eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Alpha2-Plasmin Inhibitor Deficiency

Olga Kozyreva, MD, Fellow, Department of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine
Samer A Bleibel, MD, Staff Physician, Department of Internal Medicine, Wayne State University, St John's Hospital and Medical Centers; Sarah K May, MD, Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC; Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems; Jeanine Walenga, PhD, Co-Director, Hemostasis Research Laboratory, Professor, Departments of Thoracic-Cardiovascular Surgery and Pathology, Loyola University Medical Center

Updated: Feb 5, 2009

Introduction

Background

Platelet disorders and inherited or acquired deficiencies of hemostatic factors (eg, factor VIII, factor IX, or von Willebrand factor [vWF]) lead to excessive bleeding, as is widely recognized. Widespread experience with the use of thrombolytic agents in acute myocardial infarction currently indicates that excess plasmin, generated by thrombolytic drugs, increases bleeding risk. However, the fact that a deficiency of alpha2-plasmin inhibitor (alpha 2-PI, a2-PI), a physiologic inhibitor of fibrinolysis, can lead to excessive bleeding is not widely appreciated.

To date, only 15 cases of congenital homozygous alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) and 7 molecular defects of the alpha 2-PI gene have been reported. The first reported case involved a 25-year-old Japanese homozygous male born of consanguineous parents.^{[1 ]}He had a lifelong history of severe bleeding, starting with bleeding from the umbilical cord at birth. The patient experienced hematomas, prolonged bleeding from cuts and after dental extraction, and muscle and joint bleeds following minor trauma.^{[1 ]}Central nervous system (CNS) bleeding has also been described in a Dutch patient who was homozygously deficient.^{[2 ]}

In 3 homozygous patients (sisters) from another Japanese family, bleeding was milder, with umbilical bleeding at birth followed by hematomas, gingival bleeding, and epistaxis without joint bleeding. The levels of alpha 2-PI were undetectable in all of the patients.

Most reported heterozygous patients did not have clinically significant bleeding, although some had a bleeding disorder. Currently, the reasons for variability in bleeding manifestations in heterozygous persons with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) are unclear.

Pathophysiology

Alpha 2-plasmin inhibitor (alpha 2-PI, a2-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.^{[3,4,5 ]} 

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.

Alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) belongs to the serpin family of inhibitors, is synthesized by the liver, and is present in plasma as a single-chain protein in approximately half the concentration of plasminogen. Two forms of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) are present in blood; 70% of alpha 2-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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) present in platelets contributes to inhibition of fibrinolysis in platelet-containing thrombi. Activated factor XIII (FXIIIa) cross-links alpha 2-PI to the a-chains of fibrin(ogen), thus making a cross-linked fibrin clot more resistant to lysis by plasmin.

Alpha 2-plasmin inhibitor (alpha 2-PI, a2-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 alpha 2-PI. The plasmin-alpha 2-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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI).

Alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) performs several functions. Alpha 2-PI inhibits free plasmin rapidly and more readily than fibrin-bound plasmin. Alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) 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, alpha 2-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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) to neutralize plasmin (since, in plasma, plasminogen levels are twice those of alpha 2-PI) alpha 2-macroglobulin can function as a less efficient backup inhibitor.

Conceptually, alpha 2-plasmin inhibitor (alpha 2-PI, a2-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.)^{[6 ]}

Other inhibitors, such as antithrombin, alpha 1-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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-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 (t-PA) and streptokinase, sudden generation of large amounts of plasmin overwhelms the neutralizing capacity of alpha 2-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 alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) 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.

Gene knockout mouse models of alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) show the expected accelerated clot lysis, but the mice do not manifest the bleeding disorder that is seen in humans.

Frequency

United States

Very few cases of inherited alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-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 (alpha 2-PI deficiency, a2-PI 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 (alpha 2-PI deficiency, a2-PI 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 (alpha 2-PI deficiency, a2-PI deficiency). Death may occur due to a CNS bleed or after major trauma.

• Patients with an inherited homozygous alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI 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 (alpha 2-PI deficiency, a2-PI deficiency) is described in Causes.

Race

No ethnic predilection for alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) is known at this time because the overall number of reported cases is so small.

