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Coagulation Cofactors: Why They Aren’t Catalysts

A basic coagulation question from my colleague and co-editor Kathryn Doig, PhD, Michigan State University Clinical Laboratory Science Program:

Hi, George. A student and I got into a discussion about the role of factors V and VIII.  He contends they are catalysts because they increase the rate of the reactions in which they are involved and are not changed by the reaction.  I contend that they are not catalysts because they are not then freed to react again.

On page 576 of Rodak BF, Fritsma FA, Doig K. Hematology; Clinical Principles and Applications, 3rd Edition you indicate that cofactors give their enzymes stability that increases reactivity. Would you agree that they are not truly catalysts mainly because they are not freed to react again?

Hi, Kathy,

Your student is sharp, I admire people who raise these kinds of questions. In my experience, this kind of creativity arises most often when someone is trying to argue a grade!

Enzymes are biological catalysts. An enzyme possesses a catalytic domain that triggers a definable modification of its substrate. Leaving out XIIIa, the enzymes of the coagulation system, IIa (thrombin) VIIa, IXa, Xa and XIa are categorized as serine proteases because their catalytic site contains serine. For instance, the catalytic domain of factor IXa is comprised of 235 amino acids with three principles that participate in catalysis; H221, D269 and S365. The term protease indicates that their effect is to cleave the peptide backbone of their substrate.  For instance, IXa cleaves an alanine-isoleucine bond of the heavy chain of factor X, releasing a 52-amino acid “activation” peptide.

Likewise, the serine protease domain of Xa consists of 254 amino acids including the catalytic triad H42, D88, and S185. This site cleaves an arginine259-isoleucine bond of prothrombin (factor II).

The cofactors V and VIII do not possess serine protease domains, which is why they don’t get to be called enzymes. Instead, V and VIII undergo limited proteolysis at several sites and bind their respective serine proteases Xa and IXa through a series of covalent bonds involving carbons that comprise parts of their A2 domains. This happens mostly on a cell membrane phospholipid “carpet.” The Xa and IXa require calcium to bind phospholipid, and once bound and stabilized by their cofactor, are upregulated by 300,000X their unbound rate. Cofactor-serine protease binding is stoichiometric and permanent.

Once bound, the Xa/Va/Ca++/PL complex could be thought of as an enzyme, “prothrombinase;” likewise the IXa/VIIIa/Ca++/PL complex is called “tenase.” In that sense, Va and VIIIa could be thought of as parts of an enzyme despite their lack of a serine protease active site. The complex acts upon thousands of substrate molecules, which helps it reach the definition of catalyst.

Hope this helps.

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