AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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 a₂-plasmin inhibitor (a₂PI), a physiologic inhibitor of fibrinolysis, can lead to excessive bleeding is not widely appreciated.

Very few cases of a₂PI deficiency have been reported. The first reported case involved a 25-year-old Japanese homozygous male born of consanguineous parents. 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. Central nervous system (CNS) bleeding also has been described in a Dutch patient who was homozygously deficient. 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 a₂PI 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 are unclear.

Pathophysiology

a₂PI 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. 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.

a₂PI 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 a₂PI are present in blood; 70% of a₂PI binds plasminogen and has inhibitory activity, while 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 a₂PI present in platelets contributes to inhibition of fibrinolysis in platelet-containing thrombi. Activated factor XIII (FXIIIa) cross-links a₂PI to the a-chains of fibrin(ogen), thus making a cross-linked fibrin clot more resistant to lysis by plasmin.

a₂PI 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 a₂PI. The plasmin-a₂PI complex is cleared more rapidly from the circulation. Half-life of the complex is approximately 12 hours compared to the longer half-life of 3 days for native a₂PI.

a₂PI performs several functions. a₂PI inhibits free plasmin rapidly and more readily than fibrin-bound plasmin. a₂PI 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 also are 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, a₂PI 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 a₂PI to neutralize plasmin (since in plasma, plasminogen levels are twice those of a₂PI) a₂-macroglobulin can function as a less efficient backup inhibitor. Conceptually, a₂PI neutralizes plasmin at various sites of plasmin production, including in the fibrin clot, on the surface of cells, and in the fluid phase (see Castellino, 2001, Figure 2 for an excellent diagram showing these details).

Other inhibitors, such as antithrombin, a₁-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 a₂PI, 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 a₂PI. 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 a₂PI deficiency have a clinically significant bleeding disorder 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 a₂PI deficiency show the expected accelerated clot lysis, but the mice do not manifest the bleeding disorder seen in humans.

Frequency

United States

Very few cases of inherited a₂PI 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, frequency of genetic defects will be known, and frequency of these rare disorders can then be determined.

Frequency of acquired a₂PI deficiency depends on the frequency of the underlying disorders. As discussed in Causes, excessive bleeding can occur when a₂PI levels are deficient.

Mortality/Morbidity

Homozygous patients have severe bleeding requiring plasma therapy to limit the bleed and to maintain plasma levels until the acute bleed 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 AIDS and its sequelae, are needed in patients with a₂PI deficiency. Death may occur due to a CNS bleed or after major trauma.

• Patients with an inherited homozygous a₂PI 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.
• Frequency of a bleeding disorder reportedly varies among patients who are heterozygous for a₂PI 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 a₂PI deficiency is described in Causes.

Race

No ethnic predilection is known at this time because the overall number of reported cases is so small.

Sex

The disorder is inherited as an autosomal recessive trait.

Age

Clinical manifestations of a₂PI 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

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History

• In patients with severe a₂PI 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 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

Family studies in the few cases reported thus far suggest that a₂PI deficiency is inherited as an autosomal recessive trait.

