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Antithrombotic agents have been in clinical use for more than half a century and are among the most commonly prescribed classes of medications. Established uses include the prevention and treatment of venous thromboembolism (VTE), atrial fibrillation (AF), and acute coronary syndromes (ACSs), and prevention of embolism from mechanical heart valves. Both oral and parenteral agents exist, each with various indications and therapeutic targets. The most well-known and frequently used of these are warfarin and heparin; however, recent years have seen the development of multiple novel agents, including the group referred to as the direct oral anticoagulants (DOACs). Although the new drugs provide solutions to many of the dilemmas associated with traditional drugs (e.g., dosing variability, onerous monitoring, drug-drug and drug-environment interactions), they bring with them new challenges, such as a lack of specific antidotes and, more practically, increased cost and lack of familiarity. A summary of current indications for heparin is provided in Box 27.1 .
Remains the anticoagulant of choice for cardiopulmonary bypass including brief exposure of serologically negative patients with prior HIT. Also widely used in hemodialysis patients and in patients with other indwelling devices such as left ventricular assist devices
Owing to its immediate onset of action, rapid clearance, and reversibility, intravenous unfractionated heparin remains the treatment of choice in the management of thrombosis in unstable patients, or those identified to be at high risk of bleeding. For example, the ability to tightly manage its anticoagulant effect makes it the treatment of choice around some surgeries or during childbirth
Continues to be widely used for prevention of venous thrombosis in patients at moderate risk of this complication, particularly after surgery
HIT, Heparin-induced thrombocytopenia.
Proper management of anticoagulant therapy requires striking a balance between preventing thromboembolic events and limiting potential side effects, the most concerning of which is bleeding a risk characteristic of all anticoagulants. Other complications include heparin-induced thrombocytopenia (HIT). Contemporary pharmacology and management of oral anticoagulants are presented in Chapter 37 .
Heparin was initially discovered in the 1920s, and its antithrombotic properties were applied clinically starting in the 1940s. Unfractionated heparin (UFH) is a highly heterogeneous extract of biologic tissue, containing many molecules without significant anticoagulant activity. Appreciation of this variability led to the search for more purified derivatives with greater reliability. The 1990s saw the introduction of the low-molecular-weight heparins (LMWHs) as a solution to many of these issues. LMWH allowed for a more predictable anticoagulant effect and, for the most part, obviated the need for monitoring. Research into the active component of heparin revealed the specific five-saccharide sequence involved in the heparin-antithrombin III (ATIII) complex. Pentasaccharide anticoagulants, such as fondaparinux, were subsequently developed that included only this active moiety. HIT is a rare but recognized reaction to heparin exposure and requires discontinuation of the drug (see Chapter 26 ). Non-heparin parenteral anticoagulants such as bivalirudin, argatroban, danaparoid, and perhaps the DOACs can be used as alternatives in this clinical situation. Tempering the low but constant concern of hemorrhage and other complications must be an awareness that, left undertreated or untreated, thrombotic disorders are comparatively far more dangerous than bleeding.
Heparin has no direct anticoagulant effect. Instead, it indirectly inhibits thrombin by complexing with ATIII (a natural inhibitor of thrombin), factor Xa, and other serine proteases to a lesser extent (e.g., factors IIa, IXa, XIa, and XIIa). Circulating ATIII is constitutively active at low levels, but activity increases at least 1000-fold following its interaction with the active binding site of heparin. These binding sites are randomly distributed along the heparin molecule at variable frequency. For effective thrombin inhibition via the pentasaccharide binding site, heparin molecules must be at least 18 saccharide units in length to allow for formation of a complex between heparin, ATIII, and thrombin. Heparin molecules of this length are common in UFH, uncommon in LMWH products, and totally absent in the pentasaccharides. Factor Xa inhibition by the heparin-ATIII complex does not require the 18-saccharide complex; thus even pentasaccharides are able to catalyze ATIII-mediated inactivation of factor Xa.
UFH is most commonly administered intravenously as a continuous infusion for therapeutic anticoagulation. Benefits include a nearly immediate anticoagulant effect and an ability to monitor treatment directly using the partial thromboplastin time (PTT). Limitations include a narrow therapeutic window and unpredictable dose-response relationships. The PTT range for heparin therapy falls between 1.5 and 2.5 times the normal reference value, provided that the patient's pretreatment PTT is normal. This usually corresponds to a heparin blood level of 0.2 to 0.4 U/mL using the protamine titration assay (0.3 to 0.7 U/mL by factor Xa inhibition) but should be standardized at each facility because of the potential variation in laboratory testing. Patients may have a prolonged PTT at baseline.
Before therapy is started, it is important to identify the cause of this abnormality. Possible explanations include the presence of lupus anticoagulant (LA) or a nonspecific inhibitor, or deficiencies in one or more clotting factors. One option is to measure the anticoagulant effect using anti–factor Xa instead of the PTT because these assays are not usually affected by a nonspecific inhibitor or factor deficiencies. Finally, if possible, another antithrombotic agent should be used in place of UFH to avoid the need for PTT monitoring.
Standardized nomograms are available to assist in the proper dosing of intravenous heparin in the treatment of VTE ( Table 27.1 ). Other nomograms are available for patients with ACSs and for those undergoing thrombolysis. Despite widespread use, the value of the PTT in guiding therapy remains controversial, with some centers using exclusively anti-Xa heparin levels, and at least one large study finding that PTT monitoring was not needed when heparin was used subcutaneously for the management of acute VTE.
PTT (s) a | Bolus Doses (U) | Stop Infusion (min) | Change in Infusion b | Time of Repeat PTT |
---|---|---|---|---|
Fixed-Dose Nomogram c | ||||
<50 | 5000 | 0 | +3 mL/h | 6 h |
50–59 | 0 | 0 | +3 mL/h | 6 h |
60–85 | 0 | 0 | 0 | Next morning |
86–95 | 0 | 0 | −2 mL/h | Next morning |
96–120 | 0 | 30 | −2 mL/h | 6 h |
>120 | 0 | 60 | −4 mL/h | 6 h |
PTT (s) d | Bolus (U/kg) | Infusion (U/kg/h) | ||
Weight-Based Nomogram | ||||
Initial dose is 80 U/kg given as a bolus, followed by an infusion of 18 U/kg/h. Dose adjustments are based on PTT values obtained every 6 h. | ||||
<35 | 80 | Increase rate by 4 | ||
35–45 | 40 | Increase rate by 2 | ||
46–70 | 0 | No change | ||
71–90 | 0 | Decrease rate by 2 | ||
>90 | 0 | Decrease rate by 3 |
a Therapeutic PTT range is assumed to be 60–85 s, which corresponds to a plasma heparin level of 0.3–0.7 U/mL anti-Xa activity. The therapeutic range may vary between reagents and coagulometers and may need to be adjusted.
b 1 mL/h should represent 40 U/h.
c Modifications occurred after initial heparin load and maintenance infusion. The initial infusion rate may be arbitrary or based on the weight adjusted dose from the weight adjusted nomogram.
d The “target PTT” in this case is 46 to 70 s. See footnote “a” for further discussion.
Thromboprophylactic heparin is given subcutaneously at a dosage of 5000 U every 8 to 12 hours. Some advocate a regimen of administration every 8 hours in patients at higher risk, although a systematic review failed to find evidence that thrice-daily administration was more effective than twice-daily dosing and the inconvenience and incremental cost of thrice-daily dosing is substantial. Subcutaneous heparin does not require PTT monitoring.
Some patients may fail to prolong their PTT despite high-dose intravenous heparin; such patients may also benefit from anti–factor Xa monitoring (discussed later). Platelet counts should be monitored regularly in patients receiving UFH to detect the potential development of thrombocytopenia, including immune-mediated HIT.
Measurement of anti–factor Xa activity is an alternative strategy for monitoring anticoagulation with heparin. Most assays use a chromogenic method in which the patient sample is added to a mixture of exogenous factor Xa and a chromogenic substrate. Heparin in the sample complexes with available ATIII and inhibits the interaction between factor Xa and its substrate, so that an inverse relationship is created between heparin concentration and color emitted. Some assays require separate calibration curves for different forms of heparin (i.e., UFH vs. LMWH), whereas others use a hybrid system. Correlation between anti–factor Xa levels and the PTT is variable and can be affected by concomitant use of other anticoagulants (e.g., dabigatran), vitamin K antagonism or deficiency, factor deficiencies, acute phase reactants (e.g., elevated factor VIII levels), and coadministration of UFH with LMWH or a pentasaccharide. Anti–factor Xa monitoring is gaining acceptance, especially when anticoagulation cannot be reliably assessed using the PTT (e.g., in patients with LA or those administered LMWH). Use in the context of UFH treatment has also become more prevalent and may improve dosing accuracy. In a randomized trial, patients with acute VTE and heparin resistance received significantly less UFH but had the same overall clinical outcome when therapy was determined by anti–factor Xa activity instead of the PTT.
