ArticlePDF Available

PERIOPERATIVE MANAGEMENT OF PATIENTS WITH HEMOPHILIA RECEIVING FITUSIRAN, AN INVESTIGATIONAL RNAI THERAPEUTIC TARGETING ANTITHROMBIN FOR THE TREATMENT OF HEMOPHILIA

Authors:
S74 hematol transfus cell ther. 2020;42(S2):S1–S567
122
PERFIL DOS HEMOFÍLICOS DE UMA
ASSOCIAC¸ ÃO DE PACIENTES DE
BRASÍLIA–DF, BRASIL
L.C. Souzaa, D.B. Ferreiraa, M.L. Soares a,
D.R.H. Sartoreloa, J.O.S.C. Almeidab
aCentro Universitário Euro Americano
(UNIEURO), Brasília, DF, Brasil
bAssociac¸ão dos Voluntários, Pesquisadores e
Portadores de Coagulopatias (AJUDEC), Brasil
Objetivo: O Centro Oeste apresenta o menor número de
pacientes do país, totalizando 982 hemofílicos do tipo A e B,
contudo o Distrito Federal revela aumento à prevalência esper-
ada para ambas hemofilias (1,9/10.000 homens) (Brasil, 2018).
Dessa maneira, se objetivou caracterizar o perfil de hemofíli-
cos vinculados a uma associac¸ ão de pacientes em Brasília
- DF, Brasil. Material e métodos: Pesquisa transversal com
amostragem por conveniência, realizada com 49 hemofíli-
cos adultos, do sexo masculino, vinculados à Associac¸ão
dos Voluntários, Pesquisadores e Portadores de Coagulopa-
tias (AJUDE-C). O estudo foi aprovado pelo Comitê de Ética
em Pesquisas com Seres Humanos, sob o parecer 1.300.316.
Aplicou-se um formulário para coleta de informac¸ ões sociode-
mográficas (idade, rac¸a/cor, estado civil, situac¸ão laboral,
distância entre residência/local de tratamento) e clínicas (tipo
de hemofilia, gravidade clínica e tipo de tratamento). O teste de
Shapiro-Wilk avaliou a normalidade dos dados. Analisaram-
se as frequências para a descric¸ão da amostra. Resultados:
Avaliaram-se 49 hemofílicos adultos com média de idade
37 ±8,4 anos, estando 43% na faixa etária de 30-39 anos. Pre-
dominou a rac¸ a/cor parda (49%), estado civil solteiro (61%), em
atividade laboral (57%) e 53% residiam a menos de 30 Km do
local de tratamento. Clinicamente, predominou a hemofilia A
(79,6%), doenc¸ a grave (77,6%) e o uso de profilaxia secundária
(75,5%). Discussão: A faixa etária entre 30-39 anos concentrou
maior número de participantes, divergindo do Perfil de Coagu-
lopatias Hereditárias onde a maior prevalência das hemofilias
está na faixa etária entre 20-29 anos (BRASIL, 2018). Predomi-
nou a rac¸ a/cor parda. Na região Centro Oeste há predomínio
da rac¸ a/cor parda na populac¸ ão (50,6%), o que explica esse
achado (IBGE, 2009). Kelley e Narváez (2006) relatam que,
independentemente do local, a hemofilia acomete todas as
etnias/rac¸ as. Cerca de 61% dos hemofílicos eram solteiros
e 57% exerciam atividade laboral. Tais achados corroboram
com pesquisa de Naous et al. (2019) na qual a maioria dos
hemofílicos eram solteiros (66,7%) e associavam esse fato à
doenc¸ a, e com o estudo de Cutter et al. (2017), onde cerca
de 81% dos hemofílicos estavam empregados. Cerca de 53%
dos hemofílicos residiam a menos de 30 Km do local de
tratamento. Esses resultados são explicados por Sousa et al.
