The congenital deficiency of alpha 2-antiplasmin (also referred to as alpha 2-plasmin inhibitor) was first described by Masateru Kohakura in 1969 in a child living on the island of Okinawa in southwest 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 Alpha 2-antiplasmin is a natural inhibitor of plasmin in human circulation and plays a key role in the regulation of fibrinolysis.2 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. Alpha 2-antiplasmin is the main physiological inhibitor of plasmin.
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 1988.3
Alpha 2-antiplasmin is a single-chain glycoprotein of the serpin family with a molecular mass of 67,000. It is mainly synthesized and secreted by the liver. Production has also been shown to occur in the kidney and brain. It circulates in the plasma at high concentrations (0.7 mg/L) and has a plasma half-life of 2.6 days. Plasmin-antiplasmin complexes are cleared much more quickly from circulation (t1/2=0.5 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.4
Two NH2-terminal variants of alpha 2-antiplasmin are isolated from human plasma: alpha 2-antiplasmin-Met, the full-length protein secreted into the blood comprising 464 amino acids, and alpha 2-antiplasmin-Asn, lacking the first 12 amino acids. The Asn-form makes up 60%-70% of the total alpha 2-antiplasmin in the plasma. The binding of FXIIIa and cross-linking to fibrin is more efficient in this form. There is evidence that heterogeneity in the N-terminal of alpha 2-antiplasmin may be driven by genetic variation of the SERPINF2 gene by affecting the rate of N-terminal cleavage.
Approximately 35% of circulating alpha 2-antiplasmin is lacking the C-terminus. With this modification, the molecule no longer binds to plasmin(ogen) and therefore can only slowly inhibit plasmin.
Alpha 2-antiplasmin regulates fibrinolysis in three ways:5
1) Inhibition of adsorption of plasminogen to fibrin: The C-terminal end of alpha 2-antiplasmin binds to the lysine-binding site of plasmin(ogen), 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. This crosslinking is directly responsible for clot stability.6 In addition, plasminogen activators tPA and uPA are also inhibited by alpha 2-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), amyloidosis, or during thrombolytic therapy.
Alpha 2-antiplasmin deficiency is a very rare disorder with only a handful of cases described worldwide.7 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.8
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
