Pathogenesis and Precision Treatment Advances in Immune Thrombocytopenia (ITP)

Immune Thrombocytopenia (ITP), formerly known as “idiopathic thrombocytopenic purpura,” is an autoimmune disorder caused by acquired immune dysregulation. It primarily manifests as mucocutaneous bleeding, with severe cases potentially leading to intracranial hemorrhage. According to the latest clinical consensus, ITP is defined as a highly heterogeneous syndrome rather than a single disease. Epidemiologically, with more precise diagnostic techniques, the incidence of adult ITP shows a clear bimodal distribution across genders and age groups, suggesting that different immune pathogenic drivers may predominate at different ages.

Figure 1. Simplified schematic of ITP pathogenesis and novel therapies

Pathogenic Mechanisms

The pathogenesis of ITP is complex and involves multiple pathways, including humoral immunity, cellular immunity, and megakaryocyte dysfunction. Patients produce IgG autoantibodies targeting platelet glycoproteins. These antibodies promote platelet clearance by splenic and hepatic macrophages through Fcγ receptor-mediated phagocytosis. They can also induce platelet desialylation, exposing N-acetylglucosamine residues that are recognized and cleared by the hepatic Ashwell-Morell receptor. Additionally, autoantibodies can bind to bone marrow megakaryocytes, inhibiting their maturation and platelet production, leading to reduced platelet generation. On the cellular immunity side, regulatory T cells (Treg) and regulatory B cells (Breg) are functionally defective, with Th1/Th17 subsets predominating. Cytotoxic CD8⁺ T cells directly induce apoptosis of platelets and megakaryocytes via the perforin/granzyme B pathway. Overexpression of B-cell activating factor (BAFF) further promotes the survival and antibody production of autoreactive B cells. Complement activation and epigenetic abnormalities (such as altered DNA methylation) also contribute, resulting in a dual pathology of “increased destruction + decreased production.”

Key Targets and Cutting-Edge Research Advances

In recent years, ITP treatment has entered a new era of precision immune modulation. In addition to traditional glucocorticoids, IVIG, rituximab, and thrombopoietin receptor agonists (TPO-RAs such as eltrombopag and romiplostim), several novel agents have entered clinical use or Phase III trials.

BTK Inhibitors: rilzabrutinib (Wayrilz)

BTK (Bruton’s tyrosine kinase) is a key kinase downstream of the B-cell receptor (BCR) and Fcγ receptor (FcγR) signaling pathways. In 2025, the oral reversible covalent BTK inhibitor rilzabrutinib (brand name Wayrilz) received FDA approval, becoming the first BTK inhibitor approved specifically for ITP. By selectively inhibiting BTK (via reversible covalent binding at the C481 site), the drug modulates immune responses through multiple pathways: it blocks BCR downstream signaling to inhibit autoreactive B-cell activation and autoantibody production; it also blocks FcγR-mediated macrophage phagocytosis, reducing clearance of antibody-coated platelets; meanwhile, it preserves platelet function mediated by G-protein-coupled receptors (such as CLEC-2), thereby avoiding increased bleeding risk. The LUNA 3 Phase III trial demonstrated that rilzabrutinib achieved rapid and sustained platelet increases in chronic ITP patients who had failed prior therapies, with significantly higher response rates than placebo and a favorable safety profile.

Figure 2. Mechanism of action and clinical translation of rilzabrutinib in ITP

FcRn Antagonists: efgartigimod

FcRn (neonatal Fc receptor) is a critical regulator of IgG homeostasis, protecting IgG from lysosomal degradation by binding it in acidic endosomes. The FcRn antagonist efgartigimod (an engineered IgG1 Fc fragment) competitively binds FcRn with high affinity, blocking IgG (including pathogenic autoantibodies) recycling and promoting its degradation, thereby specifically reducing circulating total IgG levels (typically by 60–80%). The ADVANCE IV Phase III trial showed that efgartigimod significantly increased the proportion of chronic ITP patients achieving sustained platelet responses (≥50×10⁹/L on ≥4 out of 6 scheduled visits), improved bleeding symptoms, and enhanced quality of life. Long-term efficacy is currently being evaluated in open-label extension studies.

Figure 3. Schematic of efgartigimod’s pharmacological action

Anti-CD38 Monoclonal Antibodies

CD38 is highly expressed on long-lived plasma cells that produce autoantibodies. Anti-CD38 monoclonal antibodies (such as mezagitamab, CM313, and daratumumab) specifically deplete plasma cells through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptosis induction, thereby reducing antibody production at its source. Phase II randomized controlled trials of CM313 and daratumumab, as well as the mezagitamab Phase II study, demonstrated rapid platelet count recovery and sustained responses in patients with refractory ITP. Phase III studies are currently underway.

Figure 4. Mechanisms of primary and acquired resistance to anti-CD38 antibodies

Syk Inhibitors: fostamatinib (Tavalisse)

Syk (spleen tyrosine kinase) is a key upstream node in the FcγR signaling pathway. The Syk inhibitor fostamatinib (brand name Tavalisse, FDA-approved in 2018) blocks macrophage phagocytosis of IgG-coated platelets and inhibits B-cell activation and antibody production by inhibiting Syk. The FIT clinical trial program confirmed its ability to significantly increase platelet response rates in chronic ITP.

Figure 5. Mechanism of action of fostamatinib’s active metabolite R406 in immune thrombocytopenia

BAFF-R Inhibitors: ianalumab (VAY736)

BAFF-R (B-cell activating factor receptor) regulates B-cell survival, maturation, and proliferation. The BAFF-R inhibitor ianalumab (VAY736, a fully human IgG1 monoclonal antibody) inhibits autoreactive B-cell function by blocking BAFF-R signaling and enhancing ADCC-mediated B-cell depletion. Results from the VAYHIT2 Phase III trial showed that ianalumab combined with eltrombopag significantly prolonged time to treatment failure (TTF) and improved the 6-month stable response rate compared with placebo plus eltrombopag in primary ITP patients who failed first-line glucocorticoids. It also helped reduce eltrombopag dosage and may have potential disease-modifying effects.

Figure 6. Mechanism of action of anti-BAFF agents

These precision targeted therapies together form the framework for a new era in ITP treatment. In the future, multi-target combinations or individualized regimens based on immune phenotypes are expected to further improve patient outcomes. In clinical practice, attention must be paid to each drug’s indications, monitoring parameters, and safety profiles.

Figure 7. 2025 clinical trial updates in immune thrombocytopenia

abinScience Related Products

Below are abinScience’s latest recombinant proteins and antibodies targeting Immune Thrombocytopenia-related pathways. Catalog numbers are clickable links to the product pages.

Protein

Antibody

Kit

References:
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