Thrombophilia Due to Acquired Antithrombin III Deficiency Clinical Trial
Official title:
Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery
The objective of this study is to prospectively evaluate the response of recombinant antithrombin (rAT) (ATRYN) in patients who are heparin resistant and are scheduled to undergo cardiac surgery.
AT is an α2-globulin that is produced primarily in the liver. It binds thrombin, as well as
other serine proteases, factors IX, X, XI, and XII, kallikrein, and plasmin irreversibly,
which neutralizes their activity. However, only inhibition of thrombin and factor Xa by AT
has physiologic and clinical significance.1 AT deficiency may occur as a congenital or
acquired deficiency. Acquired deficiencies are secondary to increased AT consumption, loss
of AT from the intravascular compartment (renal failure, nephrotic syndrome) or liver
disease (cirrhosis). A normal AT level is 80% to 120% with activity below 50% considered
clinically important based on the risk of venous thrombosis in patients with congenital
deficiency of AT.2 However, the risk of thrombosis is higher in congenital forms than
acquired forms of AT deficiency.3, 4 Unfortunately, the only abnormal coagulation test
associated with this condition is the assay for AT activity, which is diagnostic but not
readily available.
Acquired deficiencies of AT are commonly encountered in cardiac surgical patients.
Anticoagulation with heparin for CPB depends on AT to inhibit clotting as heparin alone has
no effect on coagulation. Heparin catalyzes AT inhibition of thrombin over a 1000 fold by
binding to a lysine residue on AT and altering its conformation. Thrombin actually attacks
AT, disabling it, but in the process attaches AT to thrombin, forming a complex that can be
detected and used to assess thrombin formation but has no activity. Thirty percent of AT is
consumed during this process so AT levels are reduced temporarily. If AT levels are not
restored, then a condition may arise called heparin resistance. There are other less
frequent causes of heparin resistance besides AT deficiency such as platelets, fibrin,
vascular surfaces and plasma proteins.5 There is no universally accepted definition of
heparin resistance. It is broadly defined as the failure of a specific heparin dose (300 -
400 u/kg) to prolong an ACT beyond 400 - 480 seconds in preparation for initiation of CPB.
Because the definition of heparin resistance may differ according to both heparin dose and
target ACT, the incidence of heparin resistance in the literature is very variable. A recent
randomized prospective study analyzing 2270 cardiac cases, identified 3.7% of the patients
to be heparin resistant but the incidence has been reported as high as 18% - 30% The
incidence of heparin resistance is likely to further increase as the use of heparin
infusions prior to cardiac surgery becomes more prevalent.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment