Antithrombin Deficiency Medication

A nonrandomized open-label phase III trial of recombinant human antithrombin (rhAT) in patients with hereditary antithrombin deficiency (AT deficiency) in high-risk situations for thrombosis (nonpregnant surgical patients or pregnant patients scheduled for cesarean section or delivery induction) was completed in February 2008 and approved by the US Food and Drug Administration (FDA) in early 2009 and marketed under the trade name ATryn.

Recombinant human antithrombin is also approved for use in Europe for the prophylaxis of venous thromboembolism in the surgery of patients with congenital antithrombin deficiency (AT deficiency).

Plasma-derived antithrombin has been approved by the FDA for use in patients with hereditary antithrombin III deficiency (ATIII deficiency). In patients with a congenital deficiency of antithrombin III, replacement/prophylaxis is recommended (1) before or following major surgery, (2) during bed rest for longer than 24 hours (because of the increased risk of thrombosis), (3) for thrombosis during pregnancy to allow heparin to be effective, and (4) for acute DVT/PE.

Many acquired causes have been associated with antithrombin deficiency (AT deficiency); however, none of them has garnered FDA approval based on published clinical trials. It must be stated that, in patients with shock and DIC due to trauma, sepsis, or hepatic coma, the duration of DIC symptoms was significantly shorter in patients treated with antithrombin III alone than in patients who received heparin alone. The duration of symptoms with the combined use of heparin and antithrombin III was between the other two. As expected, patients with DIC due to polytrauma who were also receiving heparin had a greater tendency to bleed.

The reader is encouraged to review the FDA package insert with each product that is used for therapy.

FFP has traditionally been the source of factors to treat coagulation factor deficiencies for which no concentrates are available. Alpha2-plasmin inhibitor falls into that category.

Careful screening of blood donors and viral testing of donated blood (HBV surface antigen [HBsAg] and antibody to HBV core antigen [HBcAg], HCV, antibody to HIV-1 and HIV-2, HIV p24 antigen, antibodies to human T-cell lymphotropic virus [HTLV]-I and HTLV-II, screening for an elevated alanine aminotransferase [ALT] level) 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 continue to cause concerns, including those for which we currently do not screen, do not have tests, or do not know of their presence. Some of the previously mentioned emerging pathogens include HIV-2, HIV type O, hepatitis G virus (HGV), TT virus (TTV), human herpesvirus (HHV)-8, the SEN family of viruses, and prions causing Creutzfeldt-Jakob disease (CJD) and new variant CJD (nvCJD).^{[42, 43, 44]}

Higher risks of virally transmitted illnesses remain among patients who are recipients of multiple units of FFP. The use of solvent (TNBP) and detergent (Triton X-100) to treat pooled human plasmas 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 (eg, Norway, Belgium).

SD-treated plasma delivers consistent and reproducible levels of coagulation factors. In contrast to the extreme variability in FFP, no leukocytes are present, and physiologic inhibitor levels are mostly in the normal range, with the exception of a moderate reduction in the levels of alpha2-plasmin inhibitor (~0.48 IU/mL) and protein S (~0.52 IU/mL). In addition, coagulation zymogens are not activated, levels of other plasma proteins and immunoglobulins are normal, and all lots have anti–hepatitis A virus (HAV) antibody levels of more than 0.8 IU/mL, providing passive administration of antibody, which may neutralize HAV. SD-treated plasma also lacks the largest von Willebrand multimers and has a proven efficacy in the treatment of a variety of bleeding disorders.

PLAS+SD's disadvantages include minor allergic reactions as observed with other blood products but which respond to antihistamines. This product should not be given to patients with known immunoglobulin A (IgA) deficiency.

Alpha2-plasmin inhibitor recovery after use of PLAS+SD: Mean recovery of alpha2-plasmin inhibitor was 237% ± 146% in 7 patients who had received SD plasma and albumin during plasma exchange after they had undergone plasmapheresis to hypofibrinogenemic levels (< 125%).^[45] All coagulation factor levels are stable for approximately 12 months when stored at -18°C, but PLAS+SD should be used within 24 hours of being thawed.

All PLAS+SD units should be ABO compatible with each patient's red blood cells. Adverse effects include minor allergic reactions and volume overload. Rarely, citrate toxicity, hypothermia, other metabolic problems (if large volumes are used rapidly), and noncardiogenic pulmonary edema arise. Antibody-induced positive direct antiglobulin test results and hemolysis may also occur rarely.

