Alpha 2-Antiplasmin Deficiency

Disease Overview

The congenital deficiency of alpha 2-antiplasmin was first described by Masateru Kohakura in 1969 in a child living on the island of Okinawa in south-west Japan.1 The child had a hemorrhagic diathesis including prolonged bleeding from cuts, subcutaneous hemorrhages and traumatic joint bleeding. Subsequently, the complete pedigree was described among the family members descended from common ancestors and with 3 consanguineous marriages, all living on the island.1

The credit for isolating alpha 2-antiplasmin from human plasma goes to two groups: Moroj and Aoki, 1976, as well as Wilman and Collen, 1977. The human gene was sequenced in 1988.2

Alpha 2-antiplasmin is a natural inhibitor of plasmin in human circulation and plays a key role in the regulation of fibrinolysis.3 The plasmin-antiplasmin system regulates the dissolution of fibrin polymers into soluble fragments.

Plasminogen is activated by two main physiological activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Plasminogen is converted into plasmin, which causes cleavage of insoluble fibrin polymers at specific sites, resulting in soluble fragments. The main physiological inhibitor of plasmin is alpha 2-antiplasmin and to some extent α2-macroglobulin.

Alpha 2-antiplasmin is a single-chain glycoprotein of the serpin family with a molecular mass of 70,000. It is synthesized mainly in the liver and kidneys. It circulates in the plasma at high concentrations (0.7 mg/L) and has a plasma half-life of 2.6 days. In humans, the gene SERPINF2 is about 16kb and is located on chromosome 17p13.3. Alpha 2-antiplasmin is also present in low concentrations in the α-granules of platelets.

Two NH2-terminal variants of alpha 2-antiplasmin are isolated from human plasma in roughly equivalent amounts: alpha 2-antiplasminMet, the full length protein secreted into the blood comprising 464 amino acids, and alpha 2-antiplasminAsn, lacking the first 12 amino acids. The Asn-form makes up 60%-70% of the total alpha 2-antiplasmin in the plasma.

Alpha 2-antiplasmin regulates fibrinolysis in three ways4:

1)    Inhibition of adsorption of plasminogen to fibrin: The C-terminal end of alpha 2-antiplasmin binds to the lysine-binding site of plasminogen, which is also the site of covalent binding of fibrin. Alpha 2-antiplasmin thus competitively inhibits the binding of plasminogen to fibrin, which is the initial step of endogenous fibrinolysis.

2)    Formation of inactive plasmin-α2-antiplasmin: alpha 2-antiplasmin is rapidly cleaved by plasmin, resulting in the release of a peptide and the covalent, inactive but stable complex, plasmin-α2-antiplasmin.

3)    Making fibrin more resistant to fibrinolysis: Plasma alpha 2-antiplasmin becomes covalently cross-linked to fibrin via factor XIIIa (FXIIIa), resulting in increased resistance to fibrinolysis. In addition, plasminogen activators tPA and uPA are also inhibited by α2-antiplasmin.

Alpha 2-antiplasmin deficiency can be congenital or acquired. Patients with congenital deficiency of alpha 2-antiplasmin may present with a severe hemorrhagic disorder due to impaired inactivation of plasmin and resulting premature lysis of the hemostatic fibrin plug. Bleeding may sometimes be delayed in onset after trauma or surgery.

Acquired alpha 2-antiplasmin deficiency may be seen with liver disease (decreased synthesis), disseminated intravascular coagulation (increased consumption), nephrotic syndrome (urinary loss) or during thrombolytic therapy.

Alpha 2-antiplasmin deficiency is a very rare disorder with only a handful of cases described worldwide.5 As a result, the prevalence and ethnic predilection of this disorder is not known. With the more widespread use of high-throughput genomic testing, more information regarding the frequency of this condition may become available.6

Clinical manifestations of alpha 2-antiplasmin deficiency may be seen at birth — for example, as excessive bleeding from the umbilical cord— although increased bleeding in heterozygous deficient patients later in life suggests that the bleeding tendency may increase with age.7 Female patients may experience menorrhagia after puberty.