Alpha2-Plasmin Inhibitor Deficiency

Alpha2–plasmin inhibitor (alpha2-PI) is the most important physiologic inhibitor of plasmin, which is the principal protease of the fibrinolytic pathway. Plasminogen activators convert the zymogen plasminogen to the active enzyme plasmin, which then hydrolyzes susceptible arginine and lysine bonds in a variety of proteins.[8, 9, 10]

Plasmin has a broad range of actions. Plasmin not only degrades fibrin, which is its principal substrate, but it also degrades fibrinogen, factors V and VIII, proteins involved in platelet adhesion (glycoprotein I and vWF), platelet aggregation (glycoprotein IIb/IIIa) and maintenance of platelet aggregates (thrombospondin, fibronectin, histidine-rich glycoprotein), and the attachment of platelets and fibrin to the endothelial surface.

A positive feedback mechanism exists whereby plasmin acts to further increase the generation of plasmin by converting Glu-plasminogen to Lys-plasminogen; Lys-plasminogen is more susceptible to activation by plasminogen activators. In addition, other noncoagulation proteins, such as complement, growth hormone, corticotropin, and glucagon, are substrates for plasmin. Therefore, the reasons for the bleeding disorder that develops due to the actions of excess unfettered and unneutralized plasmin are easily comprehended.

Alpha2-PI belongs to the serpin family of inhibitors, is synthesized by the liver, and is present in plasma as a single-chain protein at approximately half the concentration of plasminogen. Two forms of alpha2-PI are present in blood; 70% of alpha2-PI binds plasminogen and has inhibitory activity, whereas the remaining 30% is in a nonbinding form. The nonbinding form is a degradation product of the binding form and has little inhibitory activity.

A small amount of alpha2-PI present in platelets contributes to inhibition of fibrinolysis in platelet-containing thrombi. Activated factor XIII (FXIIIa) cross-links alpha2-PI to the a-chains of fibrin(ogen), thus making a cross-linked fibrin clot more resistant to lysis by plasmin.[11, 12, 13]

Alpha2-PI reacts very rapidly with plasmin to form a stable plasmin-inhibitor complex. This interaction is central to the physiologic control of fibrinolysis and irreversibly inhibits plasmin activity, which in turn, partially degrades alpha2-PI. The plasmin–alpha2-PI complex is cleared more rapidly from the circulation. The half-life of the complex is approximately 12 hours compared with the longer half-life of 3 days for native alpha2-PI.

Alpha2-PI performs several functions. It inhibits free plasmin rapidly and more readily than fibrin-bound plasmin. It is cross-linked to fibrin, thus conferring resistance to degradation by plasmin, and it interferes with the adsorption of plasminogen to fibrin. As a result, recent clots are more susceptible than older clots to degradation by plasmin.

Several other proteins are also involved in the complex process of regulation of fibrinolysis in vivo. Physiologically, the end result is that the hemostatic plug (fibrin and platelet clot) is protected from premature breakdown, leaving the fibrin meshwork intact so that it functions not only in hemostasis but also in wound repair as a scaffold for regenerating cells.

As the principal inhibitor of plasmin, alpha2-PI plays a key role in the physiologic control of fibrinolysis by helping localize reactions to the sites where they are needed and by helping prevent systemic spillover. When the amount of plasmin generated exceeds the capacity of alpha2-PI  to neutralize plasmin (since, in plasma, plasminogen levels are twice those of alpha2-PI) alpha2-macroglobulin can function as a less efficient backup inhibitor. Note the image below.

Conceptually, alpha2-PI neutralizes plasmin at various sites of plasmin production, including in the fibrin clot, on the surface of cells, and in the fluid phase (For an excellent diagram showing these details, see Figure 2 in Castellino FJ, Ploplis VA. Plasminogen and streptokinase. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. Berlin: Springer-Verlag; 2001:26-56.)[14]

Other inhibitors, such as antithrombin, alpha1-antitrypsin, and C1 inactivator of complement, have in vitro antiplasmin activity, but these inhibitors may play only a minimal role in vivo.

In the absence of alpha2-PI, plasmin degrades the primary hemostatic platelet-fibrin plug, thereby interfering with adequate primary hemostasis. Although fibrin formation is unimpaired, subsequent accelerated lysis of the formed fibrin plug (fibrinolysis) leads to the onset of delayed bleeding.