(2013), referindo que uma menor distância geográfica entre
residência e local de tratamento pode facilitar um atendi-
mento de emergência no caso de sangramentos. Os resultados
mostraram que a hemofilia A (79,6%) e a forma grave da doenc¸a
(77,6%) foram mais prevalentes, sendo a profilaxia secundária
o tratamento mais utilizado (75,5%). Corroborando com os
achados, o Perfil de Coagulopatias Hereditárias relata que no
DF há 324 hemofílicos, tendo maior prevalência da hemofilia
A (n = 264) e doenc¸a grave (n= 189); com relac¸ão à distribuic¸ão
do concentrado de fator VIII em 2016 para o DF, houve maior
utilizac¸ ão da profilaxia secundária (81,11%) (Brasil, 2018). Con-
clusão: A amostra foi composta principalmente por adultos
que exercem atividade laboral. Esse fato pode ser explicado
pela administrac¸ ão da profilaxia secundária e proximidade
entre a residência/local de tratamento, mantendo os fatores de
coagulac¸ ão em níveis seguros, e dando capacidade de rápido
atendimento em casos emergenciais, gerando maior autono-
mia nessa populac¸ão.
https://doi.org/10.1016/j.htct.2020.10.123
123
PERIOPERATIVE MANAGEMENT OF PATIENTS
WITH HEMOPHILIA RECEIVING FITUSIRAN,
AN INVESTIGATIONAL RNAI THERAPEUTIC
TARGETING ANTITHROMBIN FOR THE
TREATMENT OF HEMOPHILIA
A.N.L. Prezottia, K.J. Pasi b, C. Négrier c, M.V.
Ragnid, P. Georgieve, T. Lissitchkovf,K.
Salimg, B. Meig, S. Andersson g
aCentro de Hemoterapia e Hematologia do Espírito
Santo (HEMOES), Vitória, ES, Brazil
bRoyal London Hospital Haemophilia Centre, Barts
and the London School of Medicine and Dentistry,
London, United Kingdom
cUnité d’Hémostase Clinique, Centre Régional de
Traitement de l’Hémophilie, Hôpital Louis Pradel,
Lyon, France
dDepartment of Medicine and Hemophilia Center
of Western Pennsylvania, University of Pittsburgh,
Pittsburgh, United States
eUniversity Multiprofile Hospital for Active
Treatment Sveti Georgi and Medical University
Plovdiv, Plovdiv, Bulgaria
fSpecialized Hospital for Active Treatment of
Hematological Diseases, Sofia, Bulgaria
gSanofi, Cambridge, United States
Aims: To describe the hemostatic management of patients
with hemophilia A or B who underwent surgical procedures
while receiving fitusiran prophylaxis. Methods: Fitusiran was
evaluated in a phase 1 dose-escalation study (NCT02035605)
followed by a phase 2 open-label extension (OLE) study
(NCT02554773) that included patients with hemophilia A or
B, with or without inhibitors. Patients who were eligible to
continue in the phase 2 Open-Label Extension study received
monthly fixed subcutaneous doses of fitusiran 50 mg or 80mg.
Data on perioperative hemostatic therapies and hemostatic
response were collected for patients undergoing surgical pro-
cedures who had lowered anti-thrombin (AT) during the study.
Results: In addition to 5 previously presented surgical proce-
dures, 1 total knee replacement and 1 total hip replacement
were performed. Further details on perioperative treatment
regimens and hemostatic responses in all 7 procedures will
be presented. Conclusions: Successful perioperative hemo-
static management of patients in the context of AT lowering
hematol transfus cell ther. 2020;42(S2):S1–S567 S75
with fitusiran has now been observed in several orthopedic,
thoracic, gastrointestinal, maxillofacial, and dental surgical
procedures. Data first presented at ISTH 2020, 12th-14th July
2020. Study funded by Alnylam and Sanofi.
https://doi.org/10.1016/j.htct.2020.10.124
124
POOLED COHORT EQUATIONS RISK SCORE
AMONG HAEMOPHILIA: TIME TO FORMALLY
EVALUATE CARDIOVASCULAR RISK IN
PEOPLE WITH HAEMOPHILIA
R.M. Cameloa,b,c, B.P. Duarteb, M.C.B. Moura b,
N.C.M. Costab, I.M. Costa b, A.M. Vanderleib,
T.M.R. Guimaraesb, C.C. Deelder c,d,S.
