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Biochemistry

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Factor VIII (FVIII) is an essential clotting factor. The lack of normal FVIII causes Hemophilia A, an inherited bleeding disorder.

The gene for Factor VIII is located on the X chromosome (Xq28).

FVIII is a glycoprotein procofactor synthesized and released into the bloodstream by the liver. In the circulating blood, it is mainly bound to von Willebrand factor (vWF, also known as Factor VIII-related antigen) to form a stable complex. Upon activation by thrombin or factor Xa, it dissociates from the complex to interact with Factor IXa the coagulation cascade. It is a cofactor to Factor IXa in the activation of Factor X, which, in turn, with its cofactor Factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using Factor XIII) into a blood clot.

No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated Protein C and Factor IXa) and quickly cleared from the blood stream. [1]

Discussion

ABO blood type is one of the most significant influences on Factor VIII. Studies dating back to the 1960s have repeatedly shown that a deficiency of this important clotting factor is linked to Blood Type O, while Blood Type A and Blood Type AB have higher than average amounts. Blood Type B has an average amount. As a result, the blood of Type A and Type AB will clot more readily than the blood of Type O or Type B.

Unlike the other factors, Factor VIII is not an enzyme. Factor VIII normally circulates in the plasma bound to von Willebrand factor. When thrombin is activated by injury to the vessel wall, it chops Factor VIII free from von Willebrand factor, and activates it. Von Willebrand factor goes on to bind to the ruptured blood vessel surface, where it stimulates platelets to stick together. Active Factor VIII (now called Factor VIIIa) reacts with another factor (Factor IXa), and calcium to help localize the site of clot formation to the injured vessel.

High levels of Factor VIII have been linked to coronary artery disease, and this may in part explain why coronary artery disease shows a higher rate of occurrence in Type A and Type AB. For example, there is evidence that hemophiliacs experience less coronary artery disease than expected, so high Factor VIII levels may contribute to the incidence of coronary artery disease by increasing one's potential for developing blood clots.

ABH non-secretors are reported to have shorter bleeding times and a tendency towards higher factor VIII and vWf. This relationship appears to be another example of blood type synergy between ABO and Secretor/Non-secretor phenotypes. In fact, secretor genetics appear to interact with ABO genetics to influence as much as 60% of the variance of the plasma concentration of vWf, with secretors (Le (a- b+)) having the lowest vWf concentrations. (1,2)

Among persons belonging to blood group O (the blood type most likely to have problems with clotting), the lowest concentration of vWf:Ag and VIII:Ag is found in the group O secretors. While blood group O non-secretors will have a higher concentration of both vWf:Ag and factor VIII antigen (VIII:Ag), providing them with a better capability for clotting. (3)

Based upon this research, researchers have suggested that the Le (a-b-) phenotype (and blood groups A, B, and AB especially), by virtue of their association with raised levels of factor VIII and von Willebrand factor, might be at a higher risk for future thrombotic and heart disease. (4)

A study at St. Bartholomew's Hospital, London linked the relationship between blood type, Factor VIII activity, von Willebrand factor antigen and ischaemic heart disease in 1393 men aged between 40 and 64 years. The incidence of heart disease was significantly higher in those of blood group AB than in those of groups O, A or B, particularly for fatal events. In addition, they theorized that blood type AB may be a genetic marker of characteristics influencing other risks for heart disease such as short stature, as the type AB men studied were about 2 cm shorter than those of other groups. (5)

Measurements of von Willebrand factor antigen and Factor VIII in a group of 40 blood donors (20 type O, 20 type A) showed reduced levels of both clotting factors in the blood type O as compared with the other blod types. The data suggests an influence of blood group antigens on the interaction between von Willebrand's factor and platelets. (6)

A study looking at pairs of twins showed that the concentration of Factor VIII was lowest in type O individuals, higher in A2 individuals, and highest in A1 and B individuals. The authors concluded that "Thirty percent of the genetic variance of VIII was due to the effect of ABO blood type. The ABO locus is therefore a major locus for the determination of factor VIII concentration." (7)

Blood group ABO antigens are known to be carried by glycoproteins found on platelets. Besides these proteins, blood group A antigen was also expressed on other platelet proteins as well. (8,9) Thus it appears that the genetic expression of blood type in blood type A individuals has some intimate effect on the function of their platelets.