In pathologic states, in which there is an endogenous excessive activation of plasminogen or a secondary infusion of activators, such as tissue plasminogen activator (tPA) and streptokinase, sudden generation of large amounts of plasmin overwhelms the neutralizing capacity of alpha2-PI. In addition to degrading the primary fibrin-platelet plug, excess plasmin degrades circulating fibrinogen (fibrinogenolysis) and factors V and VIII, adding to the hemorrhagic diathesis.

Most patients with an inherited homozygous alpha2-PI have a clinically significant bleeding disorder that is characterized by prolonged bleeding and bruising following minor trauma and bleeding into the joints, similar to the manifestations seen in patients with hemophilia.[2] Gene knockout mouse models of alpha2-PI deficiency show the expected accelerated clot lysis, but the mice do not manifest the bleeding disorder that is seen in humans.[15]

Frequency

United States

Very few cases of inherited alpha 2-plasmin inhibitor (alpha 2-PI) deficiency have been reported; therefore, data do not exist to determine the true frequency. In the next several years, as widespread high-throughput genomic testing becomes commonplace, the frequency of genetic defects will be known, and the frequency of these rare disorders can then be determined.

The frequency of acquired alpha 2-plasmin inhibitor deficiency depends on the frequency of the underlying disorders. As discussed in Causes, excessive bleeding can occur when alpha 2-PI levels are deficient.

Mortality/Morbidity

Homozygous patients with alpha 2-plasmin inhibitor deficiency have severe bleeding that requires plasma therapy to limit the bleeding and to maintain plasma levels until the acute bleeding resolves.

Recurrent joint bleeds can lead to acute and chronic arthropathy, as occurs in severe hemophilia. Appropriate physical therapy, joint replacement, and treatment of chronic debilitating viral illnesses, such as hepatitis and acquired immunodeficiency syndrome (AIDS) and its sequelae, are needed in patients with alpha 2-plasmin inhibitor deficiency. Death may occur due to a CNS bleed or after major trauma. Note the following:

• Patients with an inherited homozygous alpha 2-plasmin inhibitor deficiency have a clinically significant bleeding disorder characterized by easy bruising, delayed onset of bleeding following trauma or surgery, menorrhagia, epistaxis, hematuria, and bleeding into joints, similar to the manifestations seen in patients with hemophilia.

• The frequency of a bleeding disorder reportedly varies among patients who are heterozygous for alpha 2-PI deficiency and is characterized by a milder bleeding disorder in most heterozygotes, with a tendency to worsen with age.

• The bleeding in patients with acquired disorders associated with alpha 2-plasmin inhibitor deficiency is described in Causes.

Race-, sex-, and age-related demographics

Note the following:

• No ethnic predilection for alpha 2-plasmin inhibitor deficiency is known at this time because the overall number of reported cases is so small.
• Alpha 2-plasmin inhibitor deficiency is inherited as an autosomal recessive trait. Males and females are equally susceptible.
• Clinical manifestations of alpha 2-plasmin inhibitor deficiency may start at birth, with excess bleeding from the umbilical cord. Bleeding manifestations may start later in childhood, when trauma and minor cuts occur with increasing activity. Menorrhagia manifests following puberty in women.

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.

Appropriate testing methodology (ie, functional vs antigenic, biologic vs chromogenic substrate assays) is an important consideration in the workup of patients with alpha2–plasmin inhibitor (alpha 2-PI) deficiency.

Testing blood during acute bleeding events may show reduced levels of factors, which may rise to reference range levels when patients are stable. Therefore, testing patients repeatedly when they are in a stable state is important to confirm the diagnosis.

The functional and antigenic levels of alpha2-PI are reduced to a similar extent in most patients with severe alpha2-PI deficiency. Patients with a dysfunctional molecule who have reduced functional activity with reference antigen values for the inhibitor have also been described.

Initial routine workup should include testing, as follows:

• Activated partial thromboplastin time (aPTT)
• Prothrombin time (PT)
• Thrombin-coagulable fibrinogen levels
• Euglobulin lysis time
• Whole blood clot lysis time
• Platelet counts and bleeding times (only if patient has not had antiplatelet drugs in the preceding 5-7 d)
• Factor II, V, VII, and X levels if PT is prolonged
• Platelet function
• Screening for factor XIII deficiency using a urea or monochloroacetic acid solubility test
• Thrombin time

Specialized laboratory tests are as follows:

• Alpha2-PI levels: Evaluate alpha2-PI levels with the use of antigenic and functional assays. Perform functional assays with both biologic and chromogenic tests. In addition, evaluate for a genetic defect in collaboration with a specialized laboratory.

