8  New Frontiers in Bleeding Disorders

8.1 Session Overview

Session Details
Session New Frontiers in Bleeding Disorders
Speaker Ross Baker, MBBS
Affiliation Perth Blood Institute, University of Notre Dame Australia and Murdoch University, Perth, Australia
Time Day 2, 9:00–9:30 a.m.

Rather than rehearsing well-trodden factor and gene-therapy stories, Dr. Baker focuses on the “often overlooked” end of the bleeding-disorder spectrum: Bleeding Disorder of Unknown Cause (BDUC), hereditary hemorrhagic telangiectasia (HHT), bleeding in hemophilia A carriers with “normal” factor VIII, and emerging therapeutic strategies for immune thrombocytopenic purpura (ITP) and von Willebrand disease (VWD) [slide p.3, p.4].

8.2 Speaker Spotlight

Ross Baker, MBBS is a hemostasis specialist at the Perth Blood Institute and a leading figure in the Australia/New Zealand bleeding disorders community. His research encompasses clinical trials of novel hemostatic agents, gene therapy outcomes, and the development of regional treatment guidelines adapted for the Asia-Pacific setting. He has contributed extensively to national hemophilia registries and multidisciplinary care models across Australasia.

8.3 What’s New in 2025–2026

8.3.1 The Diagnostic Challenge: Spectrum of Inherited Bleeding Disorders

Dr. Baker framed inherited bleeding disorders as a pyramid in which severe, unprovoked bleeding (hemophilia, Glanzmann thrombasthenia) sits at the apex and is managed in Hemophilia Treatment Centres with factor replacement, while the broad base is populated by patients with mild provoked bleeding or entirely normal laboratory testing–a population that is common, community-based, predominantly female, and disproportionately reliant on clinical gestalt and bleeding assessment tools (BATs) [slide p.5].

8.3.2 Bleeding Disorder of Unknown Cause (BDUC)

  • Definition. BDUC describes patients with clinical symptoms indicative of an underlying bleeding disorder yet a negative standardised hemostatic workup; it is a diagnosis of exclusion [slide p.7].
  • Burden in women. 60–90% of females with BDUC report heavy menstrual bleeding and 30–65% post-partum hemorrhage, alongside hematomas/bruising (66–78%), epistaxis (31–79%), oral mucosal bleeding, and bleeding after medical/dental procedures (36–84%) [slide p.7].
  • Assessment. The ISTH-BAT should be used to objectively assess bleeding in individuals referred for investigation; a bleeding score >10 in VWD and BDUC is a strong predictor of future bleeding. BATs have limitations in men and children, where clinical gestalt remains essential [slide p.8].
  • Initial laboratory panel (normal in BDUC): CBC and peripheral smear; PT, aPTT, fibrinogen, TT; VWD testing (VWF antigen, activity, FVIII:C); platelet aggregation with dense granule assessment; factor IX, XI, and chromogenic FVIII. Additional testing may include rare factor levels (XIII, II, V, VII, X), fibrinolysis assays, PFA-100/200, extended platelet testing (GpFL, PTEM), and global hemostasis assays [slide p.10].
  • Illustrative case (Kathie, 36 y). Life-long bleeding, ISTH-BAT = 14, blood group O, normal CBC/plasmatic coagulation and normal platelet function–an archetypal BDUC presentation with impaired health-related quality of life [slide p.9, p.11].
  • ISTH SSC guidance. Baker and colleagues have published ISTH SSC communications on standardising the definition, diagnosis, prediction of future bleeding, and peri-procedural management of BDUC, featured as the ASH 2025 BDUC educational session [slide p.6].

8.3.2.1 Peri-procedural management

Procedural risk is assessed along two axes: patient factors (ISTH-BAT score, prior surgical/procedural bleeding, response to hemostatic agents, age, medications, co-morbidities) and procedure factors (major vs. minor, bleeding and thrombotic risk, fluid administration, hemostatic product availability and monitoring) [slide p.12]. A simplified treatment algorithm follows [slide p.13]:

BDUC peri-procedural algorithm
Patient Risk Procedure Risk Management
Low Low Observation; TXA
High Low TXA
High High TXA; TXA + desmopressin; TXA + platelet transfusion

8.3.2.2 Expanded platelet testing (ASH 2025 abstract #15123)

A retrospective Mayo Clinic cohort of 108 adults referred for abnormal bleeding and PTEM (83% female, median age 45, median ISTH-BAT 7) assessed the yield of expanded platelet testing. 46 (42.6%) had normal plasmatic and platelet function profiles, and 62 (57.4%) had abnormalities (coagulation factor deficiency 21%, type 1 VWD 9.7%, PFA-100 27.4%, LTA 38.7%). Notably, 14/46 (30.4%) patients with otherwise normal hemostasis had abnormal platelet transmission electron microscopy (PTEM), glycoprotein flow cytometry (GpFL), or both, suggesting a role for expanded platelet testing in refining the BDUC label [slide p.14, p.15, p.16].

