ChemInform Abstract: Recent Advances in the Treatment of Thromboembolic Diseases: Venous...

Recent Advances in theTreatmentof Thromboembolic Diseases:VenousThromboembolism

Y.K. Agrawal,1 Hitesh Vaidya,1 Hardik Bhatt,1 Kuntal Manna,1

Pathik Brahmkshatriya2

1Institute of Pharmacy, Nirma University of Science and Technology,

Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India2Department of Medicinal Chemistry, L.M. College of Pharmacy,

Navrangpura, Ahmedabad 380009, Gujarat, India

Published online 22 February 2007 in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/med.20100

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Abstract: Venous thromboembolic diseases are the major concern of rising cost of healthcare and

are commonest health problem across the globe. Both genetic and acquired risk factors are believed

to be strongly linked with these diseases. Commonly encountered problems to the therapy include

dose fixing and routine monitoring, yet some serious problems of bleeding also necessitate the

immediate need to develop new agents. The review is primarily concerned with the new

developments in the treatment of thromboembolic diseases. Therapeutic applications of

anticoagulants, antiplatelets, and thrombolytics have been discussed in enough detail.

� 2007 Wiley Periodicals, Inc. Med Res Rev, 27, No. 6, 891–914, 2007

Key words: venous thromboembolic; antiplatelets; thrombolytics; pharmacoeconomics

1 . I N T R O D U C T I O N

Thromboembolic diseases, such as deep vein thrombosis (DVT), pulmonary embolism (PE),

myocardial infraction (MI), and thromboembolic stroke are the leading causes of mortality and

morbidity in many of developing and developed countries.1 Venous thromboemolism (VTE) is

potential fatal disorder and a significant national health problemworldwide.2–4 VTE ismanifested as

deep vein thrombosis and pulmonary embolism. The treatment of VTE is fraught with substantial

risk.5 Antithrombotic drugs require precise dosing and meticulous monitoring.6–9 In past decade,

most of the research has been carried out focusing development of novel antithrombotic agents

Correspondence to:Prof.Y.K. Agrawal, Instituteof Pharmacy,NirmaUniversityof ScienceandTechnology,Sarkhej-Gandhinagar

Highway, Ahmedabad 382481,Gujarat, India.E-mail: [email protected]

Medicinal Research Reviews, Vol. 27, No. 6, 891^914, 2007

� 2007 Wiley Periodicals, Inc.

among which thrombin inhibitors,10 inhibitors of factor Xa, fibrinogen receptor antagonists and GP

IIa/IIIb antagonists11 have drawn most of the attention.

Venous thrombosis is the thirdmost common cardiovascular disease after ischemic heart disease

and stroke. It is common in whites, affecting 1 in 1,000 individuals every year, and is strongly

associatedwith life-threatening pulmonary embolism. In addition to circumstantial predisposing risk

factors like surgery, pregnancy or immobilization; genetic abnormalities, molecular abnormalities of

components of the coagulation pathway leading to hypercoagulability, and in turn, to thrombophilia

have also been found in subjects who have had thromboembolic diseases.

2 . R I S K F A C T O R S F O R T H R O M B O E M B O L I C D I S E A S E S

The effect of risk factor in adults are additive, the greater the number of high-risk factors the greater

the risk of thromboembolic diseases. In the late 1800s, Dr Rudolf Virchow, a German pathologist,

recognized the role played by blood vessels, circulating elements in the blood, and the speed of the

blood flow in regulation of clot formation.12 Numerous risk factors for such alterations and thus, VTE

have been identified.Mechanisms that predispose individuals to thromboembolism aremany and can

be divided into two major categories: those because of a genetically inherited mutation of a gene(s)

involved in coagulation and those that are acquired as a direct or indirect result of trauma, systemic

illness (acute or chronic), or an altered physiologic state.

3 . G E N E T I C A L L Y I N H E R I T E D / H Y P E R C O A G U L A B L E S T A T E S

The earliest discoveries of genetic defects linked to venous thrombosis were the abnormalities of the

genes encoding for antithrombin III, protein C, and protein S.13–15

A. Factor V Leiden

This genetically inherited mutation was discovered in 1993 as a result of the studies done in Sweden

on patients with thromboembolic diseasewho characteristically had a poor anticoagulant response to

activated protein C. More recently, resistance to activated Protein C has been identified as the most

frequent risk factor for venous thrombosis, occurring in approximately 3%–5% of the general

population and in over 20% of patients with a history of venous thrombosis.16 This defect was first

recognized when activated Protein C failed to cleave the coagulation factors Va or VIIIa. Subsequent

genetic analysis demonstrated a unique single point mutation in the gene for factor V. This gene

mutation produces a factor Vmoleculewith glutamine instead of arginine at position 506 of its amino

acid sequence. Under normal conditions, this is the main point of factor Va cleavage by activated

Protein C. Glutamine makes this cleavage site inaccessible, leading to resistance to activated Protein

