MODERATE HAEMOPHILIA A AND B IN THE NORDIC COUNTRIES The MoHem study

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MODERATE HAEMOPHILIA A AND B IN THE NORDIC COUNTRIES The MoHem study

Ragnhild Johanne Måseide, MD

Thesis for the Degree of Philosophiae Doctor (PhD)

Department of Haematology and Research Institute of Internal Medicine,

Oslo University Hospital

Institute of Clinical Medicine, University of Oslo

2021

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© Ragnhild Johanne Måseide, 2022

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8377-959-2

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Print production: Reprosentralen, University of Oslo.

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Sammendrag

Hemofili A og B er sjeldne, arvelige blødersykdommer som rammer henholdsvis 24,6/100.000 og 5,0/100.000 av nyfødte gutter. Blødertilstanden skyldes defekt produksjon av faktor (F) VIII (hemofili A) eller FIX (hemofili B) i blodlevringen.

Hemofili A og B klassifiseres etter alvorlighetsgrad på bakgrunn av aktivitetsnivået av FVIII eller FIX i plasma. Ved alvorlig hemofili er faktor aktivitetsnivået < 1 internasjonal enhet (IU)/dL, ved moderat hemofili 1-5 IU/dL og ved mild hemofili > 5 og < 40 IU/dL.

Personer med hemofili A eller B er spesielt utsatt for blødning i ledd og muskulatur, selv etter mindre skade eller uten forutgående hendelser. Gjentatte leddblødninger kan forårsake progredierende leddskade, som er den viktigste langtidskomplikasjonen ved sykdommen. Behandlingen består først og fremst av å tilføre faktoren som mangler i form av intravenøse injeksjoner.

Behandlingen kan enten gis ved blødning, eller som forebyggende flere ganger per uke for å forhindre blødningsepisoder.

Ved alvorlig hemofili har det gjennom flere tiår vært anbefalt forebyggende behandling fra 1-2 års alder for å heve faktoraktiviteten til moderat nivå. Man har da lykkes med å redusere forekomsten av blødningsrelatert leddskade. For personer med moderat hemofili har det imidlertid manglet slike retningslinjer, og de fleste har kun fått behandling ved blødning. Ved gjentatte leddblødninger og behov for forebyggende behandling, har dette derfor vært iverksatt senere enn ved alvorlig hemofili. Omfanget av leddskade hos personer med moderat hemofili har i liten grad vært systematisk kartlagt. Noen mindre studier har imidlertid vist at også enkelte i denne gruppen har utviklet betydelig skade i ett eller flere ledd.

Formålet med MoHem studien var å undersøke forekomst og grad av leddskade, sett i forhold til behandlingsmodalitet, hos personer med moderat hemofili A (MHA) og B (MHB) i Norden. Vi ønsket også å sammenlikne to metoder som brukes for å avdekke tidlige tegn til leddskade ved blødersykdom. ‘Haemophilia Joint Health Score (HJHS)’ er basert på klinisk undersøkelse av albuer, knær og ankler, mens ‘Haemophilia Early Arthropathy Detection with Ultrasound (HEAD- US)’ er en målrettet ultralydundersøkelse av de samme leddene. I tillegg ønsket

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vi å vurdere om globale koagulasjonsanalyser som trombingenerering og tromboelastometri kan være nyttige verktøy for å kartlegge blødningsfenotypen ved moderat hemofili.

MoHem var en multisenter, tverrsnittstudie som inkluderte 145 personer med MHA (61%) og MHB (39%) fra Oslo, Malmø, Gøteborg, Stockholm og Helsinki.

Median alder var 28 år og 38% fikk forebyggende faktorbehandling, som vanligst var startet ved 10 års alder. De fleste deltagerne hadde god leddstatus vurdert ved HJHS og HEAD-US. Noen hadde imidlertid alvorlige tegn til leddskade, og 15% hadde gjennomgått kirurgisk behandling som følge av dette. Både personer med faktoraktivitet ≤ 3 IU/dL og de med MHA var kjennetegnet ved yngre alder ved første leddblødning. Personer med faktoraktivitet ≤ 3 IU/dL oppnådde også høyere skår ved HJHS som tegn på mer alvorlig leddskade, sammenliknet med de som hadde faktoraktivitet > 3 IU/dL. HEAD-US avdekket i noen tilfeller subklinisk leddskade og bidro dessuten til å avklare usikre funn ved HJHS.

Spesielt var krepitasjoner ved bøy og strekk av kneleddet et relativt vanlig funn ved HJHS uten at det ble påvist leddskade ved HEAD-US. Hos gruppen som ble undersøkt med globale koagulasjonsanalyser var trombingenerering mer sensitiv enn tromboelastometri til å skille mellom mild og mer alvorlig blødningsfenotype. Begge analysene var imidlertid bedre til å differensiere dette enn faktoraktivitetsnivået alene.

Som følge av MoHem studien har vi konkludert med at personer med moderat hemofili og faktoraktivitet ≤ 3 IU/dL bør få tidlig oppstart av forebyggende behandling på linje med personer med alvorlig hemofili. HEAD-US var et godt hjelpemiddel som avklarte og supplerte funn gjort ved HJHS. Trombingenerering og tromboelastometri bidro til å kartlegge blødningsfenotypen ved moderat hemofili og kan derfor være nyttige tilleggsundersøkelser for å kunne gi mer persontilpasset behandling.

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“Det Löser Sig”

Timbuktu

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Acknowledgements

The work presented in this Thesis was carried out at the Department of Haematology and the Research Institute of Internal Medicine, Oslo University Hospital, and the Institute of Clinical Medicine, University of Oslo during the period from December 2015 until May 2021. I am grateful for the opportunity to perform this work, which has been made possible thanks to many helpful contributors.

First, I would like to express my special gratitude to my main supervisor, Professor Pål André Holme, who introduced me to research and the field of bleeding disorders. Your scientific and clinical knowledge has been crucial for the successful completion of the project. I am impressed by your everlasting working spirit and rapid responses to my work. Many thanks for continuous support and encouragement throughout these years - your enthusiasm and optimistic approach has been inspiring.

I am also deeply grateful to my co-supervisors, Professor Erik Berntorp, Malmö and Professor Geir E. Tjønnfjord, Oslo. I highly appreciate that you have shared your experiences and given me feedback in complimentary ways. Erik, I am very thankful for your support and contribution to the study. It has been an honour and a great inspiration to work with you. Geir, thank you for giving me the opportunity to achieve a PhD education. You have facilitated the working frames, but also been of great help as a co-author. I am impressed by your comprehensive knowledge including all fields of haematology.

