Factor XII, deficiency

Activated plasma was prepared by exposing normal intact plasma to 60 mg Speedex (Great Lakes Carbon Corp., Los Angeles) per ml plasma for 10 min, centrifuging, and collecting the supernatant. Factor XII-deficient plasma was collected in a 3% sodium citrate from a patient with severe factor XII deficiency. 

Because many clotting factors are present in blood in small concentrations, direct chemical measurements often cannot be used to determine whether the factors are within normal concentration ranges or are deficient. Once a deficiency has been established, however, plasma from the affected person can be used to screen for the presence of the deficiency in other people. A rare deficiency in Factor XII leads to a prolongation of clotting time. Assuming that you have plasma from someone in which this deficiency has been estabfished, design a test that might help determine whether another person has a Factor XII deficiency. 

Prepare two samples of blood from the person to be tested. Add normal plasma to one sample and Factor Xll-deficient plasma to another. If clotting time is restored to normal in both samples, Factor XII deficiency is probably not involved. If the addition of normal plasma restores normal clotting time but the addition of Factor Xll-deficient plasma does not, then a Factor XII deficiency must be suspected. 

Congenital deficiency of Factor XII is inherited as an autosomal recessive trait. Deficiency of this factor is rarely associated with any coagulopathy. It has been observed that people deficient in this factor may have an increased frequency of thromboembolic compHcations. 

Factor Xlla is a serine protease that activates FXI to FXIa (Fig. 5). This system is not of physiologic relevance since patients with hereditary deficiencies of factor XII, prekallikrein, and high-molecular weight kininogen do not present with bleeding symptoms. 

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired Cl-inhibitor deficiencies. Immunopharmacology 1996 33 361-364. 

PrekaUikrein is converted to kaUrkrem and factor XII is activated to Xlla. Factor Xlla activates Xl-XIa, which activates factor IX, which together with its co-factor Villa forms the tenase complex, resniting in activation of factor X. The minor role that the contact activation pathway has in initiating clot formation can he Ulnstrated hy the fact that patients with severe deficiencies of factor Xn, kininogen and prekaUikrein do not exhibit a bleeding disorder. 

Another possibility is that some other clotting factor is increased or activated in such a way that the assay system responds fortuitously to it in a way indistinguishable from the usual response to factor VIII, e.g., factors XI and XII factor XII is known to rise on exercise (II). That this might occur over a limited range of the dose-response curve in the thromboplastin generation test system was shown by experiments in which the addition of activation product (Wl) simulated an increased factor VIII concentration (author s unpublished observations, 1960 FI), although statistical invalidity would probably be detectable over a series of experiments if this were the explanation. This also was looked for, but was not found (14). It is interesting that, in a patient with severe factor VIII deficiency and partial factor XI deficiency (SI), adrenaline infusion was followed by a marked rise in factor XI concentration and the appearance of a trace of factor VIII (K. Schulz, personal communication, 1964). Furthermore, the confusion that arose some years ago over factor IX assay now seems to have been due to activation of the contact factors (P4), hence... 

However, the exercise effect has been demonstrated with assays involving (supposedly maximal) activation of factors XI and XII with kaolin (13), and a system to which activation product was added (VI) duly registered the adrenaline effect. Furthermore, a rise in factor VIII concentration has now been produced by exercise in patients with severe deficiencies of factors XI and XII. Egeberg (E13) tested two patients with gross deficiencies of factor XI, and Goudemand et al. (G2) and A. Parquet-Gemez (personal communication, 1964) tested factor Xll-deficient patients. 

Accepting the above limitations of our knowledge of the true in vivo reaction sequence, a series of clot-endpoint tests has been used for many years to determine the hemostatic balance in any patient. The first, known as the thrombin time test, can be used to measure the concentration of fibrinogen (B15). The second assay, the activated partial thromboplastin time test (APTT), measures the components of the intrinsic pathway (M4). These include the serine proteases (Factors XII, XI, X, and II), the cofactors (Factors VIII and V) and again, fibrinogen. Most of the hereditary deficiencies... 

Factor XII, or Hageman factor, was named after the individual in which the deficiency was first discovered. The complete amino acid sequence of 596 residues and the identification of glycosyla-tion sites of human factor XII have only recently been determined for the human protein (24,25). The complete cDNA sequence has also been determined and verified the amino acid sequence (26, 197,198). The zymogen form of factor XII is activated in plasma... 

Understanding of the progression of this coagulation cascade has evolved over time through laboratory observations. Though this process corroborates the in vitro findings, it does not exactly match the clinical observations. For example, it has been found that some patients are deficient in the pro-teins/factors of the intrinsic pathway (such as factor XII) and yet they do not bleed, suggesting that the intrinsic pathway may not be essential. On the... 

Activated partial thromboplastin time aPTT is performed by adding calcium phospholipids and kaolin to citrated blood and measures the time required for a fibrin clot to form. In this manner, aPTT measures the activity of intrinsic and common pathways. Prolongation of aPTT may be due to a deficiency or inhibitor for factors II, V, VIII, IX, X, XI, and XII. It also may be due to heparin, direct thrombin inhibitors, vitamin K deficiency, liver disease, or lupus anticoagulant. 

Factor deficiencies include disorders of fibrinogen such as afibrinogenemia and dysfibrinogenemias, prothrombin deficiency, factor V VII, X, XI, XII, and XIII deficiency, prekallikrein and high-molecular-weight kininogen deficiency, combined factor deficiencies, a2 anti-plasmin deficiency, a] antitrypsin Pittsburgh, and protein Z deficiency. 

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