Hemofilia – Rokowania, prognozy i postęp choroby

Hemofilia
Rokowania, prognozy i postęp choroby

Hemofilia, klasyfikowana jako łagodna, umiarkowana lub ciężka na podstawie poziomu czynnika krzepnięcia, dotyka głównie pacjentów z ciężką postacią (ok. 70%). Oczekiwana długość życia u tych pacjentów wzrosła z 20-30 lat w latach 60. XX wieku do ponad 70 lat obecnie, dzięki nowoczesnym terapiom i kompleksowej opiece. Mediana długości życia mężczyzn z ciężką hemofilią w latach 2001-2018 wyniosła 73 lata, choć nadal jest o około 10 lat krótsza niż u zdrowych mężczyzn. Wskaźnik śmiertelności u pacjentów z hemofilią jest 2-6 razy wyższy, a główne zagrożenia to krwawienia śródczaszkowe (ryzyko do 8%, 30% śmiertelność) oraz krwotoki w tkankach miękkich. Roczna częstość krwawień (ABR) u pacjentów z ciężką hemofilią A i B wynosiła odpowiednio 4,9 i 3,0 przy stosowaniu standardowych koncentratów o krótkim okresie półtrwania. Wysokie ABR koreluje z aktywnym lub przebytym wirusowym zapaleniem wątroby B i C, co podkreśla potrzebę zindywidualizowanej profilaktyki.

Prognoza w hemofilii (Hemofilia Prognosis)

Czynniki wpływające na prognozę
Zagrożenia życiowe i powikłania
Wskaźniki krwawień jako wyznacznik skuteczności leczenia

Nowoczesne metody leczenia i ich wpływ na rokowanie

Profilaktyka jako standard opieki
Niskodawkowa profilaktyka
Zaawansowane terapie i przyszłe kierunki leczenia

Przewidywanie ciężkości hemofilii

Metody uczenia maszynowego w prognozowaniu
Zastosowanie nowych technologii w prognozowaniu

Aktualny stan wiedzy na temat rokowania w hemofilii

Kolejne rozdziały

Prognoza w hemofilii (Hemofilia Prognosis)

Hemofilia jest klasyfikowana jako łagodna, umiarkowana lub ciężka, w zależności od poziomu czynnika krzepnięcia we krwi. Około 70% pacjentów z hemofilią cierpi na ciężką postać choroby. Obecnie, nawet dzieci z ciężką hemofilią, jeśli rozpoczną leczenie odpowiednio wcześnie, mogą oczekiwać normalnej długości życia. ¹

Oczekiwana długość życia osób z hemofilią znacząco wzrosła na przestrzeni ostatnich dekad – z 20-30 lat w latach 60. XX wieku do ponad 70 lat w ostatnich latach. Ten znaczący postęp jest wynikiem wprowadzenia nowoczesnych metod leczenia i kompleksowej opieki nad pacjentami. ²

Czynniki wpływające na prognozę

Stopień ciężkości hemofilii ma kluczowe znaczenie dla rokowania pacjenta. Badania prowadzone w Holandii wykazały, że mężczyźni z ciężką postacią hemofilii mieli niższą medianę długości życia niż osoby z łagodną lub umiarkowaną postacią choroby. Jednak w latach 2001-2018 mediana ta wzrosła do 73 lat, co oznacza, że połowa badanych mężczyzn z ciężką hemofilią żyła co najmniej 73 lata. ³

Według szacunków Światowej Federacji Hemofilii, przewidywana długość życia mężczyzn już żyjących z hemofilią jest o około 10 lat krótsza niż mężczyzn bez hemofilii. Wskaźnik śmiertelności u mężczyzn z hemofilią jest dwukrotnie wyższy niż u zdrowych mężczyzn w populacji ogólnej, a w przypadku ciężkich postaci hemofilii – od czterech do sześciu razy wyższy. ⁴⁵

Zagrożenia życiowe i powikłania

Najważniejsze zagrażające życiu powikłania hemofilii to krwawienia śródczaszkowe oraz krwotoki w tkankach miękkich wokół dróg oddechowych lub innych narządów wewnętrznych. Około 10% osób z ciężką hemofilią doświadcza krwawienia śródczaszkowego, a 30% z nich umiera z tego powodu. Ryzyko wystąpienia krwawienia śródczaszkowego w ciągu życia u osoby z hemofilią wynosi do 8%. Co więcej, jedna trzecia wszystkich zgonów z powodu hemofilii jest spowodowana krwawieniem śródczaszkowym. ⁶

