Researchers have discovered that variants in XRCC5, a DNA repair gene, are associated with greater blood clot risk during thalidomide (Thalomid) therapy. Although researchers remain unsure of the precise mechanism underlying XRCC5’s contribution to clot formation, they hope that genetic screening could one day identify high-risk patients requiring more intensive preventative intervention.

Blood clots, in particular deep vein thrombosis – which is a clot within the deep veins of the body – can be a serious and potentially fatal condition. When clots form in blood vessels, they block blood flow and the transport of oxygen and nutrients to affected tissues. If a large clot dislodges, it may also travel to vital organs, particularly the lungs, where the blockage can quickly cause death.

Multiple myeloma, even independent of associated treatments, increases an individual’s clot risk by disrupting normal levels of blood components and clotting factors. Approximately five to 10 percent of myeloma patients will experience a venous thrombotic event, or blood clot, as a direct result of their cancer.

Treating a patient with thalidomide further increases the clot risk to between 10 and 15 percent. The precise mechanism of action remains unknown, but researchers speculate that there is more than one way in which thalidomide contributes to clot formation. Usually, clots occur quickly – around 60 days or sooner – after initiating thalidomide treatment.

In the present study, researchers examined whether specific genetic variants among patients might help explain why only some patients develop clots while taking thalidomide. Specifically, they discovered that particular variants of the XRCC5 gene were associated with higher incidences of clots during thalidomide therapy.

XRCC5 is a gene that helps repair DNA, the “blueprint” for cellular function. As DNA replicates during cellular division, breaks and other defects can occur in the DNA chain. XRCC5 helps to stabilize and repair these broken strands, and without such DNA repair, cellular function may become so disrupted that the cell induces its own death.

In this study, the XRCC5 variants in question decrease the gene’s activity, in turn decreasing the patient’s levels of DNA repair. Researchers hypothesize that decreased DNA repair ability, and higher rates of cell death, could cause more clotting proteins to rush into the bloodstream when myeloma cells are stressed by thalidomide exposure. Additionally, through a complicated pathway, DNA repair impairment could increase thalidomide’s effect on tissue lining cells, therefore setting off a clotting cascade.

Researchers emphasize that while various hypotheses exist for explaining the XRCC5-thalidomide clotting association, they cannot presently confirm a connection. That is, the patients they studied who received thalidomide were also receiving chemotherapy agents. Chemotherapy agents directly damage DNA, and it is therefore possible that chemotherapy, not the thalidomide, caused an increased clot risk in patients with XRCC5-reduced DNA repair ability.

Future studies may clarify the mechanism underlying thalidomide and increased clot formation, as well as uncover additional genetic markers associated with venous thrombosis. Already, however, the incidence of serious clots in thalidomide-treated myeloma patients has significantly decreased with the addition of prophylactic blood thinning medications.

For more information, see the full article in Blood Journal and related correspondence.