Factor XI Inhibitor Profile, Comprehensive

Plasma, frozen

6 mL (2 mL in each of three tubes)

Blue-top (sodium citrate) tubes

The patient should not be anticoagulated. Do not draw from an arm with a heparin lock or heparinized catheter.

Confirmation and characterization of factor XI inhibitor

If there is residual coagulation factor activity, it could falsely lower the Bethesda titer result. Lupus anticoagulant activity and antithrombotic agents that function as inhibitors should be ruled out prior to assaying for factor inhibitors in order to avoid factitiously positive results. Some inhibitors may fully neutralize factors in less than two hours. Autoimmune inhibitors that demonstrate second order kinetics cannot be accurately measured in the Bethesda titer system.⁶

The factor XI inhibitor (Bethesda titer) assay is performed using an activated partial thromboplastin time (aPTT)-based test system.⁶ Serial dilutions are made of patient plasma with veronal buffered saline, then mixed with normal plasma containing close to 100% factor XI activity, and are then incubated for two hours. An aPTT-based factor XI assay using factor XI-depleted plasma substrate is then performed on these incubated mixtures. Results are compared to those of incubated normal plasma. One Bethesda unit is defined as the amount of factor XI inhibitor that neutralized 0.5 IU of factor XI in this system. The number of serial dilutions tested is based on the anticipated level of the inhibitor.

Factor inhibitors (also called circulating anticoagulants or inactivators) are endogenously produced antibodies that interfere with coagulation in vivo or in vitro.⁶ These inhibitors are frequently specific for their respective coagulation factors. Specific factor inhibitors can be classified as neutralizing or non-neutralizing. Neutralizing inhibitors interact with the functional component of the coagulant protein and may cause clinical bleeding. Non-neutralizing antibodies react with the protein somewhere other than the functional epitopes and may be clinically silent. Factor inhibitors are not normally present in plasma. When present, factor inhibitors are measured by Bethesda titer units (BU). Titers <5 BUs are classified as low responders, titers >10 BUs as high responders. Responder status influences the approach for clinical treatment. Factor inhibitor assays are ordered in response to clinical impression, and are performed periodically on individuals who have inhibitors and are receiving therapy. During therapy, periodic assays are used, both to manage the dosage and to establish whether a patient is a low or high responder. Low responders maintain titers consistently <5 BUs, while high responders may generate extremely high titers and rapid anamnestic responses to therapy. Assays must also be performed repeatedly during inhibitor suppression therapy.