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396 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 397

procedures associated with a high bleeding risk should be postponed mean of the normal range. Clinically useful nomograms are available
during the first several months following acute thrombosis. The bleed- for adjusting the heparin dose using either fixed- or weight-based dos-
ing risk is usually highest during surgery and decreases rapidly to base- ing. Alternatively, monitoring can be performed using anti-Xa levels,
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line after approximately 7 to 10 days. Most surgery can be done with a which is a useful approach when the aPTT is unreliable, as in patients
minimal bleeding risk in patients receiving warfarin and an INR of 1.5 with baseline prolongation of the aPTT as a consequence of express-
or less. A recent cohort study of 1496 patients on chronic anticoagu- ing a lupus anticoagulant. Rapid achievement of a therapeutic level, as
lation undergoing periprocedural bridging therapy showed that bleed- assessed by the aPTT or anti-Xa level, is important in ensuring an ade-
ing occurred in 5.1 percent of patients, and risk factors for bleeding quate anticoagulant effect.
included mitral mechanical valve, active cancer, prior bleeding history, Some patients fail to display an adequately prolonged aPTT fol-
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and reinitiation of anticoagulation within 24 hours of procedure. A lowing treatment with unfractionated heparin, despite apparently ade-
randomized study of anticoagulated patients undergoing defibrillator quate or even supratherapeutic doses of the drug. This phenomenon
placement showed that bridging therapy was associated with a signifi- is termed heparin resistance and is usually caused by an acute-phase
cant increase in device-pocket hematoma (16 percent vs. 3.5 percent) response that results in high levels of procoagulant proteins, including
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without a reducing thromboembolic complications. Patients at mod- factor VIII. The antithrombotic effect of heparin correlates best with
erate or high risk of thrombotic recurrence should receive heparin or plasma heparin levels, which may be adequate in these circumstances
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LMWH “bridging therapy” when their INR becomes subtherapeutic. despite a subtherapeutic aPTT. For patients who require heparin doses
Postprocedural bridging therapy should be undertaken only in patients of greater than 35,000 U/day to increase the aPTT into the therapeutic
in whom the risks of this therapy (principally bleeding) are less than the range, consideration should be given to using heparin levels determined
perceived benefits (a reduced risk of thromboembolism). by an anti-Xa assay. Substitution of LMWH for unfractionated heparin
is another consideration. Although AT deficiency may cause heparin
HEPARIN resistance, most AT-deficient patients can be adequately anticoagulated
with heparin in usual doses. No monitoring is recommended when low
PHARMACOLOGY doses of heparin are used for prophylaxis of venous thromboembolic
Heparin (and the related LMWHs) is the most widely used, rapidly disease, although minimal prolongation of the aPTT may occur. Care
acting, parenteral anticoagulant. Heparin is a heterogeneous mixture is required in very light weight and frail elderly who may be anticoagu-
of sulfated glycosaminoglycan molecules with varying chain lengths lated with usual “prophylactic” doses of unfractionated heparin; aPTT
(molecular mass [Mr] 5000 to 30,000 daltons). Heparin has no direct monitoring might be considered in such patients.
anticoagulant effect, but serves to activate plasma antithrombin (AT), A large study demonstrated that patients with acute venous throm-
a serine protease inhibitor. Only about one-third of heparin molecules boembolism can be safely treated with fixed, weight-adjusted heparin
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contain the necessary unique pentasaccharide sequence required to doses without aPTT monitoring. In this study, 708 patients were allo-
interact with AT and thus display anticoagulant activity. AT inhibits cated randomly to receive either unfractionated heparin with a subcu-
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thrombin, factor Xa, and other coagulation serine proteases in a reaction taneous bolus dose of 333 U/kg followed by a twice-daily dose of 250
that is slow by itself, but is accelerated approximately 1000-fold in the U/kg, or LMWH over 3 months of follow up. Recurrent venous throm-
presence of heparin. To inhibit thrombin, heparin binds to both the boembolism occurred in 13 patients who were allocated to unfraction-
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active enzyme and AT, forming a ternary complex. The inhibition of ated heparin and in 12 who were allocated to LMWH. Major bleeding
factor Xa, however, occurs through binding to heparin–AT complex occurred in four and five patients, respectively. This study calls into
without the requirement for heparin binding directly also to factor Xa. question the need for routine aPTT monitoring of therapeutic dose,
The requirement for a ternary heparin–AT–thrombin complex requires weight-adjusted unfractionated heparin and warrants validation.
heparin molecules with 19 or more saccharide units, whereas smaller
heparin molecules are effective in promoting factor Xa inactivation. REVERSAL
Thrombin and factor Xa are relatively protected from inhibition by
the heparin–AT complex when they are surface immobilized within Heparin has a short half-life, and its anticoagulant effect disappears sev-
thrombi or on cells. 52 eral hours after discontinuation of an intravenous infusion. Therefore,
stopping the infusion and local measures are usually adequate to control
bleeding. However, in major or life-threatening bleeding, the anticoag-
ADMINISTRATION AND MONITORING ulant effect can be neutralized with protamine sulfate, which is a basic
Heparin is not absorbed after oral ingestion, so must be given either polypeptide that binds tightly to the acidic heparin molecule. The usual
subcutaneously or intravenously. The pharmacokinetics of unfraction- dose of protamine required is 1 mg to neutralize 100 units of heparin.
ated heparin is complex, a result of extensive protein binding, with a The dose to be administered is based on the amount of heparin remain-
dose-dependent half-life in the range of 1 to 2.5 hours. A common ing in the circulation. Protamine is routinely used to neutralize heparin
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protocol uses an initial intravenous bolus of 5000 units or 75 U/kg, fol- after cardiopulmonary bypass using standard formulas and activated
lowed by a maintenance infusion of 1250 to 1660 U/h or 18 U/kg per clotting time monitoring.
hour. The anticoagulant effect is immediate, but laboratory monitoring
is needed because of the variability in response among patients. Mon-
itoring is most convenient with the activated partial thromboplastin ADVERSE EFFECTS
time (aPTT), which is sensitive to plasma heparin concentrations of 0.1 The most frequent complication of heparin administration is bleeding,
U/mL or higher. Because different reagents and measuring systems have which is related to the dose and intensity of treatment, as well as to
differing sensitivities to heparin, it is recommended that the therapeu- patient characteristics. HIT is an immune-mediated platelet consump-
tic range be established for each laboratory by calibrating the aPTT to tion caused by an antibody directed against a complex of heparin and
a plasma heparin concentration of 0.2 to 0.4 units by protamine sul- platelet factor 4 (Chap. 118). Despite thrombocytopenia, HIT is more
fate titration, or 0.3 to 0.7 U/mL using an anti–factor Xa assay. The commonly associated with thrombotic complications than bleeding,
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usual aPTT range for heparin therapy is between 1.5 and 2.5 times the and it occurs in approximately 3 percent of patients, depending on the

Kaushansky_chapter 25_p0393-0408.indd 397 9/19/15 12:19 AM