Despite the benefits of anti–factor Xa testing, its greater specificity may lead to increased bleeding risk in patients whose therapy is monitored in this way. Conditions such as disseminated intravascular coagulation (DIC), chronic liver disease, and acquired vitamin K deficiency might not be detected using the specific assay but would be discovered using more standard tests of hemostasis. This is of particular importance in the critical care setting.
Heparin resistance refers to the phenomenon in which patients require unusually large dosages of UFH to achieve a therapeutic PTT (e.g., >35,000 U/24 h, excluding initial bolus). There are several potential causes for this, including increased clearance (e.g., pregnancy), increased levels of heparin-binding proteins, elevations in fibrinogen and/or factor VIII activity, and underlying ATIII deficiency. Inherited deficiency of ATIII is an uncommon but recognized hereditary thrombophilic state. Acquired ATIII deficiency is also possible and may occur in patients with DIC or extensive thrombosis, or during cardiopulmonary bypass surgery. This is likely secondary to upregulation of acute phase proteins—namely, factor VIII and fibrinogen—that are increased in acute inflammatory conditions. In patients with ongoing heparin resistance the anti–factor Xa testing is frequently used to monitor the anticoagulant effect of heparin.
The use of UFH is diminishing because of advances in the diagnosis and management of thrombosis, and the introduction of a variety of new oral anticoagulants medications. Current clinical uses include prophylaxis and treatment of VTE, management of ACS, for the preservation of extracorporeal circuits, and in the acute management of a variety of arteriovascular disorders. For acute VTE management, therapeutic-dose heparin is usually given for a minimum of 5 days, during which time warfarin administration is started. Early and adequate dosing is important because inadequate initial heparin doses are associated with an increased risk of thrombotic recurrence or extension. Various nomograms are available, with the use of weight-based protocols associated with improved outcomes. Subcutaneous UFH, without PTT monitoring, was also evaluated in the treatment of acute VTE and found to be as safe and effective as LMWH in a large prospective study; in this study the initial dose of heparin was 333 U/kg, with subsequent doses of 250 U/kg twice daily. A subsequent Cochrane meta-analysis of the initial treatment of VTE demonstrated no appreciable differences in major outcomes between UFH (given intravenously or subcutaneously) and LMWH. In patients with cardiac disease, UFH is effective in the treatment of ACS, as an adjunct to thrombolysis, and in the prevention of acute vessel reocclusion in patients undergoing percutaneous coronary intervention (PCI) and is widely used in vascular surgery. It is used intraoperatively in vascular surgery to preserve vessel patency and to maintain extracorporeal circuits during cardiopulmonary bypass and hemodialysis.
Heparin does not cross the placenta and is therefore a safe and effective option for anticoagulation during pregnancy, although increased peripartum bleeding is a possibility. Heparin can be administered intravenously for short-term therapy and then switched to subcutaneous administration for prolonged treatment. Monitoring therapy by measuring the PTT approximately 4 to 6 hours following injection is recommended. Dose escalation may be required because of the various physiologic changes during pregnancy, such as increased weight and volume of distribution, particularly during the third trimester. The short half-life of UFH is helpful when treating pregnant patients because UFH can be safely held at the start of labor, before operative delivery, or before neuraxial anesthesia; however, heparin has been associated with osteopenia if given for an extended period.
The most common adverse effect of heparin is bleeding, the frequency of which is determined in part by dose and duration of treatment, as well as by patient characteristics. Major bleeding events are estimated to occur in approximately 3% of those receiving therapeutic doses. Bleeding in patients receiving thromboprophylactic doses is much less common and should prompt an investigation into other causes for the bleeding.