8.3.3 Hereditary Hemorrhagic Telangiectasia (HHT): CHORUS Registry

  • Why HHT matters. HHT is the second-most-common inherited bleeding disorder, autosomal dominant, affecting ~1 in 3,800 people and ~1.6 million worldwide (~80,000 in the US), with equal sex distribution. Dr. Baker highlighted that HHT is the most clinically significant and morbid inherited bleeding disorder of women, and patients have reduced overall survival versus healthy controls [slide p.19].
  • Multisystem disease. Progressive vessel malformations produce mucocutaneous telangiectasias, severe recurrent epistaxis, chronic GI hemorrhage, and transfusion- or iron-infusion-dependent iron deficiency anemia, plus visceral/CNS AVMs (lung, liver, brain) causing hemorrhagic or embolic stroke, liver cirrhosis, pulmonary hypertension, pulmonary hemorrhage, and high-output heart failure. Patients rank bleeding as the most important clinical manifestation by a wide margin, and no therapies are approved worldwide [slide p.18].
  • CHORUS registry (abstract #8457, Al-Samkari et al.). 600 participants with genetically or Curaçao-criteria-confirmed HHT; median age 53 y, 60% female. Despite 60% experiencing recurrent spontaneous epistaxis before age 13, 71% were first diagnosed in adulthood, nearly half after age 40 [slide p.17, p.20].
  • Epistaxis. 95% had spontaneous recurrent epistaxis; 59% moderate-to-severe (ESS >4, systemic/surgical intervention, or IV iron/RBC transfusion). Treatments received included intranasal topical therapies (44%), nasal surgeries/procedures (43%), and medical therapies (24%; of which 56% systemic antifibrinolytics and 49% systemic antiangiogenics) [slide p.21].
  • Further manifestations. Heavy menstrual bleeding 35%, other mucocutaneous/GI bleeding 41%, iron deficiency 68%. AVMs: pulmonary 47% (2% bleed), intracranial 15% (3% bleed, particularly under age 25), and liver 40%; managed with embolisation, resection, transplantation, or antiangiogenic therapy [slide p.22].
  • Practice points. Consider the diagnosis on examination, regularly assess iron status, screen for AVMs, and new therapies are required [slide p.22].

8.3.4 Hemophilia A Carriers Who Bleed with “Normal” Factor Levels

Baker reviewed the US My Life, Our Future / ATHN SN8Check program (abstract #1997, Johnsen et al.), which reframes hemophilia A in females as a genetic rather than purely phenotypic diagnosis [slide p.23].

  • Why genotype matters. In females, diagnosis is informed by F8 genotype, FVIII level, and bleeding symptoms; in males it is defined by FVIII <40%. F8 genotyping facilitates diagnosis, personalises care, identifies at-risk relatives, and informs genetic counseling and family planning. Approximately 30% of females with HA genotypes are expected to have FVIII <40 IU/dL, and genotype-positive females with normal FVIII can still experience bleeding symptoms–a recognised knowledge gap [slide p.24, p.25].
  • Eligibility. Testing was offered to individuals with HA (FVIII <40%) or females with a first-degree (occasionally more distant) relative with HA [slide p.26].
  • Yield (March 2024–July 2025). 531 samples from eligible females; mean age 25 y (range 0.04–83 y). A clinically reportable F8 variant was found in 62% (n = 329) [slide p.27].
  • FVIII activity in genotype-positive females. Levels ranged from <1% to 213%. Mean FVIII was significantly lower in genotype-positive vs. genotype-negative females (50.4% vs. 66.4%, p = 0.004). 44.4% of genotype-positive females had FVIII <40%, and 2 had severe HA (<1%), including one heterozygous for the intron 22 inversion [slide p.28].
  • FVIII a poor predictor of bleeding. Among 270 genotype-positive females with bleeding data, 49.3% reported excessive bleeding. In those with paired FVIII and bleeding data (n = 122), mean FVIII was 44.6% in bleeders vs. 59.3% in non-bleeders (p = 0.02), but 52% of genotype-positive females who bled had FVIII ≥40%–“FVIII level is a poor predictor of variant status and bleeding risk” [slide p.29].
Reframing the “Hemophilia A Carrier”

A “normal” FVIII level does not exclude hemophilia A in a female with a consistent bleeding phenotype. Baker argued for F8 genotyping in females with abnormal bleeding or a positive family history, using the genetic diagnosis–not the factor level alone–to guide counseling, peri-procedural planning, and family screening [slide p.25, p.29].