Sex

Alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) is inherited as an autosomal recessive trait.

Age

Clinical manifestations of alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI 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.

Clinical

History

• In patients with severe alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-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

Physical findings in individuals with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) 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 arthropathy seen in patients with severe hemophilia can develop because of chronic joint bleeds.)
• Epistaxis and other mucosal bleeding
• Gastrointestinal tract bleeding
• CNS bleeding
• Menorrhagia starting at menarche

Causes

• Inherited reductions or inherited functional deficiencies of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) are due to specific defects in the gene coding for alpha 2-plasmin inhibitor, which is located on chromosome 17. The full genomic sequence and the functional implications of all its regions are not currently fully known. The molecular defect has been characterized in a few families.
  • 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 (alpha 2-PI deficiency, a2-PI deficiency) reflect the frequency of the associated disease state. Specific clinical conditions that lead to a reduction in the level of alpha 2-plasmin inhibitor are as follows:
• Neonates
  • Alpha 2-plasmin inhibitor (alpha 2-PI, a2-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-alpha 2-PI complex was increased in both healthy and ill neonates, with levels higher than those seen in adults.
• Pregnancy
  • Increased levels of alpha 2-plasmin inhibitor (alpha 2-PI, a2-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, t-PA levels increased starting early in labor and remained high after placental separation. However, after placental separation, an increase in plasmin–alpa 2-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-plasmin inhibitor (alpha 2-PI, a2-PI) has been proven in these patients.
• Liver disease
  • The liver plays a central role in hemostasis. Synthesis of alpha 2-plasmin inhibitor (alpha 2-PI, a2-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 alpha 2-plasmin inhibitor levels, and the reduction is probably a contributing factor in the well-recognized excessive fibrinolytic activity seen in some patients with liver disease.
  • Due to decreased synthesis of inhibitors, including alpha 2-plasmin inhibitor (alpha 2-PI, a2-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 thrombolytic therapy
  • Patients receiving activators of fibrinolysis, such as t-PA 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.^{[4,6,7,8 ]}Reduced alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) levels are common after the use of these agents, with a greater reduction after streptokinase than after t-PA administration. 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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-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 again undergone exploratory surgery for excessive bleeding following open heart surgery and who had negative intraoperative findings. The high local fibrinolytic activity with reduction of alpha 2-plasmin inhibitor (alpha 2-PI, a2-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.^{[9 ]}Alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) levels were reduced in the control group, with a marked increase in fibrin split-product and plasmin–alpha 2-PI complex levels, indicating fibrinolysis activation secondary to coagulation activation. Aprotinin treatment effectively suppressed hyperfibrinolysis and reduced postoperative blood loss.^{[9 ]}
• 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 t-PA levels, elevated ratios of t-PA to plasminogen activator inhibitor type 1, and reduced levels of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI). The supraceliac aortic clamping caused hepatocellular injury with prolonged circulation of t-PA, leading to a profibrinolytic state characterized by an excess generation of plasmin with alpha 2-plasmin inhibitor depletion.
• Lung cancer
  • Increased fibrinolytic activity of lung cancers has been documented over many years. In a series from Japan, 70 patients with both nonsmall cell and small cell lung cancer were studied. Increased levels of plasmin–alpha 2-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–alpha 2-PI complex, although they found a correlation between higher values of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) and histologic findings and/or the extent of disease. Plasmin–alpha 2-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-plasmin inhibitor (alpha 2-PI, a2-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-plasmin inhibitor (alpha 2-PI, a2-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-plasmin inhibitor (alpha 2-PI, a2-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.

Differential Diagnoses

Disseminated Intravascular Coagulation
Dysfibrinogenemia
Factor XIII

Other Problems to Be Considered

Other acquired causes of bleeding disorders

• Excess plasmin generated by use of thrombolytic drugs (t-PA, modified t-PA, streptokinase, modified streptokinase, urokinase)
• Excess plasmin generated by tumors that make activators (ie, acute promyelocytic leukemia, some lung cancers)
• Acquired coagulopathies
• Acquired platelet disorders
• Hemophilias
• Factor XIII deficiency
• Disease leading to reductions in alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) levels (see Causes)