C. This mutation is commonly referred to as Factor V Leiden, named after the city in the Netherlands

where this mutation was first identified. Factor V leiden is currently recognized as the most common

genetic defect associated with thrombophilia.17 Its prevalence appears to be higher in Caucasians,

found in 4.4% in the general population of Northern Europe and 3% in North America, and is less

common in African Americans.18–20

B. Prothrombin Gene 20210G/A Mutation

In 1996, Poort et al. reported a gene mutation associated with elevated levels of plasma

prothrombin.21 The mutation occurs at the 20210 position in the 3 0 untranslated region of the

prothrombin gene where glutamine is substituted for arginine. This mutation is currently recognized

892 * AGRAWAL ET AL.

as the second most common genetic abnormality associated with an increased risk of

thromboembolism.21 Surprisingly, individuals having this mutation were also positive for factor V

leiden.21 The presence of both factor V leiden and prothrombin 20210G/Amutation further increases

the risk of thromboembolism.22,23

C. Hyperhomocysteinemia

Elevated levels of homocysteine in plasma (>15mmol/L) have been found to be an independent risk

factor for vascular disease and linked to early occurrence of atherosclerosis, and should be suspected

in patients with coronary artery disease, carotid atherosclerosis, and stroke occurring at a young age.

However, thrombosis can occur on the venous side of systemic circulation, as well as the arterial.

Hyperhomocysteinemia can be due to either a mutation of the gene that encodes for

methylenetetrahydrofolate reductase or acquired as a result of poor nutrition.24–26 Several

mechanisms have been proposed for the thrombophilic state induced by the elevated plasma levels

of homocysteine. Oxidative damage to the endothelium that results in inhibition of thrombomodulin

on the surface membrane which, in turn, decreases protein C activation and increases the activity of

factors Vand XII.27 Increasing folic acid intake alone, as well as combining folic acid with vitamin

B12 or vitamin B6, will promptly lower the plasma homocysteine level in both the genetically

inherited and the acquired forms of the deficiency.27

4 . A C Q U I R E D C A U S E S O F T H R O M B O E M B O L I S M

A. Lupus Anticoagulants and Antiphospholipid Antibody Syndrome (LA/APS)

Lupus anticoagulants and antiphosholipid antibody syndrome (LA/APS) has been associated with

both arterial and venous thrombosis. Patients, with positive LA/APS, are at higher risk of recurrent

VTE.28,29 It was found that among patients with LA/APS, approximately 20% of patients suffered

with recurrent VTE and 10% of patients had first ischemic stroke.30–32 LA/APS represents a plasma

inhibitor and its prevalence in the general population is not known. This inhibitor is usually an IgG

antibody that targets the phospholipid substrate of the prothrombin complex portion of the clotting

mechanism. It is difficult to evaluate increase of thromboembolismwith this prothrombin factor. LA/

APS can occur in patients of all ages.

B. Pregnancy

Pregnancy has been associated with fourfold increase in VTE; the majority occurring during the

second and third trimesters, and an even higher risk is reported during the immediate postpartum or

puerperal period.33–35 The increased venous stasis of pregnancy is the most constant predisposing

factor. Physiological changes associated with pregnancy result in an increase in venous distensibility

and capacity. These changes are evident from the first trimester.36,37 Several independent factors have

also been shown to be associated with an increased risk of thromboembolic diseases. These include

prolonged bed rest during pregnancy or the puerperium, instrument assisted or cesarean delivery,

hemorrhage, sepsis, multiparity, and advancematernal age.38 Pregnancy is also associated with mark

alteration in the protein of coagulation and fibrinolytic system. The level of coagulation factor II, VII,

and X increases substantially by the middle of pregnancy.39,40 Generation of fibrin also increases

markedly,41–43 level of protein S appear to decrease throughout pregnancy although level of proteinC

remains normal.42,44 The increased risk has long been attributed to the elevated levels of certain

procoagulants during the later stages of pregnancy, which results in heightened state of the clotting

system prone to activation by subtle triggering mechanisms often related to the altered physiologic

state.45,46

VENOUS THROMBOEMBOLISM * 893

C. Oral Contraceptive and Hormone Replacement Therapy

It was reported as early as in 1967 and recently in 1990, that oral contraceptive users had three- to

sixfold increased risk of venous thromboembolism compared to nonusers.47–51 The use of

postmenopausal hormone substitution has become widespread in recent decades.52 Besides

relief from menopausal complaints, hormone replacement is prescribed to reduce the progression

of osteoporosis and the development of cardiovascular disease. In an early study of adverse effects of

estrogen replacement therapy, an increase risk of venous thrombosis was observed.53 This was not

confirmed in subsequent studies,54–56 and the idea that estrogen replacement could cause venous

thrombosis was dismissed as ‘‘medical superstition.’’57 However, from 1996 onward, a series of

studies has demonstrated that hormone replacement users have a two- to fourfold increased risk of

venous thrombosis.58–66

Estrogens increase the risk of venous thrombosis when used as oral contraceptives or as

postmenopausal hormone replacement.67–69 A similar effect was observed in men when estrogens

were used as a treatment of coronary disease70 or in sex-change treatment.71 Recently, it has been

demonstrated that the progestin in combination with oral contraceptives also increased the risk of

thrombosis.72–74

Estrogens havemanydifferent effects on the coagulation system.75–79 These include increases in

the levels of procoagulant factors VII, X, XII, and XIII and reductions in the anticoagulant factors