Many thanks to Jan Astermark, Anna Olsson, Maria Bruzelius, Tony Frisk, Vuokko Nummi, and Riitta Lassila representing the Nordic MoHem collaboration. You have made huge efforts enrolling the study population and provided excellent feedback on the manuscripts. It has been a pleasure to be included in the Nordic haemophilia fellowship and I look forward to future common projects.

A special thanks to Stine Bjørnsen at the Research Institute of Internal Medicine for sharing your experience in lab techniques and global coagulation assays. You have been very helpful in performing the study analyses. Thanks also to Ann Døli and Turid Pedersen for your kind help with practical challenges during these years.

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Thanks a lot to Inger Lise Pladsen Altern, Marianne Berg-Søndergaard, Ruth Elise Dybvik Matlary, Kjetil Steinsvik Paulsen, Siri Grønhaug, Vigdis Falck, and Heidi Glosli, who have been important co-workers at the Haemophilia Comprehensive Care Centre. I really appreciate your effort and flexibility.

Dear Hilde, Nina, Christian, Andrea, Kristin, Marit, Synne, Bjørn, Ruth Elise, and Marte – our unity in Forvalterboligen has been an invaluable support during this period. Thank you for sharing joys and frustrations.

The MoHem study was financially supported by an unrestricted research grant from Bayer HealthCare, which is gratefully acknowledged. I also highly appreciate the preceptorship courses in ultrasound performance, which were arranged and financially supported by Pfizer.

Lastly, I am deeply grateful for the support and encouragement I have received from family and friends throughout these years. Thanks!

Oslo, June 2021 Ragnhild J. Måseide

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Abbreviations

a activated

AAV Adeno-associated viral vectors

AIDS Acquired immunodeficiency syndrome APC Activated protein C

aPCC Activated prothrombin complex concentrate APTT Activated partial thromboplastin time

BU Bethesda units

CAT Calibrated automated thrombogram CTI Corn trypsin inhibitor

EAHAD European Association for Haemophilia and Allied Disorders ETP Endogenous thrombin potential

EDs Exposure days

EUHASS European Haemophilia Safety Surveillance EQ-5D EuroQol-5 Dimension

F Factor

FVIII:C Factor VIII activity

F8 Factor VIII gene

FIX:C Factor IX activity

F9 Factor IX gene

HCV Hepatitis C virus

HCCC Haemophilia Comprehensive Care Centre

HEAD-US Haemophilia Early Arthropathy Detection with Ultrasound HIV Human immunodeficiency virus

HJHS Haemophilia Joint Health Score

IPAQ-SF International Physical Activity Questionnaire – Short Form

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IQR Interquartile range

ISTH International Society on Thrombosis and Haemostasis ISTH-BAT ISTH/SSC bleeding assessment tool

ITI Immune tolerance induction

IU International units

MaxVel Maximum velocity MHA Moderate haemophilia A MHB Moderate haemophilia B

MIFFS Medical imaging findings in joints free of clinically evident bleeds and symptoms

MRI Magnetic Resonance Imaging PEG Polyethylene glycol

PPP Platelet-poor plasma PRP Platelet-rich plasma

ROTEM Rotational thromboelastometry SHA Severe haemophilia A

SHB Severe haemophilia B

SSC Scientific and Standardization Committee TAFI Thrombin activatable fibrinolysis inhibitor

TF Tissue factor

TFPI Tissue factor pathway inhibitor

TG Thrombin generation

tMaxVel time to maximum velocity VWF von Willebrand factor

WAPPS-Hemo Web-Accessible Population Pharmacokinetic Service-Hemophilia WFH World Federation of Hemophilia

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Thesis summary

Recurrent joint bleeds lead to progressive arthropathy, which is the main long- term complication for patients with haemophilia. Prophylactic replacement therapy has reduced the prevalence of arthropathy in severe haemophilia and is now the standard of care for this group. The prevalence of arthropathy in moderate haemophilia is not well characterised, but previous publications have suggested that these patients are undertreated. We therefore conducted the MoHem study to evaluate joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB).

The aim of the study was to describe current joint health in MHA and MHB in relation to treatment modality, and to explore and compare the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS) to detect early arthropathy. Furthermore, we wanted to explore the role of global coagulation assays to unravel the bleeding phenotype of patients with moderate haemophilia.

The MoHem study is a cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. Arthropathy was evaluated by HEAD-US and HJHS 2.1. The bleeding phenotype was evaluated by thromboelastometry and thrombin generation (TG).

We enrolled 145 patients with MHA (n = 89) and MHB (n = 56) from Oslo, Malmö, Gothenburg, Stockholm, and Helsinki. Median age was 28 years (interquartile range (IQR) 13-52 years) and 38% were on prophylaxis. Overall, HEAD-US and HJHS captured low scores close to normal. However, a subgroup had severe arthropathy and 15% had undergone orthopaedic surgery. Patients with baseline factor VIII/factor IX activity (FVIII/FIX:C) ≤ 3 International units (IU)/dL and those with MHA were characterized by a younger age at first joint bleed. Patients with FVIII/FIX:C ≤ 3 IU/dL also captured higher HJHS, implying impaired joint health. HEAD-US clarified the origin of subtle HJHS findings and detected subclinical pathology. Notably, crepitus on motion by HJHS, particularly in knees, was frequently found without corresponding HEAD-US pathology. In a subgroup of the patients, TG (n = 61), and to some extent thromboelastometry (n = 49), distinguished between patients who presented with a mild or more

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severe bleeding phenotype according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed.

Based on our results, we suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL according to similar guidelines as for severe haemophilia.

HEAD-US clarified and complemented HJHS findings, and therefore improved the joint assessment. Global coagulation assays, particularly TG, complemented FVIII/FIX:C and may assist predicting the bleeding phenotype of patients with moderate haemophilia.

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Articles in the thesis

Paper I

Måseide RJ, Berntorp E, Astermark J, Olsson A, Bruzelius M, Frisk T, Nummi V, Lassila R, Tjønnfjord GE, Holme, PA. Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B – The MoHem study.

Haemophilia. 2020;26(5):891-897.

Paper II

Måseide RJ, Berntorp E, Astermark J, Hansen J, Olsson A, Bruzelius M, Frisk T, Aspdahl M, Nummi V, Tjønnfjord GE, Holme PA. Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study. Haemophilia. 2021;27(2):e253-e259.

Paper III

Måseide RJ, Berntorp E, Nummi V, Lassila R, Tjønnfjord GE, Holme PA. Bleeding phenotype of patients with moderate haemophilia A and B assessed by thromboelastometry and thrombin generation. Haemophilia. 2021;1-9.