• Tissue plasminogen activator (tPA) antigen and activity levels

• Plasminogen functional activity levels

• Levels of other inhibitors: These include alpha2-macroglobulin, alpha1-antitrypsin, alpha1-chymotrypsin inhibitor, C1 inactivator of complement, and antithrombin

The extent of medical care depends on the severity of the bleeding. Minor bleeding can be handled with oral antifibrinolytic drugs, but more extensive bleeding may require temporary plasma supplementation. Bleeding into critical sites may also require surgical intervention.

Patients with inherited or acquired alpha2–plasmin inhibitor (alpha2-PI) deficiency that is a cause or the cause of acute significant bleeding should receive a transfusion of fresh frozen plasma (FFP) as a source of alpha2-PI.

Pooled plasma treated with solvent-detergent (SDP) is available to treat any condition in which FFP typically is used and for which no factor concentrate is available.[20, 21] In vitro treatment of donor plasma with 1% of the solvent tri(n- butyl) phosphate (TNBP) and 1% of the detergent Triton X-100 leads to significant inactivation of a broad spectrum of lipid-enveloped viruses. Although it also reduces levels of alpha2-PI,[16] an in vivo study found a statistically significant increase in plasma levels of alpha2-PI after infusion of SDP.[20] Note also the following:

• SDP is ABO blood type specific, so it should be ABO compatible with the recipient's blood type.

• The frozen product is supplied in 200-mL bags. Each 200-mL bag has been demonstrated to raise factor levels by approximately 2-3%, with 4-6 bags raising the factor level of a 70-kg person by approximately 8-18%.

• Monitoring of specific factor levels before and after product infusion is important to ensure that hemostatically adequate levels are achieved and maintained to provide adequate hemostasis.

Oral or intravenous therapy with antifibrinolytic drugs, such as epsilon-aminocaproic acid (EACA) or tranexamic acid (Cyklokapron), helps prevent the generation of plasmin and blocks its action. EACA and tranexamic acid are synthetic lysine analogues that bind to the lysine-binding sites of plasminogen and induce a conformational change, probably prevent plasminogen activation, and in large doses also bind to plasmin, preventing it from binding to fibrin. Excluding a significant element of disseminated intravascular coagulation (DIC) is essential before using drugs inhibiting fibrinolysis, because inhibition of fibrinolysis will accelerate thrombosis secondary to DIC.

Prolonged oral therapy with antifibrinolytic drugs reduces the frequency of bleeding in patients with severe congenital alpha2-PI deficiency. Patients with acquired alpha2-PI deficiency who have benefited from antifibrinolytic therapy, when appropriate, include those with acute promyelocytic leukemia, amyloidosis, and some patients with liver disease (during the anhepatic phase of liver transplantation).

Some authors have suggested prophylactic platelet transfusion, given the possible secretion of alpha2-PI contained in the alpha granules of activated transfused platelets.

Essential surgical procedures in patients with alpha2-PI deficiency should be performed only after re-evaluating the level of alpha2-PI and after deciding on the need for plasma or an antifibrinolytic agent.

Serious bleeding complications in those with alpha2-plasmin inhibitor (alpha2-PI) deficiency, such as epidural or CNS hematomas, demand immediate surgical intervention. Such interventions must be coupled with plasma infusions to correct alpha2-PI deficiency and with inhibitors of fibrinolysis to prevent rebleeding. In addition, pay careful attention to avoiding perioperative use of drugs such as NSAIDs that potentiate bleeding. Serial laboratory assessments of the level of alpha2-PI must be performed in the postoperative period to ensure maintenance of adequate levels of over 70%.

In patients undergoing open heart surgery, local and systemic use of antifibrinolytic drugs have reduced blood loss and the requirement for transfusions. Despite these beneficial results, routine use of these agents in patients undergoing open heart surgery is uncommon. After open heart surgery, local irrigation of the chest wall with EACA can arrest excessive bleeding, but it also can lead to formation of firm fibrin thrombi that do not lyse.

Antifibrinolytic therapy has been successful in reducing blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation, without causing hepatic artery thrombosis.

