Indications for Testing
Testing for uncommon factor deficiencies is appropriate in patients with abnormal bleeding that suggests an inherited blood coagulation factor deficiency after more common disorders have been excluded. It also should be considered for patients with prolonged PT and/or PTT during routine testing.
Initial testing for uncommon factor deficiencies involves testing for PT, PTT, and fibrinogen. Consider a PT/PTT 1:1 mixing study if PT and/or PTT are prolonged. (If PTT is prolonged in a hospitalized patient, consider the possibility of heparin presence.) If the mixing study demonstrates correction of the abnormal result, a factor deficiency is likely. Testing should be based on bleeding history and pattern of PT and PTT studies. If no abnormal bleeding history is present, test for the following deficiencies, which are not associated with bleeding: prekallikrein and high molecular weight kininogen (HMWK). If an abnormal bleeding history is present, focus on disorders associated with bleeding. See table below.
In patients with abnormal PT and/or PTT, if a mixing study does not demonstrate correction of the abnormal result, a coagulation factor inhibitor/antibody may be present, causing the abnormal clotting time. Test for acquired coagulation factor deficiencies caused by an inhibitor (based on the pattern of PT and PTT studies). Bethesda assays can also be performed to confirm and titer coagulation factor inhibitors. Note that lupus anticoagulants can demonstrate this pattern (abnormal PT and/or PTT and no correction with mixing study) but are typically not associated with clinical bleeding. Deficiencies in prekallikrein and HMWK are associated with a prolonged PTT but no bleeding history. Correlate findings with the medication history (particulary any anticoagulant medications), and refer to the Anticoagulants and Possible Coagulation Test Interferences table for possible drug interference with the tests.
FXIII Deficiency Testing
In patients with normal PT and PTT but abnormal bleeding history, consider FXIII deficiency testing. FXIII deficiency results in initial clot development, but the clot then breaks down, which results in recurrent bleeding. Testing depends on whether an acquired or inherited deficiency is suspected. It is useful to start with a functional assay. If a severe deficiency is identified by the functional assay, a qualitative assay can be performed to further evaluate the deficiency, because the qualitative assays typically become abnormal only with the most severe deficiencies. A 1:1 mix can also be performed using a qualitative or quantitative assay if an acquired deficiency is of concern, but may not be available in all laboratories.
Expected Laboratory Result for Factor Deficiencya Associated with History of Abnormal Bleeding
|Normal PT, Normal PTT
||Prolonged PT, Normal PTT
||Normal PT, Prolonged PTT
||Prolonged PT, Prolonged PTT
FI deficiency (hypofibrinogenemia or dysfibrinogenemia)
Other mild factor deficiencies
Vitamin K deficiency or warfarin therapy
|FI deficiency (hypofibrinogenemia or dysfibrinogenemia, afibrinogenemia)
Combined FV and FVIII deficiency
Multiple factor deficiencies due to vitamin K deficiency, vitamin K combined factor deficiency, warfarin therapy, liver disease, or disseminated intravascular coagulation
|aUsually corrects with 1:1 mixing study. Note that VWD, platelet disorders, and fibrinolytic disorders also cause bleeding but are associated with a normal PT and PTT.
Sources: Palla, 2015 ; McPherson, 2017 ; National Hemophilia Foundation, 2018 ; Sevenet, 2017
Information on mutations associated with rare bleeding disorders, including FV, combined FV and FVIII, FVII, FX, FXI, and FXIII deficiencies, is available in a mutation database created by the International Society on Thrombosis and Haemostasis.