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1. Introduction

Haemophilia A and B are rare, inherited bleeding disorders affecting approximately 24.6/100,000 and 5.0/100,000 newborn males, respectively.¹ Patients with haemophilia A or B may experience joint or muscle bleeds after minor trauma or even spontaneously. Moreover, they usually present with prolonged bleeding after surgery or tooth extractions. The bleeding disorders are due to impaired production of factor (F) VIII (haemophilia A) or FIX (haemophilia B), attenuating the haemostatic system. Haemophilia A and B are classified as severe (< 1 International units (IU)/dL), moderate (1-5 IU/dL) or mild (> 5 and < 40 IU/dL) based on residual plasma levels of FVIII/FIX activity (FVIII/FIX:C).² Moderate haemophilia is the least common type representing approximately 15% of all patients with haemophilia A and 31% of haemophilia B in high-income countries and has been less studied than severe haemophilia.³ Recurrent joint bleeds lead to joint damage, arthropathy, which is the main long- term complication in haemophilia. The regular treatment for patients with haemophilia is to replace the missing FVIII or FIX, called replacement therapy.

The treatment could be administered episodically to stop a current bleed or continuously several times a week as prophylaxis to avoid bleeds. In severe haemophilia, prophylactic replacement therapy from early age has reduced the prevalence of arthropathy and is now the standard of care.^4-6 The treatment aim has been to turn the patients’ bleeding phenotype into that of moderate haemophilia, avoiding FVIII/FIX:C from falling below 1 IU/dL. Accordingly, most patients with moderate haemophilia have been treated episodically. The prevalence of arthropathy in moderate haemophilia is not well characterized and some publications have suggested that these patients are undertreated.^7-9 Therefore, we conducted the MoHem study to evaluate joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB). The thesis includes three papers from this study. First, we aimed to explore the prevalence and severity of arthropathy among the patients in relation to their mode of treatment. Arthropathy should be detected at an early stage to avoid irreversible joint damage, and we therefore explored the role of two joint assessment tools. Finally, there is an unmet clinical need to unravel the

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individual bleeding phenotype of patients with moderate haemophilia to personalise the management.

1.1 Haemostasis

A bleed happens when there is a rupture in the wall of a blood vessel. The size and location of the vessel determine the severity of the bleeding episode. The bleed may cause damage to the organ affected and even be life threatening for the person. The process that stops a bleed is called haemostasis. Haemostasis is a complex system, which involves tissue components, platelets, and plasma proteins acting together at the site of the bleed. The balance between bleeding and haemostasis is fine-tuned. Even if the bleed may cause severe injury, it is important to limit the extension of the haemostatic process to avoid thrombotic complications. Hence, several procoagulant and anticoagulant factors control this balance.

1.1.1 Primary haemostasis

The primary haemostasis is triggered in response to damage of the vascular wall by the exposure of blood to the subendothelial tissue.¹⁰ First, the injured blood vessel contracts at the site of the bleed to limit extravascular blood leakage. Then, platelets are recruited and adhere to the vessel wall. Collagen and von Willebrand factor (VWF) from the subendothelial tissue act as bridges, binding the platelets to the site of the bleed.¹¹ Moreover, platelet adhesion leads to platelet activation. The platelets stick together, or aggregate, through fibrinogen and other bindings, forming a platelet plug to seal the vessel rupture.

Furthermore, the platelets change their morphology through a ‘flip-flop’, exposing the negatively charged inside of their membrane. In addition, activated platelets release granule content, which contributes to further platelet recruitment and continued platelet activation, as well as vascular contraction.

1.1.2 Secondary haemostasis

Different models have described the haemostatic system. According to the initial

‘waterfall’ model, the clotting factors acted together in a cascade reaction to activate thrombin.^12,13 By contrast, the cell-based model described the activation of coagulation in three phases (initiation, amplification, and propagation), taking place at the surface of tissue factor (TF) bearing extravascular cells and activated

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platelets.¹⁴ Nevertheless, thrombin is the lead enzyme, which stimulates and directs the generation of a stable haemostatic plug.

The secondary haemostasis is triggered by the exposure of TF from the subendothelial tissue to blood upon an injury to a vessel wall. Subsequently, TF binds to circulating activated FVII (FVIIa), which initiates the coagulation system (extrinsic pathway).¹⁵ The TF-FVIIa complex activates small amounts of FIX and FX. FIXa and FXa either remain associated with the TF-bearing cell or diffuse into solution and bind to the membrane of activated platelets. The membrane-bound FXa combines with FV and catalyses the cleavage of prothrombin (FII) to thrombin (FIIa). In this initiation phase, however, only small amounts of thrombin are generated (4%).¹⁶

Then, in the amplification phase, the small amounts of thrombin accelerates the haemostatic process by inducing a complete activation of platelets as well as activation of FV, FVIII, and FXI.

Finally, the propagation phase takes place on the surface of activated platelets.

The negatively charged phospholipids in the platelet membrane have the potential to bind several of the coagulation factors and their cofactors. Hence, FIXa (enzyme) and FVIIIa (cofactor) establish the tenase complex, which activates FX. Correspondingly, FXa (enzyme) combines with FVa (cofactor) to form the prothrombinase complex, which activates prothrombin (FII) to thrombin (FIIa). Ionised calcium (Ca²⁺) catalyses the haemostatic reactions.

The FVIIIa-FIXa complex is a much more potent activator of FX than the TF-FVIIa complex.¹⁷ In addition, the TF-FVIIa complex is inhibited by tissue factor pathway inhibitor (TFPI). Thus, the bulk of FXa (>90%) is produced by the FVIIIa-FIXa complex. Accordingly, this leads to an explosive burst of thrombin, which cleaves fibrinogen to fibrin and thereby strengthens the platelet plug. The generation of thrombin is maintained through a positive feedback loop activating FXI, which in turn activates FIX. In this way, an effective haemostasis is secured, which stops the bleed.

In the absence of FVIII or FIX, bleeding will ensue because the amplification and consolidating generation of FXa is insufficient to sustain haemostasis (Figure 1).

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Figure 1: Schematic model of coagulation in vivo. Reprinted from Bolton-Maggs and Pasi with permission from Elsevier.¹⁸

Hence, thrombin acts as a procoagulant in several ways through the activation of platelets, FV, FVIII, and FXI, and the cleavage of fibrinogen to fibrin. In addition, thrombin activates FXIII, which stabilizes the fibrin clot by catalysing the formation of covalent bonds between the fibrin molecules. Furthermore, thrombin establishes a complex with thrombomodulin, which activates thrombin activatable fibrinolysis inhibitor (TAFI). In turn, activated TAFI (TAFIa) slows down the fibrin degradation by plasmin. However, the thrombin- thrombomodulin complex also acts as an anticoagulant through the activation of protein C, which inactivates FVa and FVIIIa.¹⁹ Other anticoagulants include antithrombin, which directly inhibits thrombin, FXa, and FIXa, and TFPI, which blocks the TF-FVIIa complex.

