Wilbur A. Lam, MD, PhD
Anticoagulants and antiplatelet drugs are proven agents in the prevention and treatment of thrombosis. However, the bleeding risk associated with all currently available antithrombotic agents creates clinical challenges, and these treatments are dose limited or even contraindicated in some patients. In the Scientific Session “New Therapeutic Targets for Thrombosis That Do Not Cause Bleeding,” speakers will explore the latest findings related to the targets in the intrinsic pathway of the coagulation cascade and inhibitors of P-selectin. Here, session chair Wilbur A. Lam, MD, PhD, of Emory University, Georgia Institute of Technology, and Children’s Healthcare of Atlanta, previews the session.
Why were therapeutic targets in thrombosis selected for the Scientific Program?
Dr. Lam: The reason our committee put this forum together is because the field of hematology that is really focused on treating thrombosis has always dealt with the fact that the medications used to treat thrombosis cause bleeding as a side effect. With clots and medications that involve blood clotting, it is always this seesaw where the more you treat the clot and the more powerful of a drug is used to treat it, the more likely you are to tip that seesaw over, pushing you into the side effect of bleeding. You are always trying to ride that balance. However, over the past decade, there has been a lot of research looking at slightly different aspects of the coagulation and hemostatic pathways that may provide opportunities for new therapies for thrombosis that do not necessarily cause bleeding. Now is the right time to showcase the state-of-the-art science behind how targeting certain aspects of coagulation may allow this decoupling of thrombosis from hemostasis. Therefore, you could potentially have this “holy grail” medication that stops or prevents thrombosis without causing spontaneous bleeding.
How significant is the clinical need in this area?
Dr. Lam: It is always a big problem because whenever you have a patient that has a comorbid condition in addition to their clotting, anything that tips them over into a risk for bleeding makes it harder to treat them. For example, the classic antithrombotic medication warfarin is affected by diet and liver function, and that has really plagued the entire field of hematology for decades. When you do have patients with liver problems or sudden changes to diet or within their gut, then the drug gets out of whack. There are newer medications, like low-molecular-weight heparin, but there are issues for those, too.
In my field of pediatric hematology, there is a very narrow therapeutic window, meaning the drug levels must be just right to prevent thrombosis, but not so much that you are pushing the patient into the risk zone for bleeding. Imagine that the patient has a large clot, and you want to give a high dose of an antithrombotic agent, but you cannot because of this seesaw effect with bleeding risk. However, if you can use a drug to treat thrombosis without worrying about causing bleeding, then you can suddenly have a larger range of dosing, which could become a very powerful tool for clinical hematologists to treat patients with more leeway and a larger range of therapeutic efficacy.
Who are the speakers for this session and what perspectives will they offer?
Dr. Lam: The first two speakers will each talk about different aspects of the intrinsic coagulation pathway. Helen Philippou, PhD, of the University of Leeds, is a leading researcher looking at the inhibition of factor XII, which is part of the intrinsic pathway of coagulation. What is interesting is that in the past, researchers thought this part of the coagulation cascade did not matter clinically. However, newer research conducted by Dr. Philippou and her colleagues shows that if you inhibit factor XII the right way, you might be able to prevent thrombosis. At the same time, we already know that patients who had low levels of factor XII did not really have bleeding problems. So, Dr. Philippou and her colleagues are leveraging this aspect of biology so that you might no longer be dealing with a seesaw. Cristina Puy Garcia, PhD, from Oregon Health and Science University, and her colleagues, are looking at a different molecule in the same intrinsic coagulation pathway – factor XI. Factor XI and factor XII are biologically related but are two distinct molecules. Her team has laboratory data that suggest inhibition of factor XI could also be used to prevent thrombosis without causing bleeding.
Elliot Chaikof, MD, PhD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, is doing very interesting work looking at a parallel coagulation process involving P-selectin, which acts as a sort of Velcro in keeping endothelial cells and white blood cells together. As white blood cells are being implicated in thrombosis more and more, Dr. Chaikof and his colleagues are looking at whether you can inhibit that Velcro-like stickiness to prevent blood clots without causing bleeding.
New Therapeutic Targets for Thrombosis That Do Not Cause Bleeding
Sunday, December 11, 2022, 4:30 p.m. – 5:45 p.m., Ernest N. Morial Convention Center, 293-294, Level 2
How close are these new therapeutic targets to being used in clinical practice?
Dr. Lam: There are some candidate drugs already that are being explored for factor XI and factor XII inhibition, though these molecules are in the experimental phase. With P-selectin, there is already an anti-P-selectin drug, crizanlizumab, that has been approved for the treatment of sickle cell disease (SCD). There are some similarities between SCD and thrombosis and, in fact, some people argue that patients with SCD are at risk for thrombosis. Theoretically, if the data end up looking good for inhibition of P-selectin in thrombosis, crizanlizumab could be evaluated in clinical trials to look at whether it could help patients at risk for thrombosis or those with recurring thromboses.
What key message do you want clinicians to take away from this session?
Dr. Lam: We might be getting out of the classic paradigm of constantly assuming that when you have a patient who has a blood clot and you give them a medication for that clot, they are instantly at risk for bleeding. In the next few years, we might be able to have our cake and eat it, too.
