Classical Hematology: Managing Disorders of Bleeding and Clotting

Craig M. Kessler, MD, MACP

Lombardi Comprehensive Cancer Center

Georgetown University Medical Center

Washington, DC

��Disclosures

• Research- Bayer, be.bio, Genentech/Roche, NovoNordisk, Octapharma, Regeneron, Stago
• Advisory Boards- Bayer, be.bio, CSL-Behring, Genentech/Roche, NovoNordisk, Novartis, Octapharma, Pfizer, Regeneron, Stago, Takeda
• DSMB- NIH, Bayer, Octapharma
• Stock- Not applicable
• Employment – Not applicable
• Speakers’ Bureau – Not applicable

Topics

• Gene Therapy Beyond Sickle Cell Disease- Have we “cured” hemophilia?
• Guidelines for treatment of chemotherapy induced thrombocytopenia
• Novel therapies in autoimmune thrombocytopenic purpura
• Treatment of thrombotic complications of cirrhotic liver disease
• Issues in cancer associated thrombosis
• New strategies for thrombotic thrombocytopenic purpura

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Evolving Approaches to Gene Therapy in Hemophilia

Become-9: A Phase 1/2 Dose Escalation and Expansion Study of be-101 for the Treatment of Adults with Moderately Severe or Severe Hemophilia B/CRISPR/Cas9 Blood (2024) 144 (Supplement 1): 2593.1.

Gene Therapy Expressing Platelet-Derived Factor VIII for Correction of Hemophilia Α with a History of Inhibitors/Lentiviral vector Blood (2023) 142 (Supplement 1): 2249.

Overview of a CRISPR-mediated targeted gene insertion platform that utilizes the Albumin locus to express therapeutic proteins from the liver-Hemophilia B ASH 2023 Scientific Program

First Line Treatment for Primary ITP: Prednisone vs High Dose Decadron

• HD-DEX: Better and more rapid initial response;
• Less durable response

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• PDN: Longer durability response;
• Increased side effects

Mazzucconi MG et al. Blood Adv (2024) 8 (6): 1529–1540

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93.9% DXM vs 78.6% PDN initial response d42-45

58.9% DXM vs 60.4% PDN final response d180

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ITP is an Autoimmune Disorder Mediated by Autoantibodies

Cines DB, et al. N Engl J Med. 2002;346(13):995-1008.

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Platelet autoantibody production

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Platelet Opsonization

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Destruction of �Opsonized Platelets �by Splenic �Macrophages

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Anti-Glycoprotein

production

B-cell

T-cell

Activated macrophage

Antibody-coated platelet

Fcγ

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Pathogenesis

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Treatment MOA

Splenectomy,

corticosteroids, IVIg, IV Anti-D, danazol, Vinca alkaloids

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TPO receptor agonists, corticosteroids

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Azathioprine, cyclophosphamide, cyclosporin, corticosteroids, danazol, mycophenolate mofetil

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Bone Marrow Image from ASH.

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https://touchoncology.com/wp-content/uploads/sites/2/2025/01/touchONCOLOGY_touchPANEL-DISCUSSION_ITP_Practice-Aid_January2025_EN-1.pdf

Mode of Action for FcRn Receptor Antagonists in ITP

Adapted from Newland AC, McDonald V. FcRn antagonists in ITP. Ann Blood 2021;6:6

Efgartigimod= Engineered human IgG1 antibody Fc fragment without Fab region

Rozanolixizumab = Humanized high affinity anti-FcRn IgG4 mAb with Fab region

ABS 689: Time to Achieve Platelet Count Response after Intravenous Efgartigimod in Adults with Primary immune Thrombocytopenia: A Phase 3 Multicenter, Double-blinded, Placebo-controlled, Randomized Clinical Trial (Advance IV) 2023 Broome CM et al Drive Rank score = 0 �

N= 118

EFG=86

PBO=45

Concurrent Tx allowed to remain at same dose and frequency as at entry

(11/28/2023): ADVANCE-SC did not meet primary endpoint

0

Kuter DJ et al

ISTH 2024

• Mezagitamab is a full human IgG1 monoclonal anti-CD38 AB depletes B-lymphocytes