protein S and antithrombin. These changes predict a change toward amore procoagulant state (which

is confirmed in studies examining global tests, such as APC resistance or thrombin generation),80–84

which is not counter balanced by an increased fibrinolytic activity.85

D. Malignancy

It has been well established that malignancies are associated with an increased incidence of VTE and

are a common complication of advanced stage cancers, perhaps because of the procoagulant

substances elaborated by the tumor.86,87 Although the risks vary with the different types of cancer,

higher risks have been found in a variety of adenocarcinomas, for example, pancreatic, ovarian and

breast, as well as tumors of the brain.86–88 Hematologic malignancies, especially myeloproliferative

diseases, are frequently complicated by VTEs occurring in the large visceral vessels like mesenteric,

portal, and hepatic veins, as well as the deep veins of the lower extremities.

E. Infectious and Inflammatory Diseases

The clinical setting of acute and chronic infection, as well as chronic inflammatory diseases, have

been associated with some degree of endothelial cell damage resulting from a complex network of

inflammatory mediator substances and cytokines such as interleukins, C-reactive protein, tumor

necrosis factor-a, and endotoxins capable of activating the clotting mechanism, inducing a

hypercoagulable state.89–91 In addition, levels of certain clotting factors such as factor VIII and

fibrinogen are believed to increase the risk of DVT, as well as auto-antibodies, are reported to be

elevated in rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease.92–94

F. Surgery

Surgical intervention, whether elective or emergent, has been associated with an increased risk of

VTE. This risk is especially high during the first 2 weeks following surgery, but has been reported as

late as 5weeks postsurgery.95,96 Orthopedic and neurosurgical procedures have the highest incidence

of VTE and pulmonary emboli, and although these risks have been mitigated to a significant degree

by the routine use of prophylactic anticoagulants, the risk remains high, with a DVT incidence of

20%–30% in patients undergoing hip or knee replacement surgery.97–100 Additionally, reports of


fatal pulmonary emboli have been reported in 3%–6% of patients following hip replacement surgery

and 13% of those with traumatic hip fractures.101 The risk of VTE in neurosurgical patients remains

high and has been reported as occurring in 20%–50% of patients not receiving prophylactic

anticoagulant therapy and 1.5%–5% incidence of fatal pulmonary emboli, providing a compelling

need for thromboprophylaxis.102–105 The risk will be even higher in these patients with a concurrent

illness, malignancy, or predisposing geneticmutation in the patient. Another high-risk group forVTE

are those patients who have sustained major trauma, with an incidence of 50%–60% being reported

with traumatic fractures and head injuries.106,107 In the UK, the reports of the Thromboembolic Risk

Factors (THRIFT) Consensus Group108 and the Scottish Intercollegiate Guidelines Network Group

(SIGN)109 have recommended that pharmacological prophylactic regimens be used routinely after

major orthopedic procedures in the lower limb because surgical procedures, particularly on the lower

limb, predispose to both venous thromboembolism and wound complications.

G. Heparin-Induced Thrombocytopenia (HIT)

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by the immune

system with clinical manifestations triggered by antibodies directed against platelet factor IV. This

becomes an antigenic target when bound to heparin. This antibody-platelet factor IV–heparin

complex is able to activate platelets and may cause venous and arterial thrombosis. Although the

immediate discontinuation of heparin ismandatory in this condition, the strategy is insufficient, given

the high-cumulative risk of thrombosis during 30-day administration of the drug up to 53% without

antithrombotic treatment.91 Thus, for patients with suspected or confirmedHIT, the use of alternative

anticoagulants is recommended.91 The use of direct thrombin inhibitors (DTIs) for this condition is

theoretically supported by the intense thrombin activity observed in these patients.110–113

5 . T R E A T M E N T G O A L S

Therapy is directed toward management of concomitant congestive heart failure (CHF) or serious

arrhythmias when present; general patient support, including nutritional supplementation, and

correction of hypothermia; adjunctive therapies to limit thrombus growth or formation; close patient

monitoring for limb viability, heart rate and rhythm, progression or regression of CHF, creatinine and

electrolyte levels and appetite; and prevention of repeated events.

6 . T R E A T M E N T O F T H R O M B O E M B O L I S M

The treatment of venous thromboembolism has rapidly changed over the last decades. The standard

therapy, intravenous anticoagulation with unfractionated heparin, was first introduced as primary

treatment of pulmonary embolism in 1960.10 Most commonly used drug classes include:

Anticoagulan/Antithrombin therapy, Antiplatelet therapy, Thrombolytic therapy.

7 . A N T I C O A G U L A N T S / A N T I T H R O M B I N T H E R A P Y

Anticoagulants/antithrombin therapy can be either direct or indirect thrombin inhibitors. Direct

thrombin inhibitors are those inhibiting thrombin itself, while indirect inhibitors inhibit formation of

thrombin (Fig. 1). Both classes of drugs are very potent and specific to the target.


