THERAPEUTIC

Pharmacodynamics, and Adverse

REVIEW

Clinical Indications, Effects of Heparin D. Freedman,

Michael

MD,

FCP

are a heterogenous group of naturally occurring glycosaminoglycans characterized by anticoagulant activity and a wide range of molecular weights (low molecular weight or fractionated heparins evolving within the past two decades). Cofactors for endogenous inhibitors of coagulation (antithrombin III and heparin cofactor II), heparin Heparins

administration results in a hypocoagulable state. Various platelet activities, including inhibition of activity induced by platelet-derived growth factors on vascular smooth muscle,

also

have

include

been

noted.

a role in atherosclerosis

peripheral circulation (i.e., farction therapy. Established eases, unstable angina, and

The

related

antithrombotic

potential

to extracorporeal

Divorced of anticoagulant prevention, acceleration angiogenesis), indications thrombosis

of the

circulatory

nature, novel of collateral

and continued include treatment chemoprophylaxis

heparins

assistance

applications may coronary as well as

(chronic) post-myocardial inof various thrombotic disin medical/surgical patients. in thrombosis management

is used also or dialysis devices.

Heparin’s

therapeutic

potential in the postphlebitic syndrome as well as in acute treatment of myocardial infarction (primarily and adjunctively with various thrombolytic agents) continues to undergo evaluation; however, early data review shows favorable trends for its inclusion in situations that favor thrombus generation (e.g., anterior myocardial infarction). Although associated with thrombocytopenia or hypertransaminasemia, the heparins are relatively well tolerated. In a small subset of patients, a severe thrombocytopenia may ensue, which generally resolves on medication withdrawal. As this class of glycosaminoglycans becomes better characterized, new indications may emerge for both native and the newer fractionated heparins.

D iscovered

and purified by J. McLean in 1917, heparm was originally distinguished by its ability to inhibit canine blood from clotting for 24 hours (at 0#{176}C).1’2 In 1918, Howell and Holt3 described the anticoagulating moiety (molecule) in more detail and, because of its abundance in the liver, labeled it hepanfl. Heparin preparations obtained from either porcine or beef sources have been used clinically for more than half a century for prevention and treatment of thrombo-occiusive and embolic disease.7 Development of several new modalities of venous thrombosis chemoprophylaxis (including “low molecular weight heparins” [LMWHs] and “low-dose” native heparins both with and without dihydroergotamine), coincident with a renewed interest in prevention of venous thrombosis in high-risk surgical and medical populations,#{176} have reawakened interest in these molecules. From

the

New York. bie Lane,

584

Department Address

of Medicine, for reprints:

Cross River,

NY

C J Clin Pharmacol

New Michael

York

Medical

D. Freedman,

10518.

1992;32:584-596

College, MD,

Valhalla, FCP,

Deb

In addition to their role as anticoagulants, non-anticoagulant actions of the heparin glycosaminoglycans (GAGs) include regulation of angiogenesis,’1 lipoprotein lipase modulation (plasma clearing effect),12’13 maintenance of endothelial wall competence, and inhibition of vascular smooth muscle proliferation (antiproliferative effect) after endothelial injury.14”5 With special reference to this last property, and of particular public health interest, has been an association frequently made between hepanfl administration and a beneficial effect on the evolution of atherosclerosis.8

CHEMISTRY OF THE GLYCOSAMINOGLYCANS

HEPARIN

The ubiquitous metachromatically staining mast cell has long been recognized as one source of endogenous heparin’9 (along with varying but lesser amounts of heparin sulfate, dermatan sulfate, and chondroitin sulfate, other highly sulfated GAGs).