Gouwc, S.M. Rezendea, J.V.D. Bomc,d
aCiências Aplicadas à Saude do Adulto,
Universidade Federal de Minas Gerais (UFMG),
Belo Horizonte, MG, Brazil
bFundac¸ão de Hematologia e Hemoterapia de
Pernambuco (Hemope), Recife, PE, Brazil
cDepartment of Clinical Epidemiology, Leiden
University Medical Center, Leiden, Netherlands
dCentre for Clinical Transfusion Research,
Sanquin/Leiden University Medical Center, Leiden,
Netherlands
Brazil has the fourth largest haemophilia population in
the world. All patients are followed at the haemophilia treat-
ment centres, which provide them interdisciplinary care and
replacement factor concentrates as part of the public health
system. The mortality among Brazilian haemophilia people
is decreasing and the relative incidence of cardiovascular
(CVD) deaths is increasing. The aim of the current anal-
ysis of the HemoCardio Study was to describe the CVD
risk score according to the Pooled Cohort Equations Risk
(PCER) tool and its treatment recommendations. We included
men with haemophilia 40 years or older. Patients who
had previous CVD event or a low-density lipid cholesterol
5.0 mmol/L or higher were excluded. Interviews, medical file
reviews, and blood tests were performed. The PCER tool
(www.cvriskcalculator.com) was used to estimate CVD risk,
considering age, gender, race, total cholesterol, high-density
lipid cholesterol (HDL), systolic and diastolic blood pressures,
treatment for systemic arterial hypertension, diabetes and
smoking status. Among the 30 included patients, the median
[interquartile range; IQR] age was 51.5 [IQR;46.0-59.5] years.
The majority had haemophilia A, 43% were severe, 57% were
on prophylaxis and 7% were inhibitor positive in the last year.
The frequencies of obesity, current smokers, hypertension,
diabetes, hypertriglyceridaemia, hypercholesterolaemia, and
hypoHDLaemia were 20%, 13%, 67%, 24%, 14%, 47%, and 23%,
respectively. Median PCER score was 6.9 [IQR;3.1-13.2], with
50% of the patients having a moderate-to-high risk. Statin use
was suggested for 46% of the patients. Blood pressure was
poorly controlled in 47% of the patients. In conclusion, almost
half of the men with haemophilia had a moderate-to-high
PCER score with strong recommendations to improve control
of dyslipidaemia and blood pressure.
https://doi.org/10.1016/j.htct.2020.10.125
125
ROTURA HEPÁTICA ESPONTÂNEA PELA
SÍNDROME HELLP: ABORDAGEM
HEMATOLÓGICA, CIRÚRGICA E
INTERVENCIONISTA
R.B.C. Fagundesa, M.R. Castro a, R.H.T.M.
