Factor XII Deficiency

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					Factor XII Deficiency
                                                                    Factor XII Deficiency                         1

                                                                               Roger S. Riley, M.D., Ph.D.

                                                                                                   April, 2005

    Feature                                             Disease Facts
 Synonyms               Hageman trait, Hageman factor deficiency.

 Epidemiology           Rare disorder, actual prevalence unknown because disease is usually asymptomatic.
                        Relatively more common in the Netherlands.

 Etiology and           Factor XII ia a single-chain beta-globulin serine protease with a molecular weight of
 Pathogenesis           80,000 - 84,000 daltons and a plasma concentration of approximately 30 pg/mL.
                        Proteolytic cleavage of factor XII is mediated by charged surfaces (glass, kaolin, cel-
                        lite, dextran sulfate, endotoxin, urates, crude collagen, sulfatides), autoactivation,
                        and kallikrein. Prekallikrein, factor XI, factor VII, plasminogen, and complement
                        C1are proteolytically cleaved by activated factor XII (factor XIIa) into their active

                        Hageman factor fragments and kallikreln link the contact system to the kinin system,
                        the intrinsic fibrinolytic system, and the complement system in addition to liberating
                        renin from prorennin and priming neutrophils for chernotactic activity. An antithrom-
                        botic role for factor XII as a platelet aggregation inhibitor or plasminogen activator
                        has been proposed. C1 esterase inhibitor is the major inhibitor of factor XIIa . Anti-
                        thrombin III (AT-III), alpha-2-antiplasmin, and alpha-2-macroglobulin also inhibit
                        factor XIIa.

                        Acquired factor XII deficiency is most common in patients with nephrotic syndrome.
                        The pathological basis of this acquired deficiency has not been established since uri-
                        nary loss of factor XII alone may not account for the reduced plasma activity of this

 Pattern of             Factor XII deficiency is usually transmitted as an autosomal recessive trait, although
 Inheritance            dominant and codominant patterns of inheritance have been reported in some fami-

                        Plasma levels of factor XII vary from 0.17 to 0.83 U/mL in different studies, with
                        about one-half showing levels below the normal range. Homozygotes (or double het-
                        erozygotes) have very low levels < 0.01 U/mL of factor XII. Most individuals with
                        homozygous factor XII deficiency are cross-reacting material negative (CRM-).

 Clinical               Congenital Factor XII Deficiency. Factor XII deficiency is the most common cause of
 Presentation           an isolated prolongation of the aPTT in a nonbleeding child or adult; consequently,
                        most patients are detected during a routine preoperative coagulation study. Most pa-
                        tients withstand severe challanges to the hemostatic system, such as dental extrac-
                        tions or major surgery, without bleeding, although easy bruising or epistaxis has
                        been reported in an occasional factor XII-deficient patient.
Factor XII Deficiency                                                                                                                     2

    Feature                                                     Disease Facts
 Clinical               In contrast to the usual lack of bleeding manifestations, there is an increased inci-
 Presentation           dence of serious thromboembolic problems in patients with hereditary factor XII defi-
 (Cont’d)               ciency. The first patient discovered to have factor XII deficiency, John Hageman,
                        died of a pulmonary embolus and an unusually high incidence of strokes, deep ve-
                        nous thrombosis, and myocardial infarction has been described in other patients with
                        factor XII deficiency, as well as in families with the anomaly. The incidence of serious
                        thromboembolic disease has been reported as 1-8% in different studies.

                        Acquired Factor XII Deficiency. Activation of the contact factor system is seen in a
                        wide variety of disease states, including the nephrotic syndrome, endotoxin-induced
                        sepsis and shock, disseminated intravascular coagulation, adult respiratory distress
                        syndrome, polycythemia vera, hepatic cirrhosis, and other diseases. Although de-
                        creased contact factor levels have been demonstrated in these diseases, the patho-
                        physiologic significance of this findings is uncertain. A spontaneous increase in factor
                        XII activity occurs in pregnancy and with the use of oral contraceptives. A spontane-
                        ous increase in factor XII also occurs with cold storage of plasma (cold-promoted ac-

 Laboratory             The platelet count, bleeding time, prothrombin time, and thrombin time are normal
 Features               in patients with isolated factor XII deficiency. The aPTT is markedly prolonged in pa-
                        tients with homozygous factor XII deficiency, but corrects to the normal range by 1:1
                        mixing with normal plasma, aged normal serum, and adsorbed normal plasma. The
                        "Fletcher factor" screening test (10-min incubation of the patient's plasma) does not
                        correct the prolonged aPTT to near normal. Prothrombin consumption and thrombo-
                        plastin generation are retarded.

                        Individuals with heterozygous factor XII deficiency have normal to mildly prolonged
                        aPTT values. The immediate family members (who are potential heterozygotes) of a
                        patient found to have a homozygous contact factor deficiency should be iscreened to
                        prevent future expensive evaluations of a mildly prolonged APTT.

                        The definitive diagnosis of factor XII deficiency requires a specific factor XII assay
                        utilizing factor XII deficient plasma.

Treatment               No treatment necessary for hereditary type. Management of nephrotic syndrome in
                        acquired type.

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Factor XII Deficiency                                                                                                                     3

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                        Koster T, Rosendaal FR, Briet E,      Wallock M, Arentzen C, Perkins J:
                        Vandenbroucke JP: John Hage-          Factor XII deficiency and cardio-