HEPARIN,

PHARMACODYNAMICS,

Tissues rich in mast cells (e.g., lung, intestine) become those from which commercial hepanin is extracted. Hepanin also may be found in other hematopoietically derived cells, such as basophils (where the principal GAGs are dermatan or chondroitin sulfate).20 Hepanin GAGs also are produced in lesser quantity by various other cell lines, including vascular endothelium. Characterized by elongated polysulfated GAG polymers (formerly referred to as mucopolysacchanides), these lengthy molecules are conspicuous in terms of alternating sulfoaminoglucosamine and uronic acid units (glucunonic or iduronic), the occurrence of small amounts of N-acetylglucosamine (or unsubstituted glucosamine), and the presence (in varying quantities) of a unique pentasacchanide sequence found to be necessary for antithrombin III (ATIII) binding (Figure 1). With a mean molecular weight of about 15,000 Da (range, 1,800-30,000 Da), hepanins are remarkably heterogenous in both size and structure.21’22 Only a portion of the hepanin used clinically has high ATIII affinity, thus exhibiting very high anticoagulant activity. These high ATIII affinity-high anticoagulant activity molecules are characterized by a molecular weight of 1800 to 5500 Da23’24 and constitute less than 5% of native heparin (by mass). Referred to as “low molecular weight polymers” or “fractions,” they may be obtained by separation from the larger molecules by gel filtration or ATIII affinity column chromatography. Both methods effectively “filter” or “screen out” higher molecular weight molecules. More efficient methods of LMWH production involve modification of the entire molecular weight spectra of the native molecules by various chemical or enzymatic agents.25

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Figure

1. AT-Ill

THERAPEUTIC

binding

REVIEW

pentasacchonide.

CLINICAL

INDICATIONS

PREXALUKREINTISSUE

FACTOR HEFARIN-Alill XII -XIIA XI

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-

PIXA

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2. Heparin

ii, ENOOTHELIUM

.

PT

I

THROMBIN II

“.

NUSCIC

actions.

Impurities found in chemically or enzymatically modified hepanin preparations, include dermatan sulfate,26’27 which is of course capable itself of (effective) antithrombotic activity,28 although possibly being less hemorrhagic than equally antithrombotic doses of hepanin.29’3#{176} Ethylenediaminetetra-acetic acid also has been found in some heparin and LMWH formulations,31 although to a much lesser degree, and is additionally capable of perturbing hemostasis. Finally, the presence of nitrosamines (potent carcinogens) remains more than a theoretical possibility in some low molecular weight fractions. PHARMACOLOGY

AND

PHARMACODYNAMICS

Heparin interacts with plasma serine protease inhibitors ATIII and heparin cof actor II (or dermatan cofacton). Binding to aminolysyl residues in ATIII, heparin is believed to cause a conformational change in this enzyme, resulting in a multi-fold increase in its inhibitory effects. Once formed, the hepanin-ATIIIserine protease complex rapidly disassociates into an inactive ATIII-serine protease complex, and the heparm molecule itself, which then will bind another ATIII complex. Inhibition of activated coagulation factors IX, X, XI, XII, and Kallikrein by the hepaninATIII complex has been reported (Figure 2).3233 The hepanin-HC II complex, however, appears to react only to inhibit formation of thrombin.34 Heparins also have been reported to have high affinity to platelet factor 4, effectively competing with ATIII for heparin binding.35 To the extent that most of the hepanins can cause inhibition of platelet aggregation to some degree, as well as inhibition of the effects of platelet-derived growth factors on vascular smooth muscle, these agents are properly considered “platelet active anticoagulants.”3’8 Finally, the hep-

585

FREEDMAN

arms specifically bind to vascular endothelium,39 causing the release of at least two distinct GAGs (chondroitin sulfate being one) while altering the permeability of the vessel wall.40’41 Prolonged heparin administration has been associated with development of osteopenia. Interestingly, this property appears to have a molecular weight dependence, because LMWHs have been shown to be less “osteopenic” than endogenous* heparms.42 This “calcium-sparing” feature may be of some consequence in the patient requiring longterm administration of this type of anticoagulant (e.g., pregnancy, cardiac valve replacement, chronic venous thrombosis prophylaxis, etc.).43 The exact nature of heparin-induced bone loss has not as yet been adequately elucidated. Heparin pharmacokinetics have largely been determined using surrogate or biologic markers of activity. Most widely used has been the activated partial thromboplastin time (APTT), whole blood clotting time, or activated clotting time.45 Novel methods include determination of anti-factor Xa using either clotting or amidiolytic assays. Experimental methods include ATIII labeling and radiolabeled heparin. Because large interpatient variability to the effects of heparin has been noted, individualized therapy to attain a given endpoint, generally a particular APTT, is often undertaken. Systemic absorption of native hepanins is negligible after oral or nasal administration and present but erratic after aerosolized inhalation.46 Therefore, hepanins have generally been administered subcutaneously or intravenously. They do not cross the placental barrier and hence are the drugs of choice for pregnant patients requiring anticoagulation.479 After single injection of (unfractionated) native hepanin, half-life (t1/2) is dose dependent, the volume of distribution remaining constant with decreasing total Cl as dose is increased. At any particular dose, it appears that the LMWHs have a more lengthy halflife (t#{189} 2 3 X native heparin) than their parent molecules. Elimination kinetics (determined by anti-factor Xa or APTT determinations) appear to be principally mediated by a nonsaturable mechanisms. Concordant with this, elimination half-life is increased in patients with kidney disease,50’51 strongly suggestive of a major renal component to clearance.

