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Alpha2-Plasmin Inhibitor Deficiency Medication

  • Author: Olga Kozyreva, MD; Chief Editor: Perumal Thiagarajan, MD  more...
 
Updated: Oct 21, 2015
 

Medication Summary

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.

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Antihemophilic Agents

Class Summary

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

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

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.

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.

Aminocaproic acid (Amicar)

 

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

Tranexamic acid (Cyklokapron)

 

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

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.

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Contributor Information and Disclosures
Author

Olga Kozyreva, MD Attending Physician, Division of Hematology-Oncology, St Elizabeth's Medical Center; Assistant Professor, Tufts University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

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, International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Jeanine Walenga, PhD 

Jeanine Walenga, PhD is a member of the following medical societies: American Society of Hematology, American Association for Clinical Chemistry, American Heart Association, American Society for Clinical Pathology, International Society on Thrombosis and Haemostasis

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.

Samer A Bleibel, MD Staff Physician, Department of Internal Medicine, Wayne State University School of Medicine, 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.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

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, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Investigation, Association of American Physicians, American Society for Biochemistry and Molecular Biology, American Heart Association, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

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 Transfusion

Disclosure: Nothing to disclose.

References
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  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. 1982 Jun. 59(6):1169-80. [Medline]. [Full Text].

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

  4. Bachmann F. The fibrinolytic system and thrombolytic agents. 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. Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 975-1002.

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The role of alpha2-plasmin inhibitor (alpha2-antiplasmin) in fibrinolysis.
 
 
 
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