Factor XI activity and factor XI antigen in homozygous and heterozygous factor XI deficiency

A relatively potent antiserum against highly purified, unactivated human factor XI antigen was raised in a rabbit. This antiserum, after concentration, neutralized 50% of the factor XI clotting activity of a standard normal plasma at an antiserum dilution of 1/900. The antiserum was used in a neutralization-inhibition assay to study the relation between factor XI clotting activity and factor XI antigen in plasma from ten unrelated patients with homozygous factor XI deficiency and from 12 heterozygous family members of these patients. No evidence of factor XI antigen significantly in excess of factor XI activity was found in either group. All data to date have been consistent with the hypothesis that hereditary factor XI deficiency represents a genetic disorder resulting from the absence of factor XI molecule. Severity of bleeding in factor XI deficiency could not be correlated with the level of factor XI activity or factor XI antigen.     

Factor VIII-induced superaggregation of human platelets

High concentrations of bovine factor VIII cause clumping of platelets into a few very large aggregates. This response is termed superaggregation. It is distinct from factor-VIII-induced agglutination but is also independent of both extracellular calcium ions and platelet energy metabolism. Neither agglutinating lectins nor aggregating agents, including thrombin, ADP, the ionophore A23187, and U46619, a prostaglandin analog, can induce superaggregation, even at very high concentrations. Washed platelets undergo superaggregation, and superaggregation does not increase the amounts of fibrinogen or albumin trapped by agglutinated platelets. It is not inhibited by membrane- stabilizing drugs or by colchicine or cytochalasin-B. Formaldehyde and glutaraldehyde prevent superaggregation without affecting the binding of radiolabeled factor VIII to the platelets. Superaggregated platelets are separated by approximately 50 nm and are not shape-changed or degranulated. In adenosine diphosphate (ADP) induced aggregation, the platelets are distorted and only 30 nm apart. Superaggregation is reversed by dextran sulfate, and the dispersed platelets are still able to respond to ADP. Our observations are consistent with the binding of high molecular weight multimers of bovine factor VIII to more than one receptor on each platelet, with superaggregation occurring through recruitment of additional receptors. This process may be interrupted by protein crosslinking reagents, such as formaldehyde and glutaraldehyde.     

Factor XI deficiency

Summary. Although factor XI (FXI) deficiency has a particularly high incidence in Ashkenazi Jews, it is now frequently diagnosed in other ethnic groups. This review gives an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency. The correlation between FXI levels and the bleeding phenotype is much less clear than in the haemophilias, and consequently the bleeding risk can be difficult to predict. Two well‐characterized mutations in the F11 gene are responsible for the majority of Jewish cases, but new mutations are becoming increasingly recognized. The publication of the crystal structure has greatly enhanced our understanding of the structure–function relationship in FXI. The impact of recent studies on our understanding of the role of FXI in coagulation is discussed.     

Factor XI deficiency

Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity. Bleeding in this disorder occurs especially in areas of high fibrinolytic activity. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably persons of Ashkenazi descent and the Basque population of Southern France. In these populations, five mutations of the FXI gene have been identified and a founder effect has been confirmed for three of these. This paper reviews the role of FXI in coagulation and documents factors known to modify the bleeding tendency. Treatment of surgical bleeding in patients with FXI deficiency is reviewed with emphasis on the combined use of recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) and the antifibrinolytic agent, tranexamic acid.     

Type XI collagen-degrading activity in human osteoarthritic cartilage

Homogenates of 6 samples of human osteoarthritic cartilage were shown to degrade exogenous type XI collagen. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the cleavage products generated by each homogenate were similar, and they were identical to those obtained by cleavage of the substrate with purified gelatinase. Enzyme activity, which was inhibited by EDTA, was greater in extracts of fibrillated osteoarthritic cartilage than in extracts of grossly normal cartilage from the same joint or in extracts of cartilage from joints with osteonecrosis. Activation with APMA enhanced digestion, but breakdown was apparent in extracts of fibrillated osteoarthritic cartilage even without APMA. Enzymatic degradation of type XI collagen could play a significant role in the turnover of articular cartilage in health and disease states.     

Factor VIII-associated antigen in human lymphatic endothelium

Lymphatic vascular endothelium both on tissue section and in culture exhibits positivity for Factor VIII-associated antigen although staining is generally less intense and more spotty than in comparable blood vascular endothelium. Lymphatic endothelium also exhibits Weibel-Palade bodies. Neither marker, therefore, reliably distinguishes blood vascular endothelium from lymphatic endothelium.     

Factor XI deficiency in women

Factor XI (FXI) deficiency is an uncommon autosomally transmitted coagulopathy found predominantly in Jewish kindreds. It is associated with variable bleeding tendency that usually manifests after trauma, surgery, or other challenges to hemostasis. Therefore, women with FXI deficiency are at risk of excessive bleeding during their menstrual periods, childbirth, and after surgery. Increased awareness and close collaboration among hematologists, obstetricians, and gynecologists and availability of management guidelines is essential to minimize these risks. This review provides data from current research in FXI deficiency and pregnancy care, menstrual problems, and the role of screening for this disorder in women referred with menorrhagia. Am. J. Hematol. 60:48–54, 1999. © 1999 Wiley-Liss, Inc.     

Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindreds

The relationship of clinical bleeding tendency and factor XI antigen (XI:Ag) in factor XI deficiency was studied in 78 members of 25 factor XI-deficient kindreds. Factor XI:Ag was measured in a competitive radioimmunoassay, using monospecific, heterologous anti-factor XI antibody. 125I-labeled factor XI, and staphylococcal protein A as the precipitating agent. Deficiency of factor XI clotting activity (XI:C), less than 0.62 U/mL, occurred in 48 individuals, 22 of whom experienced postoperative or posttraumatic bleeding: Their mean factor XI:C was 0.21 +/- 0.04 U/mL (SEM), and factor XI:Ag was 0.23 +/- 0.04 U/mL. The remaining 26 had no clinical bleeding, many despite surgical challenge: Their mean factor XI:C was 0.30 +/- 0.04 U/mL, and factor XI:Ag was 0.34 +/- 0.05 U/mL. In all, 13 kindreds had between 1 and 11 members with bleeding; the other 12 had none with deficient hemostasis. Two heterozygous factor XI-deficient individuals appeared to be positive for cross-reacting material (CRM+). The slope of the regression line for factor XI:C and factor XI:Ag data points in the 78 individuals tested did not differ from control, and all points fell within 95% confidence limits derived from control. In conclusion, bleeding tendency appears to be consistent within a given kindred and is not determined exclusively by factor XI:C or factor XI:Ag levels.     

Factor VIII coagulant activity and factor Vlll-related antigen released from isolated perfused human spleens

Summary Eight human spleens were perfused for up to 65 h at normothermia and the coagulant Factor VIII activity measured in the perfusate. In addition, in three experiments Factor VIII-related antigen was determined in the perfusate. Although the spleens were pathologically enlarged and the normal structure involved by different diseases, all spleens released Factor VIII coagulant activity and Factor VIII-related antigen. On average the total amount of Factor VIII coagulant activity released was equivalent to that of 3.5 1 of human plasma.

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Zusammenfassung Bei der normothermen Langzeitperfusion von 8 menschlichen Milzen wurde ein Anstieg des Gerinnungsfaktors VIII im Perfusat gemessen und in 3 FÄllen die Konzentration des Faktor VIII-assoziierten Antigens bestimmt. Obwohl es sich um pathologisch verÄnderte Milzen handelte, stieg in allen FÄllen die Faktor-VIII-AktivitÄt und die Konzentration des Faktor-VIII-assoziierten Antigens an. Der Mittelwert des maximalen Gehalts an Faktor VIII entsprach der GerinnungsaktivitÄt von 3,5 1 menschlichen Plasmas.

     

Factor XI and Platelets: Evidence that Platelets Contain only Minimal Factor XI Activity and Antigen

Factor-XI activity of platelets has been studied in platelet-rich plasmas and isolated platelet suspensions. Fresh platelets in both environments had little or no measurable factor-XI activity. Frozen and thawed platelet-rich normal plasma had markedly elevated apparent factor-XI activity and factor-IX activity as compared to platelet-poor plasma. Frozen and thawed platelet-rich and platelet-poor normal plasmas had equivalent factor-XI antigen. Platelets isolated from normal blood and from factor-XI deficient blood had the same small amounts of apparent factor-XI activity, which increased slightly on freezing and thawing. The data indicates that minimal factor XI is associated with the platelet. The markedly elevated apparent factor-XI activity of frozen and thawed platelet-rich plasma is shown to reflect the interaction of a platelet activator with plasma clotting factors to produce a later activated-clotting-intermediate.     

Factor XI/ADAMTS13 complexes are quantitatively insignificant in human plasma

Reportedly, complexes between factor XI and ADAMTS13 are detected with a commercial ADAMTS13/FXI ELISA kit in plasma and are decreased in thrombotic thrombocytopenic purpura (TTP). Using this kit, control and TTP patient plasma contained varying amounts of signal (25-670% of a reference plasma) but no signal was observed for mixtures of recombinant enzymes, suggesting little interaction. ADAMTS13/FXI complexes were undetectable by immunoprecipitation or gel filtration chromatography in control plasma or mixtures of recombinant proteins. These results suggest that ADAMTS13/FXI complexes are insignificant in plasma and unlikely to affect the function of either protein during normal hemostasis or in TTP.     

Factor XI deficiency and its management

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype.
Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups.
Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

Factor XI deficiency and its management

The meeting offered participants, mostly interested in the manufacture or clinical application of factor XI concentrates, an opportunity to review evidence of their efficacy and some recent concerns about their safety.