Workup

Laboratory Studies

• Appropriate testing methodology (ie, functional vs antigenic, biologic vs chromogenic substrate assays) is an important consideration during the workup of patients with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) are reduced to a similar extent in most patients with severe alpha 2-plasmin inhibitor 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
  • Alpha 2-plasmin inhibitor levels
    • Evaluate alpha 2-plasmin inhibitor (alpha 2-PI, a2-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.
  • t-PA antigen and activity levels
  • Plasminogen functional activity levels
  • Levels of other inhibitors, including the following:
    • Alpha 2-macroglobulin
    • Alpha 1-antitrypsin
    • Alpha 1-chymotrypsin inhibitor
    • C1 inactivator of complement
    • Antithrombin

Imaging Studies

• Use computed tomography (CT) scanning, magnetic resonance imaging (MRI), or ultrasonography as needed for objective documentation of the size and resolution of bleeds.

Procedures

• Essential surgical procedures in those with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) should be performed only after re-evaluating the level of alpha 2-PI and after deciding on the need for plasma and administration of aminocaproic acid (Amicar).

Treatment

Medical Care

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 alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) that is a cause or the cause of acute excessive bleeding should receive a transfusion of fresh frozen plasma (FFP) as a source of alpha 2-plasmin inhibitor (alpha 2-PI , a2-PI) .
• Pooled plasma treated with solvent-detergent (PLAS+SD) is available to treat any condition in which FFP typically is used and for which no factor concentrate is available.^{[10,11 ]}Viral inactivation using the solvent-detergent (SD) process has been used in preparation of coagulation factor concentrates in the past. 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.
  • Studies of viral inactivation using the solvent-detergent process show significant inactivation of the human pathogenic viruses hepatitis B (HBV) and C (HCV) and human immunodeficiency virus (HIV). Other lipid-enveloped viruses (eg, Sindbis virus, bovine viral diarrhea virus) have also been used to monitor inactivation.
  • Information made available by the American Red Cross shows that although antiplasmin levels were somewhat reduced following solvent-detergent treatment, a higher-than-expected recovery of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) levels occurred in vivo after infusion of solvent detergent-treated plasma (untreated plasma = 0.70-1.30 U/mL, 5 lots tested; SD-treated plasma = 0.48 +/– 0.04 U/mL, 5 lots tested; in vivo recovery, 237 +/– 146%; n = 7).
  • PLAS+SD is ABO blood type specific, and solvent detergent-treated plasma should be ABO compatible with the recipient's red cells.
  • 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 IV therapy with antifibrinolytic drugs, such as EACA or tranexamic acid (AMCA; trans -p -aminomethyl-cyclohexane carboxylic acid, Cyklokapron), helps prevent the generation of plasmin and blocks its action.
  • EACA and AMCA 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.
  • Prolonged oral therapy with antifibrinolytic drugs reduces the frequency of bleeding in patients with severe alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency).
  • Other patients who have benefited from antifibrinolytic therapy, when appropriate, include individuals with acute promyelocytic leukemia, amyloidosis, some patients with liver disease (during the anhepatic phase of liver transplantation), some types of cancers, and acquired alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency).
  • Excluding a significant element of DIC is essential before using drugs inhibiting fibrinolysis, because thrombosis secondary to DIC is accelerated by adequately inhibiting fibrinolysis.
  • The increase in serious thrombotic complications, such as acute myocardial infarction and stroke, which was anticipated with wider use of antifibrinolytic drugs, has not materialized.
• Some authors have suggested prophylactic platelet transfusion, given the possible secretion of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) contained in the alpha granules of activated transfused platelets.

Surgical Care

Serious bleeding complications in those with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency), such as epidural or CNS hematomas, demand immediate surgical intervention. Such interventions must be coupled with plasma infusions to correct alpha 2-plasma inhibitor 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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-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.

Consultations

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

Diet

A patient with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) should follow a normal healthy diet.

Activity

• 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.

Medication

Traditionally, FFP has been the source of factors used to treat coagulation factor deficiencies for which no concentrates are available. Alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) falls into this category.

