Alpha2-Plasmin Inhibitor Deficiency Clinical Presentation

In patients with severe alpha 2–plasmin inhibitor (alpha 2-PI) deficiency, bleeding patterns are similar to those seen in patients with hemophilia, as follows:

• Delayed onset of bleeding after minor trauma
• Prolonged bleeding from cuts and wounds, including mucosal bleeding
• Increased bruising and hematomas, including muscle bleeding
• Bleeding into joints following trauma rather than spontaneous joint bleeding
• Excessive postsurgical bleeding (may be a clue in milder cases)
• Excessive bruising
• Increased bleeding following ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs)

Physical findings in individuals with alpha2–plasmin inhibitor (alpha2-PI) depend on the site of bleeding, as follows:

• Joint bleeds resulting in pain, swelling, and limitation of joint movement (acute and chronic arthropathy similar to the arthropathy seen in patients with severe hemophilia can develop because of chronic joint bleeds)
• Epistaxis and other mucosal bleeding
• Gastrointestinal tract bleeding
• Central nervous system bleeding
• Menorrhagia starting at menarche

Family studies in the few cases reported thus far suggest that alpha2–plasmin inhibitor (alpha2-PI) deficiency is inherited as an autosomal recessive trait. Acquired alpha2-PI deficiency may occur in individuals with severe liver disease or cancer, or be induced iatrogenically by fibrinolytic therapy. ^[1]

Inherited reductions or inherited functional deficiencies of alpha2-plasmin inhibitor

Inherited reductions or inherited functional deficiencies of alpha 2-PI are due to specific defects in the gene that encodes it, SERPINF2, which is located on chromosome 17. ^[16] The full genomic sequence and the functional implications of all its regions are not currently fully known. The molecular defects have been characterized in a few families, and have included both qualitative deficiency (normal amounts of dysfunctional alpha2-PI) and quantitative deficiency (alpha2-PI levels as low as < 1%). ^[1] Note the following:

• In a family with severe deficiency, a trinucleotide deletion led to the synthesis of a dysfunctional protein, which was retained within the cell.

• In another family, trinucleotide duplication led to production of a dysfunctional protein that could not inhibit plasmin.

• In a third family, a single base insertion in a codon near the 3' end was the molecular basis for the transcription of an abnormal protein, which had abnormal intracellular transport leading to a plasma deficiency.

• One specific polymorphism has been found in several white and Japanese persons and will help in the search for future defects.

Acquired causes of alpha 2-plasmin inhibitor deficiency

Acquired causes of alpha2-PI deficiency reflect the frequency of the associated disease state. Specific clinical conditions that lead to a reduction in the level of alpha 2-PI are described below.

Neonates

Alpha2-PI levels in ill neonates are lower than the reference range levels found in healthy full-term neonates and are similar to adult levels. However, the level of the plasmin–alpha2-PI complex was increased in both healthy and ill neonates, with levels higher than those seen in adults.

Pregnancy

Increased levels of alpha 2-PI contribute to inhibition of fibrinolysis during pregnancy. However, recognizing the significant role played by plasminogen activator inhibitor type 2 in dampening fibrinolysis is important. Plasminogen activator inhibitor type 2 is produced in increasing amounts by the placenta as the pregnancy advances.

In a study involving women in labor, tissue plasminogen activator (tPA) levels increased starting early in labor and remained high after placental separation. However, after placental separation, an increase in plasmin–alpha2-PI complex levels occurred together with an increase in fibrinopeptide A and thrombin-antithrombin complex levels, indicating activation of fibrinolysis before the development of a hypercoagulable state induced by placental separation.

Physiologic examples of increased local fibrinolysis include ovulation and the fluidity of menstrual blood loss. Patients with menorrhagia may have excessive local fibrinolysis and may benefit from antifibrinolytic therapy, but no relationship to reduced levels of alpha 2-PI has been proven in these patients.

Liver disease

The liver plays a central role in hemostasis. Synthesis of alpha2-PI and other physiologically important inhibitors of hemostasis, synthesis of procoagulant, and clearance of activated coagulation factors are regulated by the liver. Severe liver disease is associated with reductions in alpha2-PI levels, and that reduction is probably a contributing factor in the well-recognized excessive fibrinolytic activity seen in some of these patients.

Due to decreased synthesis of inhibitors, including alpha 2-PI, and a decreased ability to clear activated coagulation factors, patients undergoing orthotopic liver transplantation have excess fibrinolytic activity, particularly during the anhepatic phase, which contributes to increased bleeding.

Systemic fibrinolytic therapy

Patients receiving activators of fibrinolysis, such as tPA or streptokinase, for the treatment of acute myocardial infarction or for extensive venous thromboembolic disease develop a systemic fibrinogenolytic state, with excess plasmin generation resulting from the use of pharmacologic doses of the activators. ^{[9, 14, 17, 18]} Reduced alpha2-PI levels are common after the use of these agents, with a greater reduction after streptokinase than after tPA.