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• 3 dose cohorts vs placebo

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• All 3 groups demonstrated rapid and sustained platelet responses that persisted for 16 wks in dose response manner

5 Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Adults with Previously Treated Immune Thrombocytopenia (ITP): A Phase 3, Placebo-Controlled, Parallel-Group, Multicenter Study (LUNA 3) Kuter DJ et al

Platelet response:

Rilzabrutinib = 65%

Placebo = 33%

Occurred for most by 2 wks

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Durable response:

Rilzabrutinib = 23%

Placebo = 0%

P<0.0001

Abs. 2600. Primary Care Screening for Von Willebrand Disease in African American Adolescents with Heavy Menstrual Bleeding Agarwal S et al. ASH, 2024

Establishing dx of VWD is difficult in African Americans using VVWF:RCo/WF:Ag

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VWF polymorphism D1472H is found in 50% AA; VWF:Rco/VWF:Ag<.7 but with normal BAT

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Compare VWF activities using VWF:RCo vs Gb1b M assay.

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Hypothesis: Type I VWD is over diagnosed in AAs with D1472H and VWF:RCo assays

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32/163 AA women with HMB worked up for VWD had low VWF:RCo; only 9 with low GP1bM

Abs 2600. Primary Care Screening for Von Willebrand Disease in African American Adolescents with Heavy Menstrual Bleeding Agarwal S et al Blood (2024) 144 (Supplement 1): 2600.

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LBA-3 Extended Treatment of Venous Thromboembolism with Reduced- Vs Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence Couturand F et al.�

composite of recurrent VTE or clinically relevant bleeding, 

16.5%

11.8%

RENOVE Trial

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• N=2768 Pts with high risk of recurrent VTE

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• Received std anticoagulation for 6–24 months

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• Subsequently, randomized to reduced dose DOACs (2.5 mg apixaban bid or 10 mg riva qd)
• VS full dose apixaban 5 mg bid or 20 mg riva qd

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• The primary outcome was adjudicated

symptomatic recurrent VTE

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The 5-year cumulative incidence of symptomatic recurrent VTE was 2.2% in the reduced-dose arm and 1.8% in the full-dose arm (adjusted HR 1.32; 95% CI 0.67–2.60; P_{non-inferiority}=0.23).

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Abs 15871. Glucagon-Like Peptide 1 Receptor Agonists and Venous Thromboembolism in Type 2 Diabetes: A Target Trial Emulation Chiang CH et al. Blood Adv bloodadvances.2025015871.

Abs 15871. Glucagon-Like Peptide 1 Receptor Agonists and Venous Thromboembolism in Type 2 Diabetes: A Target Trial Emulation Chiang CH et al. Blood Adv bloodadvances.2025015871.

https://doi.org/10.3389/fphys.2022.983961

Abs 701. Glucagon-Like Peptide 1 Receptor Agonists and Venous Thromboembolism in Type 2 Diabetes: A Target Trial Emulation Chiang CH et al. Blood Adv bloodadvances.2025015871.

Irrespective of BMI at baseline, GPL-1 like drugs remained associated with decreased risk of VTE at 1 year

Retrospective study :

250 million database : DM2 patients

GPL-1 drugs (n=279,064) vs

DPP4-Inhibtors ( n=279,064)

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VTE rates at 1 year:

20% lower for patients starting on a GLP-1 drug vs a DPP-4 inhibitor (6.5 vs 7.9 per 1,000 patient-years, HR 0.80, 95% CI 0.75-0.85, P<0.001)

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GLP-1 use:

P E-3.1 vs 3.9 per 1,000 patient-years, HR 0.78, 95% CI 0.71-0.85)

DVT-4.2 vs 5.0 per 1,000 patient-years, HR 0.82, 95% CI 0.75-0.88

Hemostatic Rebalancing in Chronic Liver Disease�Hematology Am Soc Hematol Educ Program (2023) 2023 (1): 274–280

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Hemostatic Testing in CLD

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• PT/INR does not predict procedural bleeding risk

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• Uncertain whether procedural bleeding risk is predicted by platelet counts or fibrinogen

