also stated that “Due to the inherently low and extremely variable bioavailability of heparin, finished drug product potencies are generally specified with ±10 percent of the potency values” .
Accordingly, changing to the new heparin unit is not likely to have clinical significance for most applications. However, it may be important when UFH is administered as a bolus intravenous dose and an immediate anticoagulant effect is clinically important, prompting consideration about what initial dose to administer. Monitoring of the effect of therapeutic doses of UFH via the aPTT (or the activated clotting time (ACT) in the case of the high doses of heparin as used in interventional cardiology) will be of critical importance in determining the overall effect, if any, of this change in UFH potency. (See ‘Heparin monitoring’ above.)
Addition of warfarin — Warfarin generally is begun concomitantly with heparin in patients with venous thromboembolism. The simultaneous use of the two drugs complicates the assessment of the degree of anticoagulation due to heparin if only the aPTT is monitored. As an example, one study of 24 patients with venous thromboembolism found that the effects of heparin and warfarin on the aPTT were additive, and that the aPTT was prolonged approximately 16 seconds for each 1.0 increase in the international normalized ratio . Heparin levels were subtherapeutic in 10 of 29 cases of a supratherapeutic aPTT in this setting. However, the practical implications of this study are unclear because simultaneously administered heparin and warfarin have been shown to be safe and effective in large randomized trials . A discussion of how to initiate and transition from heparin to warfarin therapy can be found elsewhere. (See “Treatment of lower extremity deep vein thrombosis”, section on ‘Initial anticoagulation regimen’ and “Anticoagulation in acute pulmonary embolism”, section on ‘Warfarin’.)
Prolonged baseline aPTT — The presence of a prolonged baseline aPTT makes this test unreliable for monitoring therapy with unfractionated heparin (UFH). (See “Clinical use of coagulation tests”, section on ‘Causes of prolonged aPTT’.)
The cause of the prolonged aPTT should be investigated prior to initiating therapy whenever possible. For example, if the reason is a lupus anticoagulant, then an alternative monitoring system may be employed. However, if the patient has a compromised coagulation system (eg, liver disease, DIC) and prolonged clotting times due to one or more factor deficiencies, then the risk/benefit assessment and therapeutic goals of anticoagulation need to be individualized.
A number of options are available for monitoring UFH therapy in patients with prolonged baseline aPTTs:
- Monitor UFH dosing by using an anti-factor Xa assay or a specific heparin assay. In general, these are not affected by the presence of a lupus anticoagulant or factor deficiency.
- Alternatively, if the reason for a prolonged baseline aPTT is a lupus anticoagulant, one can employ 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 for UFH corresponds to established ranges for UFH by protamine titration (0.2 to 0.4 Units/mL) or anti-Xa activity (0.3 to 0.7 Units/mL). (See ‘Heparin monitoring’ above.)
- Use subcutaneous LMW heparin in therapeutic doses rather than UFH. Routine monitoring of LMW heparin is not generally required. However, a LMW heparin-specific anti-factor Xa assay can be used for monitoring if questions concerning dosing arise (eg, pregnancy, obesity, renal insufficiency). Note that the therapeutic range for LMW heparin is different from UFH. As an example, the therapeutic range for enoxaparin is generally 0.5 to 1.0 anti-Xa Units/mL when measured four to six hours following injection. (See ‘Anti-factor Xa testing’ below.)
In general, the most practical solution will be to use a LMW heparin as an alternative to UFH. Where rapid anti-Xa levels or other heparin assays are available (with rapid turnaround for dose adjustments), the use of UFH with such monitoring would also be acceptable.
Platelet count monitoring — For patients receiving unfractionated heparin (UFH), the 2008 ACCP Guidelines suggest that platelet counts be obtained regularly to monitor for the development of thrombocytopenia. The frequency and timing of such counts depends upon the clinical situation :
- For patients receiving therapeutic-dose UFH, every other day platelet count monitoring is suggested from day 4 to day 14, or until UFH is stopped, whichever occurs first.