See 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 also remove prions, thus making blood and blood components safer than they are today. These newer technologies attempt to preserve the clinically useful components of blood while improving its safety. These methodologies could 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 (epsilon amino-caproic acid) (6-aminohexanoic acid [Amicar]) and trans- p-aminomethyl-cyclohexane carboxylic acid (AMCA, tranexamic acid [Cyklokapron]). These synthetic lysine analogues induce a conformational change in plasminogen when they bind to its lysine-binding site. The plasminogen has the shape of a prolate ellipsoid after EACA binds to it. It elongates into a long structure in which the interaction between the parts of plasminogen as they existed is lost. In vivo, they probably prevent plasminogen activation and, in large doses, also bind plasmin, thereby preventing it from binding to its substrate, fibrin.

When looking at binding sites on plasminogen for EACA, the tightest binding is to kringle 1 followed by kringles 4 and 5. The 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 the hydrophobic amino acids is surrounded by positively and negatively charged amino acids at an ideal distance to interact with EACA.

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

AMCA is also rapidly excreted in the urine, with more than 90% excreted in 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 given 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. It is approved by the FDA for use in patients undergoing open heart surgery to reduce operative blood loss. Aprotinin administration has also reduced blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation and in patients undergoing elective resection of a solitary liver metastasis originating from colon cancer. Aprotinin is the most expensive of the 3 drugs discussed here, and it is now only available via a limited-access protocol. Fergusson et al reported an increased risk for death compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery.^[46]

Class Summary

Antithrombin concentrates are used to raise the plasma antithrombin level from a reduced value to approximately 120%. The goal is to maintain the level of antithrombin activity at a minimum of about 80% at all times. Serial monitoring of levels is necessary to ensure an adequate level. The anticoagulant effect of heparin is enhanced by antithrombin; thus, monitoring of the aPTT is necessary to determine the need to reduce the heparin dosage when heparin is being concomitantly administered with antithrombin. Both HBV and HIV are inactivated in this product, but viral transmission has not been completely eliminated. A recombinant product would solve that problem.

Dosage calculation guidelines

The required dose = (%desired –%baseline) × body weight (kg) divided by 1.4.

This calculation is based on an expected rise of 1.4% with 1 IU/kg given intravenously. Recoveries vary from patient to patient and are also affected by the underlying disease. Therefore, baseline and 20-minute postinfusion samples should be tested for antithrombin activity to determine the initial response to a dose. Subsequently, predose trough level and immediate postdose values provide trough and peak values to help in further dosing. Minimum levels of approximately 80% are suggested. Surgery, bleeding, and active thrombosis all affect the level and half-life. The disappearance time in normal volunteers was 22 hours, but this is physiologic information. Following the initial loading dose to raise the value to 120%, approximately 60% of that dose is administered every 24 hours as a maintenance dose.

Antithrombin III, human (ATnativ, Thrombate III)

A serine protease inhibitor (an alpha2-globulin) that inactivates thrombin, plasmin, and other serine proteases of coagulation, including factors IXa, Xa, XIa, XIIa, and VIIa. Made from pooled human plasma and is heat treated. Do not refrigerate after reconstitution, and administer within 3 h of reconstitution.

Antithrombin, recombinant (Atryn)

Antithrombin (AT) regulates hemostasis by inhibiting thrombin and factor Xa, key proteases for blood coagulation. Indicated for prevention of perioperative and peripartum thromboembolic events in patients with hereditary AT deficiency. Not indicated for treatment of thromboembolic events.

Class Summary

Use inhibitors of fibrinolysis together with FFP replacement for minor surgical procedures (eg, dental extractions, sinus surgery) so that they can be accomplished on an outpatient basis with the use of a single dose of product.

Concern about the possible relationship 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)

See details of discussion under Medical Care. SD treatment of pooled human plasma removes lipid-enveloped viruses, making this product safer than untreated FFP. SD treatment, however, does not remove all viruses from plasma. Efficacy and safety has been proven in the treatment of several coagulopathies. Per the package insert from the American Red Cross, the half-life of the coagulation factors in recipients of this product were similar to normal values at the time they were measured.

If available, SD-treated plasma can be used in patients with alpha2-antiplasmin deficiency, because no concentrate is available to treat this coagulation factor deficiency. As with any bleeding disorder, serial measurement of the specific coagulation factor in question is essential to assure hemostatic adequacy of levels. On average, 1 U of SD plasma raises factor levels by ~2-3%, whereas 4-6 U raises factor levels by ~8-18% in a 70-kg person. These numbers do not specifically apply to alpha2-antiplasmin and are being provided only as a general guide.

Serial monitoring of required alpha2-antiplasmin levels is necessary to follow these patients. This product should be stored at -18°C or colder, and thawed at 30-37°C in a water bath with very gentle shaking; once thawed, keep at room temperature and use as soon as possible, preferably within 24 h. Do not store thawed material in the cold.