8.3.5 Advances in ITP Therapies

Dr. Baker framed current ITP care as a cycle from first-line corticosteroids/IVIG/anti-D, to second-line TPO-RAs, rituximab, fostamatinib, splenectomy and MMF, to emerging FcRn, BTK, SYK, complement, anti-CD38 and BAFF inhibitors, increasingly delivered as combination therapy and selected on availability/cost, durability of response, and safety/quality of life [slide p.30].

Key ASH 2025 ITP trials summarised [slide p.31]:

Selected ITP trials at ASH 2025
Trial (Abstract) Drug / target Setting Result
VAYHIT2 (#LBA-2, Al-Samkari) Ianalumab (anti-BAFF-R) + eltrombopag, Phase 3 Failed prednisolone Time to treatment failure 13 vs ~4 months [slide p.35]
VAYHIT3 (#844, Choi) Ianalumab (anti-BAFF-R), Phase 2 Failed ≥2 lines 44% response
Linperlisib (#2373, Zhou) PI3K-AKT inhibitor, Phase 2 Second-line 50% response
ESLIM-OL (#4368, Hu) Sovleplenib (BTK/SYK), Phase 3 extension – 61.5% response
PROLONG (#7613, Ghanima) Rituximab ± dexamethasone ± low-dose rituximab maintenance Failed prednisone Induction response 61.3% vs 38.5% (p = 0.01) [slide p.41]
  • VAYHIT2 (Phase 3, NCT05653219). Adults with primary ITP after corticosteroids (±IVIG) with platelets <30 × 10⁹/L were randomised 1:1:1 to ianalumab 3 mg/kg or 9 mg/kg (4 once-monthly infusions) plus eltrombopag vs placebo plus eltrombopag, followed by eltrombopag tapering and up to 39 months of follow-up. TTF was significantly longer with ianalumab 9 mg/kg + eltrombopag (HR 0.55, 95% CI 0.32–0.92; p = 0.021) and 3 mg/kg + eltrombopag (HR 0.58, 95% CI 0.34–0.98; p = 0.023) vs placebo; median TTF 13.0 months (9 mg/kg) vs 4.7 months (placebo); 3 mg/kg arm not reached [slide p.34, p.35]. Ianalumab has a dual mechanism–enhanced B-cell depletion via ADCC and BAFF-R blockade reducing B-cell activation/survival [slide p.33]. Safety: Grade ≥3 neutropenia 14% (9 mg/kg) and 6% (3 mg/kg) vs 0% placebo; no febrile neutropenia or neutropenic sepsis; infusion-related reactions all Grade 1–2 [slide p.36].
  • PROLONG (abstract #7613). A two-phase, double-randomised trial optimising rituximab response with dexamethasone (induction) and low-dose rituximab maintenance. Induction phase: rituximab 1000 mg days 1 and 15 ± two cycles of dexamethasone 20 mg × 4 days. Maintenance: responders re-randomised to rituximab 500 mg or placebo at weeks 0 and 24. Induction response at week 24 was 61.3% with dexamethasone vs 38.5% without (p = 0.01) [slide p.37, p.39, p.40]. Maintenance showed numerically fewer losses of response at 52 weeks with rituximab (3.4% vs 23%), though the overall log-rank was not significant (p = 0.15) [slide p.41].

8.3.6 Von Willebrand Disease: Rebalancing Therapy with VGA039

  • Rationale. VGA039 (abstract #7717, Wheeler et al.) is a fully human IgG4 monoclonal antibody that modulates Protein S, a cofactor for TFPIα and activated protein C, thereby enhancing thrombin generation–the first rebalancing therapy targeting Protein S for VWD [slide p.42, p.43].
  • VIVID 3 Phase 1/2 design. Patients aged 12–60 with symptomatic VWD of any type, baseline FVIII <LLN, and no history of thromboembolism received a loading dose followed by subcutaneous VGA039 every 4 weeks (17-week treatment period) in flat-dose (225 mg) or weight-banded cohorts [slide p.43].
  • Efficacy. Subcutaneous every-four-week dosing was well tolerated and substantially reduced bleeding rates: median bleed reduction 81% (range 41–100%), with reductions of 73–87% in Phase 3-eligible participants (historic ABR ≥12). Patients switching from prior IV prophylaxis also benefited (e.g., 56.8 → 14.1, a 75% reduction) [slide p.44].
Rebalancing Hemostasis in VWD

VGA039 is an early proof-of-concept that the rebalancing strategy already validated in hemophilia (anti-TFPI, siRNA antithrombin) can be extended to VWD of any type, using a monthly subcutaneous injection rather than plasma-derived or recombinant VWF infusions–particularly attractive in Asia-Pacific settings where VWF concentrate access is uneven [editorial].

