Key Takeaways in Bleeding Disorders From ASH

Dr. Kouides: Hello, I'm Dr. Peter Kouides and I'm going to a review in the next five minutes or so key takeaways from the most recent meeting of the American Society of Hematology. There were a number of different studies that would be of interest to those who are interested in bleeding disorders.

Effects of Tranexamic Acid Prophylaxis on Bleeding Outcomes in Hematologic Malignancy: The a-TREAT Trial

Beginning with the plenary session Professor Terry Gernsheimer presented on the effect of tranexamic acid to reduce bleeding in patients undergoing high dose chemotherapy, predominantly stem cell therapy, who are thrombocytopenic.

As you know, tranexamic acid is used a fair amount as a blood sparing agent, particularly in people undergoing orthopedic surgery and other types of procedures. But in bone marrow transplant, there's a high risk of bleeding, obviously, as it thrombocytopenic. This was a well conducted multi-center randomized study.

It did not show any benefit to tranexamic acid. That was the take home message. There was no effect on the incidence of a grade 2+ bleeding. One potential concern was that the analysis did not include those patients who had become platelet refractory, so it's possible a subset of patients may benefit, but interestingly, this was a negative study. They also showed a higher rate of occlusions of the central line catheter of those who were randomized to tranexamic acid.

Platelet Dysfunction and Persistent Fibrinolysis in Pediatric Scoliosis Surgery Patients Receiving Tranexamic Acid

To continue this theme of a tranexamic acid, there was a study, abstract number 381, that looked at the benefit and role of tranexamic acid in pediatric scoliosis surgery patients. And there was a very interesting study in that they did a number of laboratory studies to correlate the response, and they showed that there was persistent fibrinolysis and activation of coagulopathy despite optimal dosing of tranexamic acid. So it's possible that one has to fine tune their dosing.

And finally, regarding tranexamic acid, for as much as I just reviewed two negative studies, there was a positive study, abstract number 863, by Naveed et al., from Michelle Sholzberg's group in Toronto. This was a retrospective cohort study of the use of tranexamic acid for women with inherited bleeding disorders undergoing childbirth. Their study did show a relative benefit of tranexamic acid consistent with other studies. In the literature, most of the studies involve women in general, who don't have a bleeding disorders, so this study involves specifically women with underlying bleeding disorders. There still was a rate of bleeding, but it was lower than what has been typically reported in the literature: the rate of bleeding was only 13% compared to about 20 to 40% risk of a postpartum hemorrhage that we see in the bleeding disorder population.

Regarding new hemophilia products, a new and old product of course, is emicizumab (Hemlibra). It's now been available the last two years plus, and there's a number of abstracts that reported on real-time use of emicizumab, including looking at database reviews--abstract number 866 and abstract number 1791--and also larger multi-center studies that are developing databases, including the European Haemophilia Safety Surveillance Database.

They have reported their initial results of emicizumab, abstract number 2685. And the American counterpart, led by Tyler Buckner through the ATHN Network, reported on their initial experience of approximately 300 patients, abstract number 510.

In general, there have been no major adverse events in terms of thrombosis through these registries. There was in the ATHN report one unexpected bleed of a late subdural hematoma in a patient who suffered head trauma from a fall and did receive promptly a standard factor, and yet had a delayed hemorrhage. This patient was on emicizumab. We're anxiously looking for these studies to mature with larger numbers of patients and observations in comparing emicizumab to standard and extended half-life products in that sense.

Lastly regarding emicizumab, there were a number of reports of its use in acquired hemophilia. As you know, it's only approved for inherited hemophilia. A very provocative study, though a small sample of patients, comprised of eight patients from the Brigham and Women's Hospital, abstract number 872, did show a benefit in using emicizumab upfront. This may prove to be a new option for these patients. Though, certainly, we'll need a larger sample size to look for safety, because this was a small study. They didn't report any untoward events in these patients.

Regarding other hemophilia products as a separate segment, I will discuss the study of Eloctate for previously untreated patients. That's the first extended half-life study studying previously untreated patients. And also, in a separate segment, I will discuss a study of Fitusiran, which is a small interfering RNA against antithrombin III.

Finally, with von Willebrand's, there were some interesting studies, including abstract number 573 from the Dutch, which suggests that the cutoff level for von Willebrand's and bleeding probably should be 60% and not 50%. So, that's very provocative. We do know that those patients with low von Willebrand's factor, between 30 to 50%, can bleed, but we don't know as much about whether one could bleed slightly above this, 50 to 60%. This analysis suggests otherwise; it was in over 400 patients.

574 Genotype Analysis of Adolescents With Heavy Menstrual Bleeding and Low Von Willebrand Activity – Report of a Multi-Center Study

Regarding patients who have low von Willebrand factor levels, there was another study, abstract number 574. They did a full genetic sequencing of adolescents with heavy menstrual bleeding and low von Willebrand activity. They reported a number of a novel gene variants. I do want to disclose I was part of this group, but what's interesting is they found variants and novel genes that have not been associated with von Willebrand's and bleeding, including FERMT2 and ABCA13. FERMT2 codes for Kindlin-2, which has been known to be critical for vascular integrity. That's a good hypothesis-generating study, and it'd be important to look at a larger number of patients.

2688 Iron Deficient Anemia May Obscure a Diagnosis of Low VWF, VWD or Mild Hemophilia a in Biological Females With Heavy Menstrual Bleeding

Lastly, there's a very provocative poster presentation from Genevieve Moyer and Patricia Huguelet from Denver, number 2688. They report that iron deficiency anemia may obscure a diagnosis of low von Willebrand's or VWD. In other words, when someone first presents with heavy menstrual bleeding, the stress of that where one is being evaluated could raise the VWF levels. In retesting, they found a number of patients did have, after all, low levels. So this is very provocative and also will deserve further follow-up.