Filhoa, L.G. Constantino a, N.I.D.S. Netob,
P.C.F.M. Bezerrab,c, M.D. Leãoc,d
aUniversidade Potiguar (UnP), Natal, RN, Brasil
bHospital UNIMED, Natal, RN, Brasil
cUniversidade Federal do Rio Grande do Norte
(UFRN), Natal, RN, Brasil
dHospital do Corac¸ão, Natal, RN, Brasil
Relato de caso: BFBV, sexo feminino, 31 anos, previa-
mente hígida, 23 semanas de gestac¸ ão gemelar, admitida em
centro obstétrico com dor abdominal de início súbito, em
epigástrio, associada à hipertensão (190×110 mmHg) respon-
siva à administrac¸ão de hidralazina e nifedipino. Evoluiu após
algumas horas com náuseas, vômitos e lipotímia. Aos exames,
apresentava elevac¸ ão de transaminases (TGO 1924 e TGP
1.300 U/L), plaquetopenia (83.000/mm3), anemia (Hb 6,0 g/dL),
hiperbilirrubinemia e LDH elevado (3.271 U/L). Pré-eclâmpsia
grave complicada com síndrome HELLP constituiu o diagnós-
tico provável. Foi encaminhada para cesariana de emergência
e laparotomia exploratória, a qual identificou morte fetal e
hemoperitônio, confirmando hepatomegalia importante com
rotura da cápsula de glisson, tratada com hemostasia cirúr-
gica. Após 24 horas da intervenc¸ão, manteve-se hipotensa,
com distensão abdominal e queda de hematócrito refratária às
hemotransfusões, optando-se por reabordagem para remoc¸ão
de compressas e tamponamento da superfície hepática com
polímero hemostático reabsorvível. Em seguida, como nova
tentativa de controle do sangramento por via intravascular, foi
realizada embolizac¸ ão da artéria hepática e de microfístulas
arterioportais. Evoluiu com coagulac¸ão intravascular dissem-
inada (CID), manejada com hemoderivados. Permaneceu em
terapia intensiva por 08 dias, seguindo com melhora clínico-
laboratorial, regressão das lesões hemorrágicas em controle
tomográfico e alta hospitalar para homecare após 05 dias.
Discussão: A rotura hepática, complicac¸ão potencialmente
letal da Síndrome HELLP, possui evoluc¸ão repentina e con-
stitui importante causa de morte materna. Sua fisiopatologia
envolve a deposic¸ão de fibrina nos sinusóide, o que causa
obstruc¸ ão e congestão vascular, aumento da pressão intra-
hepática e dilatac¸ ão da cápsula de glisson, resultando em
hematoma subcapsular e rotura hepática. A suspeita clínica
deve ser suscitada diante de grávidas com início súbito
de dor abdominal ou hipotensão. O diagnóstico, apesar de
clínico, é quase sempre realizado no intraoperatório de uma
cesariana ou no pós-parto. Embora bem estabelecido na liter-
atura, o tratamento conservador dessa condic¸ ão é considerado
inaplicável quando no contexto da HELLP. A razão disso é
o risco aumentado de sangramento em virtude do processo
inflamatório agudo que, no fígado, desencadeia ativac¸ão do
sistema de coagulac¸ ão e microangiopatia trombótica. Esse
fenômeno, definido como CID obstétrica, torna a intervenc¸ão
... A single preliminary report of five surgical operations done in four PWH A receiving fitusiran in the phase 2 extension trial is available. 25 All patients had AT levels <20%, and no thromboprophylaxis was administered. One inhibitor patient was treated with rFVIIa (90 μg/kg, three times) for a bleeding complication after dental extraction. ...
Article
The performance of surgery and invasive procedures in patients with haemophilia is currently facing new challenges globally. The first is the appropriate application of low‐dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resource constraint environments. The increasing availability of CFC through humanitarian aid programmes allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half‐life CFC that are increasingly available in many countries represent valuable alternatives to standard half‐life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half‐life factor IX. Third, in the era of recently introduced non‐factor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low‐dose administrations of CFC or bypassing agents. Additional factor VIII or bypassing treatment has proven to be safe and effective in association with emicizumab for major surgeries, and it was effectively given at low doses in association with fitusiran. No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.
... Five surgical procedures in 4 HA patients (2 inhibitor and 2 noninhibitor) treated with fitusiran have been reported. 71 Two inhibitor patients were treated with 80 mg once monthly. One patient had teeth extracted and was given rFVIIa (90 mg/kg, 3 times) for postoperative bleeding. ...