• Inherited reductions or inherited functional deficiencies of a₂PI are due to specific defects in the gene coding for a₂PI, 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 one family with severe deficiency, a trinucleotide deletion led to the synthesis of a dysfunctional protein, which was retained within the cell.
  • In a second 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 a₂PI deficiency reflect the frequency of the associated disease state. Specific clinical conditions that lead to a reduction in the level of a₂PI are as follows:
• • Neonates: a₂PI 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-a₂PI complex was increased in both healthy and ill neonates, with levels higher than those seen in adults.
  • Pregnancy
    • Increased levels of a₂PI 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–a₂PI complex levels occurred together with an increase in fibrinopeptide A and thrombin-antithrombin complex levels, indicating activation of fibrinolysis prior to 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 a₂PI has been proven in these patients.
  • Liver disease
    • The liver plays a central role in hemostasis. Synthesis of a₂PI 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 a₂PI 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 a₂PI, 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. Reduced a₂PI 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 a₂PI 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 a₂PI 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. a₂PI levels were reduced in the control group, with a marked increase in fibrin split-product and plasmin-a₂PI complex levels, indicating fibrinolysis activation secondary to coagulation activation. Aprotinin treatment effectively suppressed hyperfibrinolysis and reduced postoperative blood loss.
  • 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 a₂PI. 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 a₂PI depletion.
  • Lung cancer: Increased fibrinolytic activity of lung cancers has been documented over many years. In a recent series from Japan, 70 patients with both nonsmall cell and small cell lung cancer were studied. Increased levels of plasmin-a₂PI complex had prognostic significance and predicted poor survival independent of other factors, such as histologic findings, age, sex, and presence of metastatic disease, compared to control subjects. Other studies of patients with lung cancer confirmed the presence of increased levels of plasmin-a₂PI complex, although they found a correlation between higher values of a₂PI and histologic findings and/or the extent of disease. Plasmin-a₂PI 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-a₂PI complex. In addition, the former group had higher thrombomodulin levels, while the latter 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 a₂PI 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 a₂PI levels were reduced, with increased levels of plasmin-a₂PI complex present before hemodialysis. Serial sampling during a hemodialysis session showed a continuous fall in a₂PI levels, with rising levels of plasmin-a₂PI 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 a₂PI levels have been used as a criterion to treat these patients with e-aminocaproic acid (EACA) in combination with heparin, with improvement in bleeding and in abnormal laboratory test findings.

DIFFERENTIALS

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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 a₂PI levels (see Causes)

WORKUP

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Lab Studies

• Appropriate testing methodology (ie, functional vs antigenic, biologic vs chromogenic substrate assays) is an important consideration during the workup of patients with a₂PI 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 a₂PI are reduced to a similar extent in most patients with severe a₂PI deficiency. Patients with a dysfunctional molecule who have reduced functional activity with reference antigen values for the inhibitor also have 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
• • a₂PI levels: Evaluate levels using antigenic and functional assays. Perform functional assays using 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:
    • a₂-Macroglobulin

    • a₁-Antitrypsin

    • a₁-Chymotrypsin inhibitor

    • C1 inactivator of complement

    • Antithrombin

Imaging Studies

• Use CT scan, MRI, or ultrasound as needed for objective documentation of size and resolution of bleeds.

Procedures

• Essential surgical procedures should be performed only after re-evaluating the level of a₂PI and deciding on the need for plasma and administration of Amicar.

TREATMENT

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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 also may require surgical intervention.

• Patients with inherited or acquired a₂PI 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 a₂PI.


• 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. 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 SD process show significant inactivation of the human pathogenic viruses hepatitis B and C and HIV. Other lipid-enveloped viruses (eg, Sindbis virus, bovine viral diarrhea virus) also have been used to monitor inactivation.
  
  
  • Information made available by the American Red Cross shows that although antiplasmin levels were somewhat reduced following SD treatment, a higher-than-expected recovery of a₂PI levels occurred in vivo after infusion of SD-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 SD-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), helps prevent the generation of plasmin and blocks its action.
• • EACA and AMCA are synthetic lysine analogs 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 a₂PI 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 transplant), some types of cancers, and acquired a₂PI 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.

Surgical Care

Serious bleeding complications, such as epidural or CNS hematomas, demand immediate surgical intervention. Such interventions must be coupled with plasma infusions to correct a₂PI 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 a₂PI 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 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 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

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Traditionally, FFP has been the source of factors used to treat coagulation factor deficiencies for which no concentrates are available. a₂PI falls into this category.

Careful screening of blood donors and viral testing of donated blood (testing for hepatitis B surface antigen and antibody to hepatitis B core antigen, hepatitis C virus, antibody to HIV types 1 and 2, HIV p24 antigen, antibodies to human T-cell leukemia virus 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 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 (TT) virus, human herpesvirus 8, the SEN family of viruses, and prions causing Creutzfeldt-Jacob disease (CJD) and new variant Creutzfeldt-Jacob disease (nvCJD).^{1, 2, 3}

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, hepatitis C, hepatitis B). 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 a₂PI (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 deficiency.