8.4 Clinical Pearls

Five Key Takeaways
  1. Bench-to-bedside medicine is crucial to advancing bleeding management–and the next frontier is the large, community-based population with mild provoked bleeding and “normal” tests, not the apex of severe hemophilia [slide p.5, p.45].
  2. BDUC is a diagnosis of exclusion that still bleeds. Use the ISTH-BAT, complete a standardised panel, and consider expanded platelet testing (PTEM, GpFL)–30% of otherwise “normal” patients have detectable platelet ultrastructural or glycoprotein abnormalities [slide p.8, p.16].
  3. Think HHT early. 95% of HHT patients have spontaneous recurrent epistaxis and 68% iron deficiency, yet 71% are diagnosed in adulthood; examine for telangiectasia, monitor iron, screen for pulmonary/hepatic/cerebral AVMs, and remember that no HHT-specific therapies are yet approved [slide p.18, p.20, p.21, p.22].
  4. A “normal” FVIII does not exclude hemophilia A in a bleeding female. 62% of eligible females tested in the US SN8Check program had a clinically reportable F8 variant, 52% of genotype-positive bleeders had FVIII ≥40%, and FVIII level is a poor predictor of variant status and bleeding risk–genotype-driven diagnosis is essential [slide p.27, p.29].
  5. Additional bleeding factors still need to be discovered; combination and rebalancing therapies enhance efficacy and safety. VAYHIT2 (ianalumab + eltrombopag) and PROLONG (rituximab + dexamethasone) illustrate combination gains in ITP, while VGA039 anti-Protein S extends rebalancing to VWD of any type [slide p.35, p.40, p.44, p.45].

8.5 Key References

  1. Baker RI, O’Donnell JS. How I treat bleeding disorder of unknown cause. Blood. 2021;138(19):1795–1804. [slide p.5]
  2. Baker RI, Choi P, Curry N, et al. Standardization of definition and management for bleeding disorder of unknown cause: communication from the ISTH SSC. J Thromb Haemost. 2024. [slide p.6, p.8]
  3. Pradeep A, Sridharan M, Chen D, et al. Bleeding disorder of unknown cause (BDUC): is there a role for expanded platelet testing? Blood. 2025;ASH abstract #15123. [slide p.14]
  4. Al-Samkari H, Friday C, Kasthuri RS, et al. Clinical spectrum of hereditary hemorrhagic telangiectasia (HHT): data from the Comprehensive HHT Outcomes Registry of the United States (CHORUS). Blood. 2025;ASH abstract #8457. [slide p.17]
  5. Johnsen JM, Fletcher SN, Aires L, Sandoval C, Konkle BA. Females affected by hemophilia A: data from the United States SN8Check program. Blood. 2025;ASH abstract #1997. [slide p.23]
  6. Al-Samkari H, Cuker A, Zaja F, et al. Primary results from VAYHIT2: a randomized, double-blind, Phase 3 trial of ianalumab plus eltrombopag vs placebo plus eltrombopag in ITP after first-line corticosteroid failure. Blood. 2025;ASH abstract LBA-2. [slide p.32]
  7. Ghanima W, El Demerdash D, Frederiksen H, et al. The PROLONG trial: a two-phase randomized placebo-controlled trial of rituximab + dexamethasone induction and low-dose rituximab maintenance in ITP. Blood. 2025;ASH abstract #7613. [slide p.37]
  8. Choi P, et al. VAYHIT3: ianalumab (anti-BAFF-R) in ITP after ≥2 prior lines, Phase 2. Blood. 2025;ASH abstract #844. [slide p.31]
  9. Zhou H, et al. Linperlisib, a PI3K-AKT inhibitor, in second-line ITP: Phase 2. Blood. 2025;ASH abstract #2373. [slide p.31]
  10. Hu Y, et al. ESLIM-OL: sovleplenib Phase 3 extension in ITP. Blood. 2025;ASH abstract #4368. [slide p.31]
  11. Wheeler AP, Kshirsagar S, Giermasz A, et al. Subcutaneous every-four-week VGA039, a novel anti-Protein S antibody, in von Willebrand disease: results from VIVID 3, a Phase 1/2 multi-dose study. Blood. 2025;ASH abstract #7717. [slide p.42]