Stopping the Bleeding: Hemophilia and VWD

The ASH annual meeting has traditionally provided a forum for the hemophilia and basic science communities to come together and share their data, not only with each other, but with the general hematology audience. This year has been no exception. Beginning Sunday, new insights into the pathophysiology of hemorrhagic diseases and advances in clinical management have permeated the meeting. We just can’t resist reporting on a few of the tantalizing tidbits from the sessions on hemophilia and von Willebrand Disease.

Hemophilia is a simple disease at the molecular level: patients have Factor VIII gene mutations. The solution also appears simple. Recombinant Factor VIII provides relief from hemorrhage, and prophylaxis can prevent morbid complications. But, of course, it is not that simple. Factor VIII inhibitors can severely hamper therapy, and factor replacement therapy can be a cumbersome magic bullet. In the Sunday Simultaneous Session on Hemophilia, multiple abstracts highlighted progress in dealing with Factor VIII inhibitors. The session opened with a talk by Dr. Santagostino, who presented a case-control study in children with hemophilia A showing that early prophylaxis had a favorable impact on the inhibitor risk, independent from the age of first exposure. Three abstracts dealing with inhibitors immediately followed, including a presentation by Dr. Rawle et al., who induced Factor VIII tolerance orally by feeding hemophilic mice high doses of recombinant FVIII-C2 domain. There’s more hemophilia to come in today’s Simultaneous Session on Animal Models in Coagulation and Fibrinolysis. Dr. Xu et al. will be presenting an interesting abstract on the modulation of hemophilia by Factor V Leiden in mice.

Von Willebrand Disease has also been a hot topic. Although VWD is the most common inherited bleeding disorder in humans, the physiology responsible for most cases of Type 1 VWD, and even normal VWF homeostasis, remain largely unknown. To date, ABO blood group is the only major modifier clearly implicated in VWF levels in normal humans. Yesterday’s VWF/ADAMTS13 Simultaneous Session speakers compiled evidence for accelerated clearance as a mechanism for lowering VWF levels. Dr. Dai et al. examined healthy individuals of all blood groups for anti-VWF antibodies. They found three-fold higher anti-VWF titers in blood group O individuals, implicating antibody-mediated clearance as a mechanism for the low VWF levels associated with blood group O in normal subjects. Dr. Millar et al. reported accelerated VWF clearance after ddAVP stimulation in Type 1 VWD patients, but, interestingly, they found that the rate of clearance was unrelated to ABO blood group or the Tyr1584Cys VWF polymorphism, suggesting another mechanism for VWF clearance in these patients. Of course, bleeding is multifactorial, and Dr. Rand et al. presented additional data on the influence of GPIb and integrin polymorphisms on type 1 VWD. The authors report that a polymorphism in GPIbalpha is associated with increased bleeding risk in Type 1 VWD, but refute a previously reported association between bleeding in VWD and alpha2 integrin polymorphisms, illustrating the difficulty in teasing out modifiers in VWD.

The ASH annual meeting has once again succeeded in producing a stimulating dialogue on hemorrhagic disorders. We suspect we will hear much more about the exciting advances presented this year in the very near future.