Careful screening of blood donors and viral testing of donated blood (testing for hepatitis B surface antigen [HBsAg] and antibody [HBsAb] to hepatitis B core antigen [HBcAg], HCV, antibody to HIV types 1 and 2, HIV p24 antigen, antibodies to human T-cell leukemia virus [HTLV] types I and II, and screening for elevated alanine aminotransferase [ALT] levels) have improved the safety of blood products, but risks remain for a variety of reasons, including failure to detect infections during the window or incubation period before the results of currently available tests become positive.

Other types of infections for which screening or testing is not available or for which the presence is unknown continue to cause concerns. Some emerging pathogens previously referred to include HIV type 2, HIV type O, hepatitis G, transfusion transmitted virus (TTV), human herpesvirus (HHV) 8, the SEN family of viruses, and prions causing Creutzfeldt-Jacob disease (CJD) and new variant Creutzfeldt-Jacob disease (nvCJD).^{[12,13,14 ]}

Higher risks of contracting virally transmitted illnesses remain in patients who are recipients of multiple units of FFP. The use of the solvent TNBP and the detergent Triton X-100 to treat pooled human plasmas (PLAS+SD) results in significant inactivation of lipid-enveloped viruses (eg, HIV, HCV, HBV). The greater degree of viral safety assured by this treatment has led to the exclusive use of PLAS+SD instead of FFP in some countries (Norway and Belgium).

PLAS+SD 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 alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) falls (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, PLAS+SD lacks the largest von Willebrand multimers and has proven efficacy in the treatment of a variety of bleeding disorders.

Disadvantages of PLAS+SD use include minor allergic reactions as observed with other blood products but which respond to antihistamines. PLAS+SD should not be administered in patients with known immunoglobulin A (IgA) deficiency.^{[10,11 ]}

Recovery of alpha 2-plasmin inhibitor (alpha 2-PI, a2-PI) after use of PLAS+SD: Mean recovery of alpha 2-plasmin inhibitor was 237% +/– 146% in 7 patients who received PLAS+SD and albumin during plasma exchange after they had undergone plasmapheresis to attain hypofibrinogenemic levels (<125 mg%).

All coagulation factor levels are stable for approximately 12 months when stored at – 18ºC, but they should be used within 24 hours of being thawed. Based on additional data that were submitted, PLAS+SD has a US Food and Drug Administration (FDA)-approved 2-year shelf life, according to Fred Darr, MD, of the American Red Cross (e-mail communication, February 2002). Therefore, evidence exists that activity remains stable during long-term storage.

All PLAS+SD units should be ABO compatible with the patient's red blood cells. Adverse reactions include minor allergic reactions and volume overload. 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.^{[10 ]}

See the drug tables in the Medication section below for further details of the use of PLAS+SD instead of FFP.

Newer emerging technologies, such as those using nucleic acid chemistry, are being used to inactivate viruses, bacteria, and parasites with an attempt to remove prions as well, thus making blood and blood components safer than they are currently. The newer technologies attempt to preserve clinically useful components of blood while improving its safety. The methodologies could potentially be used to improve the safety of a wide variety of products.

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 EACA and AMCA. 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.

Please see the References section for sources that provide further details of these interactions.

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.

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

The dose of EACA and AMCA must be reduced when renal failure is present.

Aprotinin, an antifibrinolytic agent used to reduce operative blood loss in patients undergoing open heart surgery,^{[9 ]}is now only available via a limited-access protocol. Fergusson et al reported an increased risk for death compared with tranexamic acid (AMCA) or aminocaproic acid (EACA) in high-risk cardiac surgery.^{[15 ]} For more information, see the Further Reading section.

Aprotinin administration has also reduced blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation or in patients undergoing elective resection of a solitary liver metastasis originating from colon cancer.

Antihemophilic Agents

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.

Pooled plasma, solvent-detergent treated (PLAS+SD)

Manufactured by the American Red Cross and VI Technologies, Inc, SD treatment of pooled human plasma removes lipid-enveloped viruses, making this product safer than untreated FFP.

SD treatment does not remove all viruses from plasma. Efficacy and safety has been proven in the treatment of several coagulopathies. Per the package insert, the half-life of coagulation factors in recipients of this product were similar to reference values.^{[11 ]}

If available, SD-treated plasma can be used in patients with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency), because no concentrate is available to treat alpha 2-plasmin inhibitor deficiency. As with any bleeding disorder, serial measurement of the specific coagulation factor is essential to assure hemostatically adequate levels.