- For patients receiving prophylactic dose UFH or LMW heparin, platelet count monitoring is suggested every two to three days from day 4 to day 14, or until heparin is stopped, whichever occurs first.
- For patients who have received UFH in the past 100 days and who are starting treatment with UFH or LMW heparin, who are therefore at risk of developing accelerated thrombocytopenia, a baseline platelet count should be obtained and repeated within 24 hours. (See “Heparin-induced thrombocytopenia”, section on ‘Onset and degree of thrombocytopenia’.)
- For medical/obstetric patients who are only receiving LMW heparin, or medical patients who are receiving only intravascular catheter UFH “flushes”, in whom the incidence of HIT is expected to be <0.1 percent, routine platelet count monitoring is not suggested.
- Guidelines for the extremely short use of heparin in patients with a prior diagnosis of heparin-induced thrombocytopenia are presented separately. (See “Heparin-induced thrombocytopenia”, section on ‘Use of heparin after an episode of HIT’.)
Heparin resistance — The phenomenon of heparin resistance refers to patients requiring unusually large doses of heparin in order to achieve an aPTT in the therapeutic range (eg, >35,000 units of heparin per 24 hours, excluding initial bolus doses). Causes of this phenomenon include increased heparin clearance, increased levels of heparin-binding proteins, elevations of fibrinogen and factor VIII levels, certain medications (eg, aprotinin), and antithrombin deficiency [1,23].
A randomized controlled study evaluated the therapeutic benefit when subjects with heparin resistance were randomly assigned to have their heparin dosage adjusted either to achieve an anti-factor Xa activity of 0.35 to 0.67 International Units/mL or an aPTT in the range of 60 to 80 seconds, both of which were equivalent to a heparin level of 0.2 to 0.4 Units/mL by protamine titration . 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 their anti-factor Xa activity.
Accordingly, it has been suggested that adjustment of heparin dosing in patients with heparin resistance should be based upon anti-Xa levels rather than the aPTT .
Antithrombin deficiency — Some patients with deficiency of antithrombin (AT, heparin cofactor I, formerly known as ATIII) are resistant to heparin and require large doses. This is in part due to the action of heparin to further lower AT levels by approximately 30 percent. In addition, the majority of patients with heparin resistance are AT-deficient [25,26]. Treatment of the AT-deficient subject with AT concentrates results in potentiation of the heparin effect and reduction in total heparin usage [27,28].
Antithrombin concentrate has been used safely and effectively in patients with AT deficiency and acute venous thrombosis [29,30]. It is recommended in those patients who have unusually severe thrombosis, develop recurrent thrombosis despite adequate anticoagulation, or have difficulty achieving adequate anticoagulation . (See “Antithrombin (ATIII) deficiency” and “Management of inherited thrombophilia”, section on ‘Antithrombin deficiency’.)
The intravenous infusion of 50 units/kg of AT concentrate will usually raise the plasma AT level to approximately 120 percent in a congenitally deficient individual with a baseline value of 50 percent [30,32-34]. Plasma levels should be monitored to ensure that they remain above 80 percent; the administration of 60 percent of the initial dose at 24-hour intervals is recommended to maintain AT levels in the normal range .
Use of AT concentrate as adjunctive therapy or as an alternative to heparin in patients with AT deficiency and venous thromboembolism has not been studied in a controlled trial [35,36].
Interference with thrombophilia testing — Use of heparin reduces antithrombin levels and interferes with testing for an inherited deficiency of antithrombin. Testing for a lupus anticoagulant, which requires use of a modification of the aPTT, cannot be performed until heparin is stopped (table 1). (See “Evaluation of the patient with established venous thrombosis”, section on ‘Technical screening issues’.)
