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  • 6th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1st Dutch-Belgian meeting for patients and health professionals

    21st - 22nd November 2015

    Amsterdam - The Netherlands

    Vascular Effects of Hemolysis

    Gregory J. Kato, MD

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Disclosures Company name Research

    support Employee

    Consultant Stockholder Speakers bureau Advisory board Other

    AesRx, LLC

    Biogen Idec

    Baxalta √ √

    CSL Behring

    Mast Thera- peutics

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    This talk is applicable for:

    Definite Probable

    Thalassemia’s √

    Sickle cell disease √

    Membrane disorders (e.g. spherocytosis)

    Enzyme defects (e.g. PKD, G6PD) √

    PNH √

    Other forms of hemolytic disease √

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Hemolysis Promotes Vascular Complications

    Blood Clots

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    What is hemolysis?

    Mild Hemolysis

    Severe Hemolysis

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Categories of Hemolysis

    EXTRAVASCULAR HEMOLYSIS Macrophage takes up damaged red blood cells and digests them NOT SO BAD

    INTRAVASCULAR HEMOLYSIS Red blood cells break apart in the blood vessels AFFECTS BLOOD VESSELS

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Intravascular Hemolysis

    Deficit in Nitric Oxide (NO) and

    Oxidative stress

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    NO• Release of procoagulant factors

    Inflammatory cell attachment ( via

    VCAM-1)

    Release of growth factors

    Vasoconstriction

    Platelet aggregation and attachment

    Plasma Hb

    X

    +

    +

    +

    +

    +

    Nitric Oxide promotes good blood flow Its inhibition interferes with blood flow

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Intravascular Hemolysis and ↓NO

    Arginase

    NO +

    NO-3 +

    Reactive Oxygen Species

    ADMA

    LDH

    Marker of hemolysis

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Intravascular Hemolysis

    Deficit in Nitric Oxide (NO) and

    Oxidative stress

    VASCULOPATHY Constricted, adhesive blood vessels

    High blood pressure Pulmonary hypertension

    Blood clots

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    How Does Pulmonary Hypertension Develop?

    • Chronic constriction of blood vessels

    • Vessel wall thickening

    • Blood clots

    Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary hypertension in sickle cell disease: relevance to children. Pediatr Hematol Oncol. 2007; 24:159-70

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Hemolysis and Vasculopathy

    • Who is affected?

    • Most of this research has been done in sickle cell disease.

    • Some patients with thalassemia are also affected

    • Rare reports also in other hemolytic diseases

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Echocardiography Screening for PH

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    TRV

    2.5 - 2.9

    24%

    TRV > 2.9

    9%

    Distribution of TRV in SCD

    Gladwin et al., NEJM 2003

    n = 195

    TRV < 2.5

    67%

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Thalassemia Intermedia

    Pulmonary Hypertension Screening Prevalence of 11%

    Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned MS, El-Chafic AH,

    Fasulo MR, Cappellini MD. Overview on practices in thalassemia intermedia management aiming

    for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010; 115:1886-92.

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Paroxysmal Nocturnal Hemoglobinuria

    Pulmonary Hypertension Screening Prevalence up to 36%

    Hill A, Sapsford RJ, Scally A, Kelly R, Richards SJ, Khurisgara G, Sivananthan MU, Hillmen P. Under-recognized complications in patients

    with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function. Br J Haematol. 2012;

    158:409-14.

    Hill A, Rother RP, Wang X, Morris SM Jr, Quinn-Senger K, Kelly R, Richards SJ, Bessler M, Bell L, Hillmen P, Gladwin MT. Effect of

    eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with

    paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2010; 149:414-25.

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    PH Priapism

    Leg

    Ulcers

    Thalassemia * * *

    Pyruvate Kinase deficiency * *

    Hereditary spherocytosis * *

    Unstable Hemoglobins * *

    Paroxysmal Nocturnal

    Hemoglobinuria

    * *

    Autoimmune Hemolytic Anemia *

    Congenital Dyserythropoietic

    Anemia

    * *

    Other Hemolytic Anemias

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Treatment of PH

    • Treat the underlying hemolytic disorder

    • Endothelin receptor antagonists

    – Bosentan, ambrisentan (macitentan?)

    • Prostacyclins

    – Epoprostenol, treprostinil and iloprost

    • Soluble Guanylate Cyclase Stimulators

    – Riociguat

    • PDE5 Inhibitors?

    – Sildenafil, tadalafil

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Summary

    • Intravascular hemolysis is an important part of many anemias

    • Depending on its severity, hemolysis may contribute to vascular complications

    – Pulmonary hypertension, stroke, blood clots, leg ulcers, priapism

    • Screening strategies and treatments have been developed in SCD

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Experts

    • Who are some clinician-scientist experts in hemolysis and vascular complications?

    • US: Kato GJ and Gladwin MT

    • Netherlands: Landburg PP, Teerlink T, Biemond BJ, Brandjes DP, Muskiet FA, Duits AJ, Schnog JB

    • Switzerland: Dominik Schaer

    • Lebanon: Musallam KM, Taher AT

    • Italy: Cappellini MD

    • Israel: Rachmilewitz EA

    And many others…

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    References • Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role

    of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007; 21:37-47. PMID: 17084951; PMC2048670.

    • Gladwin MT. Revisiting the hyperhemolysis paradigm. Blood. 2015; 126:695-6. PMID: 26251222.

    • Kato GJ, Taylor JG 6th. Pleiotropic effects of intravascular haemolysis on vascular homeostasis. Br J Haematol. 2010 Mar;148(5):690-701. PMID: 19958359; PMC3210728.

    • Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood. 2013 Feb 21;121(8):1276-84. PMID: 23264591; PMC3578950.

    • Cappellini MD, Musallam KM, Poggiali E, Taher AT. Hypercoagulability in non-transfusion- dependent thalassemia. Blood Rev. 2012; 26 Suppl 1:S20-3. PMID: 22631037.

    • Musallam KM, Taher AT, Karimi M, Rachmilewitz EA. Cerebral infarction in β-thalassemia intermedia: breaking the silence. Thromb Res. 2012; 130:695-702. PMID: 22857801.

    • Morris CR, Kim HY, Klings ES, Wood J, Porter JB, Trachtenberg F, Sweeters N, Olivieri NF, Kwiatkowski JL, Virzi L, Hassell K, Taher A, Neufeld EJ, Thompson AA, Larkin S, Suh JH, Vichinsky EP, Kuypers FA; Thalassemia Clinical Research Network. Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia. Br J Haematol. 2015; 169:887-9

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