On average, one 200-mL bag of PLAS+SD raises factor levels by approximately 2-3%, whereas 4-6 bags raise factor levels by approximately 8-18% in a 70-kg person. These numbers do not specifically apply to alpha 2-plasmin inhibitor and are being provided only as a general guide. Serial testing of required alpha 2-plasmin inhibitor levels is necessary to monitor patient levels.

Store PLAS+SD at -18°C or lower and thaw at 30-37°C in a water bath with very gentle shaking. Once thawed, keep at room temperature and use as soon as possible and preferably within 24 hours. Do not store thawed material in the refrigerator.

Dosing

Adult

10-15 U/kg IV or one 200-mL bag IV initially, depending on cardiovascular tolerance of patient and rapidity of desired effect

Pediatric

Administer as in adults, based on body weight.

Interactions

None reported

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Viral contamination and infection are possible but unlikely due to prescreening; ineffective in patients with factor IX inhibitors; may induce anamnestic response; use in pregnancy only when specifically indicated; see package insert regarding lack of mutagenicity and lack of reproduction toxicity by residual small amounts of TNBP and Triton X-100; no studies have been conducted on carcinogenicity or impairment of fertility

Aminocaproic acid (Amicar)

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

Dosing

Adult

5 g PO initially, followed by 1 g/h PO for 8 doses or until active bleeding controlled, then taper

Frequency of maintenance dosing can be lengthened if needed (2 g PO q2h) to reduce frequency for patients taking the drug at home

Alternatively, 5 g IV over 30 min to 1 h, followed by 1 g/h IV, followed by maintenance dose of 1 g/h or equivalent dose q2h, q3h, or q4h PO/IV or 0.1 g/kg q4-6h IV; not to exceed 30 g/d

Pediatric

Not established.

Suggested loading dose is 100-200 mg/kg IV over 30 min, followed by maintenance dose of 30 mg/kg/h or 100 mg/kg q6h; alternatively, 1 g/m²/h; not to exceed 18 g/m²/d

Interactions

Coadministration with estrogens may cause an increase in clotting factors, leading to hypercoagulability.

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; aminocaproic acid can be fatal in patients with DIC; therefore, differentiating between hyperfibrinolysis and DIC is important

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer unless a definitive diagnosis of hyperfibrinolysis has been made; caution in patients with cardiac, hepatic, or renal disease (reduce dose); benzyl alcohol can cause toxicity in newborns and is not recommended; continuous IV infusion is generally not recommended; one third of patients receiving large and prolonged PO doses experience adverse GI tract effects (eg, abdominal pain, nausea, diarrhea); dizziness may occur; occasional reports of myopathy and rhabdomyolysis have been recorded after prolonged high-dose therapy, with resolution after withdrawal.

Tranexamic acid (Cyklokapron)

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

Dosing

Adult

25 mg/kg PO tid/qid starting 1 d before surgery, continue for 2-8 d prn; combine with IV factor IX concentrate just before surgery

Alternatively, 10 mg/kg IV together with factor IX concentrate (single dose) just before dental extraction, continue tid/qid for several days prn

Dose adjustment in renal failure:

Mild failure: Change to bid from tid/qid frequency

Moderate failure: 10 mg/kg/d IV or 15 mg/kg/d PO

Severe impairment: 7.5 mg/kg/d IV/PO

Pediatric

10 mg/kg IV slowly initially, followed by 25 mg/kg IV q6-8h

Interactions

Reduces effects of fibrinolytic agents

Contraindications

Documented hypersensitivity; active DIC; acquired defective color vision; subarachnoid hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Dose reduction in the presence of renal failure; possibly associated with thrombosis or thromboembolism; continuous IV infusion generally not recommended

Aprotinin injection (Trasylol)

5/14/08: Only available via limited-access protocol.

Broad-spectrum protease inhibitor that modulates the systemic inflammatory response associated with bypass surgery and results in attenuation of inflammatory response and thrombin generation and in fibrinolytic response. In platelets, reduces glycoprotein loss, whereas in granulocytes, prevents expression of proinflammatory adhesive glycoproteins. Thus, not a pure inhibitor of fibrinolysis.