The increased incidence of bleeding into the CNS in older patients and of large hematomas at invasive sites are the result of excess plasmin, which degrades all recent thrombi and cannot distinguish between a physiologic hemostatic plug and a pathologic thrombus.

Bleeding after cardiopulmonary bypass surgery

Reduced alpha2-PI levels with reduced fibrinogen levels, increased fibrin split products, and higher levels of plasminogen activator inhibitor type 1 were found in mediastinal blood that was shed by patients who had undergone exploratory surgery for excessive bleeding following open heart surgery and who had negative intraoperative findings. The high local fibrinolytic activity with reduction of alpha2-PI levels was believed to be secondary to clot formation in the chest; irrigation and removal of the clots along with the use of inhibitors of fibrinolysis help reduce excess local fibrinolytic activity in the chest cavity

In a study, patients undergoing bypass surgery for coronary artery disease were evaluated prospectively, with the study group receiving aprotinin priming of the pump and an intravenous (IV) infusion during bypass surgery. ^[19] Alpha2-PI levels were reduced in the control group, with a marked increase in fibrin split-product and plasmin–alpha2-PI complex levels, indicating fibrinolysis activation secondary to coagulation activation. Aprotinin treatment effectively suppressed hyperfibrinolysis and reduced postoperative blood loss. ^[19]

Primary fibrinolysis during supraceliac aortic clamping

Excessive fibrinolysis was found within 20 minutes of clamping in patients undergoing supraceliac aortic clamping but not in patients undergoing infrarenal aortic clamping. Laboratory tests revealed the presence of a primary fibrinolytic state, as evidenced by a reduction in euglobulin lysis times (measure of total fibrinolytic activity in the absence of physiologic inhibitors within the testing system), increased tPA levels, elevated ratios of tPA to plasminogen activator inhibitor type 1, and reduced levels of alpha2-PI. The supraceliac aortic clamping caused hepatocellular injury with prolonged circulation of tPA, leading to a profibrinolytic state characterized by an excess generation of plasmin with alpha2-PI depletion.

Lung cancer

Increased fibrinolytic activity of lung cancers has been documented over many years. In a series from Japan, 70 patients with both non–small cell and small cell lung cancer were studied. Increased levels of plasmin–alpha2-PI complex had prognostic significance and predicted poor survival independent of other factors, such as histologic findings, age, sex, and presence of metastatic disease, compared with control subjects.

Other studies of patients with lung cancer confirmed the presence of increased levels of plasmin–alpha2-PI complex, although they found a correlation between higher values of alpha2-PI and histologic findings and/or the extent of disease. Plasmin–alpha2-PI complex might be useful as a marker to predict outcomes in patients with malignancies.

Arterial disease and atherosclerosis

One group of patients with intermittent claudication and another group with coronary artery spasm were found to have increased levels of plasmin–alpha 2-PI complex. In addition, the group with intermittent claudication had higher thrombomodulin levels, whereas the coronary artery spasm group had high levels of thrombin-antithrombin complex. The complex is a sign of activation of coagulation and fibrinolysis secondary to vascular injury.

Fibrinolytic parameters after severe trauma

In a prospective study of the fibrinolytic system in patients admitted with severe trauma, patients had a reduced level of alpha 2-PI at admission, with increased levels of t-PA antigen and plasminogen activator inhibitor activity.

Enhanced fibrinolysis during hemodialysis

In a study of patients undergoing regular hemodialysis, plasminogen and alpha 2-PI levels were reduced, with increased levels of plasmin–alpha 2-PI complex present before hemodialysis. Serial sampling during a hemodialysis session showed a continuous fall in alpha 2-plasmin inhibitor levels, with rising levels of plasmin–alpha 2-PI complex at the end of hemodialysis.

t-PA activity and antigen levels rose concomitantly, but plasminogen activator inhibitor type 1 antigen levels dropped, without any further rise in the basal level of cross-linked fibrin degradation products. These findings suggest the presence of a hyperfibrinolytic state before hemodialysis, with further increase during hemodialysis.

Acute leukemia

Patients with acute promyelocytic leukemia are treated routinely with heparin for disseminated intravascular coagulation (DIC), but the hemostatic defect may be due to accelerated fibrinolysis resulting from the release of both t-PA and urokinase-type plasmin activator (u-PA) by leukemic cells. Reduced alpha 2-PI levels have been used as a criterion to treat these patients with epsilon-aminocaproic acid (EACA; 6-aminohexanoic acid, Amicar) in combination with heparin, with improvement in bleeding and in abnormal laboratory test findings.