Alpha-2-Plasmin Inhibitor Deficiency - Unmasking a Camouflaged Clotting Disorder

Introduction

Blood hemostasis is a complex physiological process where a cascade of clotting and counter-clotting mechanisms balance each other to prevent excessive blood loss and regulate blood flow and its fluidity. It also maintains a constant total blood volume in the body. Disruption in any of these hemostatic pathways leads to excessive bleeding or hypercoagulability of blood. Alpha-2-plasmin inhibitor deficiency is one such camouflaged coagulopathy (bleeding disorder due to impaired hemostasis) which occurs due to a defect in the fibrinolytic system. Alpha-2-plasmin inhibitor is a key factor in tertiary hemostasis by controlling intravascular fibrinolysis. Reduced levels of alpha-2-plasmin inhibitor result in hemorrhagic diathesis which includes profuse bleeding after minor trauma or surgery, ecchymoses (skin discoloration due to bleeding underneath), and epistaxis (nasal bleeding). Alpha-2-plasmin inhibitor deficiency gains its clinical importance because missing its diagnosis often results in fatal hemorrhagic complications. This article reveals more about its physiopathology, clinical signs and symptoms, investigations, and management.

What Is the Role of Alpha-2-Plasmin Inhibitor in fibrinolysis?

• Blood clotting is triggered as a quick hemostatic response whenever a blood vessel is damaged due to external injury or internal trauma.

• Blood clotting mechanism is continuously amplified by positive feedback cycles and if left unchecked, would lead to thrombogenic effect in normal undamaged blood vessels.

• Fibrinolysis acts as a counter mechanism which dissolves the inappropriate clot formation once the injury is repaired.

• Plasmin (serine protease) is a fibrinolytic enzyme that continuously dissolves unwanted fibrin clots (in vivo), thereby establishing normal blood flow to the injury site which is healing.

• Plasmin activity is precisely regulated since excess fibrinolysis would dislodge the newly formed clot resulting in recurrent bleeding.

• Alpha-2-plasmin inhibitor is a primary protease inhibitor that deactivates plasmin by a negative feedback mechanism, thus preventing premature dissolution of the fibrin clots before clot retraction occurs.

• The overall clotting mechanism is a cascade of pathways that are executed in a stepwise manner, where components released from one pathway activate or inhibit the consecutive pathway depending on the demand of hemostasis.

What Are the Functions of Alpha-2-Plasmin Inhibitor?

Alpha-2-plasmin inhibitor is naturally produced in the body (synthesized in liver) and plays a vital role in the fibrinolytic system in neutralizing plasmin by forming plasmin-alpha-2-antiplasmin (PAP) complexes. These complexes help in tertiary hemostasis which involves localization of the clot at the site of injury, adherence, and stabilization of the clot (coagulation), and also removal of unwanted fibrin clots (fibrinolysis).

The predominant functions of alpha-2-plasmin inhibitor are,

• Prevent dislodgement of blood clots.

• Favor wound healing.

• Prevents exhaustion of clotting factors and plasma proteins that are used up in extended fibrinolysis.

• Acts as an adjunct regulator in vascular regeneration and tissue remodeling.

• Therapeutically used as a hemostatic agent in regenerative surgeries.

What Is Alpha-2-Plasmin Inhibitor Deficiency?

Alpha-2-plasmin inhibitor deficiency is a rare bleeding disorder caused due to decreased levels of circulating alpha-2-plasmin inhibitor in the blood. This hemorrhagic dysfunction is due to the lack of inhibitory effect of alpha-2-plasmin inhibitor on plasmin resulting in excessive fibrinolysis and clotting dysregulation. There are two types of alpha-2-Plasmin Inhibitor deficiency as follows:

Congenital Alpha-2-Plasmin Inhibitor Deficiency

• It is a genetic disorder inherited by an autosomal recessive gene.

• In homozygous inheritance, manifestations of bleeding episodes occur in early childhood.

• The deficiency is asymptomatic and only detected during minor trauma, surgeries, or dental extractions in the heterozygous state.

Acquired Alpha-2-Plasmin Inhibitor Deficiency

• Acute promyelocytic leukemia (due to antileukemic treatment).

• Glomerular proteinuria ( to leak through damaged glomeruli).

• Amyloidosis (decreased production due to amyloid deposit in liver).

• Disseminated intravascular coagulation (excessive use of clotting factors increases the plasmin-antiplasmin complexes formation leading to lower levels of circulating antiplasmin).