HIT is a clinicopathologic syndrome in which there exists a temporal association between development of thrombocytopenia and formation of a pathologic antibody (see Chapter 26 ). These antibodies are directed against a complex of heparin and platelet factor 4 (PF4) and are platelet activating, which leads to both thrombocytopenia and potential arterial and venous thrombosis. Skin necrosis has also been associated with similar heparin-dependent, platelet-activating immunoglobulin G antibodies, even in the absence of thrombocytopenia. HIT occurs in approximately 1% of those receiving UFH for the treatment of VTE, compared with 0.1% of those treated with LMWH. Classic HIT occurs 5 to 10 days following heparin exposure and is associated with a more than 50% reduction in platelet count (nadir ≥ 20 × 10 9 /L) in the absence of another cause for the thrombocytopenia. More rapid development of HIT (i.e., within 24 hours of exposure) can occur in those who were treated with heparin in the preceding weeks to months. Circumstances affecting the development of HIT include the duration and timing of heparin administration (e.g., the risk is higher with >1 week of treatment), type of heparin used (HIT occurs more frequently with UFH than with LMWH), patient population (e.g., the risk is higher in postsurgical patients), and sex (the risk is greater risk in women). The clinical likelihood of HIT can be predicted using one of a variety of scoring systems, the most widely used of which is the 4Ts score. If the clinical suspicion of HIT is moderate or high, heparin should be discontinued immediately, the patient's plasma should be sent for confirmatory testing, and an alternative anticoagulant should be started—failure to start an alternate anticoagulant is associated with a very high risk of arterial and/or venous thrombosis.
Long-term heparin use has been associated with bone demineralization and osteoporosis. The most common such scenario is treatment or prophylaxis of VTE during pregnancy. Radiographic evidence of bone loss occurs in more than 15% of pregnant women, and symptomatic vertebral fractures have been reported in approximately 2%. Discontinuation of therapy is usually associated with the return of normal bone formation, although the effects of heparin may not be completely reversible.
Because of the short half-life of intravenously administered heparin, minor bleeding during intravenous heparin therapy may best be controlled with local measures and cessation of heparin administration ( Table 27.2 ). The anticoagulant effect of subcutaneous therapy is less predictable because of variable bioavailability. If immediate reversal is required, protamine sulfate can be given (see Chapter 28 ). Its strongly basic polypeptide chains bind with high affinity to the acidic heparin molecules. Dosing is based on the amount of circulating UFH that needs to be neutralized, with 1 mg protamine expected to reverse the effects of 100 U of UFH. Smaller repeated doses may be required in patients receiving subcutaneous UFH. Protamine is also used to reverse the effects of heparin administered during cardiopulmonary bypass surgery. Protamine is derived from fish sperm. Because of this, patients with previous exposure to protamine or protamine-containing insulins (e.g., NPH [neutral protamine Hagedorn]), those who have had vasectomies, and those with true fish allergies (i.e., not shell fish allergic) may have preformed antibodies and may be at risk of allergic reactions including anaphylaxis. FFP, PCCs, and other plasma products have neither a rationale for use nor an effect on heparin and should not be given for reversal.
Question | Considerations | Actions |
---|---|---|
Is the bleeding due to heparin? | Bleeding may not be directly due to the heparin. Evaluate the patient for an underlying predisposition to bleeding from structural causes (e.g., peptic ulcers, tumors, nonligated vessels) or functional causes (e.g., inherited or acquired bleeding diathesis). | Use local measures if possible (e.g., application of pressure, cautery, ligation, topical antifibrinolytics). Correct structural and functional causes. |
Are there aggravating factors? | Look for contributing factors such as thrombocytopenia, use of antiplatelet agents (e.g., aspirin, other NSAIDs, clopidogrel or other thienopyridines), thrombolytic exposure, oral anticoagulant therapy, or acquired vitamin K deficiency. | Consider administering 1-deamino-8- d -arginine vasopressin (desmopressin) for reversal of antiplatelet agent effects, vitamin K for deficiency, and platelet transfusion if patient is thrombocytopenic. |
If heparin is the cause, is the concentration too high? | Identify the precise time and dose of the last heparin administration (confirm with pharmacy or nursing staff). Estimate plasma half-life of the remaining heparin, and check anti–factor Xa level. | Discontinue heparin infusion. Consider administration of protamine sulfate in exceptional cases. Do not administer FFP or PCC. |
Do the benefits of continuing heparin outweigh the risks? | Failure to treat an acute thromboembolic event with heparin, with the potential for recurrence or progression, may be more hazardous than the risk of bleeding-associated morbidity or mortality. Decisions must be made on a case-by-case basis. | If the bleeding is deemed safe and acceptable, consider lowering the dose of heparin, and transfuse as necessary. Consider placement of IVC filters only in exceptional cases to prevent PE. |