Article
Regular prophylaxis with factor VIII (FVIII) or FIX products to prevent bleeding in patients with severe hemophilia A (HA) and HB, respectively, results in marked suppression of the onset of arthropathy and contributes greatly to improvements in quality of life. Some issues remain with the use of clotting factor replacement therapy, however. The need for multiple IV infusions is associated with a substantial mental and physical burden, and the hemostatic effect of bypassing agents (BPAs) in patients with inhibitor is inconsistent. The development of subcutaneous products with prolonged hemostatic efficiency, irrespective of the presence of inhibitors, has been a longtime wish for patients. A new class of therapeutic agents that act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these nonfactor products are ongoing. The current findings have demonstrated that prophylaxis by nonfactor products supports marked reductions of bleeding episodes in hemophilia patients with or without inhibitor. Emicizumab has already been approved for use internationally. Some concerns are evident, however. Thrombotic microangiopathy and thromboembolism have occurred in 5 emicizumab-treated patients receiving repeated infusions of activated prothrombin complex concentrates, and a sinus vein thrombosis has occurred in a fitusiran-treated patient receiving repeated infusions of FVIII product. Moreover, reliable techniques to monitor hemostatic function in patients receiving nonfactor products with concomitant BPA or FVIII/FIX therapies require further assessment. These novel therapeutic agents have promising hemostatic properties, although wider experience in hemophilia centers is warranted to establish appropriate therapeutic strategies.
... In early clinical trials several participants required surgical procedures while receiving fitusiran and provided some information in this area. 22 Four patients with severe hemophilia A, including two with inhibitors, have undergone surgical procedures while on fitusiran. These procedures included endoscopic cholecystectomy, thoracotomy/partial lung segmentectomy, molar tooth extraction, and premolar tooth extraction. ...
Article
Full-text available
Nicoletta Machin, Margaret V Ragni Department of Medicine, University of Pittsburgh, Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA Abstract: Fitusiran is an RNA interference therapeutic that targets antithrombin (AT) in the liver and interferes with AT translation by binding and degrading messenger RNA-AT, thereby silencing AT gene expression and preventing AT synthesis. In both preclinical and clinical studies, AT knockdown results in dose-dependent AT lowering when fitusiran is given weekly or monthly subcutaneously. In clinical trials, fitusiran dose escalation has resulted in improved thrombin generation and clinical hemostasis as measured by reduction in annualized bleed rate. Unlike currently licensed drugs, this improvement was not only in patients with hemophilia A but in also those with hemophilia B, with or without inhibitors. In dental and surgical procedures, fitusiran also provided perioperative hemostasis in association with AT lowering. Fitusiran is well tolerated, with minor local injection site reactions, but in one subject with severe hemophilia A, the concomitant use of daily high-dose factor VIII, inconsistent with trial guidance to avoid high, repeat doses of clotting factor, was associated with fatal thrombosis, suggesting the need for caution when using hemostatic agents in conjunction with fitusiran. Preclinical in vitro and in silico studies indicate improvement in thrombin generation in rare bleeding disorder plasmas, including in plasmas from patients with severe factors V, VII, and X deficiency, suggesting potential therapeutic benefit. Keywords: congenital bleeding disorder, clotting factor, fitusiran, mRNA, novel bypass
Article
Some non‐factor products that work by facilitating the coagulation pathway (emicizumab) and blocking the anticoagulant pathway (fitusiran, concizumab and marstacimab) for patients with haemophilia (H) have been developed, and clinical trials using these products are currently ongoing. Prophylaxis using non‐factor products by subcutaneous administration provides marked reductions of bleeding episodes in patients with HA or HB, regardless of the presence of inhibitor. Emicizumab has already been approved globally. Emicizumab alters the phenotype of patients with HA from severe to mild by maintaining trough levels of equivalent factor VIII activity (15–20 iu/dl). Phase 3 clinical trials and long‐term observations assessing emicizumab revealed tolerable safety and efficacy. However, thrombotic events have occurred in patients receiving these non‐factor products. Furthermore, monitoring of the haemostatic function of these products with concomitant therapy is also required in clinical practice. These products have promising haemostatic efficiency, but wider clinical experience is needed to provide optimal therapeutic strategies in the future.