The coagulation process could also be initiated through the intrinsic pathway, which provides an alternative route to activate FIX. However, FXII, which is part of this pathway, has no known bleeding disorder associated with it. The intrinsic pathway is therefore considered accessory to haemostasis. In vitro, however, FXII is part of the contact activation system.

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5 1.1.3 Fibrinolysis

When the ruptured vessel wall has been repaired, the fibrin clot is resolved by the fibrinolytic system, and a normal blood flow is restored.²⁰ Plasmin is the key enzyme, which degrades fibrin. As for haemostasis, there are stimulating and inhibiting enzymes of the fibrinolysis. Among these, the thrombin- thrombomodulin complex acts antifibrinolytic through the activation of TAFI, which attenuates the fibrin degradation by plasmin. Thus, the impaired generation of thrombin in haemophilia promotes fibrinolysis. D-dimer is a specific fibrin degradation product, and thereby a marker of ongoing fibrinolysis.

1.2 Haemophilia A and B

Haemophilia A and B are inherited bleeding disorders caused by defects in the genes encoding FVIII (F8) or FIX (F9), respectively. Accordingly, the production of FVIII or FIX is impaired. The clotting factors may be absent, significantly decreased, or dysfunctional, thus, the secondary haemostasis is attenuated (Figure 1). Many different types of mutations may cause gene defects in haemophilia. Known F8 or F9 mutations are recorded in databases such as the CDC Haemophilia Mutation Project (CHAMP and CHBMP mutation lists).²¹ In moderate haemophilia, these are mostly missense point mutations, which means exchange of a single base in the F8 or F9 gene. The base exchange leads to a different amino acid in the final protein, which thereby reduces the clotting factor activity. The majority of FVIII is produced in liver sinusoidal endothelial cells.^22,23 However, FVIII is also expressed by non-hepatic cells like lymphatic and glomerular endothelial cells, and high endothelial venules.²⁴ FIX production is restricted to liver sinusoidal endothelial cells and hepatocytes.²⁵

Female carriers

The F8 and F9 genes are localized to the X-chromosome. Thus, mothers are carriers who transfer the mutated X-chromosome to their sons. However, in approximately one third of the patients, the mutations are newly emerged.

Accordingly, not all patients have a family history of haemophilia. In female carriers, the expression of the two X-chromosomes may be skew, which is called lyonization.²⁶ If the mutated X-chromosome dominates the expression, the carriers may present with impaired synthesis of FVIII/FIX corresponding to moderate or even severe haemophilia. Accordingly, these women are not only

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disease carriers, but also affected by haemophilia themselves and should be managed as such.²⁷

1.2.1 Severity classification

The severity classification in haemophilia is based on the residual plasma activity levels of FVIII and FIX.² Accordingly, patients with haemophilia are classified as severe (< 1 IU/dL), moderate (1-5 IU/dL), or mild (> 5 and < 40 IU/dL). The normal range of FVIII/FIX:C is 50-150 IU/dL. The severity classification was first described in 1958 by Biggs and Macfarlane and adopted by the Standardization and Scientific Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) in 2001.²⁸ Since then, it has remained unchanged as the worldwide standard.

1.2.2 Bleeding phenotype

Even if the severity classification mostly corresponds with the bleeding phenotype, persons who have the same degree of factor deficiency may express clinical heterogeneity. Accordingly, approximately 10% of persons with severe haemophilia A present as mild bleeders.²⁹ The distinction between severe and non-severe haemophilia A was confirmed in a large single centre Dutch study.³⁰ However, the moderate group demonstrated a wide variability in the haemophilia milestones like ages at diagnosis, first treatment and first joint bleed, which made the difference between moderate and mild haemophilia less clear. The curves displayed a sharp bend around 3 IU/dL, suggesting a more severe clinical phenotype below this value (Figure 2). Moreover, in a study on outcome in moderate haemophilia, patients with FVIII/FIX:C 1-2 IU/dL had higher bleeding rates and received prophylactic treatment more frequently than those with levels 3-5 IU/dL.⁸ However, joint health assessed by Haemophilia Joint Health Score (HJHS, version 1.0) and prevalence of orthopaedic surgery was similar across FVIII/FIX:C levels.

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Figure 2. Annual number of joint bleeds according to FVIII activity. Black lines are medians, shaded areas interquartile ranges. Reprinted from den Uijl et al with permission from John Wiley and Sons.³⁰

Haemophilia A vs B

Haemophilia A and B have usually been considered indistinguishable diagnoses, but some studies have suggested that patients with severe haemophilia B (SHB) display a less severe bleeding phenotype. In Sweden, Schulman et al reported a difference in total severity score and annual factor consumption in favour of a milder phenotype in SHB.³¹ Furthermore, in Italy, patients with severe haemophilia A (SHA) had a 3-fold higher risk to undergo joint replacement (arthroplasty) than observed in SHB.³²The Italian results was also supported by a systematic review of the literature. Recently, the B-Nord study detected a lower HJHS among Nordic adults with SHB compared with registry data on age- matched patients with SHA, implying a less severe bleeding phenotype in SHB.³³ In moderate haemophilia, data comparing the bleeding phenotypes in MHA and MHB are scarce with no clear difference between them.^31,34In the PedNet/RODIN cohorts, prophylactic replacement therapy was equally distributed among children with MHA and MHB.³⁴However, as prophylaxis was initiated <3 years of age, a difference in bleeding phenotype between the diagnoses could have been masked by treatment.

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8 Joint bleeds

Recurrent joint bleeds represent the hallmark of patients with haemophilia.³⁵ The ISTH/SSC has defined a joint bleed as an unusual sensation ‘aura’ in the joint in combination with any of the following: (a) increasing swelling or warmth of the skin over the joint; (b) increasing pain or (c) progressive loss of range of motion or difficulty in using the limb as compared with baseline.² In infants and young children, reluctance to use the limb alone may be indicative of a joint/muscle bleed. Joint bleeds may occur spontaneous or after trauma. Ankles, knees, and elbows (synovial joints) are most commonly affected, called index joints.³⁶

Bleeding rates, including annual overall bleeding rate and annual number of joint bleeds, are commonly used patient-reported outcomes to guide the haemophilia treatment. However, the accuracy of these subjective reports is limited. In particular, patients may not be able to distinguish between pain due to chronic arthritis and acute joint bleeds.³⁷ Furthermore, subclinical bleeds are overlooked, which leads to under treatment.⁵

ISTH-BAT

In 2010, Rodeghiero et al introduced the ISTH/SSC bleeding assessment tool (ISTH-BAT) as a bleeding score to be used mainly for the diagnostic evaluation of patients referred for a possible bleeding disorder.³⁸ Hence, only symptoms reported before and at the time of diagnosis should be included. ISTH-BAT may be used in children and adults. The score provides high accuracy by considering the frequency of bleeding episodes in addition to their severity. A physician or another trained health-professional should collect the questionnaire. The established normal range is 0-3 points for adult males, 0-5 points for adult females, and 0-2 points in children (males and females). Thus, the cut-off for a positive or abnormal bleeding score is ≥4 in adult males, ≥6 in adult females, and

≥3 in children.³⁹ 1.3 Arthropathy

Recurrent joint bleeds lead to progressive and disabling joint damage, called haemophilic arthropathy, which is the main long-term complication in haemophilia. The joint damage includes synovial hypertrophy, cartilage

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destruction, and bone irregularities with osteophytes. Arthropathy causes chronic pain and impaired joint function, which in turn may affect the quality of life.^40-42 Accordingly, some patients undergo orthopaedic surgery such as arthrodesis or joint replacement to relief pain and improve gait function.

