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MINIREVIEW

Antiplasmin

The forgotten serpin?

Paul B. Coughlin

Australian Centre for Blood Diseases, Monash University, Prahran, Australia

Introduction

The fibrinolytic system is clearly important in human

biology and its major components are highly conserved

through vertebrate evolution. It is therefore very sur￾prising that it is so hard to find good evidence of

genetic anomalies in the fibrinolytic system commonly

associated with thrombotic or other diseases. Patients

deficient in plasminogen suffer from ligneous conjunc￾tivitis but not thrombosis [1,2] while there have been

no convincing reports of tissue plasminogen activator

(tPA) deficiency associated with thrombosis. On the

other hand mice rendered deficient in the fibrinolytic

proteases urokinase plasminogen activator (uPA), tPA

and plasminogen demonstrate significant phenotypes,

particularly when challenged with thrombotic or

inflammatory stimuli. Regulators of fibrinolytic pro￾teases should be important in thrombolysis and indeed

variation in the levels of plasminogen activator inhib￾itor-1 (PAI-1) appear to be important in the genesis of

atherothrombotic disease (reviewed in [3]). It may be

that these effects relate more to the role of PAI-1 in

regulating cell growth and migration rather than any

direct relationship to fibrinolysis. While there is no evi￾dence for variation in the level of antiplasmin (AP)

playing a part in thrombotic disease, complete defici￾ency causes a variable, but often severe, bleeding dis￾order [4].

Although at a clinical level it is unclear how import￾ant fibrinolytic abnormalities are in pathological clot

formation, it is well known that the rate and complete￾ness of clot lysis play a role in determining patient

outcomes. On the venous side of the circulation partic￾ularly the persistence of clot burden in leg veins is

Keywords

antiplasmin; fibrinolysis; plasminogen;

serpinF2

Correspondence

P. Coughlin, Australian Centre for Blood

Diseases, Monash University, Level 6,

Burnet Tower, Commercial Road, Prahran,

3181, Australia

E-mail: [email protected]

(Received 9 May 2005, accepted 25 July

2005)

doi:10.1111/j.1742-4658.2005.04881.x

Much of the basic biochemistry of antiplasmin was described more than

20 years ago and yet it remains an enigmatic member of the serine protease

inhibitor (serpin) family. It possesses all of the characteristics of other

inhibitory serpins but in addition it has unique N- and C-terminal exten￾sions which significantly modify its activities. The N-terminus serves as a

substrate for Factor XIIIa leading to crosslinking and incorporation of

antiplasmin into a clot as it is formed. Although free antiplasmin is an

excellent inhibitor of plasmin, the fibrin bound form of the serpin appears

to be the major regulator of clot lysis. The C-terminal portion of anti￾plasmin is highly conserved between species and contains several charged

amino acids including four lysines with one of these at the C-terminus.

This portion of the molecule mediates the initial interaction with plasmin

and is a key component of antiplasmin’s rapid and efficient inhibitory

mechanism. Studies of mice with targeted deletion of antiplasmin have con￾firmed its importance as a major regulator of fibrinolysis and re-empha￾sized its value as a potential therapeutic target.

Abbreviations

AP, antiplasmin; PAI-1, plasminogen activator inhibitor-1; PEDF, pigment epithelium derived factor; serpin, serine protease inhibitor; tPA,

tissue plasminogen activator; TUG, transverse urea gradient; uPA, urokinase plasminogen activator.

4852 FEBS Journal 272 (2005) 4852–4857 ª 2005 FEBS