Article
Full-text available
Management of patients with severe bleeding disorders, particularly haemophilia A and B, and to a lesser extent, von Willebrand disease, has come on leaps and bounds over the past decade. Until recently, patients relied upon the administration of factor concentrates to prevent or treat bleeding episodes. Factor administration requires intravenous access and, in up to one‐third of patients, leads to the development of neutralising antibodies, or inhibitors, which are associated with more frequent bleeding episodes and higher morbidity. Novel non‐factor therapies may offer a solution to these unmet needs. In this review, we discuss the factor mimetics, particularly emicizumab, and the rebalancing agents, which inhibit antithrombin, tissue factor pathway inhibitor and activated protein C, and novel treatments to enhance von Willebrand factor levels. We review the available trial data, unanswered questions and challenges associated with these new treatment modalities. Finally, we provide practical management algorithms to aid the general haematologist when faced with a patient receiving emicizumab who requires surgery or may develop bleeding.
Article
Introduction: Novel non-replacement therapies (e.g. emicizumab) have improved the management of patients with hemophilia A with and without inhibitors while introducing new challenges and increasing the complexity of clinical decision-making. Areas covered: Use of emicizumab can substantially delay initial exposure to FVIII thereby altering the natural history of inhibitor development, but it remains unclear whether later exposure to FVIII might modify the incidence of inhibitor development. Moreover, decisions regarding initiation of immune tolerance induction (ITI) therapy in patients with newly diagnosed inhibitors have become more complicated since emicizumab was introduced. Using emicizumab in lieu of ITI has implications such as precluding the use of FVIII for breakthrough bleeds and surgery, and possibly impacting on patients’ future ability to receive gene therapy. Although bypassing agents are the mainstay of managing acute bleeds and surgery in inhibitor patients, their concomitant use with novel therapies can be difficult to manage/monitor. Evidence from the HAVEN clinical trials program suggests that minor surgeries in inhibitor patients can be performed with emicizumab alone, whereas major surgeries require the use of perioperative bypassing agents. Expert opinion: Until the long-term effects of non-replacement therapies become known, patients who develop inhibitors should continue to receive ITI.
Article
: Although the use of clotting factor concentrates is the mainstay of haemophilia care, the development of inhibitors complicates disease management. Perioperative management of patients with inhibitors is therefore a challenge. A systematic literature review was performed to identify literature reporting on the perioperative monitoring and management of haemophilia. MEDLINE, Embase and Cochrane databases were searched from database inception to 26 March 2018. Recent congress proceedings were also searched. Titles and abstracts, then full texts, were screened for relevance by two reviewers. Quality of included studies was assessed using the Critical Appraisal Skills Programme checklist. Of the 2033 individual entries identified, 86 articles met the inclusion criteria. The identified studies were screened again to find articles reporting perioperative laboratory monitoring in patients with congenital haemophilia A or B, resulting in 24 articles undergoing data extraction. Routine perioperative assay monitoring practices were the most commonly reported (n = 20/24); thrombin generation assay was the least commonly reported (n = 2/24). Other monitoring practices described were factor VII and factor VIII coagulation activity (n = 8/24, n = 5/24, respectively), and thromboelastography or rotational thromboelastometry assessments (n = 3/24). The impact of monitoring on treatment decisions was, however, rarely reported. In conclusion, many methods of perioperative monitoring of haemophilia patients with inhibitors have been identified in this review, yet there is a lack of reporting in larger scale cohort studies. More detailed reporting on the impact of monitoring outcomes on treatment decisions is also needed to share best practice, particularly as new therapeutic agents emerge.
ResearchGate has not been able to resolve any references for this publication.