Development of the LMWHs has addressed many of the issues that make treatment with UFH challenging and provided products with an improved therapeutic profile. LMWH has much more predictable absorption, bioavailability, and overall anticoagulant effect. Each product is slightly different, but all are prepared by depolymerization using chemical or enzymatic processes. Molecules in UFH range in size from 3000 to 30,000 Da, with a mean molecular weight of approximately 15,000 Da. This corresponds to an average of 45 saccharide units. In comparison, LMWH has an average molecular weight of 4000 to 5000 Da (range, 2000 to 9000 Da) and an average of 15 saccharide moieties. The decreased molecular weight imparts an important pharmacologic difference between UFH and LMWH in terms of thrombin inhibition, because the smaller molecules are unable to form the requisite ternary complex. LMWH still potently inhibits factor Xa; to a variable extent it retains its ability to inhibit thrombin with those molecules of greater molecular mass having more thrombin inhibitory ability. A comparison of the pharmacologic features of UFH, LMWH, and fondaparinux is presented in Table 27.3 . The various LMWH products do have differences among them, including average molecular weight and the ratio of anti–factor Xa and anti–factor IIa activities; however, the clinical significance of this is unclear.
Heparin | LMWH | Fondaparinux | |
---|---|---|---|
Bioavailability with subcutaneous administration | Dose dependent, variable or low | High | High |
Plasma half-life | 1–2 h | 3–5 h | 17 h |
Need for monitoring | Routine (PTT > anti–factor Xa) | Occasional (anti–factor Xa) | Unlikely (anti–factor Xa) |
Cost | Negligible | Moderate | Moderate |
PTT prolongation | Dose dependent | Minimal, variable | Minimal or none |
LMWH is usually administered subcutaneously with near-complete absorption. The elimination half-life is dose independent and ranges from 3 to 6 hours following injection. Anti–factor Xa levels typically reach their peak within 5 hours after the dose is given. The longer plasma half-life of LMWH, in large part caused by decreased plasma and cellular protein binding, also allows for once- or twice-daily dosing. These factors together make LMWH much more convenient and allow for rather straightforward outpatient management.
Dosing of LMWH depends on its indication. Fixed doses are typically used for thromboprophylaxis, whereas therapeutic doses are weight adjusted. The predictability of LMWH activity minimizes the need for regular monitoring and allows the routine treatment of VTE in the outpatient setting. There are few data to support the clinical utility of anti–factor Xa heparin levels; furthermore, no comparative data are available exploring clinical outcomes in patients assigned to treatment based on different target anti–factor Xa levels.
LMWH is primarily cleared renally and therefore must be used with caution in patients with renal insufficiency. Dose modification is recommended with some products in patients with impaired renal function; in each case the appropriate package insert should be consulted for dose considerations.
Clinicians may have reservations when prescribing LMWH to obese patients. However, at therapeutic doses of LMWH, there do not appear to be differences in the rates of major bleeding for the various products, nor increased major bleeding with LMWHs compared with UFH. When weight-based dosing is used, appropriate anti–factor Xa activity has been measured in patients taking enoxaparin at weights of up to 144 kg, in those taking dalteparin at weights of up to 190 kg, and in those taking tinzaparin at weights of up to 165 kg. Thromboprophylaxis with LMWH in the obese may require modification from the standard fixed dose. Because of the apparently increased risk of VTE associated with bariatric surgery, increased prophylactic doses have been used in this specific patient population. Although available evidence suggests that patients who receive weight-adjusted doses have lower rates of VTE, this hypothesis has not been tested in rigorous studies.
LMWH dosing in pregnant patients should be administered using weight-adjusted therapeutic regimens and fixed-dose thromboprophylaxis. Physiologic changes, such as weight gain, increased volume of distribution, and rising glomerular filtration rate may alter LMWH requirements as the pregnancy progresses. Periodic measurement of anti–factor Xa levels may help guide dose modification, although the evidence does not consistently support this practice. Because LMWH therapy cannot be monitored with the PTT, it should be discontinued 24 to 36 hours before delivery. To assist with this timing, planned delivery is preferred in many patients treated with heparin or LMWH; particularly at therapeutic doses. Close collaboration between hematology, anesthesia, and obstetrics is required to ensure a high likelihood of thrombosis avoidance while minimizing the risk of bleeding. In some cases, switching from LMWH to UFH towards the end of pregnancy is practiced, particularly in the case of early threatened labor, or where planned delivery cannot be ensured.