ADMINISTRATION AND EFFICACY — Audits of heparin therapy indicate that administration of intravenous heparin is fraught with difficulty and that the clinical practice of using an ad hoc approach to heparin dose-titration frequently results in inadequate therapy [37-40]. As an example, a 1988 audit of physician practices at three university-affiliated hospitals documented that 60 percent of treated patients failed to achieve an adequate aPTT response (ie, at least 1.5 times the control value) during the initial 24 hours of therapy, and that 30 to 40 percent of patients remained subtherapeutic over the next three to four days . Several practices were identified that led to inadequate therapy. The common theme was fear of bleeding complications on the part of clinicians. These problems have subsequently been alleviated via the use of protocols for the administration of heparin, some of which are described immediately below. However. despite the presence of such protocols, underdosing, along with failure to achieve an adequate aPTT response during the initial 24 hours, is still a problem, especially in the obese patient .
Treatment of VTE
Intravenous heparin — The use of a prescriptive approach or protocol for administering intravenous heparin therapy has been evaluated in two studies in patients with venous thromboembolism (VTE):
- The first trial evaluated patients with proximal venous thrombosis who were given either intravenous heparin alone followed by warfarin, or intravenous heparin and simultaneous warfarin . The heparin nomogram used in this study is summarized in the tables (table 2 and table 3). Only 1 percent and 2 percent of the patients were subtherapeutic for more than 24 hours in the heparin group and in the heparin and warfarin group, respectively. Objectively documented recurrent VTE occurred infrequently in both groups (7 percent), a rate similar to that previously reported. These findings demonstrated that subtherapeutic dosing was avoided in most patients and that use of this heparin protocol resulted in effective delivery of heparin therapy in both groups.
- The second trial compared a weight-based heparin dosing nomogram with a standard-care nomogram (table 4) . Patients treated with the weight-adjusted heparin nomogram received a starting dose of 80 units/kg as a bolus and 18 units/kg per hour as an infusion. Patients on the standard-care nomogram received a bolus of 5000 units followed by 1000 units/hour by infusion. The heparin dose was adjusted to maintain an aPTT of 1.5 to 2.3 times control. A higher percentage of patients in the weight-adjusted group achieved the therapeutic range within 24 hours (89 versus 75 percent). The risk of recurrent VTE was higher in the standard-care group (relative risk 5.0, 95% CI 1.1-22), supporting the previous observation that subtherapeutic heparin during the initial 24 hours is associated with a higher incidence of VTE recurrence.
In addition to patients with VTE, this study included patients with unstable angina and arterial thromboembolism, suggesting that the principles applied to a heparin nomogram for the treatment of VTE may be generalizable to other clinical conditions .
Subcutaneous UFH — The use of subcutaneous (SQ) unfractionated heparin (UFH) for the initial treatment of acute VTE was evaluated in a randomized open-label study which compared unfractionated heparin (initial dose 333 units/kg SQ followed by a fixed dose of 250 units/kg SQ every 12 hours) to LMW heparin (100 international units/kg SQ of dalteparin or enoxaparin every 12 hours) in 708 adults with acute VTE . As a departure from standard care, the aPTT was not monitored and platelet counts were not routinely obtained.
The majority of patients were able to receive treatment on an outpatient basis. Further, despite concerns about lack of monitoring [45-47], this trial indicated that the use of twice-daily unmonitored subcutaneous weight-adjusted UFH was as effective and safe as twice-daily subcutaneous LMW heparin and less expensive.
A Cochrane review of 15 randomized controlled trials comparing subcutaneous UFH to continuous intravenous UFH or subcutaneous LMW heparin for the initial treatment of VTE found no statistically significant differences for any of the major efficacy and safety outcomes (ie, recurrent DVT, recurrent PE, major bleeding, death) .
Prevention of VTE — A different regimen, low dose subcutaneous heparin, is often given for prophylaxis of venous thrombosis, primarily in the perioperative setting, but also in certain medical conditions. The usual dose is 5000 units subcutaneously two hours preoperatively and then every 8 or 12 hours postoperatively (ie, either three times daily or twice daily, respectively). Pooled data from meta-analyses have confirmed that low dose heparin reduces the incidence of all deep vein thrombosis, proximal deep vein thrombosis, and all pulmonary emboli, including fatal pulmonary emboli [49,50]. (See “Prevention of venous thromboembolic disease in surgical patients”, section on ‘Low dose unfractionated heparin’.)