The prevalence of arthropathy in moderate haemophilia is not well known, but some previous publications have suggested that these patients have been undertreated. In a systematic review, Di Minno et al reported that 15%-77% of patients with moderate haemophilia had overt arthropathy.⁷ The prevalence of subclinical arthropathy could not be determined because the studies did not include sensitive joint assessment tools like magnetic resonance imaging (MRI) and/or ultrasound. In 2014, den Uijl et al evaluated arthropathy in Dutch patients with moderate haemophilia treated at the van Creveldkliniek in Utrecht by using the HJHS version 1.0.⁸ Eighty-two per cent captured HJHS <10/128 points, considered as a good joint function. According to the THUNDER study from the UK, HJHS among patients with SHA and MHA increased by age.⁹ The progressive arthropathy was explained by inadequate treatment regimens in past decades.

1.3.1 Pathogenesis

Recurrent joint bleeds induce a cascade of inflammatory and degenerative processes injuring the synovium, cartilage, and subchondral bone.^43,44 However, there is a marked variability in the extent of joint damage among patients with similar bleeding history. While some present with chronic synovitis, others develop osteochondral degeneration.

A synovial joint is illustrated below (Figure 3). The normal synovium consists of two layers: the lining and sublining.⁴⁵ The superficial lining, which is in contact with the synovial cavity, contains macrophage- and fibroblast-like cells.

Respectively, the sublining is vascularized to provide nutrients, oxygen, and growth factors to the synovium and articular cartilage. These vessels are the source of joint bleeds. Hence, upon a bleed, mechanical factors damage the vascular network in the synovium.⁴⁶ Moreover, the expression of TF (coagulation trigger) in joints is relatively low while the expression of TFPI (coagulation inhibitor) is high.^47,48 Furthermore, in haemophilia specifically, local fibrinolysis

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in joints is increased.⁴⁹ Recurrent joint bleeds cause iron deposition, inflammation, and neo-angiogenesis.^50-52 The iron-loaded synovium produces various inflammatory cytokines such as tumour necrosis factor α and interleukine-1 and 6, which enhance synovial hypertrophy and induce expression of c-myc and mdm2 oncogenes.^53,54 Hence, the proliferation of synovial fibroblasts and vascular cells display an invasive and destructive behaviour resembling malignant tissue. The new blood vessels are fragile and more susceptible to recurrent bleeds. In addition, the hypertrophic synovium is more vulnerable to mechanical damage. Thus, the synovial changes may induce a vicious circle leading to chronic synovitis.

The cartilage degeneration is synovial dependant and independent.⁴⁴ The hypertrophic synovium produces cartilage-destructive pro-inflammatory cytokines and cartilage degrading enzymes. However, blood also induces a direct toxic effect on the cartilage, which is more pronounced in immature than on mature cartilage. In adults, the replenishment of chondrocytes is low and apoptosis of chondrocytes leads to permanent disturbance and destruction.

The bone alterations in haemophilic arthropathy include cyst formation, subchondral sclerosis, osteophyte formation, epiphyseal enlargement, and osteoporosis. It is still unknown if the bone changes are a consequence of the processes in the cartilage and synovium or may occur simultaneously.

Figure 3. Schematic figure of the knee (sagittal plane) representing a synovial joint. Reprinted from Valentino with permission from John Wiley and Sons.⁴³

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11 Microbleeds and subclinical bleeds

Early stage arthropathy may occur after one or more joint bleeds. However, as demonstrated by Manco-Johnson et al some 6-year-old boys had MRI findings suggesting arthropathy without clinically evidence of joint bleeds.⁵ Thus, the authors proposed that chronic microbleeds into the joint or subchondral bone might have caused joint deterioration. In contrast, some other boys in the study had normal MRI score despite many (>10) reported joint bleeds. Similarly, in a Canadian cohort 31% of index joints with no history of clinically reported bleeding episodes had soft tissue changes on MRI.⁵⁵ Moreover, hemosiderin deposition was detected in 26% of joints without acknowledged bleeding episodes. Inter-individual variation in inflammatory responses or iron handling may explain some differences in arthropathy development among the boys.⁴⁴ In addition, bleeding rates including joint bleeds are mostly subjective reported outcomes, thus the reported numbers should be handled with caution, particularly in children. Unexpected MRI findings may therefore be explained by subclinical bleeds, which are not recognized by the boys or the parents rather than joint microbleeds. In fact, the term ‘joint microbleeding’, representing an asymptomatic (subclinical) leakage of microscopic amounts of blood into a joint is controversial.⁵⁶ There is currently no evidence that so called medical imaging findings in joints free of clinically evident bleeds and symptoms (MIFFS) are clinically relevant and cause joint disease. Moreover, MIFFS are commonly seen in healthy, asymptomatic persons and could be part of the natural aging process.

Nevertheless, MIFFS may resemble expected findings in patients with haemophilia, such as synovitis, cartilage erosion, and subchondral cysts.

1.3.2 Physical examination

Prevalence and severity of haemophilic arthropathy are commonly evaluated by physical examination and/or radiologic imaging of the six index joints (elbows, knees and ankles). In 1985, Pettersson and Gilbert developed the first physical examination scale endorsed by the Orthopaedic Advisory Committee of the World Federation of Hemophilia (WFH).⁵⁷ However, the emergence of prophylactic replacement therapy to prevent the development of arthropathy required more sensitive joint assessment tools. Hence, the International

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Prophylaxis Study Group developed the Haemophilia Joint Health Score (HJHS, version 1.0).⁵⁸

Haemophilia Joint Health Score

HJHS is a sensitive, reliable, and validated tool to assess arthropathy in haemophilia, which was developed for use among children on prophylaxis.⁵⁸ In 2011, the current HJHS version 2.1 was introduced.⁵⁹ Moreover, the reliability and validity have been extended to include young adults reaching 30 years of age.⁶⁰ The joint evaluation comprises a structured physical examination of elbows, knees, and ankles performed by trained physiotherapists, including structural and functional items. However, in a multicentre setting, inter-observer variation have been reported.⁶¹ Furthermore, HJHS has been compared with MRI findings in healthy and physically active young adults.⁶² Thus, low scores up to three points may be considered as normal, depending on the HJHS items affected, and if the score is based on findings in one or more joints. The current WFH guidelines for the management of haemophilia recommend annual assessment of joint structure and function including HJHS in children and adolescents.⁶ However, the performance of the score is time consuming and a multidisciplinary expert group has intended to develop a HJHS short form.⁶³ 1.3.3 Radiology

In 1980, Pettersson et al introduced a radiologic classification of haemophilic arthropathy based on the degree of joint destruction.⁶⁴ The Pettersson classification complemented the Gilbert physical examination scale as the first joint scoring system endorsed by the WFH. However, the score had low sensitivity and reflected late stage arthropathy. Today, radiologic evaluation of haemophilic arthropathy includes MRI and ultrasound. MRI is highly sensitive to demonstrate early intra-articular changes and is considered the gold standard.