Each LMWH product is marketed for specific indications. Few studies have been performed directly comparing different LMWHs in terms of clinical outcomes; thus few or no data exist to support therapeutic substitution. Some have dosing based on anti–factor Xa units and others are dosed in milligrams, and specific uses should be guided by available evidence and product monographs. In general, 1 mg of LMWH is equivalent to 100 U of anti–factor Xa activity. Product availability varies by jurisdiction.
Approved uses of LMWH essentially echo those of UFH. For comprehensive recommendations, readers are directed to the published guidelines. With the advent of DOACs the “traditional uses” of LMWH are changing; previously frequent uses of LMWH such as acute treatment of VTE are less common, highlighting its continued use for the prevention of thromboembolism.
The LMWHs were widely used over the past two decades as the concept of “bridging” was popularized. The use of LMWH during temporary cessation of warfarin was felt necessary for patients undergoing invasive procedures. However, the notion that such “bridging” was both safe and effective has not been substantiated by studies. In fact, it is likely that for most patients, bridging is both unneeded and is associated with avoidable bleeding without a reduction in thrombosis. Enthusiasm for bridging has waned further with the advent of the DOACs; their much shorter half-life compared with warfarin necessitates only brief interruptions for most procedures, attenuating the risk of thrombosis that is accentuated by the slow offset and onset of the anticoagulant effect of warfarin. Contemporary perioperative management is discussed in Chapter 35 .
In cancer patients, LMWH has been shown to be more effective in preventing VTE recurrence than warfarin, with no increase in bleeding. LMWH administered in usual therapeutic doses for the first 3 to 6 months after a diagnosis of cancer-associated VTE remains the standard despite the availability of DOACs. How long-term therapy is managed in these patients remains controversial because some patients are unable to tolerate long-term subcutaneous treatment.
LMWH is used frequently in the management of ACSs (e.g., unstable angina [UA], non–ST segment elevation myocardial infarction [NSTEMI], and ST segment elevation myocardial infarction [STEMI]). Readers are directed to comprehensive peer guidelines for up-to-date treatment recommendations, because the available options for such patients are broad and are impacted by coincident therapy (such as the use of antiplatelet agents in patients undergoing coronary stenting) (see Chapter 21 ).
The main complication of LMWH use is bleeding. Bruising may occur at the injection site, but this is only bothersome and, for most patients, not clinically significant. Rates of bleeding with LMWH depend on the dose used, with lower frequencies observed at prophylactic levels, and higher rates seen with therapeutic dosing. A meta-analysis of bleeding events in patients treated with LMWH compared with heparin for prophylaxis during medical illness found no difference in bleeding rates (relative risk, 1.13; 95% confidence interval, 0.53 to 2.44). In pregnant women receiving LMWH a study reported an overall rate of 1.98%. Accumulation of anti–factor Xa activity is a concern in patients with significant renal impairment (i.e., CrCl of <30 mL/min), but there does not appear to be increased bleeding with prophylactic doses of LMWHs, particularly dalteparin and tinzaparin ; in fact, short courses of “usual therapeutic doses” of dalteparin were associated with reduced bleeding compared with UFH in patients with impaired renal function in a large retrospective study.
Development of HIT is significantly less likely in patients receiving LMWH, with an approximately tenfold reduction noted compared with UFH. However, cross-reactivity is frequent because the smaller molecules may still interact with PF4 and platelet-activating HIT antibodies. Patients with a history of recent UFH or LMWH therapy in whom a diagnosis of HIT was confirmed or suspected should be carefully monitored and treated with nonheparin anticoagulation. LMWH should never be used to treat active HIT, nor should patients with prior HIT be re-exposed to LMWH or to extended UFH.
The incidence of osteoporosis appears to be lower with LMWH than with UFH. The overall risk is likely related to both the dosage and duration of treatment. Prophylactic LMWH therapy in pregnant patients does not seem to produce any additional osteopenic effect beyond the normal physiologic pregnancy-related bone loss observed.
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