Aniara | Shaping the Future with Innovative Solutions

Learning Center

Coagulation Corner

Wednesday, June 3, 2009



Thrombosis and genetics is a complex mix. Not only do genetics play a role but so do environmental factors. It is like a domino effect- combine genetic risks, environmental factors the greater the stimulus the greater the risk. So, if you have a genetic risk and you add things like stasis, obesity, pregnancy, smoking, cancer, hormones, you don't add, but multiply your risk of a thrombotic event. Did you know that in the Genetic Analysis of Idiopathic Thrombosis family-based study estimated a heritability of 60% for thrombosis suggesting that genes would represent the largest single underlying cause of this disease? Yikes! That is more than or equal to Type 2 diabetes, gallbladder disease, alcoholism, and obesity.

This field has really made headway since 1994 when the Factor V Leiden mutation was identified. FV Leiden is an abnormal mutation, a substitution of arginine by glutamine but doesn't interfere with the activity of Factor V it was named after the city in the Netherlands where it was identified. The gene is not susceptible to cleavage resulting in more factor Va is available within the prothrombinase complex increasing the generation of thrombin. This mutation identified a fair amount (about 40%) of people who were previously deemed as having idiopathic thrombosis. It accounts for about 6% of thrombosis in the general population, with a high prevalence in Greece, Sweden, and Lebanon, with almost no incidence in African Blacks, or Asian population. FV Leiden, discovered in the Netherlands, was said to have been a mutation that developed as a protection from the cold weather and the risk of bleeding during childbirth, by making them mothers more hypercoaguable.

The prothrombin G20210A mutation was discovered in 1996, it is a substitution of guanine to adenine. It is present in about 2.3% of the population is also common in the Caucasian population, with a prevalence in southern Europe and Spain, rarely in the Black or Asian population. This is through to be due to the mutation most likely occurring after the divergence of Africans from non-Africans and of Caucasians from Mongoloid subpopulations. These patients may also present with elevated FII levels greater than 115% as opposed to controls. .

What about the risks of increased factor VIII and von Willebrand Factor (vWF)? These are also acute phase reactants, which mean that they are elevated during times of inflammation and stress, or they can be elevated due to a hereditary persistence. How can you diagnosis that? Well, lets look at the most sensitive marker of inflammation C Reactive Protein, if this is tested and is normal , and you still have an elevated FVIII (>150%) or vWF, you may be at risk for venous and arterial thrombosis. So, it would make sense since FVIII is a cofactor of FIXa this can also cause thrombosis, and it increases with age (Yippee). Did you know that von Willebrand levels are also blood group dependent, and people with Type O blood have the lowest normal levels of vWF? This is said to have a protective thrombotic effect on people with blood type O. Let us not forget fibrinogen, which is the same acute phase reactant, but can also have a hereditary persistence for elevation. This is a marker that has a higher risk for an MI than elevated cholesterol.
Other studies have also demonstrated thrombotic risk factors in elevations of Factors VII, IX, XI and XII.

A relatively small population of people (3-5% of the thrombotic population) has deficiencies of Protein C, S or Antithrombin. The basis for looking into genetics of thrombophilia (which is a genetic tendency towards thrombosis) was the occurrence of a thrombotic event at an early age (35-50). However, with the discovery of so many new mutations, that is no longer the case. Patients with FVL may not have an event until their system is challenged. This is called the "double hit theory". They may have a mutation, but they may not have an event until they have surgery, or become pregnant, etc.

Hypercoagulable testing is expensive, and you should screen with a functional assay. If this is abnormal, and it is not abnormal due to an acquired deficiency or because of consumption, you will then proceed to antigen testing. This will distinguish between a qualitative (dysfunctional) or quantitative deficiency.
Also, because you get an abnormal in one test, doesn't mean you won't get an abnormality in another test- so you might want to keep testing. In a study it was demonstrated many patients have more than one defect, putting them at a higher risk for thrombosis increasing their odds ratio to 20!

When do you test these patients? Not and I reply Not when they are having an event, there is consumption occurring, and it the result will not be accurate. . Let's face it; if someone has a clot, they have to be treated, with heparin, either with unfractionated or low molecular weight. The cause is not important, they need to be treated, to prevent further thrombosis, and not overly ant coagulated and has them at a risk for bleeding. Most likely a course of anticoagulation will be followed for about 6 months. However, if you know they have more than one abnormality, it may change the course and length of treatment and involve a course that is life long. When do you test them? They should be removed from anticoagulation for a period of time (2 weeks) and then testing should be performed.

What is the best way to test? Decide what your population is- and the prevalence in your testing. The most common inherited disorder is FV Leiden, but not the highest risk of thrombosis, and remember all of these can be acquired through many disorders such as liver disease, during DIC and from many medications. A test menu should begin with those functional assays and your physicians should begin with a complete patient history as well as taking into consideration environment factors that can enhance risks

Donna Castellone

Bookmark and Share


About the Author

Donna Castellone,  MS, MT(ASCP)SH

Donna Castellone,

View Complete Profile


Previous Posts


RSS Feed

This website contains information on products which is targeted to a wide range of audiences and could contain product details or information otherwise not accessible or valid in your country. Please be aware that we do not take any responsibility for accessing such information which may not comply with any legal process, regulation, registration or usage in the country of your origin.