Recovery of a₂PI after use of PLAS+SD: Mean recovery of a₂PI 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 should be used within 24 hours of being thawed. Currently, based on additional data 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 (Fred Darr, MD, email, 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 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.⁴

See the drug tables 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 analogs such as EACA (6-aminohexanoic acid, Amicar) and AMCA (trans-p-aminomethyl-cyclohexane carboxylic acid, Cyklokapron).

These synthetic lysine analogs 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 analogs 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 Bibliography for references 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 also is 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 (Trasylol), a third antifibrinolytic drug obtained from bovine lung, is a nonhuman protein inhibitor of several serine proteases, including plasmin. Aprotinin is approved by the FDA for use in patients undergoing open heart surgery to reduce operative blood loss. Aprotinin administration also has 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. Aprotinin is the most expensive of the 3 drugs discussed here.

Drug Category: Antihemophilic agents

Administer inhibitors of fibrinolysis together with FFP replacement in patients 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.

FOLLOW-UP

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Further Inpatient Care

• Prolonged therapy with FFP or PLAS+SD and antifibrinolytics may be needed 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. 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 a₂PI deficiency.

In/Out Patient Meds

• Long-term maintenance therapy with oral antifibrinolytic agents has reduced the incidence of bleeding complications. For dosing, please see Medications.


• Avoidance of antiplatelet drugs is essential because they increase bleeding risk.

Transfer

• A patient with persistent bleeding in the postoperative period resulting from a₂PI 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. Prenatal testing of a known defect may be attempted in a family in which members experience severe bleeding.


• Immunization against hepatitis A and B 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.^{5, 1} HAV vaccination conforms with recommendations of the National Hemophilia Foundation for patients receiving any kind of blood products on a recurrent basis.

Complications

• Complications 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 or other NSAIDs. Other complications include the following:^{2, 5, 1}
• • Infection by HIV (including type 2 and HIV group O), human herpesvirus 8, AIDS, hepatitis (hepatitis A-E viruses, hepatitis GB virus C, hepatitis G virus), parvovirus infection, and SEN viruses
  
  
  • CJD and nvCJD resulting from prions: A recent review raises concerns about the transmission of CJD or its variant form (vCJD) from blood products. 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.⁶
  
  
  • Other complications may result from viral illnesses transmitted by human plasma.

Prognosis

• People who are homozygous 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, TT virus, nvCJD due to prions, and other pathogens.
• People who are heterozygous 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 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).


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

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to make a timely diagnosis 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 disorder
• Discussion with patients of role of consanguinity as appropriate
• Carrier detection in the future in families in which the defect is known to exist

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Alpha2-plasmin inhibitor deficiency. The role of α2-plasmin inhibitor (α2-antiplasmin) in fibrinolysis.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Report published Nov 16, 2001.
2. 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].
3. 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].
4. ARC. PLAS+SD (pooled plasma, solvent-detergent treated). Monograph by the American Red Cross and V. I. Technologies, Inc. Monograph No. VIT-001A9/99. 1999:1-56.
5. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. Dec 8 2001;358(9297):1925-6. [Medline].
6. Senior K. New variant CJD fears threaten blood supplies. Lancet. Jul 28 2001;358(9278):304. [Medline].
7. ARC. Product circular (package insert) for pooled plasma, solvent-detergent treated (PLAS+SD). VI Technologies and American Red Cross;Oct 2000.
8. Bachmann F. Disorders of fibrinolysis and use of antifibrinolytic agents. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill;2001:1829-40.
9. Bachmann F. Plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Lippincott Williams & Wilkins;2001:275-320.
10. Bachmann F. The fibrinolytic system and thrombolytic agents. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. Berlin: Springer-Verlag;2001:3-15.
11. Castellino FJ, Ploplis VA. Plasminogen and streptokinase. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. Berlin: Springer-Verlag;2001:26-56.
12. 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].
13. 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. 4th ed. Lippincott Williams & Wilkins;2001:975-1002.
14. 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. 4th ed. Lippincott Williams & Wilkins;2001:796-813.
15. 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].
16. 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].
17. Lijnen HR, Okada K, Matsuo O, et al. Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood. Apr 1 1999;93(7):2274-81. [Medline].
18. 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].

Article Last Updated: May 23, 2007