To investigate possible associations between ABO blood system and coagulability levels, fibrinolysis, total lipids, cholesterol, and triglycerides, the plasma and serum of 300 Rh-positive male blood donors were tested. The tests performed were: RT, PTT, K-PTT, PT, F.V, F.II, F.VII, Complex II, VII, and X, TGT, fibrinogen, HAE 0.2, HAE 0.5, ELT, LIP, Col.1, Col.2 and TRI. Analysis of the laboratory data shows a lower coagulability in O blood group individuals. This result was obtained in coagulation tests (RT, PTT, and K-PTT) specific for factor VIII level. In addition, a higher sensitivity to the in vitro heparin anticoagulant effect in O group individuals was confirmed. Nevertheless, these conclusions are specific for Negroids, the same effects not being observed in Caucasians. None of the other laboratory tests revealed any differences related to either blood group or race. (10)

In white men with blood groups A, B, or AB, and the Le(a-b-) phenotype, significantly higher levels of factor VIII (p < 0.01) and von Willebrand factor (p < 0.03) were observed than in those with other Lewis phenotypes (Le[a+b-] or Le[a-b+]). Two-way analysis of variance indicated a significant interaction between blood group and Lewis phenotype (p = 0.0053) in terms of relationship to factor VIII. A similar trend was observed in black men with blood type A, B, or AB, and phenotype Le(a-b-) for factor VII/von Willebrand factor and in women with blood type A, B, or AB, and phenotype Le(a-b-) for factor VIII. Our data suggest that the Le(a-b-) phenotype and blood groups A, B, and AB, by virtue of their association with raised levels of factor VIII and von Willebrand factor, may be risk markers for future atherothrombotic disease. (11)

The ABO “O” and “A” alleles also show a significant association with the quantitative traits, VWF:Ag, VWF:RCo and FVIII:C. (12)

References


1. Wahlberg TB, Blomback M, Magnusson D. Influence of sex, blood group, secretor character, smoking habits, acetylsalicylic acid, oral contraceptives, fasting and general health state on blood coagulation variables in randomly selected young adults. Haemostasis 1984;14(4):312-9

2. Orstavik KH. Genetics of plasma concentration of von Willebrand factor. Folia Haematol Int Mag Klin Morphol Blutforsch 1990;117(4):527-31

3. Orstavik KH, Kornstad L, Reisner H, Berg K. Possible effect of secretor locus on plasma concentration of factor VIII and von Willebrand factor. Blood 1989 Mar;73(4):990-3

4. Green D, Jarrett O, Ruth KJ, Folsom AR, Liu K. Relationship among Lewis phenotype, clotting factors, and other cardiovascular risk factors in young adults. J Lab Clin Med 1995 Mar;125(3):334-339

5. Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V, Miller GJ. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994 Nov;88(3):601-7

6. Sweeney JD, Labuzetta JW, Hoernig LA, Fitzpatrick JE. Platelet function and ABO blood group. Am J Clin Pathol 1989 Jan;91(1):79-81

7. Orstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985 Jan;37(1):89-101

8. Stockelberg D, Hou M, Rydberg L, Kutti J, Wadenvik H. Evidence for an expression of blood group A antigen on platelet glycoproteins IV and V. Transfus Med 1996 Sep;6(3):243-8

9. Hou M, Stockelberg D, Rydberg L, Kutti J, Wadenvik H Blood group A antigen expression in platelets is prominently associated with glycoprotein Ib and IIb. Evidence for an A1/A2 difference. Transfus Med 1996 Mar;6(1):51-9

10. Colonia VJ, Roisenberg I. Hum Genet 1979 Apr 27;48(2):221-230 Investigation of associations between ABO blood groups and coagulation, fibrinolysis, total lipids, cholesterol, and triglycerides.

11. Green D, Jarrett O, Ruth KJ, Folsom AR, Liu KJ. Lab Clin Med 1995 Mar;125(3):334-339 Relationship among Lewis phenotype, clotting factors, and other cardiovascular risk factors in young adults.

12. http://www.path.queensu.ca/queens/labs/lillicrap/docs/isth_paula.ppt.

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