activity and those secondary to nonanticoagulant tivity as well. The latter category probably sents the majority of applications. Venous

Thrombosis

acrepre-

Prophylaxis

Factors predisposing to the development of venous thrombosis include disorders associated with or leading to venous stasis, hypercoagulability, or venous trauma (Figure 3).5253 Although the majority of venous thrombosis prevention trials have been carried out in the postorthopedic or abdominal surgery patient population (a commonly encountered high-risk group), there are several studies involving other high-risk groups, e.g., postneurosurgery, postcranial trauma, post major trauma, thermal burn, congestive heart failure, acute myocardial infarction (MI; considered separately, see below), and other medically related conditions requiring prolonged immobility. The rate of deep venous thrombosis (DVT) formation after general surgical procedures may be as high as 28%, whereas the rate after open prostatectomy or hip fracture is as high as 5Q%54.55 Consequently, rates of fatal pulmonary embolism in this patient population may be as great as 2%.56 When compared with placebo or physical methods alone, a preponderance of data has demonstrated superiority of heparm (either low dose or “full dose”)5762 (Table I) for venous thrombosis prophylaxis. Several meta-analyses using the results of well over 100 studies have6365 suggested the same. Augmentation with dihydroergotamine (DHE) (a potent vasoconstrictor) has recently undergone clinical evaluation. A meta-analysis examining results

ASNO

ALITIES MAJOC

OF

51.000

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N IN CONSTITUENTS

OF

nypeav,aooar,y

CLINICAL into *

those

that

Endogenous

describe

586

applications

ESTIIOSEN

C

of the hepanins

are primarily

SUEMCES

eLoo

related

or native are used synonymously

nonfractionated

heparins.

J Clin Pharmacol

1992;32:584-596

can be divided

E,ASETES

ASEARA!

SaTES

ION

OF

SLOOP

PAERPERIUM OBESITY

THeRAPY

NYPERCOASULASLE

Clinical

SYNDROMe

ARTIFICIAL

MALISNASCY

APPLICATIONS

TIISOIISOHMSOLISM

NEPIIROTIC

MRLLIYUS

SaTE

PROLOSSER

SERPENT

PROLOSSED

IMMOPILIZATION

CONJESTIVE

HEART

RCLURI

to anticoagulant in this article

to Figure

3. Predisposing

factors

for thrombosis

development.

LOW

HEPARIN,

PHARMACODYNAMICS,

CLINICAL

INDICATIONS

TABLE I

Prevention of Thrombosis in Medical/Surgical

Patients: Selected Studies DVI

Reference

Indication

Rosenberg et al.

s/p Major surgery

Nicolaides et al.

s/p Emergency admission to ROMI s/p Major surgery

Gordon-Smith et al. Belch

Kakkar

et al.

CHF/COPD Medical patients s/p Major surgery

et al.

Group

Patient Number (n)

Randomized Prospective

Heparin 50001U q8hr X 18 Leg stim.3 Control Ml with heparin4 Ml without heparin NoMI Controls Heparin 5000IU ql2hr X 3 Heparin 50001U ql2hr X 10 Controls Heparin 50001U q8hr

(55) (50) (89) (18) (13) (20) (50) (52) (48) (50) (50)

7.3 24 23.6 5.5 38 20 42 13.5k 8.3** 26 4*

Randomized Double blinded

Heparin 50001U SC 2hr prior to surgery then; 50001U ql2hr

(39)

8***

Study

Randomized Prospective Prospective Randomized Prospective Randomized Prospective

Control

Handley

A.

s/p Admission to ROMI

Prospective Randomized

#{149} P < 0.003 compared with controls, * * P