What Are the Signs and Symptoms of Alpha-2-Plasmin Inhibitor Deficiency?

It is reported that bleeding episodes vary from moderate to severe in the early onset of deficiency in childhood. Though asymptomatic individuals experience mild to moderate bleeding in their first traumatic incidents, the severity of bleeding increases after surgical procedures or dental extractions.

The most commonly documented signs and symptoms include,

• Spontaneous and post-trauma spontaneous bleeding in joints, and muscles.

• Post-traumatic umbilical bleeding.

• Epistaxis (nose bleed).

• Subcutaneous hematoma.

• Intramedullary hematoma.

• Spontaneous post-traumatic and postsurgical bleeding after trauma and surgery.

• Post-trauma muscular hematoma.

• Hematuria (blood in urine).

• Severe bleeding after an elective adenoidectomy.

• Delayed bleeding after surgeries and dental extraction.

• Spontaneous bleeding into his kidney, and spleen.

• Easy bruising.

• Spontaneous bleeding after tooth extraction.

• Severe postpartum hemorrhage.

• Bone pain (hemorrhage in joints of long bones).

What Are the Screening Tests to Detect Alpha-2-Plasmin Inhibitor Deficiency?

Regular screening tests that are done to detect bleeding and coagulation disorders, do not identify Alpha-2-plasmin inhibitor deficiency. Most of the tests like bleeding time (BT), clotting time (CT), prothrombin time (PT), and activated partial thromboplastin time (aPTT) assess the functioning of clotting factors and clot formation. Since alpha-2-plasmin Inhibitor is activated only in tertiary hemostasis (after clot formation) if left unassessed, the diagnosis of its deficiency becomes challenging.

Previous history of bleeding episodes, where routine screening test results are normal should be evaluated under a high suspicion index. Extended screening tests should be carried out to exclude the presence of any unknown hemorrhagic disorder.

Specific tests done for alpha-2-plasmin inhibitor deficiency are,

• Shortened euglobulin-lysis time.

• Reduced whole-blood clot lysis time.

• Immunological assay to detect alpha-2-plasmin inhibitor (undetectable levels indicate deficiency).

• Decreased levels of PAP (peroxidase anti-peroxidase) complex in circulating blood is a vital indicator of alpha-2-plasmin Inhibitor deficiency (absence of antiplasmin to counter plasmin).

What Is the Therapeutic Management of Alpha-2-Plasmin Inhibitor Deficiency?

Managing hemorrhagic episodes in alpha-2-plasmin inhibitor deficiency disorders involves administering drugs that inhibit fibrinolysis (Tranexamic acid and Aminocaproic acid). Antifibrinolytic and hemostatic agents like therapeutic alpha-2-plasmin inhibitors inhibit the activation of plasmin. Tranexamic acid is used in response to hemorrhagic complications and as prophylaxis before elective surgical procedures. Fresh frozen plasma (FFP) is used only as an alternative to antifibrinolytic agents. The following are the various therapeutic agents reported in case studies.

• Antifibrinolytic and hemostatic agents like therapeutic alpha-2-plasmin inhibitors (first line of drugs).

• Fresh frozen plasma (FFP infusion).

• Tranexamic acid (antifibrinolytic effect).

• Surgical hemostasis (post-traumatic and post-surgical hemorrhage).

• Blood transfusion (postpartum hemorrhage).

• Red blood cells and platelet concentration (hemorrhagic shock).

• Intramedullary infusion of fibrin glue and antifibrinolytic agents.

Conclusion

To summarize, alpha-2-plasmin inhibitor deficiency is an uncommon bleeding disorder characterized by premature degradation of clotting plugs that occurs before the repair and reconciliation of blood vessels or tissues. Clinically this deficiency has gained its significance because of profuse bleeding after surgical interventions, which is also diagnostically missed in normal screening tests. It is mandatory to suspect and rule out alpha-2-plasmin inhibitor deficiency in patients with unidentified bleeding history yet showing normalcy in typical clotting test reports. Since the prevalence of this deficiency is unknown, more epidemiological studies need to be conducted to understand the inheritance patterns. The discovery of alpha-2-plasmin inhibitor deficiency has enhanced further understanding of the fibrinolytic system and hemostasis. Prospective genetic and molecular research would lead to increased awareness, early detection, and improved management of such rare coagulopathies.