However, MRI is relatively expensive, time consuming, and less available. In addition, young children need sedation to pull through the examination.

Therefore, MRI is not feasible as routine assessment of multiple joints in haemophilia.

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Haemophilia Early Arthropathy Detection with Ultrasound

Point-of-care ultrasound refers to the practice of trained performers using ultrasound to assess specific problems. In 2013, Martinoli et al developed the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) as a simplified evaluation of early arthropathy by non-radiologists.⁶⁵ HEAD-US intends to assess synovial hypertrophy, cartilage degeneration, and bone surface irregularities in patients with haemophilia with limited joint disease, and may serve as routine evaluation of early arthropathy. Studies on reliability and validity have supported the use among clinicians after limited ultrasound training.^66-68 In addition, HEAD-US may be easily repeated in the patients’ follow- up. However, reference data on healthy persons are lacking, in particular among the elderly.

In some previous publications, HEAD-US and HJHS have been considered as supplementary tools to evaluate early arthropathy in haemophilia (Table 1).^69-74

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Table 1. Studies reporting on Haemophilia Joint Health Score (HJHS) 2.1 and Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US)

Authors Patients Methods Outcome

Foppen et al.

Haemophilia 2015⁶⁹

32 children, haemophilia A/B (30 severe, 2 moderate).

All on prophylaxis

HJHS and HEAD-US, only 2 joints per patient

Strong correlation HEAD-US and HJHS (r = .70).

6.4% discordance

Altisent et al.

Haemophilia 2016⁷⁰

25 SHA (4-19 years).

All on prophylaxis

Annual joint bleeding rate, HJHS and HEAD-US

Correlation between HEAD-US and bleeding rate, but not with HJHS. 27%

discordance Timmer et al.

Haemophilia 2017⁷¹

15 adults (76 joints), haemophilia A/B, all severities (8 severe).

33% prophylaxis

HJHS (- gait score) and HEAD-US

Strong overall HEAD- US and HJHS

correlation (r = .88) and separately for ankles (r = .65), knees (r = .98), elbows (r = .81).

7% discordance De la Corte-

Rodriguez et al.

Expert Rev Hematol 2018⁷³

167 patients (4-69 years), haemophilia A/B (111 severe, 24 moderate, 32 mild).

57% prophylaxis

Lifetime joint bleeds, HJHS and HEAD-US in asymptomatic joints

HEAD-US better than bleeding rate and HJHS to detect early arthropathy

Aspdahl et al.

Eur J Physiother 2018⁷²

32 children (6-17 years): 28 SHA and 4 MHA.

91% prophylaxis

Annual joint bleeding rate, HJHS and HEAD-US

Strong correlation HEAD-US and HJHS (r = .63)

(patient level) Stephensen et al.

Haemophilia 2018⁶⁷

21 adults (63 joints) with severe

haemophilia

HEAD-US reliability and HJHS

19% HEAD-US and HJHS discordance:

16% HEAD-US

≥1/HJHS 0 and 4%

HEAD-US 0/HJHS ≥1 (joint level)

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1.4 Treatment modalities

For decades, the treatment modality in haemophilia has been guided by the severity classification targeting trough levels of FVIII/FIX:C ≥ 1 IU/dL.⁴ The trough level is the minimum level measured just before the next injection. The aim of prophylaxis has therefore been to turn severe haemophilia into moderate severity. Today, the WFH recommendations acknowledge the individual bleeding phenotype as most important, thus aiming at zero bleeds.⁶

1.4.1 Historical development

The first medical treatment of a patient with haemophilia was performed in 1840 when Samuel Armstrong Lane in London rescued an 11-year-old boy from a life- threatening bleed by fresh blood transfusion.⁷⁵ Moreover, the use of citrated plasma was described in 1923.⁷⁶ However, blood and plasma transfusions had limited efficacy because the concentrations of FVIII and FIX were low. Thus, high volumes were necessary to achieve haemostasis.⁷⁷

Since the middle of the 1940s, fractionated human plasma including FVIII and fibrinogen, called Cohn’s fraction I was used in the haemophilia treatment.⁷⁸ However, the results were hampered by instability of the preparation and probably because both haemophilia A and B were treated.⁷⁹ In 1952, Biggs and colleagues made the discovery of haemophilia B representing FIX deficiency.⁸⁰ In 1956, Inga Marie Nilsson in partnership with Margareta and Birger Blombäck (Sweden) introduced a more stable fraction, called fraction I-0 to treat haemophilia A.⁸¹ In 1964, Judith Pool (USA) reported on cryoprecipitate containing FVIII and fibrinogen, which was observed when plasma was cooled to a very low temperature.⁸² Then, in the 1970s, human freeze-dried FVIII and FIX became available, which made the patients able to treat themselves at home.

Since then, blood-derived products have improved to the high-purity concentrates available today.

Unfortunately, the treatment with biologic plasma substances had harmful side effects. In the 1980s, transfusion of plasma products caused transmission of serious viral infections including Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV).⁸³ Thus, many patients developed chronic hepatitis, liver cirrhosis, and even hepatocellular carcinoma. Most patients

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transmitted with HIV died of Acquired immunodeficiency syndrome (AIDS), as there was no available antiviral treatment at that time.

Therefore, the development of recombinant FVIII in 1989, which was safe with respect to viral transmission, represented an important improvement of the haemophilia treatment.⁸⁴ Recombinant FIX was introduced in 1997.⁸⁵ Today, both plasma derived and recombinant FVIII/FIX concentrates are commonly used. The haemostatic efficacy of the products is considered equal. However, there is still some fear of contaminated plasma-derived products, despite awareness and virus inactivating procedures. Thus, the use of recombinant products has increased. Since 2010, extended half-life products have further improved the haemophilia treatment.