Low molecular weight (LMW) heparin appears to have equivalent or even superior efficacy to standard unfractionated heparin in this setting. (See ‘Use of LMW heparin’ below and “Prevention of venous thromboembolic disease in medical patients”, section on ‘Unfractionated versus LMW heparin’.)
Available heparin nomograms — Nomograms for the use of intravenous unfractionated heparin other than the ones discussed above have also been published. They differ mainly in the initial rate of infusion, as well as the suggested changes to the infusion rate according to subsequent values of the aPTT. As an example, one of the dosing schedules for heparin cited in the 2008 ACCP Guidelines is an initial bolus of 5000 units followed by an infusion of 1300 units per hour, rather than the 1680 units per hour employed in the study noted above (table 2) [1,15,39,42].
A survey of available weight-based nomograms supports the view that they represent a safe and cost-effective strategy for unfractionated heparin dosing in a number of different health care settings .
COMPLICATIONS — The main side effects of heparin therapy are bleeding, thrombocytopenia, and osteoporosis.
Bleeding — Although there is a strong correlation between subtherapeutic aPTT values and recurrent thromboembolism, the relationship between supratherapeutic aPTT (aPTT ratio >2.5) and bleeding is less clear . In a review of 416 patients treated with heparin, hemorrhagic complications occurred in 5.5 percent and were more closely related to underlying clinical risk factors than an aPTT elevation above the therapeutic range . Patients at particular risk are those who have had recent surgery or trauma, or who have other clinical factors which predispose to bleeding, such as peptic ulcer, occult malignancy, liver disease, hemostatic defects, age >65 years, female gender, and a reduced admission hemoglobin concentration [21,42,52,53].
The management of bleeding in a patient receiving heparin depends upon the location and severity of bleeding, the risk of recurrent venous thromboembolism (VTE), and the level of the aPTT.
- Patients with recent VTE and clinically important heparin- associated bleeding should be considered for discontinuation of heparin and insertion of an inferior vena cava filter. (See “Inferior vena cava filters”.)
- General measures that should be taken in any patient with anticoagulant-associated severe bleeding are presented separately. (See “Anticoagulants other than heparin and warfarin”, section on ‘Emergency treatment of bleeding’.)
Heparin reversal with protamine — If urgent reversal of heparin effect is required, protamine sulfate can be administered by slow intravenous infusion (not greater than 20 mg/minute and no more than 50 mg over any 10 minute period). The appropriate dose of protamine sulfate is dependent upon the dose of heparin given and the elapsed time since the last heparin dose. Full neutralization of heparin effect is achieved with a dose of 1 mg protamine sulfate/100 units heparin. Because of the relatively short half life of intravenously administered heparin (approximately 30 to 60 min), the protamine sulfate dose used must be calculated by estimating the amount of heparin remaining in the plasma at the time that reversal is required.
Bolus doses of more than 25 to 50 mg of protamine sulfate are seldom required. 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.
Adverse reactions — Patients who have previously received protamine (including diabetic patients under treatment with protamine-containing insulin (eg, NPH, PZI) and those with fish allergy) have an approximately 1 percent risk of anaphylaxis when protamine sulfate is administered .
Thrombocytopenia — Heparin-induced thrombocytopenia (HIT) is a well-recognized and potentially fatal complication of heparin therapy, usually occurring within 5 to 10 days after the start of heparin therapy. The pathogenesis, clinical manifestations, diagnosis, and treatment of HIT are discussed in detail separately. (See “Heparin-induced thrombocytopenia”.)
Skin necrosis — Skin necrosis is a well-described complication of treatment with unfractionated or LMW heparin. Affected patients develop heparin-dependent antibodies but most do not experience thrombocytopenia. (See “Heparin-induced thrombocytopenia”, section on ‘Skin necrosis’.)
Osteoporosis — Osteoporosis has been reported in patients receiving unfractionated heparin for more than six months [1,54]. 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’.)