A. Unfractionated Heparin

Since 1930s, clinicians have used unfractionated heparin (UFH) (1) for the prevention and treatment

of thrombosis.8,113 McLean discovered UFH in 1916, when he found that extract of dog liver was an

inhibitor of heparin co-factor to produce anti-coagulant effect.114While it has been known since 1939

that UFH requires a ‘heparin cofactor’ to produce an anticoagulant effect, it was not until 1968 that

antithrombin (previously known as antithrombin-III) was identified and isolated.10 Soon thereafter, it

was recognize that UFH greatly accelerates the activity of antithrombin.

Figure 1. Sites ofactionofanticoagulants.


The anticoagulant effect of UFH is mediated through a specific pentasaccharide sequence of the

heparin molecule that binds to antithrombin, provoking conformational changes.8,113 The UFH-

antithrombin complex is 100–1,000 timesmore potent as an anticoagulant compared to antithrombin

alone.10 Antithrombin inhibits factor IXa, Xa, XIIa, and thrombin(IIa). The UFH–antithrombin

complex also inhibits thrombin-induced activation of factorVandVIII. Factor IIa andXa are themost

sensitive to inhibition by the UFH–antithrombin complex. To inactivate thrombin, heparin molecule

must form a ternary complex as a bridge between antithrombin and thrombin,8 which requires

minimum 18 saccharide units and thus smaller heparin molecules cannot facilitate the interaction

between antithrombin and thrombin.

Major drawbacks of UFH involve bleeding115,116 and poor absorption of UFH because of its

large molecular size and anionic structure.8 Hirsh et al.117 described the hemorrhagic risk of heparin

therapy in 100 consecutive patients treated with continuous IV heparin, which was adjusted

according to the results of the whole blood clotting time. Four patients had major hemorrhagic

episodes, and in three, the results ofwhole blood clotting timewere prolonged considerably above the

upper limit of the targeted therapeutic range (three times control). Recently, a lipophilic vehicle

sodiumN-(8-(2-hydroxy benzoyl)) amino caprylate has been developedwhich facilitated absorption

of UFH.112

Propensity of UHF to bind with plasma proteins, platelets factor-IV, macrophages, and

endothelial cells limits the bioavailability and biologic activity.8,113,118 Patients with active

thrombosis have rapid changes in the circulating levels of heparin-binding proteins and often appear

to have heparin resistance and hence require high dose of UHF to achieve therapeutic response.8,119

Thrombocytopenia, defined as platelets count lesser than 150,000, is common with UFH

therapy.120–123 Heparin use commonly leads to mild reductions in the level of circulating

antithrombin III and rarely has been reported to induce disseminated thrombosis.124 Long-term high-

dose (4 months at 15,000 U or more) heparin administration can lead to severe osteopenia.125–129

In the rare patient with hypoaldosteronism, heparin may induce hyperkalemia.130

B. Low-Molecular-Weight Heparin (LMWH)

In recent years, low-molecular-weight fractions of commercial heparin have been prepared by either

enzymatic or chemical depolymerization. They are believed to be fragments of UFH,8,118,131 that

have a mean molecular weight of 4,000–5,000 d in contrast to unfractionated heparin, which has a

mean molecular weight of 15,000 d.132,133 Low-molecular-weight heparin (LMWHs) are

heterogeneousmixtures of sulfated glycosaminoglycans. LMWHs are resembled in their mechanism

of action with UFH, and they have excellent bioavailabity, together with a longer plasma half-

life.134–139 These agents have advantages over UFHwhich includes: predictable anticoagulant dose:

improved subcutaneous bioavailability; dose-independence clearance; longer biological half life;

lower incidence of thrombocytopenia; and a reduced need for routine laboratory monitoring.131

Currently, there are three LMWH products available in the US market: dalteparin, enoxaprin,

and tinzaprin. They prevent the growth and propagation of formed thombi.8,131,140,141 Like UFH, the

LMWHs enhance and accelerate the activity of antithrombin by binding to a specific pentasaccharide

sequence. The principle difference in pharmacological activity of LMWHs and UFH is their relative

inhibition of factor Xa and thrombin (IIa). LMWHs have requisite chain length to simultaneously


bind antithrombin and thrombin. For these reasons, LMWHs have proportionally greater anti-factor

Xa activity. Studies in experimental animal models of venous thrombosis have shown that some low-

molecular-weight fractions have equal (or greater) antithrombotic efficacy, but less hemorrhagic

effects, in comparison to heparin (UFH).132,133,142–145 Currently a clinical study have been carried

out between heparin (UFH) and LMWHs and with venographically proven proximal deep vein

thrombosis; group of 85 patients received standard heparin (to achieve an activated partial

thromboplastin time of 1.5–2.0 times the pretreatment value) and 85 patients received LMWH

(adjusted only for body weight) for 10 days. Oral coumarin therapy was started on day 7 and

continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed

objectively did not differ significantly between the standard heparin and LMWH groups. Clinically

important bleeding was infrequent in both groups.146

C. Heparinoids

Currently, danaparoid sodium is themost frequently prescribe heparinoid. Chemically, it is amixture

of three sulfated glycosaminoglycans: heparan (84%), dermatan (12%), and chondroitin (4%). It is

derived from the porcine gut mucosa. Danaparoid binds to antithrombin and heparin cofactor II and

greatly accelerates their activity.97 It inhibits factor Xa and to a lesser extent thrombin. Randomized

trials have demonstrated that danaparoid sodium is effective and safe for prevention of postoperative

venous thromboembolism in patients undergoing general or orthopaedic surgery.147 and 148 However,

because it is substantially more expensive than other LMWheparin preparations, danaparoid sodium

is rarely used for this indication. Currently, danaparoid sodium is used mainly to treat immune

heparin-induced thrombocytopenia and for prevention and treatment of venous thromboembolism or

arterial thrombosis in patients with a past history of immune heparin-induced thrombocytopenia149