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• Coag testing to predict bleeding for procedures is not advised; baseline coag testing may be helpful if bleeding occurs

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• Coag testing indicates severity of CLD

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TGA show normal to enhanced hemostasis despite clearly abnormal conventional coag testing

(Lisman T et al. Jhep. 2022;76:1291)

Hemostatic Rebalancing in Chronic Liver Disease

Hepatology. 2006;44(1):53-61

rpth 2023;7(1):100055

AC= Acute decompensated

ACLF= Acute on chronic

Liver Int. 2022;42(2):435)

Anticoagulation Improves Morbidity and Survival in Splanchnic Thrombosis and Cirrhosis drive rank score=1

Adjusted HR .59 (95% CI 0.49, 0.70)

p<0.001

Anticoagulation vs None

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Liver related mortality %

9.3 20.3 p.=0.001

Liver transplantation %

12.7 8.5 p=0.129

Recanalization %

57.1 37.2 p<0.001

Stable thrombus %

28 51.8 p=0.000

Thrombus progression %

14.1 14.6 p=0.360

Total bleeding events %

19.0 15.6 p=0.315

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Guerrero A et al. JHep 2023;79(1):69-78 

DOACs for the treatment of cirrhosis-related splanchnic thrombosis drive rank score N/A

Caveat: No adequately powered, prospective, randomized, controlled trials with DOACs

Hematology Am Soc Hematol Educ Program (2023) 2023 (1): 274–280

16 studies on 648 patients with any SVT treated with DOACs vs AC (Meta-analysis)

Any recanalization in 60.3% (95% CI: 41.8%-76.3%; I² = 84.9%; P < .001)

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Full recanalization in 51.7% (95% CI: 36.0%-67.0%; I² = 87.4%; P < .001)

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Recurrent VTE in 2.8% (95% CI: 1.4%-5.9%; I² = 0%; P = .787)

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Death in 3.4% (95% CI: 1.6%-7.3%; I² = 13.2%; P = .318) 

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“Cirrhosis: associated with a higher rate of major bleeding/mortality”

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Calcatera I et al. ;DOI:https://doi.org/10.1016/j.jtha.2023.10.023

ABS 138: Overall Survival of Warfarin Compared to LMWH/DOACs in Cancer-Associated Venous Thromboembolism: VA Cohort Study Ryu J

Survival with warfarin in CA compared to other anticoagulants (mainly LMWH)

Chiasakul and Zwicker. Thromb Res. 2022;213(Suppl 1): S113–S119

Warfarin

Non-warfarin

58% LMWH

38% DOACs

N=20.078 Warfarin=8383

Non-warfarin=11.696

Median OS=1204d vs 703d; HR 0.79, p<2x10^-16

ABS 1279: Predictive Efficacy of the Khorana Score in Black Patients: Retrospective Cohort Study Akpoviroro O drive rank score=2

https://www.jacc.org/cms/asset/7ae5cec0-35da-45e8-8755-cacf1871b7de/gr4.jpg

• Studies indicate that the risk of VTE is increased in Blacks
• Original KS study did not stratify patients based on race
• Is the KS appropriately predictive of VTE in Black patients with cancer?

• Retrospective study: 233 patients; 39.9% Black
• Mean CA-to-VTE: AA-4.4 mos vs 4.3 mos in WP
• VTE Incidence at 1yr post CA dx: AA=8.4%; WP=5.8%
• Positive Predictive Value of the KS:

AA: HR 13% IR 31% LR 17%

WP: HR 65% IR 54% LR 34%

• Step wise increase in PPV for KS prediction of VTE in WP; no such pattern was seen in AA.
• KS may not be an adequate predictor of VTE in AA

P<0.001

Thrombotic thrombocytopenic Purpura: New Strategies

ABS 2636: Caplacizumab frontline added to TPE and immunosuppression prevents unfavorable outcomes in iTTP: Real world experience Coppo P

ABS 692: Recombinant ADAMTS13 for the treatment of acute events in cTTP: Results from phase 3 randomized, controlled, crossover study Scully M

Platelet counts during the first 3 days of Tx for cTTP: rADAMTS13 vs SOC