Heparin contamination — Serious reactions following the use of unfractionated heparin were reported in late 2007, leading to urgent recall of some of these preparations. Adverse events included allergic or hypersensitivity-type reactions (eg, low blood pressure, shortness of breath, nausea, vomiting, diarrhea, abdominal pain), at least 81 reports of death, and an increase in the incidence of heparin-induced thrombocytopenia [55-58].
The suspect heparin products originated in China; heparin products available in at least 12 countries were contaminated with oversulfated chondroitin sulfate (OSCS), representing up to 30 percent by weight in suspect lots of heparin [59,60]. OSCS- containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation and subsequent bradykinin generation when administered by intravenous infusion in swine, suggesting that this contaminant was responsible for the adverse reactions seen. Additionally, OSCS induced generation of C3a and C5a, potent anaphylaxis toxins derived from complement proteins.
Whether this contamination was deliberate or the result of faulty processing of pig intestines, the major source for commercial heparin, is not clear. Currently available unfractionated heparin available in the United States is safe from this contamination now that the contaminant has been identified and assays have become available to screen for the presence of OSCS and other highly sulfated polysaccharide contaminants that can activate the contact system. These manufacturing and testing modifications have also resulted in a change in the reference standard for heparin, which has reduced the potency of unfractionated heparin products made in the United States by about 10 percent. (See ‘Effect of the change in heparin potency’ above.)
Low molecular weight heparin, which undergoes an additional fragmentation process, has not been associated with these adverse reactions or contamination with chondroitin sulfate.
USE OF LMW HEPARIN
Comparison with heparin — The type of unfractionated heparin in current clinical use is polydispersed unmodified heparin, with molecular weight ranging from 3000 to 30,000 daltons and a mean molecular weight of approximately 15,000, corresponding to approximately 45 saccharide units. Low molecular weight (LMW) derivatives of commercial heparin have a molecular weight range from 2000 to 9000 daltons and a mean molecular weight of 4000 to 5000, corresponding to about 15 saccharide units [1,8,61-63].
As with unfractionated heparin, LMW heparins inactivate factor Xa, but have a lesser effect on thrombin because most of the molecules do not contain enough saccharide units to form the ternary complex in which thrombin and AT are bound simultaneously (figure 1) [8,9,64]. As a result, LMW heparins (and fondaparinux) do not prolong the aPTT. (See “Clinical use of coagulation tests”.)
LMW heparins are at least as effective as unfractionated heparin for the treatment and prevention of VTE [65,66]. They are also equally effective for preventing thromboembolism prior to the use of long-term oral anticoagulation after a mechanical heart valve replacement as well as for patients with a mechanical valve who have a contraindication to the use of oral anticoagulation [67,68]. (See “Management of anticoagulation before and after elective surgery” and “Periprocedural complications of percutaneous coronary intervention”, section on ‘Stent thrombosis’ and “Prevention of venous thromboembolic disease in medical patients”, section on ‘Unfractionated versus LMW heparin’ and “Prevention of venous thromboembolic disease in surgical patients”, section on ‘Low molecular weight heparin’.)
Advantages — The LMW heparins have a number of advantages over unfractionated heparin (UFH) . (See “Low molecular weight heparin for venous thromboembolic disease”.)
- They have greater bioavailability than UFH when given by subcutaneous injection.
- The duration of the anticoagulant effect is greater because of reduced binding to macrophages and endothelial cells, permitting administration only once or twice daily.
- The anticoagulant response (anti-Xa activity) to LMW heparin is highly correlated with body weight, permitting administration of a fixed dose. However, the dose may have to be adjusted for patients who are extremely obese or have renal failure (see ‘Special patient groups’ below) .
- Laboratory monitoring is not necessary in nonpregnant patients; in fact, there is little correlation between anti-Xa activity and either bleeding or recurrent thrombosis.
- They are much less likely to induce immune-mediated thrombocytopenia than unfractionated heparin: 0 versus 2.7 percent in one study . (See “Heparin-induced thrombocytopenia”, section on ‘Incidence and risk factors’.)