Bleeding is the most common side effect associated with its use.150,151

D. Factor Xa Inhibitors

Anumber of direct and indirect factor Xa inhibitors are currently under development.152Direct factor

Xa inhibitors thwart thrombin generation by binding directly to circulating or clot-bound factor Xa.

They are not dependent on antithrombin to produce their antithrombic effects. Some natural direct

factor Xa inhibitors such as tick anticoagulation peptide (TAP), antistasin, and lefaxin from leeches

are also under investigation.

Similar to UFH and LMWHs, the indirect factor Xa inhibitors bind to antithrombin, greatly

accelerating their activity.152,153 UFH and LMWHs possess varying proportions of factor Xa and

factor IIa inhibitory activity. Understanding of the structure activity relationship of heparin resulted

in the development of the synthetic pentasaccharide with only anti-Xa activity.154–156 A recently

developed synthetic analogue of UFH and LMWHs like Fondaparinux and idraparinux have high

affinity for antithrombin.156

Factor Xa inhibitors may be separated into three broad classes: (a) proteins derived from natural

sources which include TAP, antistasin, soya trypsin inhibitor, yagin, and tissue factor pathway

inhibitor and its variants; (b) synthetic peptides, peptidomimetics, and other organicmolecules (non-

heparinomimetics), which are low-molecular-weight (<1,000 Da) agents; and (c) synthetic

heparinomimetics (see Table I). The relative specificity and the mode of the inhibitory actions of

each of these agents vary.157

DX-9065a (2) [Ki ¼ 41 nM] is an inhibitor of factor Xa. Currently it is in Phase-II clinical

trials in Japan and US for the treatment of general thrombosis and unstable angina. Razaxaban (3)

DPC-906, BMS-561389 is factor Xa inhibitor in development by Bristol-Myers Sqibb for

venousthrombosis and is in phase-II trials. It is a potent, selective non-covalent inhibitor of factor Xa


(Ki, factor Xa 0.19 nM, thrombin 540 nM), with IC50 values>2 mM against all other enzymes in the

coagulation cascade.

Compared with antithrombin agents such as the recombinant hirudin, factor Xa-inhibiting agents

aremore safer andmaynot inducebleeding and a fibrinolytic deficit. In preclinical studies, the efficacy-

safety ratios with these agents were better than those of heparin and antithrombin agents.157

E. Direct Thrombin Inhibitors

Direct thrombin inhibitors stand out as a relatively new class of very potent anticoagulant agents,

include lepirudin, bivalirudine, argatroban (4), and ximelagatran (5) BIBR 953 (6). These agents are

directly interacting with the thrombin molecule and they do not require antithrombin or heparin

cofactor II to have antithrombotic activity. Moreover, they are capable of inhibiting both circulating

and clot-bonded thrombin, which distinguishes them fromUFHand the LMWHs.158Also they do not

induce immune mediated thrombocytopenia.

Table I. Classification of Factor Xa Inhibitors


Hirudin, the prototype of this class, was isolated from salivary secretion of medicinal leech.155

Bivalirudin, formally known as hirulog, is a semisynthetic polypeptide and a reversible inhibitor of

thrombin.152,159

Argatroban is a small synthetic molecule derived from arginine that reversibly binds to the

catalytic site of thrombin.160 Ximelagetran is a prodrug which gets converted by hydrolysis and

reduction in the liver to melagatran, the active moiety.152,159 Contraindication for the use of direct

thrombin inhibitors are similar to those for the other antithrombic drugs. Hemorrhage is the most

common and dreadful side effect associated with all thrombin inhibitors.120,159

F. Synthetic Analogue of UFH and LMWHs

Recently, two new parenteral agents (Fondaparinux and Idraparinux) have been evaluated in patients

with VTE. Parenteral agents with longer half-lives than heparin or LMWH have the potential to

simplify initial or extended treatment of VTE. Fondaparinux and Idraparinux are antithrombin-

dependent inhibitors of activated factor X (factor Xa), by targeting factor Xa, fondaparinux and

idraparinux block thrombin generation (Fig. 2).

Figure 2. Sites of action of fondaparinux, idraparinux. [Color figure can be viewed in the online issue, which is available at

www.interscience.wiley.com.]


G. Fondaparinux and Idraparinux

A synthetic analog of the antithrombin-binding pentasaccharide sequence found on heparin or

LMWH, fondaparinux (7) binds antithrombin with high affinity. Once bound, fondaparinux evokes

conformational changes in the reactive center loop of antithrombin that enhance its reactivity with

factor Xa.161,162 Fondaparinux is a catalytic inhibitor; thus, after promoting the formation of the

factor Xa/antithrombin complex, fondaparinux dissociates from antithrombin and is available

to activate additional antithrombin molecules. A second-generation synthetic pentasaccharide,

idraparinux (8) is more negatively charged than fondaparinux. Consequently, idraparinux binds to

antithrombin with an affinity higher than that of fondaparinux.156 Because it binds antithrombin so

tightly, idraparinux has a plasma half-life similar to that of antithrombin, 80 hr.