Is a nonhuman protein obtained from bovine lung, with a potential for sensitization and allergic reactions, especially with repeated administration. Reactions range from rashes to anaphylaxis and death. A 5% risk exists for sensitization with repeated exposure. Premedication with 50 mg of diphenhydramine and 300 mg of cimetidine IV with 650 mg of acetaminophen PO is administered 30 min before a small test dose, followed by a 30-min infusion of the regular dose to avoid hypotension.

Is an injectable drug that has been used successfully to reduce bleeding in patients undergoing cardiopulmonary bypass, which is the FDA-approved indication.

Two dosage regimens (A and B) have been shown to reduce bleeding in patients in a randomized clinical trial who underwent repeat CABG surgery. Patients receiving drug regimen A or B were compared with patients receiving only placebo or patients in whom the drug was only injected into the priming fluid.
Interestingly, 1100 patients in the study who were older than 65 years had outcomes no different than the outcomes seen in younger adults.

Dosing

Adult

Regimen A: 2 million kallikrein-inhibiting units (KIU) IV loading dose, 2 million KIU into pump prime volume during bypass surgery, and 500,000 KIU/h during surgery as continuous infusion

Regimen B: 1 million KIU loading dose IV, 1 million KIU into pump prime fluid, and 250,000 KIU/h during surgery as continuous infusion

Open heart surgery: 280 mg IV followed by infusion of 70 mg/h with additional 280 mg added to pump; half dose has been used in low-dose regimen; range of 2-5 million KIU has been suggested

Pediatric

Not established

Interactions

Inhibits fibrinolytic activity; likely to interfere with effects of thrombolytic agents; prolongs ACT in presence of heparin; kaolin-activated clotting time is affected much less; not a heparin-sparing agent; has been shown to block antihypertensive effect of captopril in patients with hypertension

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Administer test dose in all patients per the package insert; administer 1 mL IV at least 10 min before the IV loading dose; allergic reactions can occur later, even if test dose was uneventful; in case of allergic reaction, discontinue immediately and use standard antianaphylaxis measures; patients with allergies to other drugs may be at higher risk for allergic reactions.

Administer loading dose over 20-30 min with patient supine; possible hypotension with rapid IV infusion; approximately 2.7% of 387 European patients (retrospective review) who were re-exposed to aprotinin developed hypersensitivity/anaphylactic reactions, with 2 of 387 patients dying postoperatively; before re-exposure, administer H1 and H2 blockers 15 min before the test dose; delay addition of aprotinin into pump after loading dose; good IV access and availability of epinephrine and steroids have been suggested as useful measures; if patient has experienced anaphylaxis with aprotinin and requires use of antifibrinolytic drug, use alternative drugs (ie, EACA or AMCA)

Follow-up

Further Inpatient Care

• Prolonged therapy with FFP or PLAS+SD and antifibrinolytics may be needed in those who have alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency), depending on the clinical circumstance.

Further Outpatient Care

• 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 alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency). Monitor patients closely, and determine the appropriate duration of therapy by clinical observation of the patient.
• Prophylactic care: Long-term oral therapy with antifibrinolytics has successfully reduced the incidence of bleeding in patients with inherited alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency).

Inpatient & Outpatient Medications

• Long-term maintenance therapy with oral antifibrinolytic agents has reduced the incidence of bleeding complications in alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency). For dosing, please see the Medication section.
• Avoidance of antiplatelet drugs is essential because these agents increase bleeding risk.

Transfer

• A patient with persistent bleeding in the postoperative period resulting from alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) may require transfer to a tertiary medical center if specialists with expertise are not available at the local community hospital.

Deterrence/Prevention

• Avoidance of trauma and the use of NSAIDs can minimize the frequency of bleeding complications.
• Prevention is not feasible for the genetic defect that causes alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency). Prenatal testing of a known defect may be attempted in a family in which members experience severe bleeding.
• Immunization against HAV and HBV is useful in patients who require administration of plasma products. Although reports of blood-borne 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 hepatic failure. Therefore, immunizing patients against any form of hepatitis for which a vaccine is available is wise.^{[12,16 ]}HAV vaccination conforms with recommendations of the National Hemophilia Foundation for patients receiving any kind of blood products on a recurrent basis.