- They do not increase osteoclast number and activity as much as unfractionated heparin, and may therefore produce less bone loss [70,71]. (See “Drugs that affect bone metabolism”, section on ‘Low molecular weight heparin’.)
- LMW heparin can be safely administered in the outpatient setting [72,73].
Two Cochrane reviews have explored the benefits of LMW heparin over unfractionated heparin, with the following conclusions:
- In patients with acute VTE, fixed-dose subcutaneous LMW heparin is more effective than adjusted-dose unfractionated heparin for reducing the incidence of symptomatic recurrent VTE, major hemorrhage, and all-cause mortality .
- Home management using LMW heparin is cost effective, and is likely to be preferred by patients and become the norm , although reimbursement issues may exist among some third-party payers. (See “Treatment of lower extremity deep vein thrombosis”, section on ‘Outpatient use’.)
Differences among products — Commercially available LMW heparins are made by many different processes (eg, nitrous acid, alkaline, or enzymatic depolymerization) and differ from one another both chemically and pharmacokinetically [61,63]. Variations in molecular weights of the various LMW heparin preparations also result in different ratios of antifactor Xa to antifactor IIa activity , although the clinical significance of these differences is unclear.
There have been very few studies comparing different LMW heparins with respect to clinical outcomes. As a result, the doses of the different LMW heparins have been established empirically and are not necessarily interchangeable. Accordingly, the effectiveness and safety of each LMW heparin for each clinical setting (eg, renal insufficiency, VTE, unstable angina) must be tested separately [63,76,77].
Several different LMW heparins and one heparinoid are available for the prevention and treatment of venous thromboembolism in various countries. (See “Anticoagulants other than heparin and warfarin”, section on ‘Danaparoid’.)
- Three LMW heparins have been approved for clinical use in the United States (enoxaparin, dalteparin, tinzaparin). A closely related synthetic pentasaccharide, fondaparinux, has also been approved, although this product is not generally classified as a low molecular weight heparin. (See “Therapeutic use of fondaparinux”.)
- Additional LMW heparin products are either commercially available in Europe and other countries or are in phase III clinical trials . These include fraxiparin, reviparin, nadroparin, bemiparin, and certoparin .
One randomized study compared the clinical efficacy and safety of two different LMW heparin preparations, tinzaparin (175 international units/kg SQ every 24 hours) and dalteparin (200 international units/kg SQ every 24 hours) given for at least five days as initial outpatient treatment in 505 patients with deep vein thrombosis or pulmonary embolus .
There were no significant differences between the two treatment arms for the two composite end points, major hemorrhage and recurrent VTE, with 11 events in the dalteparin treatment arm (4.4 percent; 2 major hemorrhages and 9 recurrent VTE events) and 15 in the tinzaparin treatment arm (5.9 percent; 5 major hemorrhages and 10 VTE recurrences).
This study was terminated early when an interim analysis indicated that over 32,000 subjects would have to be enrolled in order to detect a statistically significant difference between the two treatment arms. It was therefore concluded that either tinzaparin or dalteparin provided effective and safe outpatient treatment for DVT or PE, and that the choice of agent might be based on practical issues (eg, price, drug delivery systems, availability) .
Bleeding and protamine reversal — Unlike its efficacy with unfractionated heparin, protamine does not completely abolish the anti-Xa activity of LMW heparins . However, for patients who experience bleeding while receiving LMW heparin, protamine sulfate (1 mg/100 anti-Xa units of LMW heparin) may reduce clinical bleeding [1,81], presumably by neutralizing the higher molecular weight fractions of heparin within the product, which are thought to be most responsible for this complication. Smaller doses are needed if the LMW heparin was injected more than eight hours before the event requiring neutralization .
Skin lesions — 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 . Delayed-type hypersensitivity (DTH) reactions were identified as the cause in all 24. Lesions were mostly either eczematous or pruritic erythematous placques; necrosis was not seen. Thrombocytopenia was noted in only one 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 .
Switching to another LMW heparin product in such cases is reasonable, although cross-reactivity between LMW heparin preparations has been described . 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 .