Fondaparinux and Idraparinux have potential advantages like Table II.

1. Rapid onset of action.

2. Fondaparinux and idraparinux exhibit almost complete bioavailability and has half life of 17 H

and 80 H, respectively, after subcutaneous administration.161–163

3. Subcutaneous fixed doses, of fondaparinux produces a predictable anticoagulant response.

4. Fondaparinux has no effect on routine tests of coagulation, such as the activated partial

thromboplastin time (APTT) or activated clotting time.164 Fondaparinux and idraparinux do not

cause HIT because they do not bind to platelets or platelet factor 4 (PF4). Thus, HIT is triggered

Table II. Comparison of Fondaparinux and Idraparinux with LMWH

LMWHindicates low-molecular-weightheparin; SC, subcutaneous; HIT,heparin-inducedthrombocytopenia.


by antibodies directed against the heparin/PF4 complex.165 Fondaparinux and idraparinux do

not bind to platelets. Therefore, they do not cause platelet activation and subsequent PF4 release.

Likewise, because these agents do not bind to PF4, they do not induce the conformational

changes in PF4 that render it antigenic. These properties endow fondaparinux and idraparinux

with a safety advantage over heparin and LMWH and may render these new agents useful for

HIT treatment.

Fondaparinuxwas developed to replace heparin or LMWH for initial treatment of VTE, whereas

idraparinux were designed to compete with vitamin K antagonists. Because of its rapid onset of

action, however, idraparinux may be useful for initial treatment of VTE, as well as for extended

therapy. Osteoporosis can occur after long-term treatment with heparin or LMWH166,167 and the risk

of this complication should be lower with fondaparinux and idraparinux because shorter heparin

chains cause less bone loss than longer chains in cell culture systems and in laboratory animal

models.168,169 Like all anticoagulants, the major side effect of these new drugs is bleeding. To

counteract this problem, a safe rapidly acting antidote is desirable. Unfortunately, none of these new

agents has an antidote.

8 . T H R O M B O L Y T I C T H E R A P Y

Thrombosis is a pathologic event that results in the obstruction of coronary, cerebral, or peripheral

blood flow.170 Thrombolytic agents dissolve thrombi by activating a zymogen, plasminogen, to the

active agent, plasmin. Plasmin, when in proximity to a thrombus or a hemostatic plug, degrades fibrin

to soluble peptides (Fig. 3).171 Circulating plasmin also degrades soluble fibrinogen and, to some

extent, several other plasma proteins. The advantages of this type of therapy include potentially rapid

resolution of acute disease and shorter recovery times. The disadvantages, which are extensive,

include risk of hemorrhage, little to no clinical data regarding efficacy or safety in domestic animals,

and potentially prohibitive costs. The two main thrombolytic drugs available are streptokinase/

urokinase and recombinant tissue plasminogen activator (see Table III).

Streptokinase is a plasminogen activator derived from b-hemolytic Streptococcus spp. It

catalyzes the conversion of plasminogen to plasmin, which is the primary protein responsible for

Figure 3. Common mechanism of thrombolytic agents. [Color figure can be viewed in the online issue, which is available at

www.interscience.wiley.com.]


fibrinolysis. Unfortunately, streptokinase is active in vivo against all circulating plasminogen, and

causes fibrinolysis systemically. This creates a risk of hemorrhage. Because it is of bacterial origin,

anaphylactic reactions are also a risk.Unlike streptokinase, urokinase directly activates conversion of

plasminogen to plasmin.10Urokinase is a protein produced endogenously by the kidney and exists in

high- and low-molecular-weight forms, both with similar clinical effects.172 Both Streptokinase and

Urokinase have similar thrombolytic effects as judged by large clinical trials in pulmonary

embolism.173,174 Using paired angiographic comparisons in each patient, resolution of thromboem-

bolus, seen with 12 or 24 hr of UK or with 24 hr of SK, was comparable at 24 hr and was

approximately three times that seen with heparin alone.173

A recombinant form of endogenous tissue plasminogen activator (TPA) was created for human

medicine to address some of the disadvantages of streptokinase, most notably its lack of clot

specificity. TPA’s mechanism of action is the same as streptokinase; it is released from vascular

endothelial cells and acts to balance coagulation with fibrinolysis in vivo. In circulation, however,

TPA is bound to an inhibitory protein, plasminogen activator inhibitor (PA-i), until it comes in contact

with a fibrin clot, at which point TPA is cleaved, becoming active. This relative fibrin specificity

allows use of TPA therapy with a significantly reduced risk of systemic hemorrhage. The extremely

short half-life of TPA in vivo (2–3 min) also reduces the risk of unintended hemorrhage. However,

this risk is still present because of residual anticoagulant effects, and may increase with higher

doses, such as those needed to break up large thrombi175 In humans, TPA is used often for cerebral,

cardiac, and pulmonary embolisms, which are typically smaller than those seen in aortic

thromboembolism. This raises the possibility of decreased clot specificity at clinically useful doses

for canine peripheral thromboembolism. Finally, TPA is extremely expensive; the cost of the drug

alone for a large-breed dog exceeds $1,000.

