By Vivienne Baillie Gerritsen
This is not an article on the protein which multiplies your cholesterol level over the Christmas period. Or the protein which bestows - on some - terrible bouts of depression as Christmas draws in on them. Here, in fact, is a December article which has nothing whatsoever to do with the intake of calories or the oncoming of uneasiness. But it does have to do with the festivity - in a way. The Christmas factor is indeed a protein whose deficiency was first discovered in the 1950s in a little boy by the name of Stephen Christmas. The Christmas factor (also known as factor IX, or FIX) is involved in the blood clotting process and its deficiency causes the rare form of congenital male hemophilia: hemophilia B. It so happened that the article announcing the discovery of the Christmas factor was actually published in the 1952 Christmas edition of the British Medical Journal.
Fig. 1 A blood clot
The art of coagulation is not recent. It is believed that primitive forms of the cascade already existed in jawed vertebrates 450 million years ago. The first recordings of troubles in blood clotting are found in Jewish texts of the second century A.D. The reference is indirect and suggests the exemption of circumcision to any male subject if two brothers of his had already died of bleeding as a consequence of the ritual. The first modern description of hemophilia was made by an American physician John Conrad Otto in the very beginning of the 19th century. Otto described the predisposition of the male members in certain families to suffer from frequent hemorrhages. The famous account many of us are acquainted with is that which involved the British Royal family, namely Queen Victoria and her descendants. How many of us have had to puzzle out the genetics behind the disease - also sometimes referred to as the Royal disease - which appeared as a result of a spontaneous mutation in Leopold, Queen Victoria’s eighth child and son? Leopold died young from a brain hemorrhage but left behind him two daughters who, unknowingly, were at the heart of the spread of hemophilia which struck many royal families throughout Europe and Russia. The disease eventually died out completely due to the lack of effective treatment but also war. As a consequence, it is not known today whether Queen Victoria’s son suffered from hemophilia B, or the more classic form of hemophilia: hemophilia A.
So, what’s the difference between the two forms? They are both X-linked recessive congenital diseases; only the mutation is not the same. Hemophilia B is caused by a mutation resulting in the deficiency of the Christmas factor (FIX), and is in fact also known as the Christmas disease. Amongst those who suffer from hemophilia A or B, hemophilia B is the rarer form, affecting 20% of the patients. The discovery of hemophilia B is interesting. In the beginning of the 20th century, hemophilia was just known as hemophilia, a blood clotting disorder. However, towards the middle of the century, an important observation was made. The blood of one hemophiliac patient could clot the blood of another. Hence, there were two forms - at least - of hemophilia. The forms became hemophilia A and hemophilia B; the latter being the hemophilia first described in Stephen Christmas.
As the 20th century rolled on, it became evident that there were other abnormalities in blood clotting which were the result of deficiencies in one or another component. The process of blood coagulation was proving to be a complicated process. Today almost twenty different proteins are known to be directly involved in blood coagulation or coagulation inhibition. The British biochemist R.G. MacFarlane was one of the first to describe the blood-clotting cascade as we know it today. And it will come as no surprise that the Christmas factor is at the heart of it.
What does Christmas factor do? Where is it in the coagulation cascade? What happens during coagulation? There is a factor, known as the Tissue Factor (TF), which is not found normally in the blood stream. If a blood vessel’s endothelium is damaged, or activated by various chemicals, cytokines or inflammation, it presents this tissue factor to the blood stream. Tissue factors are found on the surface of platelets, which themselves synthesize a number of proteins involved in blood coagulation. In short, TF with the help of another factor, FVII, activates FIX. FIX then activates FVIII which in turn activates FX itself directly involved in thrombin generation and ultimately fibrin formation. In fact, hemophilia A - the most common form of hemophilia - is a deficiency of FX. Once FX has been activated by FIX via TF, it then takes part in activating FIX in a kind of feedback loop - nourishing the blood clot process. In this loop, a FXI (and not TF) activates FIX which, with the aid again of FVIII, activates FX. It is now known that the activation of FX via TF is far less effective than its activation via the feedback loop. Confusing isn’t it?
So FIX activates FX via two pathways. How does it do this? FIX is made up of four different domains: a gamma-carboxyglutamic acid (Gla) domain, two epidermal growth factor domains (EGFI and II) and a serine protease domain. FIX binds to the platelet surface with the TF/VII complex via its Gla N-terminus region. In its activated form, a short peptide is cleaved between EGFII and the serine protease thus forming a light chain (Gla, EGFI and II) and a heavy chain (the serine protease). The two chains are held together via a single disulfide bond. FVIII is thought to bind to the EGFII and serine protease domain of FIX. There are a number of calcium and magnesium binding sites in the light chain of FIX and it is thought that both ions confer a certain tertiary structure to the Gla domain which in turn twists the EGFII and serine protease domain in such a way that FVIII can bind to them, and FIX can then do its job as a serine protease and activate FVIII which will shoot off and activate FX. It sounds as entwined as the tinsel we put on our Christmas trees doesn’t it?
The message is that FIX or the Christmas factor is essential in the blood clotting process and its deficiency causes severe problems. Until the middle of the 20th century and a good understanding of blood groups and coagulation, treatment was poor. Today Western patients can benefit from plasma-derived factors or recombinant factors and gene transfer therapy - though quite unsatisfactory to this day - may well be the future treatment of hemophilia. One of the greatest problems are the hemophiliacs who develop inhibitors to the treatments, and drugs which could bypass the FIX/FVIII pathway are needed. Inversely, thrombosis could be treated by creating drugs which would interfere with the interactions between FIX and TF, or FIX and FVIII, thus preventing coagulation.
So the name of Stephen Christmas has come a long way. Besides the naming of a protein which is at the heart of treatments for hemophiliacs - something Stephen Christmas fought for all his life - many coincidences surrounding Christmas haunted him. The article announcing the discovery of the Christmas factor was actually published in the 1952 Christmas edition of the British Medical Journal…and met with some negative reactions. Should a disease be related to the image of Christmas? To which the authors answered that they promised the precursor protein of the Christmas factor would not be called the ‘Christmas Eve factor'… Sadly, Stephen Christmas died at the age of 46 from HIV contracted through treatment with tainted blood products… just five days before Christmas in 1993.http://www.chelationtherapyonline.com/articles/p198.htm
Cross-references to Swiss-Prot
P00740: Human coagulation factor IX (Christmas factor)
References
1. Schmidt A.E., Bajaj S.P.
Structure-function relationships in factor IX and factor IXa
Trends Cardiovasc. Med. 13:39-45(2003)
PMID: 12554099.
2. Mannucci P.M:
Hemophilia: treatment options in the twenty-first century
Journal of Thrombosis and Haemostasis 1:1349-1355(2003)
3. Giangrande P.L.F.
Six characters in search of an author: the history of the nomenclature of coagulation factors
Br. J. of Haematol. 121:703-712(2003)
PMID: 12780784.
Protein Spotlight (ISSN 1424-4721) is published by the SWISS-PROT group at the Swiss Institute of Bioinformatics (SIB). Authorization to photocopy or reproduce this article for internal or personal use is granted by the SIB provided its content is not modified. Please enquire at spotlight@isb-sib.ch for redistribution or commercial usage.