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Factor XIII, α 2 -Antiplasmin, and Plasminogen Activator Inhibitor-1 Deficiencies
Factor XIII (FXIII), α 2 -antiplasmin (α 2 -AP), and plasminogen activator inhibitor type 1 (PAI-1) deficiencies are all very rare bleeding disorders. These proteins play a critical role in stabilizing a fibrin clot (FXIII) and regulating fibrinolysis through the inhibition of plasmin (α 2 -AP) or the inhibition of plasminogen conversion to plasmin (PAI-1). FXIII affects 1 in 2 to 3 million individuals worldwide; the true incidence of α 2 -AP and PAI-1 deficiencies is unknown.
Pathophysiology
FXIII circulates in plasma as a transglutaminase heterotetramer that consists of two catalytic A subunits and two carrier B subunits. The A subunit homodimers are present in platelets and monocytes; the B subunits are synthesized in the liver and circulate in excess of the A subunit. FXIII has a half-life of 9–10 days.
α 2 -AP is a serine protease inhibitor that is synthesized in the liver. It circulates in the plasma in free form or bound to plasminogen. α 2 -AP has a plasma concentration of 0.7 mg/mL and a half-life of 2–6 days.
PAI-1 is a serine protease inhibitor synthesized and released from hepatocytes, endothelial cells, adipocytes, and megakaryocytes. Although the majority of PAI-1 exists in an active form, there is a portion of PAI-1 that exists in an inactive (or latent) form that can be activated with denaturants or phospholipids in vitro. PAI-1 has an exceptionally short half-life of 10 minutes.
Role in Coagulation
Formation of a fibrin clot followed by fibrinolysis for repair of damaged endothelium after vessel injury is tightly regulated pathways that must be balanced to avoid pathologic thrombosis from excess clot formation and bleeding from excess clot degradation. Thrombin generated during the activation of the coagulation cascade catalyzes the conversion of fibrinogen to fibrin and the activation of FXIII to FXIIIa that exposes the A subunits and releases the B subunits. In turn, FXIIIa cross-links fibrin to α 2 -AP and enables incorporation of antifibrinolytic proteins within fibrin to form a stable clot that is resistant to early degradation by fibrinolytic proteins. FXIII/FXIIIa also cross-links fibrinogen, fibronectin, and collagen to form a clot resistant to fibrinolysis. Additionally, FXIII/FXIIIa plays an important role in wound healing, tissue repair, and embryonic implantation.
After the formation of the fibrin clot, the zymogen plasminogen is able to bind to the fibrin surface. Plasminogen is proteolytically cleaved to form plasmin, which is the primary protease responsible for the initiation of fibrinolysis. Plasmin formation is catalyzed by tissue-plasminogen activator (t-PA). α 2 -AP is a competitive inhibitor of plasminogen and prevents its absorption within fibrin. When cross-linked to fibrin, α 2 -AP can inactivate free plasmin and induce increased fibrin resistance to local plasmin via FXIIIa. The plasminogen activator t-PA is also inhibited by α 2 -AP. PAI-1 is the main inhibitor of t-PA ( Fig. 116.1 ).
Genetics
FXIII deficiency is an autosomal recessive disorder. It is caused by defects in either the F13A gene that encodes the A subunit on chromosome 6 or the F13B gene that encodes the B subunit on chromosome 1. The majority of disease-causing mutations are missense mutations in the A subunit. Generally, patients with severely low FXIII levels have homozygous or compound heterozygous mutations, whereas patients with levels approaching 30 IU/dL tend to have heterogyous mutations.
The α 2 -AP and PAI-1 genes are located on chromosomes 17 and 7, respectively. Both deficiencies are inherited in an autosomal recessive manner. Homozygous and compound heterozygous mutations in the PAI-1 gene associated with bleeding have been described. There is a slightly increased incidence of PAI-1 deficiency reported in Amish populations of Eastern and Southern Indiana.
Clinical Manifestations
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