Beside the lack of a provenmortality effect, thrombolytic therapy ofVTE differs from therapy of

myocardial infarction in another way. In myocardial infarction, thrombolytic therapy appears to

dissolve the coronary thrombus in most cases, but in VTE, particularly PE, complete dissolution of

thrombus is the exception.176–179 Partial dissolution is the rule because venous thromboemboli are

older, larger, and more organized than coronary thrombi. Since no currently available agent or

regimen usually dissolves the VTE completely, interest has turned to smaller doses and shorter

duration of therapy in an effort to achieve the desired clinical effect with less bleeding. It is not yet

clear that these regimens will cause less bleeding, but they appear to effect comparable thrombus

resolution to regimens of longer duration.180,181 Contraindications of thrombolytic therapy are

absolute and relative (see Table IV).

9 . A N T I P L A T E L E T T H E R A P Y

Antiplatelet therapy consists of aspirin, ticlopidine hydrochloride (9), clopidogrel bisulfate (10), and

Glycoprotein (Gp) IIb/IIIa inhibitors. Figure 4 shows the sites of action of these platelet inhibitors.185

Table III. Thrombolytic Agents Approved by the Food and Drug Administration

*Recentlyapproved,PifarreandScanlon.182


Aspirin inhibits irreversibly cyclooxygenase activity irreversibly so that the platelet is not able to

make thromboxane A2.185 Four major trials have shown that aspirin decreases the risk of MI in

unstable angina. These studies consistently showed a significant decrease in risk of death and nonfatal

MI by approximately one half to two thirds in patients with unstable angina.

GpIIb/IIIa inhibitors target the GpIIb/IIIa receptor on the membrane of the platelet.182,183,185

The GpIIb/IIIa platelet receptor binds to fibrinogen, which is important in platelet aggregation and

thrombus formation. The GpIIb/IIIa inhibitors thus block fibrinogen binding to platelets and

thrombin-induced platelet aggregation.183,185 The first GpIIb/IIIa inhibitor to be studied was

abciximab, amonoclonal antibody to the platelet IIb/IIIa receptor.117,118 Eptifibatide (11) is a peptide

GpIIa/IIIb inhibitor and tirofiban (12) is a small molecule GpIIb/IIIa inhibitor.184,185 These three

drugs are currently approved for IV use in the United States. Oral GpIIa/IIIb inhibitors are not

effective.185 Currently, studies support the use of GpIIb/ IIIa inhibitors for patients with high-risk

unstable angina who are to undergo PCI or stent intervention.

Table IV. Absolute and Relative Contraindications to Thrombolytic Therapy

CPR,cardiopulmonaryresuscitation; SK,streptokinase; APSAC,anistreplase; rt-PA, recombinant tissueplasminogenactivator.Reprinted

withpermissionfromWaters.185


Figure 4. Site of action of platelet inhibitors. [Color figure can be viewed in the online issue, which is available at www.

interscience.wiley.com.]


1 0 . P H A R M A C O E C O N O M I C S

Ahealth economics analysis is the evaluation of the consequences (outcomes) and/or costs (inputs) of

health care therapies and services with the goal of obtaing the highest possible value of health care

expenditures. In economics terms, thee analysis are used to try to improve the efficiency bywhich we

produce health outcomes.186,187 Pharmacoeconomics is the branch of health economics specifically

focused upon the evaluation of pharmaceutical consequences and/or cost. A well-constructed

pharmacoeconomic (PE) study identifies, measures, and compares the benefits and cost of various

treatment alternatives; it looks beyond the direct acquisition cost by including the impact of drug on

total health resources utilization and cost.186,188 John E. Murphy, PharmD, Professor and Head,

Department of Pharmacy Practice and Science, The University of Arizona College of Pharmacy,

Tucson, discussed pharmacoeconomic issues regarding the LMWH, enoxaparin versus unfractio-

nated heparin in venous thromboembolism. DrMurphy described a cost-effectiveness comparison of

enoxaparin to unfractionated heparin,189 They looked at probabilities for clinical outcomes from a

meta-analysis they had conducted; costs were determined from Medicare reimbursements. The

population was a hypothetical cohort of 60-year-olds, and the interventionwas fixed dose enoxaparin

compared to adjusted dose unfractionated heparin. The perspective was societal. The total costs for

inpatient treatmentwere $26,516 for enoxaparin and $26,361 for unfractionated heparin, a difference

of $155 in favor of unfractionated heparin. However, patients treated with enoxaparin had a reduced

risk for early major bleeding complications, recurrent DVT, and death.

Gould and colleagues also performed a sensitivity analysis. The sensitivity analysis varied costs

and probabilities in the model along a range of conservative to liberal estimates of variation. They

used the following ranges: a 6-day hospitalization costs $2,100–3,500; unfractionated heparin costs

$9–15 plus $33–55 for supplies and ancillary resources; enoxaparin costs $63–105 plus $8–14 for

supplies and ancillary resources. There was a cost saving with enoxaparin when as few as 8% of

patients were treated at home.