Patients undergoing supraceliac clamping of the aorta develop a predictable hyperfibrinolytic state that should be treated with antifibrinolytic drugs if bleeding is excessive.

Close consultation with a hematologist is necessary. A geneticist should also be consulted as needed. Collaboration with a specialized hemostasis laboratory is indicated.

If active bleeding occurs, either spontaneously or postoperatively, rest is appropriate, depending on the site and extent of the bleeding. Physical therapy for patients receiving FFP replacement therapy is necessary following joint bleeding.

Traditionally, fresh frozen plasma (FFP) has been the source of clotting factors used to treat coagulation factor deficiencies for which no concentrates are available. Alpha2–plasmin inhibitor (alpha2-PI) falls into this category.

Careful screening of blood donors and viral testing of donated blood (ie, for hepatitis B virus [HBV], hepatitis C virus [hPC], HIV, and human T-cell leukemia virus [HTLV] and screening for elevated alanine aminotransferase [ALT] levels) have improved the safety of blood products. Nevertheless, risks remain for a variety of reasons, including failure to detect infections during the incubation period before the results of currently available tests become positive, as well as the possible presence of other types of infections for which screening or testing is not available or for which the presence is unknown.

Those risks spurred the development of solvent/detergent-treated plasma (SDP; Octaplas). Solvent/detergent treatment results in significant inactivation of lipid-enveloped viruses (eg, HIV, HCV, HBV). In addition, SDP delivers consistent and reproducible levels of coagulation factors. In contrast to the extreme variability in FFP, leukocytes are not present, and physiologic inhibitor levels are mostly in the reference range, with the exception of a moderate reduction in the levels of alpha2-PI (approximately 0.48 IU/mL) and protein S (approximately 0.52 IU/mL).

In addition, coagulation zymogen activation does not occur, reference values of other plasma proteins and immunoglobulins are seen, and all lots have anti-hepatitis A virus (HAV) antibody levels of greater than 0.8 IU/mL, providing passive administration of antibody that may neutralize HAV. In addition, SDP lacks the largest von Willebrand multimers and has proven efficacy in the treatment of a variety of bleeding disorders.

SDP should not be used in patients with known immunoglobulin A (IgA) deficiency.[20, 21] All SDP units must be compatible with the patient's ABO blood group. Adverse reactions include minor allergic reactions, which respond to antihistamines. Rarely, noncardiogenic pulmonary edema, citrate toxicity, hypothermia, and other metabolic problems arise if large volumes are used rapidly. In addition, positive results using the direct antiglobulin test may be induced by antibodies, and hemolysis may occur, rarely.[20]

Recognition of the importance of the lysine-binding sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogues such as epsilon-aminocaproic acid (EACA) and tranexamic acid. These synthetic lysine analogues induce a conformational change in plasminogen when they bind to its lysine-binding site. After EACA binds to it, plasminogen takes the shape of a pronate ellipsoid. The plasminogen elongates into a long structure in which former interactions between the parts are lost.

In vivo, synthetic lysine analogues probably prevent plasminogen activation and, in large doses, also bind plasmin, thereby preventing plasmin from binding to its substrate, fibrin. The tightest binding on EACA-binding sites on plasminogen occurs on kringle 1, followed by kringles 4 and 5. Interaction with kringle 2 is weak, and kringle 3 does not interact at all. A model of the structure of kringle 4 shows that the shallow trough formed by hydrophobic amino acids is surrounded by positively and negatively charged amino acids at a distance ideal for interacting with EACA.

EACA is the most widely used antifibrinolytic drug in the United States. The minimum dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed well orally, and 50% is excreted in the urine within 24 hours. Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit fibrinolysis until excess bleeding is controlled. Then, the maintenance dose is tapered until EACA can be discontinued. Rarely, myopathy and muscle necrosis can develop. Lower doses are adequate when bleeding involves the urinary tract because drug concentrations are 75-100–fold higher in urine than in plasma.

Tranexamic acid is also excreted rapidly in the urine, with more than 90% excreted within 24 hours; however, its antifibrinolytic effect lasts longer than that of EACA. Tranexamic acid inhibits fibrinolysis at lower plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, tranexamic acid can be administered less frequently and at lower doses.

The dose of EACA and tranexamic acid must be reduced in patients with kidney failure.

