Uncommon Factor Deficiencies

Patients who present with an abnormal bleeding history require evaluation. Abnormal bleeding may be due to acquired or inherited conditions. Once acquired causes are excluded, an investigation for inherited blood coagulation factor deficiencies should be initiated. If mixing studies demonstrate correction of prolonged prothrombin time (PT) and/or partial thromboplastin time (PTT), specific factor assays can be used to identify the deficiency. After exclusion of factor (F) VIII and FIX deficiencies and von Willebrand disease (VWD), rare factor deficiencies should be investigated; these include deficiencies in fibrinogen (FI), FII, FV, FVII, combined FV plus FVIII, FX, FXI, and FXIII. These rare deficiencies account for approximately 3-5% of all coagulation disorders in the general population but may occur with greater incidence in specific populations, such as Ashkenazi Jewish individuals. Abnormal clotting time results should guide further test selection.

Quick Answers for Clinicians

When should a patient be assessed for a possible rare factor deficiency?

A patient with an abnormal bleeding history that suggests an inherited coagulation factor deficiency should be assessed, whether or not the patient has had an abnormal prothrombin time (PT) or partial thromboplastin time (PTT) result, once the more common deficiencies such as hemophilia and von Willebrand disease (VWD) have been ruled out. Note that if the patient being evaluated is hospitalized and the PTT is prolonged, heparin presence should be considered. In some uncommon factor deficiencies, such as FXIII, the PT and PTT results will be normal. See Expected Laboratory Result for Factor Deficiency Associated with History of Abnormal Bleeding table.

Which tests are most useful for evaluating patients for rare factor deficiencies?

Initial testing typically involves prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen tests. A reflex panel may be helpful because it provides a comprehensive workup to determine the cause of prolonged clot times and includes testing for lupus anticoagulants and factor deficiencies or inhibitors.

How are mixing studies interpreted when assessing patients for factor deficiencies?

If a mixing study demonstrates correction of an abnormal prothrombin time (PT) or partial thromboplastin time (PTT) result, a factor deficiency is likely, as opposed to an inhibitor. Testing should be based on bleeding history and the pattern of PT and PTT studies. See Laboratory Testing for more information.

What is the role of factor XIII, and how does factor XIII deficiency manifest?

Factor XIII (FXIII) is essential for normal hemostasis and is activated by thrombin and calcium into FXIIIa, which is involved in wound repair, cytoskeletal remodeling, placental attachment, and other functions. FXIII deficiency can be either inherited or acquired. Inherited FXIII deficiency is associated with intracranial hemorrhage (in severe cases), umbilical cord bleeding, delayed postsurgical or traumatic bleeding, and poor wound healing, among other conditions. Acquired FXIII deficiency, which is caused by decreased production or increased consumption of FXIII, often presents as a severe deficiency. Autoantibodies may form against FXIII due to autoimmune disease, malignancy, or the use of certain drugs (eg, isoniazid, penicillin, valproate, tocilizumab) and result in acquired FXIII deficiency. See the FXIII Deficiency Testing section, and the Factor XIII Deficiency Testing Test Fact Sheet for additional information.

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.

Laboratory Testing

Diagnosis

Initial Testing

Initial testing for uncommon factor deficiencies involves testing for PT, PTT, and fibrinogen. Consider a PT/PTT 1:1 mixing study if the 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 the 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. Refer to the Expected Laboratory Result for Factor Deficiency Associated with History of Abnormal Bleeding table.

Inhibitor Testing

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. Testing should be performed 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 (particularly any anticoagulant medications), and refer to Impacts of Common Anticoagulants on Coagulation Testing 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 subsequently 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 suspected; however, this testing may not be available in all laboratories.

Expected Laboratory Result for Factor Deficiency^a Associated with History of Abnormal Bleeding
Normal PT, Normal PTT	Prolonged PT, Normal PTT	Normal PT, Prolonged PTT	Prolonged PT, Prolonged PTT
FXIII deficiency FI deficiency (hypofibrinogenemia or dysfibrinogenemia) Other mild factor deficiencies	FVII deficiency Vitamin K deficiency or warfarin therapy	FVIII deficiency FIX deficiency FXI deficiency	FI deficiency (hypofibrinogenemia or dysfibrinogenemia, afibrinogenemia) FII deficiency FV deficiency FX deficiency 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

Molecular Testing

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.