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
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.
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.
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.
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.
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.
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.
|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.
ARUP Laboratory Tests
Electromagnetic Mechanical Clot Detection/Immunoturbidimetry/Microlatex Particle-Mediated Immunoassay/Platelet Agglutination/Chromogenic Assay
Electromagnetic Mechanical Clot Detection
Electromagnetic Mechanical Clot Detection
For additional test information, refer to the Factor XIII Deficiency Test Fact Sheet
Qualitative Solubility Assay
Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052-2061.
Henry's Clinical Diagnosis and Management by Laboratory Methods
McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier; 2017.
James P, Salomon O, Mikovic D, et al. Rare bleeding disorders - bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency. Haemophilia. 2014;20 Suppl 4(0 4):71-75.
NHF for all bleeding disorders - Other Factor Deficiencies
National Hemophilia Foundation for all bleeding disorders. Other factor deficiencies. National Hemophilia Foundation. [Accessed: Aug 2020]
Kohler HP, Ichinose A, Seitz R, et al. Diagnosis and classification of factor XIII deficiencies. J Thromb Haemost. 2011;9(7):1404-1406.
Yan MTak Sheng, Rydz N, Goodyear D, et al. Acquired factor XIII deficiency: a review. Transfus Apher Sci. 2018;57(6):724-730.
Rare Coagulation Disorders Research Room
Rare Coagulation Disorders Resource Room: rare coagulation disorders. Rare Coagulation Disorders Subcommittee of the National Hemophilia Foundation, and Indiana Hemophilia & Thrombosis Center. [Accessed: Aug 2020]
Sevenet PO, Kaczor DA, Depasse F. Factor VII deficiency: from basics to clinical laboratory diagnosis and patient management. Clin Appl Thromb Hemost. 2017;23(7):703-710.
ISTH - Mutations causing rare bleeding disorders
International Society on Thrombosis and Haemostasis. Mutations causing rare bleeding disorders. [Accessed: Aug 2020]
Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2014;167(3):304-326.
For additional test information, refer to the Prolonged Clot Time Reflexive Profile Test Fact Sheet