Penetrating Blood Clots – Enlightening
Investigations

Five percent of most Western populations harbor Factor V Leiden (FVL), the most common known inherited thrombotic risk factor. So how come only about 10 percent of FVL carriers develop thrombosis in their lifetime? And why do some patients develop significant, recurring thromboses by age 35 whereas others can make it to age 75 before they even have their first minimal clot? Up until now, the genetic factors responsible for the incomplete penetrance of FVL remained largely unknown.

Now, Dr. David Ginsburg and colleagues at the Howard Hughes Medical Institute at the University of Michigan have developed a mutagenesis screen in the mouse to identify potential genetic modifiers of thrombosis. This abstract will be the second abstract presented in the Plenary Scientific Session today and will be introduced by Dr. Lawrence Leung. Dr. Ginsburg’s group has previously shown a synthetic lethality in mice carrying the FVL mutation as well as partial deficiency of tissue factor pathway inhibitor (TFPI), a key coagulation component. Homozygosity for FVL in the context of heterozygosity for TFPI is uniformly lethal due to disseminated perinatal thrombosis.

But this group of clever investigators exploited this lethal genetic interaction and developed it as a phenotyping tool for a sensitized ENU mutagenesis screen in lab mice. So they set about breeding different cohorts of mice, crossing this way and that way. They mutagenized male mice with ENU and bred them with FvQ/+ Tfpi+/- females. Preliminary results, which Dr. Westrick will present at the plenary session, demonstrate the feasibility of this sensitization screen for identifying dominant suppressor of thrombosis. These investigators estimate that there are likely as many as 10-20 mammalian genes for which a reduction in expression of 50 percent or more may be sufficient to cause a major shift in the hemostatic balance. It is this kind of brilliant science and ingenuity that is paving the way for us to learn not only about genetic modifiers for thrombosis, but also to develop techniques to unravel genetic modifiers in a multitude of other diseases. Such genetic modifiers are likely the key to answering the clinical questions as to why there are differences in morbidity in the same disease. Another perfect example of this in hematology is sickle cell disease, wherein genetic modifiers likely play a major role in disease severity determination. Eventually, identification of genetic modifiers in patients will work its way into the clinical practice and prognostic models of hematology and medicine in general.