From the Guidelines
Bruton's tyrosine kinase (Btk) inhibitors, such as ibrutinib, can cause platelet aggregation defects, leading to an increased bleeding risk in patients, as evidenced by off-target effects of ibrutinib on platelet aggregation with bleeding complications described in CLL trials 1. The relationship between Btk and platelet aggregation is complex, with Btk playing a role in platelet function through the GPVI and GPIb receptors. When Btk is inhibited, platelets have reduced ability to aggregate in response to collagen and von Willebrand factor, impairing clot formation.
- Key points to consider:
- Btk inhibitors like ibrutinib can increase the risk of bleeding, particularly in patients who require other anticoagulants or medicinal products that inhibit platelet function 1.
- The use of ibrutinib in patients with a history of bleeding diathesis requires careful consideration, and testing for von Willebrand activity may be reasonable before starting ibrutinib 1.
- In case of surgery, ibrutinib should be held at least 3 to 7 days pre- and postsurgery, depending upon the type of surgery and the risk of bleeding 1.
- The platelet dysfunction caused by Btk inhibitors is reversible, with platelet function typically normalizing within days after discontinuation of the Btk inhibitor.
- It is essential to monitor patients on Btk inhibitors for bleeding events, especially if they are on concomitant antiplatelet or anticoagulant medications, and to use clinical judgment when assessing whether to prescribe ibrutinib to patients at risk from further shortening of their QT interval 1.
From the FDA Drug Label
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. In vitro Platelet Aggregation Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at 4.6 µM (2026 ng/mL), 0. 8 µM (352 ng/mL), and 3 µM (1321 ng/mL) in blood samples from healthy donors, donors taking warfarin, and donors with severe renal dysfunction, respectively.
The relationship between Bruton's tyrosine kinase (Btk) and platelet aggregation is that inhibition of BTK by ibrutinib can lead to inhibition of platelet aggregation, specifically collagen-induced platelet aggregation, as demonstrated in vitro studies 2. Key points about this relationship include:
- Ibrutinib inhibits BTK enzymatic activity
- Inhibition of BTK leads to inhibition of collagen-induced platelet aggregation
- The degree of inhibition varies depending on the population (healthy donors, donors taking warfarin, and donors with severe renal dysfunction)
From the Research
Relationship between BTK and Platelet Aggregation
There is no direct evidence in the provided studies to suggest a relationship between Bruton's tyrosine kinase (BTK) and platelet aggregation.
BTK Inhibitors and Their Effects
- BTK inhibitors (BTKis) are used to treat B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) 3, 4.
- The first-generation BTKi, ibrutinib, has been shown to have cardiovascular side effects, such as atrial fibrillation and hypertension 4.
- Second-generation BTKis have improved selectivity and demonstrate reduced rates of cardiovascular complications 4.
- BTKis can also affect the tumor microenvironment and indirectly impact innate and adaptive immunity 5.
Resistance to BTK Inhibitors
- Resistance to BTK inhibitors is a major clinical challenge, with the BTK(C481S) mutation being a known mechanism of resistance 6.
- MALT1 overexpression has been associated with resistance to BTK inhibitors in mantle cell lymphoma, and cotargeting MALT1 and BTK may be a promising therapeutic strategy to overcome resistance 7.