Special patient groups — Certain patient groups may require special dosing of LMW heparin (eg, older age, obesity, renal failure).
Anti-factor Xa testing — If there is any question as to the correct dose of LMW heparin for these special groups, it is reasonable to consider anti-factor Xa activity testing. Dose reduction should be considered if the anti-factor Xa activity four hours after subcutaneous injection is excessive. However, “optimal” target ranges differ, depending not only upon the schedule of treatment (eg, once or twice daily), but also on the preparation used.
Target (peak) ranges, measured four hours after dosing, are approximately 0.6 to 1.0 International Units/mL for twice-daily enoxaparin or nadroparin; target levels for these two agents given once-daily are >1.0 and 1.3 International Units/mL, respectively, and are 0.85 and 1.05 for tinzaparin and dalteparin, respectively .
Elderly patients — In general, elderly patients should be treated with LMW heparin at the same weight-adjusted doses as employed in other adults. However, in elderly patients weighing <45 kg, such dosing may result in an increased incidence of bleeding.
Obese patients — Data are sparse on whether patients with extreme obesity should be given weight-based [86,87] or fixed doses of LMW heparins. Available studies suggest no change in weight-based dosing of enoxaparin, dalteparin, or tinzaparin for subjects with weights less than or equal to 144, 190, or 165 kg, respectively. The 2008 ACCP Guidelines suggest that weight-based prophylactic dosing is preferable to fixed dosing for obese patients . The table outlines information available on this subject for a number of the different LMW heparins and indications (table 5). This subject is discussed separately. (See “Management of the critically ill obese patient”, section on ‘Anticoagulants’.)
Renal failure — There is no clear recommendation for the dosing of LMW heparins in patients with reduced renal function. However, it is important that such patients be adequately anticoagulated despite a potential increase in the rate of bleeding. This was shown in a study of 10,526 patients with VTE, most of whom were initially treated with LMW heparin . Results included:
- The incidence of fatal pulmonary embolism within 15 days of diagnosis was 1.0, 2.6, and 6.6 percent for those with estimated creatinine clearances of >60, 30 to 60, and <30 mL/min, respectively.
- The rate of fatal bleeding from anticoagulation was highest for those with the lowest values of creatinine clearance (0.2, 0.3, and 1.2 percent for estimated creatinine clearances of >60, 30 to 60, and <30 mL/min, respectively).
- The rate of fatal PE was higher than the rate of fatal bleeding for all three groups of patients.
It is unclear whether the increased risks of bleeding and fatal pulmonary embolism are directly related to renal insufficiency or the associated co-morbidities. Both are likely contributors.
Setting a lower limit (eg, creatinine clearance <30 mL/min) on permissible renal function for weight-based dosing does not seem to be appropriate for some of the available products . This is because the pharmacokinetic response to impaired renal function may differ among LMW heparin preparations [76,89]. As examples:
- Tinzaparin sodium (Innohep), a LMW heparin with a higher-than-average molecular weight distribution, did not exhibit accumulation in patients with creatinine clearances as low as 20 mL/min [90,91]. However, based upon preliminary data from the IRIS study (Innohep in Renal Insufficiency Study), including an increased risk for death, the United States FDA has advised that clinicians should consider the use of alternative treatments to Innohep when treating elderly patients >70 years of age with renal insufficiency and VTE .
- There was a significantly increased level of anti-factor Xa activity following the use of enoxaparin (1 mg/kg every 12 hours) in patients with a creatinine clearance ≤30 mL/min . If enoxaparin is chosen in such a patient, using 50 percent of the recommended dose seems reasonable (eg, 30 mg once/day) .
- There was a significant bioaccumulation of dalteparin at a median of 6 days following the use of therapeutic doses of dalteparin (100 units/kg every 12 hours) in patients with a creatinine clearance <30 mL/min . If dalteparin is chosen in such a patient, frequent monitoring should be performed via determination of anti-factor Xa activity. No single dosing scheme could be suggested in this study, due to wide inter-individual variation.