1.4.2 Clotting factor replacement therapy

Today, clotting factor replacement therapy is the mainstay treatment in haemophilia, which could be administered on-demand or prophylactically. By on-demand treatment, the clotting factor concentrate is given at an episodic basis to treat bleeds. Respectively, by prophylaxis, the treatment is regular to avoid bleeds. The main long-term aim is to prevent haemophilic arthropathy.

Prophylactic treatment

Prophylactic treatment is classified as primary, secondary, or tertiary.² All categories include regular continuous replacement therapy with an intent to treat for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration. In primary prophylaxis, the replacement therapy is started in the absence of documented joint disease, determined by physical examination and/or imaging studies, and before the second clinically evident joint bleed and age 3 years.² The aim is to prevent joint bleeds and the development of arthropathy. In secondary prophylaxis, the replacement therapy is started after two or more joint bleeds, but before the onset of joint disease documented by physical examination and/or imaging studies. In tertiary prophylaxis, replacement therapy is started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints. In addition,

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replacement therapy given to prevent bleeding for periods not exceeding 45 weeks in a year is defined as intermittent ‘periodic’ prophylaxis.

Treatment guidelines

Inga Marie Nilsson pioneered the prophylactic treatment in haemophilia (Figure 4). Since 1958, Swedish patients with SHA have received prophylactic replacement therapy from an early age to convert the disease to a milder form.⁴ Respectively, prophylaxis in SHB was introduced in 1972. Since the early beginning, the Swedish treatment regime was successively intensified to comprise 25-40 IU FVIII/kg three times weekly in haemophilia A and 25-40 IU FIX/kg twice weekly in haemophilia B in 1990, representing a high-dose regime.

The treatment should be initiated at 1-2 years of age as primary prophylaxis and aimed to avoid FVIII/FIX:C from falling below 1% of normal (= 1 IU/dL).

Accordingly, joint bleeds and arthropathy were prevented. Furthermore, based on observational data, the age at start of prophylaxis was found to be an independent predictor for arthropathy development.⁸⁶ Boys who started prophylactic treatment before the age of 3 obtained better joint health than those who started at higher ages.

Figure 4. Professor Inga Marie Nilsson (1923-1999). Reprinted from Astermark et al with permission from John Wiley and Sons.⁷⁹

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In 2007, a randomized trial from the USA by Manco-Johnson et al confirmed the gain of primary prophylaxis vs on-demand treatment to prevent joint disease in SHA.⁵ At 6 years of age, 93% of boys receiving prophylactic treatment started before 30 months of age had normal index joint structure on MRI as compared with 55% in the on-demand group. Primary prophylaxis also decreased the bleeding rates. Recently, Warren et al presented long-term observational data until 18 years of age based on the randomized study, which emphasized the benefit of early prophylaxis.⁸⁷ However, a primary prophylaxis of 25 IU/kg every other day was insufficient to fully protect joints against arthropathy development. Moreover, according to the SPINART study, even late prophylaxis (secondary or tertiary) was associated with lower bleeding rates and improved joint health and quality of life compared with on-demand treatment.^88,89 Today, the use of prophylaxis is always recommended over episodic therapy.⁶

In the Netherlands, the prophylactic treatment comprised an intermediate-dose of replacement therapy instead of the Swedish high-dose regime. A comparison between the two strategies (median 2100 IU/kg/year in the Netherlands vs 4000 IU/kg/year in Sweden) demonstrated higher annual number of joint bleeds according to the Dutch regime.⁹⁰ In addition, more Dutch patients captured HJHS

>10/144 points implying impaired joint function, but quality of life was similar.

Notably, the Swedish patients started prophylaxis at a younger age than the Dutch did (median 1.5 vs 4.5 years), which certainly influence on arthropathy development.⁸⁶ Annual total costs were higher in the Swedish group. Moreover, according to a retrospective study from Utrecht, the Netherlands, patients with severe haemophilia on long-term prophylaxis reported higher bleeding rates including joint bleeds and captured higher HJHS than patients with moderate haemophilia, who were mainly treated on-demand.⁹¹ Hence, the intermediate- dose prophylaxis did not fully convert the bleeding phenotype of severe haemophilia to that of moderate haemophilia. Of note, as illustrated by Collins et al, patients with severe haemophilia on prophylaxis spend most of their times with FVIII/FIX:C > 5 IU/dL and should therefore be expected to have a better outcome than patients with moderate haemophilia treated on-demand, who mostly are ≤ 5 IU/dL (Figure 5).⁹²

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Figure 5. Schematic representation of the time spent at different factor levels comparing (A) moderate haemophilia treated episodically and (B) severe haemophilia on prophylaxis with trough level at 2 IU/dL. At all times, the person with severe haemophilia has higher factor levels and spends the majority of time with a level in the mild range. The y-axis is arbitrary. Reprinted from Collins et al with permission from John Wiley and Sons.⁹²

The Canadian model, called tailored primary prophylaxis, represents another reduced-intensity treatment program. The model included a once weekly starting dose (50 IU/kg), which was escalated in frequency and dose according to the bleeding frequency.⁵⁵ However, when 24 Canadian boys with SHA on primary prophylaxis were evaluated at a median age of 8.8 years, 9% of the index joints representing 50% of the boys had osteochondral changes at MRI. Thus, the treatment regime had not completely protected against structural joint changes.

Nevertheless, according to long-term observational data, the joints attained low scores by physical examination, implying good joint function.⁹³

In Norway, prophylaxis for younger patients was first introduced in the early 1990s.⁹⁴ Thus, the Nordic countries have different traditions with respect to haemophilia treatment. Today, they follow common treatment guidelines determined by the Nordic Hemophilia Council in line with the WFH recommendations.^6,95

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The current prophylactic strategies for severe haemophilia is illustrated below (Figure 6).⁹⁶ An optimal protection against bleeds needs to be balanced with venous access, which may be challenging in young children. According to the strategy including initial administration of clotting factor concentrates ≥ 3x/week, most children needed insertion of a central venous access.⁹⁷ Thus, the current Nordic regime is in line with the intermediate strategy. An early start of prophylaxis should be emphasised.⁸⁶

Figure 6. Prophylactic treatment strategies for haemophilia A. *Joint bleed, muscle bleed or other critical/significant bleeding episode. Reprinted from Fischer et al with permission from John Wiley and Sons.⁹⁶

Trough level

The minimum FVIII/FIX:C measured just before the next injection is called the trough level (Figure 5). According to the prophylactic regime introduced by Inga Marie Nilsson, FVIII/FIX:C should not fall below 1 IU/dL to prevent haemophilic arthropathy.⁴ In addition, the Swedish group suggested that maintaining higher trough levels of about 5 IU/dL would further improve the protection against bleeds and arthropathy. More recently, a Dutch study reported baseline FVIII levels of 12 IU/dL as the threshold to avoid all joint bleeds (Figure 2).³⁰ However, as illustrated by Collins et al (Figure 5), baseline and through levels are very different measures.⁹² The Dutch findings should therefore not be extrapolated to aim for trough levels on prophylaxis of about 12 IU/dL. Nevertheless, the development of extended half-life products (see below) has improved the possibility to obtain higher trough levels in the prophylactic treatment.