A study by Witter and colleagues compared enoxaparin to unfractionated heparin for DVT in a

long-term care facility versus a hospital190 Enoxaparin was more cost effective. The authors found

that the pharmacoeconomic analysis was robust in favor of LMWH, with a large degree of change

necessary before unfractionated heparin would become beneficial. A study by Devlin et al.191

examined enoxaparin versus low-dose heparin for prophylaxis after major trauma. Although

enoxaparin increased overall health care costs, it was associated with an incremental cost per

additional life-year saved of only $2,300, which is lower than the convention for ‘‘a good use of

resources’’ of $30,000 for each life year saved.

1 1 . C O N C L U S I O N

Multiple risk factors (most of which are beyond control) associated with venous thromboembolic

diseases have triggered medicinal chemists to develop new chemical entities in this category. The

usual problems of dose fixing and tedious routine monitoring are also best overcome by these newer

anticoagulants. Novel thrombolytics and antiplatelets are rapidly emerging as an attractive

therapeutic tool for intervention of thromboembolic diseases. Besides these newer approaches, the

future research will also focus on mechanical thrombectomy and surgical intervention.

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Prof. Y.K. Agrawal, M.Sc. Ph.D., D.Sc. (USA) in Pharmaceutical Science, D.Sc. (India), F.R.S.C., C.Chem.

(U.K.) is working as a Director in Institute of Pharmacy, Nirma University of Science & Technology. Formerly, he

worked as the Director in School of Sciences, Gujarat University, Ahmedabad and Professor and Head in

Pharmacy Department, Faculty of Technology Engineering, The M.S. University of Baroda. Prior to this he

served at various prestigious institutions of the country like IIT, Bombay, Bhabha Atomic Research Centre,

Trombay, etc. in various capacities. He has visited various countries, viz. USA, Australia, Spain, and Germany.

He is a fellow and member of several Chemical Societies of the country and also abroad. He has 38 years of

teaching and research experience and published 400 research papers in International Journals, 5 patents,

guided 90 Ph.D. students (Pharmacy, Chemistry, Engineering and Bio-sciences), 15 M.Pharm., 5 M.Phil and


ME students. Recipient of ‘‘Russian Academy Award 1985’’, Hari Om Ashram Award 1989, Hari Om Ashram

Award 1991, Royal Society of Chemistry, London Research Award in 1997, 1998 (on Supramolecules), H.K. Sen

Memorial Award in Pharmaceutical Science, 1998, Dr. A.K. Ganguli Oration Award 2000, P.K. Bose Memorial

Award 2001, IDMA Eminent Analyst Award 2003, CSIR Bronze Medal for research contribution in Chemistry

2004. Member of Editorial Board, Indian Journal of Pharmaceutical Sciences, Indian Drugs, Indian Journal of

Chemistry, Chemical Research, etc. Member of the UGC, DST, CSIR, DSIR, etc.

Mr. Hitesh B. Vaidya, M.Pharm., has more than 2 years of Teaching and Research experience. He has worked

on Quantitative Structure Activity Relationship (QSAR) Models and on Molecular Modeling. He has published

two review articles in reputed international journals also has participated in various International & National

Conferences, Seminars, Symposiums and Workshop conducted by AICTE, DST, and various agencies. His main

areas of research are synthetic chemistry, microwave synthesis, and computer added drug design. He is a life

member of association of Pharmacy Teachers of India (APTI).

Mr. Hardik G Bhatt, M.Pharm., has 2 years of teaching and research experience. He is the recipient of the

GOLD MEDAL for standing FIRST in M.Pharm. (Department of Pharmaceutical Chemistry) from Gujarat

University. He is an author of ‘‘Practicals in Organic and Medicinal Chemistry’’ book for B.Pharm. students. He

has published two Research articles and three Review articles in reputed International and National journals. He

has attended and presented two research articles in various international and national level seminars and

conferences conducted by DST, AICTE, CSIR, UGC, and various universities. His areas of research are

Molecular Modeling, Drug Design, QSAR, Synthetic Heterocyclic Ring Systems. He is life member of Indian

Pharmaceutical Association (IPA) and Association of Pharmacy Teachers of India (APTI).

Mr. Kuntal Manna, Lecturer in Pharmaceutical Chemistry, has more than 3 years Teaching and Research

experiences. He has published three scientific research and two review articles in various reputed International

and National journals. He has presented two research articles and has participated in more then five

international & National Conferences, Seminars, Symposiums, and Workshop conducted by DST, AICTE, CSIR,

UGC, and various universities. His areas of research are synthetic chemistry (heterocyclic, asymmetric, and

supramolecular compounds), microwave synthesis, computer added molecular modeling & drug design.

Mr.PathikBrahmkshatriya, M.Pharm., has worked more than 2 year as a lecturer, and currently he is doing his

Ph.D. He has published three international publications in reputed journals. He has presented one research

article and has participated in more then five International and National Conferences, Seminars, Symposiums

and Workshops conducted by DST, AICTE, CSIR, UGC, and various universities.


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