vascular effects of hemolysis - enerca · •intravascular hemolysis is an important part of many...

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

√


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 √


Hemolysis Promotes Vascular Complications

Blood Clots


What is hemolysis?

Mild Hemolysis

Severe Hemolysis


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


Intravascular Hemolysis

Deficit in Nitric Oxide (NO) and

Oxidative stress


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


Intravascular Hemolysis and ↓NO

Arginase

NO +

NO-3

+

Reactive Oxygen Species

ADMA

LDH

Marker of hemolysis


Intravascular Hemolysis

Deficit in Nitric Oxide (NO) and

Oxidative stress

VASCULOPATHY Constricted, adhesive blood vessels

High blood pressure Pulmonary hypertension

Blood clots


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


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


Echocardiography Screening for PH


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%


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.


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.


PH Priapism

Leg

Ulcers

Thalassemia * * *

Pyruvate Kinase deficiency * *

Hereditary spherocytosis * *

Unstable Hemoglobins * *

Paroxysmal Nocturnal

Hemoglobinuria

* *

Autoimmune Hemolytic Anemia *

Congenital Dyserythropoietic

Anemia

* *

Other Hemolytic Anemias


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


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


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…


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; 169:887-98. PMID: 25907665; PMC4452408.


Acknowledgments

• Mark Gladwin and Martin Steinberg

• Victor Gordeuk, Seyed Mehdi Nouraie, Roberto Machado, Claudia Morris, Solomon Ofori-Acquah, Caterina Minniti

• Eduard van Beers and Enerca

• Funding:

vascular effects of hemolysis - enerca · •intravascular hemolysis is an important part of many...

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