Aprotinin, an antifibrinolytic agent used to reduce operative blood loss in patients undergoing open heart surgery,[19] has also been shown to reduce blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation and in patients undergoing elective resection of a solitary liver metastasis originating from colon cancer. It was removed from markets worldwide after Fergusson et al reported an increased risk for death with aprotinin compared with EACA or tranexamic acid in high-risk cardiac surgery, but was subsequently relicensed in Europe; however, it remains unavailable in the United States.[22, 23]

Class Summary

Administer inhibitors of fibrinolysis together with FFP replacement in patients with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) who are undergoing minor surgical procedures (eg, dental extractions, sinus surgery), so that the procedures can be accomplished on an outpatient basis with the use of a single dose of product.

Concern about the possible relationship of antihemophilic agents to acute thrombotic events remains, although a causal relationship is being questioned, because the underlying disease state determines the site and extent of thrombosis.

Fresh frozen plasma (Octaplas, FFP)

Fresh frozen plasma (FFP) is plasma from a unit of whole blood separated by centrifugation and frozen within 8 hours of collection. Each unit provides all plasma proteins and clotting factors to support adequate hemostasis to treat or prevent bleeding or to treat other protein deficiencies that cannot be replaced with protein-specific concentrates.

Aminocaproic acid (Amicar)

Hemostatic agent that diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. Can be used PO/IV.

Tranexamic acid (Cyklokapron)

Fibrinolytic inhibitor that can be used with FFP replacement to inhibit fibrinolysis.

Prolonged therapy with fresh frozen plasma (FFP) or solvent/detergent-treated plasma (SDP) or antifibrinolytic agents may be needed in patients with alpha2–plasmin inhibitor (alpha2-PI), depending on the clinical circumstance.

Continuation of oral antifibrinolytic therapy on an outpatient basis is warranted, particularly if the drug was effective in controlling bleeding, as in persons with hemophilia following oral surgical procedures. Only a brief period of therapy is recommended for acquired disorders of alpha2-PI deficiency. Monitor patients closely, and determine the appropriate duration of therapy by clinical observation of the patient.

For prophylactic care, long-term oral therapy with antifibrinolytics has successfully reduced the incidence of bleeding in patients with inherited alpha2-PI deficiency.

Avoidance of antiplatelet drugs is essential because these agents increase bleeding risk.

To minimize the frequency of bleeding complications, patients with alpha2–plasmin inhibitor (alpha2-PI) deficiency should avoid contact sports and other activities with a significant risk of trauma, and should not take nonsteroidal anti-inflammatory drugs (NSAIDs).

Prevention is not feasible for the genetic defect that causes alpha2-PI deficiency. Prenatal testing of a known defect may be attempted in a family whose members experience severe bleeding.

Immunization against hepatitis A and hepatitis B is useful in patients who require administration of plasma products. Although reports of blood-borne hepatitis A virus (HAV) infection resulting from tainted donations are sporadic only, the superimposition of acute HAV infection on chronic hepatitis (which may exist in patients with repeated exposure to blood products) clearly puts patients at higher risk of liver failure. Therefore, immunizing patients against any form of hepatitis for which a vaccine is available is wise. HAV vaccination conforms with recommendations of the National Hemophilia Foundation for patients receiving any kind of blood products on a recurrent basis.

Persons who are homozygous for alpha2–plasmin inhibitor (alpha2-PI) deficiency have a severe bleeding disorder, but if appropriate treatment is received, long-term survival is possible. However, the frequent need for plasma transfusions exposes the patient to the risks of transfusion-transmitted diseases.

Persons who are heterozygous for alpha 2-PI deficiency have variable bleeding, generally mild or none. Cautious treatment is warranted to protect the patient from unneeded surgery with subsequent bleeding.

Educate patients with alpha2–plasmin inhibitor (alpha2-PI) deficiency on a continuing basis, and encourage them to seek appropriate information, which will strengthen their ability to deal with this inherited disorder.

Discuss the potential thrombotic risk of antifibrinolytic agents. This author's practice is to request the pharmacist to provide the patient and family with package inserts for special drugs.

If plasma is used, discuss the potential risks of blood product use. No source of plasma is 100% safe. Moreover, the risks of transmission of viral illnesses vary according to the country of source of the plasma (see Factor VIII for a discussion of these issues, as well as Transfusion-Transmitted Diseases).

The National Hemophilia Foundation provides information and support for patients with bleeding disorders and their families.