Complications

• Complications of alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) relate to the site at which excessive bleeding develops. Bleeding is aggravated by concomitant use of drugs that induce additional hemostatic dysfunction, such as acetylsalicylic acid (ASA) or other NSAIDs. Other complications include the following^{[12,13,16 ]}:
  • Infection by HIV (including type 2 and HIV group O), HHV-8, acquired immunodeficiency syndrome (AIDS), hepatitis (hepatitis A-E viruses, hepatitis GB virus C, hepatitis G virus), parvovirus infection, and SEN viruses
  • CJD and nvCJD resulting from prions: One review raised concerns about the transmission of CJD or its variant form (vCJD) from blood products.^{[17 ]}The FDA's Transmissible Spongiform Encephalopathies Advisory Committee has proposed excluding donors who have resided or traveled in Europe for more than 5 years starting in 1980 or donors who have resided in the United Kingdom for more than 3 months. The availability of a new test for vCJD is anticipated.
  • Other complications may result from viral illnesses transmitted by human plasma.

Prognosis

• People who are homozygous for alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) have a severe bleeding disorder, but if appropriate treatment is received, long-term survival is possible. The frequent need for plasma transfusions exposes the patient to the risks of virally transmitted illnesses, including HIV, hepatitis, parvovirus, TTV, nvCJD due to prions, and other pathogens.
• People who are heterozygous for alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) have variable bleeding, generally mild or none. Cautious treatment is warranted to protect the patient from unneeded surgery with subsequent bleeding.

Patient Education

• Educate patients with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-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 the eMedicine topic 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.

Miscellaneous

Medicolegal Pitfalls

• Failure to make a timely diagnosis of alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) due to lack of recognition
• Failure to obtain appropriate laboratory tests
• Failure to alert patients to the risk of thrombosis with use of antifibrinolytic agents
• Failure to alert patients to the risk of viral transmission with use of blood products

Special Concerns

• Difficulty of diagnosing the disorder of alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency)
• Discussion with patients regarding the role of consanguinity, as appropriate
• Carrier detection in the future in families in which the defect is known to exist
• Perform fibrinolytic tests in patients presenting with bleeding episodes, particularly if delayed after surgical procedures, and no other type of hemostatic disorders. This is particularly relevant in those countries with high rates of consanguinity and a higher incidence of recessively inherited disorders.

Multimedia

Media file 1: The role of alpha2-plasmin inhibitor (alpha2-antiplasmin) in fibrinolysis.

References

1. Koie K, Kamiya T, Ogata K, Takamatsu J. Alpha2-plasmin-inhibitor deficiency (Miyasato disease). Lancet. Dec 23-30 1978;2(8104-5):1334-6. [Medline].

2. Kluft C, Vellenga E, Brommer EJ, Wijngaards G. A familial hemorrhagic diathesis in a Dutch family: an inherited deficiency of alpha 2-antiplasmin. Blood. Jun 1982;59(6):1169-80. [Medline]. [Full Text].

3. Bachmann F. Plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:275-320.

4. Bachmann F. The fibrinolytic system and thrombolytic agents. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. Berlin, Germany: Springer-Verlag; 2001:3-15.

5. Francis CW, Marder VJ. Physiologic regulation and pathologic disorders of fibrinolysis. In: Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:975-1002.

6. Castellino FJ, Ploplis VA. Plasminogen and streptokinase. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. Berlin: Springer-Verlag; 2001:26-56.

7. Hedner U, Hirsh J, Marder VJ. Therapy with antifibrinolytic agents. In: Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:796-813.

8. Bachmann F. Disorders of fibrinolysis and use of antifibrinolytic agents. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6^th ed. New York, NY: McGraw-Hill; 2001:1829-40.

9. Davis R, Whittington R. Aprotinin. A review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs. Jun 1995;49(6):954-83. [Medline].

10. American Red Cross. PLAS+SD (pooled plasma, solvent-detergent treated) (monograph). Arlington, Va: American Red Cross, VI Technologies, Inc.; 1999.

