A 2-year-old boy was referred for evaluation of excessive bleeding and easy bruising since birth. As an infant, he was circumcised on day two of life and developed bleeding complications requiring stitches. He also had a history of epistaxis secondary to trauma that required nasal packing, antifibrinolytics, and fresh frozen plasma to control bleeding. His mother also bruises easily.
Activated partial thromboplastin time (APTT), PT, thrombin time, platelet count, fibrinogen levels, and alpha 2 antiplasmin levels done previously were normal.
The correct answer is ...
Factor XIII deficiency.
In Factor XIII deficient individuals, standard clotting test time, activated partial thromboplastin time, prothrombin time, and thrombin time are normal as the clotting endpoint is not affected, but the quality of clot is poor. Additional testing with factor XIII levels should be requested in suspicious cases with appropriate history.
Congenital Factor XIII deficiency (FXIIID) is a rare bleeding disorder. The worldwide incidence of FXIIID, inherited as an autosomal recessive disorder, is approximately one per 1 million–3 million people. Its prevalence is higher in areas where consanguineous marriage is common. Clinically, most patients present with lifelong bleeding and rebleeding, notably 80% bleed from the umbilical stump; 30% die of intracranial hemorrhage.
For our patient, two prior factor XIII screens came out normal, since the testing was conducted following the administration of fresh frozen plasma. Additional testing on this visit resulted an abnormal factor XIII screen. Subsequently, quantitative factor XIII assay revealed 10% activity, confirming congenital factor XIII deficiency.
Factor XIII, also known as the "fibrin stabilizing factor," circulates in plasma as a protransglutaminase of tetrameric structure (A2B2) that converts the loose fibrin polymer into a firm organized structure by forming peptide bonds between adjacent fibrin monomers. It also binds α2 antiplasmin to provide resistance to thrombolysis.
The action of thrombin converts fibrinogen to fibrin monomer.
Initial fibrin clot is crosslinked through the action of thrombin activated factor XIIIa, making the final fibrin clot insoluble.
Initial fibrin clot (soluble hydrogen bonds)
Factor XIIIa ⇩
(This function is not tested
by the PT, aPTT, or TT)
Crosslinked fibrin clot (insoluble covalent bonds)
In the absence of factor XIII, initial fibrin clot held together by hydrogen bonds can be dissolved by 5 M urea or weak acid solutions.
Factor XIII screen is the Clot solubility test (CST), a qualitative test for factor XIII activity.
The plasma sample (patient and control) is clotted by the addition of an excess of calcium and incubated at 37°C for 30 minutes. Subsequently, a solubilizing agent is added and observed over two hours for abnormal clot dissolution.
Although easy to perform, the test lacks sensitivity and standardization. In addition, the test is unable to detect mild or moderate deficiency, including heterozygous carriers, and leads to delayed or missed diagnosis.
The quantitative FXIII activity assay is based on the transglutaminase reaction in the cross-linking process and is the recommended first-line screening test for FXIIID whenever possible.
Incorrect answer explanation: Factor VIII and Factor V deficiency is unlikely with a normal APTT and PT, respectively. Dysfibrinogenemia is less likely due to a normal thrombin time.
Saadiya Nazli, M.D.
Resident, Anatomic and Clinical Pathology
Meera Sridharan, M.D., Ph.D.
Assistant Professor of Medicine
Assistant Professor of Oncology
Mayo Clinic College of Medicine and Science