- An increased risk of bleeding in patients with renal insufficiency (creatinine clearance <30 mL/min) was not reported with prophylactic doses (3000 anti-Xa units/daily) of the LMW heparin certoparin .
A meta-analysis in non-dialysis-dependent patients with a creatinine clearance ≤30 mL/min also noted elevated levels of anti-Xa and an increased risk for major bleeding in those treated with weight- adjusted therapeutic doses of enoxaparin . It was concluded that empirical dose adjustment of enoxaparin may reduce the risk for bleeding in such patients. The authors could make no conclusions regarding other LMW heparins in this setting.
If a LMW heparin is to be used in a patient with renal failure, it has been recommended that frequent monitoring be performed via the direct determination of anti-factor Xa activity, since drug accumulation may occur over time in these patients .
However, such monitoring may not be necessary in patients with impaired renal function receiving the LMW heparin dalteparin in prophylactic doses.
- In a study of 156 critically ill patients with severe renal insufficiency and a mean creatinine clearance of 19 mL/min (range: <10 or on dialysis to 30 mL/min), the use of prophylactic doses of dalteparin (5000 international units once daily) was not associated with an excessive anticoagulant effect due to drug accumulation .
- In a prospective cohort study of patients with normal renal function or mild or severe renal insufficiency, patients received dalteparin in prophylactic doses (ie, fixed daily subcutaneous dose of 5000 Units with reduction to 2500 Units for a body weight <50 kg and 7500 Units for a body weight >100 kg) . In all three patient groups, adjusted peak anti-Xa levels were not different on day 10 compared with day one. No bioaccumulation >30 percent could be found up to day 10 even in patients with severe renal insufficiency.
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 5th to 6th 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 10th to 12th 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.)
- Beyond the Basics topics (see “Patient information: Deep vein thrombosis (DVT)”)
SUMMARY AND RECOMMENDATIONS
Mode of action — Heparin is an indirect thrombin inhibitor which complexes with antithrombin, converting this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa. Low molecular weight (LMW) heparins have less antithrombin activity than does unfractionated heparin (UFH). (See ‘Mechanism of action’ above.)
Monitoring of heparin activity — The anticoagulant response to UFH is most frequently monitored through the activated partial thromboplastin time (aPTT). The protamine sulfate titration assay and antifactor Xa assays can also be employed. (See ‘Heparin monitoring’ above and “Clinical use of coagulation tests”, section on ‘Activated partial thromboplastin time’.)
LMW heparins are less efficient inhibitors of thrombin; their use cannot be monitored through use of the aPTT. If monitoring is required, LMW heparin blood levels can be evaluated though antifactor Xa assays.
Monitoring of platelet counts — For all patients receiving unfractionated heparin (UFH) and some patients receiving LMW heparin, platelet counts must be obtained regularly to monitor for the development of heparin-induced thrombocytopenia. The frequency and timing of such counts depends on the clinical situation. (See ‘Platelet count monitoring’ above and “Heparin-induced thrombocytopenia”, section on ‘Onset and degree of thrombocytopenia’.)
Dosing of the heparins — Dosing of UFH or LMW heparins for treatment or prevention of VTE is discussed in the appropriate UpToDate treatment reviews.
- Unfractionated heparin — If urgent reversal of the effect of unfractionated heparin is required, protamine sulfate can be administered by slow intravenous infusion. The appropriate dose of protamine sulfate is dependent upon the dose of heparin given and the elapsed time since the last heparin dose. (See ‘Heparin reversal with protamine’ above.)
- LMW heparin — Unlike its efficacy with unfractionated heparin, protamine does not completely abolish the anti-Xa activity of LMW heparins. However, for patients who experience bleeding while receiving LMW heparin, protamine sulfate may reduce clinical bleeding. (See ‘Bleeding and protamine reversal’ above.)
Use of LMW heparin in special patient groups — Certain patient groups may require special dosing of LMW heparin (eg, older age, obesity, renal failure). If there is any question as to the correct dose of LMW heparin for these special groups, it is reasonable to consider anti-factor Xa activity testing. (See ‘Special patient groups’ above.)
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