11. PLAS+SD (Pooled Plasma, (Human) Solvent Detergent Treated) [package insert]. Washington DC: American Red Cross, VI Technologies, Inc; October 2000.

12. MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Paper presented at: 53rd Annual Meeting of the National Hemophilia Foundation. November 16, 2001; Nashville, Tenn.

13. Rigas B, Hasan I, Rehman R, et al. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. Dec 8 2001;358(9297):1961-2. [Medline].

14. Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. Oct 15 2001;98(8):2571-3. [Medline]. [Full Text].

15. [Best Evidence] Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. May 29 2008;358(22):2319-31. [Medline]. [Full Text].

16. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. Dec 8 2001;358(9297):1925-6. [Medline].

17. Senior K. New variant CJD fears threaten blood supplies. Lancet. Jul 28 2001;358(9278):304. [Medline].

18. Dale GL, Friese P, Batar P, et al. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature. Jan 10 2002;415(6868):175-9. [Medline].

19. Favier R, Aoki N, de Moerloose P. Congenital alpha(2)-plasmin inhibitor deficiencies: a review. Br J Haematol. Jul 2001;114(1):4-10. [Medline].

20. Hanss MM, Farcis M, Ffrench PO, de Mazancourt P, Dechavanne M. A splicing donor site point mutation in intron 6 of the plasmin inhibitor (alpha2 antiplasmin) gene with heterozygous deficiency and a bleeding tendency. Blood Coagul Fibrinolysis. Jan 2003;14(1):107-11. [Medline].

21. Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M. Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood. Apr 1 1999;93(7):2274-81. [Medline]. [Full Text].

22. Maino A, Garagiola I, Artoni A, Al-Humood S, Peyvandi F. A novel mutation of alpha2-plasmin inhibitor gene causes an inherited deficiency and a bleeding tendency. Haemophilia. Jan 2008;14(1):166. [Medline].

23. Mangel WF, Lin BH, Ramakrishnan V. Characterization of an extremely large, ligand-induced conformational change in plasminogen. Science. Apr 6 1990;248(4951):69-73. [Medline].

Keywords

alpha2-plasmin inhibitor deficiency, alpha 2-PI deficiency, a2-PI deficiency, α₂ -plasmin inhibitor deficiency, alpha2-antiplasmin, fast-acting plasmin inhibitor, α₂ PI deficiency, bleeding disorders, hemostasis, plasmin inhibitors,

inherited alpha2-plasmin inhibitor deficiency, acquired alpha2-plasmin inhibitor deficiency, prolonged bleeding, mucosal bleeding, increased bruising, increased hematomas, muscle bleeding, bleeding into joints, excessive bleeding, excessive bruising

Contributor Information and Disclosures

Author

Olga Kozyreva, MD, Fellow, Department of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Samer A Bleibel, MD, Staff Physician, Department of Internal Medicine, Wayne State University, St John's Hospital and Medical Centers
Samer A Bleibel, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Sarah K May, MD, Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC
Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Jeanine Walenga, PhD, Co-Director, Hemostasis Research Laboratory, Professor, Departments of Thoracic-Cardiovascular Surgery and Pathology, Loyola University Medical Center
Jeanine Walenga, PhD is a member of the following medical societies: American College of Angiology, American Heart Association, American Society for Clinical Pathology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

S Gerald Sandler, MD, FACP, FCAP, Professor of Medicine and Pathology; Director, Transfusion Medicine, Department of Laboratory Medicine, Georgetown University Hospital
S Gerald Sandler, MD, FACP, FCAP is a member of the following medical societies: American Association of Blood Banks, College of American Pathologists, International Society of Blood Transfusions, and Medical Society of the District of Columbia
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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• Hepatitis E

Suggested Reading

• Ray WA, Stein CM. The aprotinin story--is BART the final chapter?. N Engl J Med. May 29 2008;358(22):2398-400. [Medline].
• Food and Drug Administration. 2007 safety alerts for drugs, biologics, medical devices, and dietary supplements: Trasylol (aprotinin injection). Updated: May 14, 2008. Available at: http://www.fda.gov/medwatch/safety/2007/safety07.htm#Trasylol. Accessed: February 5, 2009.

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