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21 Tailored prophylactic treatment

Patients with different lifestyle and activity level may need different trough levels to prevent bleeds. Moreover, the pharmacokinetic response to FVIII and FIX products varies between patients.^98-101 An individualized prophylactic treatment in haemophilia should therefore be tailored according to pharmacokinetics in addition to clinical factors like bleeding phenotype and physical activity patterns.^6,102 Measuring plasma concentrations of FVIII/FIX:C at several time points provide information of the individual drug clearance, which is the rate at which the body removes the drug from the circulation. Half-life of the clotting factor and dose frequency are major determinants for trough level.¹⁰³ Thus, pharmacokinetic-guided prophylaxis enables adjustment of dosing level and frequency to maintain adequate haemostatic levels and prevent bleeding.¹⁰⁴ In addition, pharmacokinetics facilitate a cost-effective prophylaxis in both diagnoses.^99,100 Pharmacokinetic data may be obtained individually based on real measurements or population based. However, multiple sampling hampers the individual approach. In contrast, the population based ‘Bayesian’ method uses an algorithm with only a few time points and the population profile to estimate an individual’s pharmacokinetic profile.¹⁰⁵ The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) network is based on this approach.^106,107 Notably, patients with short half-life with standard products will have short half-life with extended half-life products as well.¹⁰⁸ Determining the individual half-life is therefore particularly important in children and should be performed before switching to extended half-life products.

Extended half-life products

In haemophilia B, the development of extended half-life products has improved the replacement therapy. Through different mechanisms including PEGylation and fusion proteins, the half-life of FIX products has increased 3- to over 5-fold that of standard half-life products.¹⁰⁹ In haemophilia A, however, the development of extended half-life products has been constrained by the half-life of VWF, which carries FVIII in the blood stream.¹¹⁰ Thus, the FVIII half-life extension has been limited to 1.4-1.6 fold that of standard half-life products.

PEGylation attaches polyethylene glycol (PEG) to the clotting factor. Accordingly, elimination of the product is reduced due to steric hindrance, which in turn

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prolongs the plasma half-life. Respectively, fusion proteins comprise a fusion between the clotting factor and other recombinant proteins such as the Fc domain of IgG or albumin. Thus, the modified clotting factor is protected from lysosomal degradation and recycled into the circulation.^111,112 Moreover, in haemophilia A, single-chain design introduces a bond between the light and heavy chains of FVIII, which enhances the affinity to VWF. Accordingly, proteolysis and clearance of the FVIII product is prevented.¹¹³

The benefits of extended half-life products include less frequent injections to maintain a targeted FVIII/FIX:C and/or the possibility to achieve higher trough levels of FVIII/FIX:C to improve bleed prevention. How to balance these benefits needs to be tailored individually. Moreover, there are ongoing studies on extended half-life FVIII/FIX products administered subcutaneously. The immunogenicity of extended half-life products is considered lower than for standard products, but needs to be shown. However, there is a potential for anti- PEG antibodies.¹¹⁴

Moderate haemophilia

In moderate haemophilia, treatment guidelines have been absent, and most patients receive episodic replacement therapy.⁸ Some previous studies have suggested that these patients are undertreated.^7-9 Already in 1965, observational data from Sweden described elevated joint scores among patients with moderate haemophilia A and B having baseline FVIII/FIX:C 1-3 IU/dL, but rarely among those > 2-3 IU/dL.³⁶ In 2014, den Uijl et al reported on outcome in moderate haemophilia based on a cross-sectional study from Utrecht.⁸ Twenty-nine per cent had a history of secondary prophylaxis because of high bleeding rates, and 52% of those who had experienced their first joint bleed before the age of five years needed prophylaxis later in life. The authors proposed that patients with moderate haemophilia having residual factor activity level < 3 IU/dL should receive prophylaxis after their first joint bleed, if this occurred within 5 years of age. Moreover, the THUNDER study reported high bleeding rates among patients with MHA in the UK, which were higher than for SHA in both the prophylactic and episodic treatment groups.⁹ Accordingly, the current WFH recommendations have acknowledged that patients remain at risk of bleeding at a trough factor level of 1 IU/dL, suggesting targeting levels > 3-5 IU/dL or

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higher.⁶ In particular, the current guidelines emphasize that the patients’

bleeding phenotype exceeds the severity classification.

FVIII and FIX inhibitors

Inhibitor formation is a serious complication in haemophilia treatment.

Inhibitors are anti-FVIII or FIX neutralizing alloantibodies, which nullify the effect of replacement therapy.² In mild and moderate haemophilia, inhibitors may also interact with the endogenous factor, worsening the severity of the bleeding disorder.¹¹⁵ Moreover, the bleeding pattern may resemble acquired haemophilia. Inhibitors are classified as low (≤ 5 Bethesda units (BU)/mL) or high responding (> 5 BU/mL).² In SHA, inhibitors affect approximately 30% of the patients.^116,117 Respectively, inhibitors in SHB are more rarely encountered.^118-120

The INSIGHT study reported on inhibitors in non-severe haemophilia A in Europe and Australia.¹²¹ The cumulative incidence of inhibitor formation was 5.3% after 28 exposure days (EDs) (median), rising to 6.7% after 50 EDs and 13.3% after 100 EDs. Accordingly, 69% of the inhibitors developed within 50 EDs. Thus, as for severe haemophilia, the risk of inhibitor strongly depended on the cumulative number of exposure days. Patients with non-severe haemophilia who are treated on-demand may therefore have a persistent risk of inhibitor development as adults. Inhibitor screening should therefore be performed after intensive exposure to clotting factor concentrate such as after surgery or severe bleeds.115,122,123 Moreover, the INSIGHT study identified 19 of 214 missense F8 mutations, which were associated with increased risk of inhibitor development.

Patients with inhibitors had higher mortality with bleeding complications as the major cause of death (70%).¹²⁴

Furthermore, based on the European Haemophilia Safety Surveillance (EUHASS), Fischer et al reported an inhibitor rate of 0.43/100 treatment years for non-severe haemophilia A.¹²⁵ The inhibitors occurred at a median age of 35 years and after 38 EDs (median), increasing to 72% after the first 50 EDs. For non-severe haemophilia B, only one inhibitor was detected in 2149 treatment years, resulting in an inhibitor rate of 0.05/100 treatment years. The inhibitor

MODERATE HAEMOPHILIA A AND B IN THE NORDIC COUNTRIES The MoHem study