Pomimo postępów w leczeniu, zwyrodnienie stawów pozostaje przewlekłym powikłaniem hemofilii. Jednakże szybkie i właściwe leczenie może znacznie zmniejszyć ryzyko zagrażających życiu epizodów krwawienia oraz nasilenie długotrwałych uszkodzeń stawów. ⁷

Wskaźniki krwawień jako wyznacznik skuteczności leczenia

Roczna częstość krwawień (Annual Bleeding Rate, ABR) jest ważnym wskaźnikiem skuteczności leczenia i prognozy pacjentów z hemofilią. W badaniach z zastosowaniem standardowych produktów o krótkim okresie półtrwania, mediana ABR u pacjentów z ciężką hemofilią A i B stosujących profilaktykę wynosiła odpowiednio 4,9 i 3,0. ⁸

Badania wykazały także, że wyższe wartości ABR były istotnie związane z aktywnym lub przebytym wirusowym zapaleniem wątroby typu B i C. Zwiększenie liczby osób objętych profilaktyką oraz ustanowienie zindywidualizowanych koncepcji leczenia, szczególnie dla osób z historią wirusowego zapalenia wątroby, może dodatkowo zmniejszyć ABR i poprawić funkcję stawów oraz jakość życia. ⁹

Nowoczesne metody leczenia i ich wpływ na rokowanie

Dwa główne osiągnięcia przyczyniły się do wydłużenia oczekiwanej długości życia pacjentów. Pierwszym z nich są leki promujące krzepnięcie, znane jako koncentraty czynnika antyhemofilowego, które zapobiegają poważnym krwawieniom. Drugim jest kompleksowa opieka nad pacjentem. ¹⁰

Profilaktyka jako standard opieki

Leczenie hemofilii znacznie poprawiło się w ciągu ostatnich 5 dekad. Sukces terapii profilaktycznej w zapobieganiu krwawieniom i zmniejszaniu progresji choroby stawów ustanowił nowy standard opieki, stopniowo wdrażany od wczesnego dzieciństwa. ¹¹

Badania wielokrotnie dokumentowały przewagę profilaktyki w redukcji częstości krwawień. Dzięki nowoczesnym technikom badań przesiewowych, ryzyko zakażenia związanego z leczeniem hemofilii obecnie jest minimalne lub żadne, co przyczyniło się do poprawy wyników u pacjentów diagnozowanych i leczonych w XXI wieku. ¹²

Niskodawkowa profilaktyka

Badania prowadzone w Senegalu (Afryka Zachodnia) oceniały wyniki kliniczne i rozwój inhibitorów u osób z hemofilią otrzymujących niskodawkową profilaktykę (Low-Dose Prophylaxis, LDP). Wyniki sugerują, że LDP jest korzystniejsza niż leczenie na żądanie w redukcji krwawień oraz poprawie zdrowia układu mięśniowo-szkieletowego i sprawności fizycznej, bez zwiększania częstości rozwoju inhibitorów. ¹³

Częstość występowania inhibitorów w badaniu mieściła się w zakresie wartości raportowanych w literaturze, od 15% do 33% u pacjentów z ciężką hemofilią A. Występowanie inhibitorów zwiększa ryzyko niekontrolowanych krwawień i niepełnosprawności z powodu zniszczenia stawów, obniżonej jakości życia i zwiększonego ryzyka zgonu, a także trudności w leczeniu choroby. ¹⁴

Zaawansowane terapie i przyszłe kierunki leczenia

Pojawienie się terapii genowej i mimetyków koagulacji, dających bezprecedensowe wyniki pod względem poziomu i trwałości efektu krzepnięcia, wymaga całkowitej ponownej oceny wyników mierzonych w badaniach nad hemofilią w świetle postępu w nauce o pomiarach wyników. ¹⁵

Zaawansowane terapie wykazują zwiększoną skuteczność przy zmniejszonym obciążeniu chorobą i potencjale wyleczenia. Systematyczne zbieranie wyników istotnych dla pacjenta (Patient Important Outcomes, PIOs) jest kluczowe w tym procesie, ponieważ osiągnięcie prawie normalnych poziomów aktywności czynników może zmienić postrzegany wpływ urazowych krwawień. ¹⁶

Częstość krwawień, poziom aktywności czynników, czas ekspresji, przewlekły ból, wykorzystanie zasobów opieki zdrowotnej i zdrowie psychiczne zostały zidentyfikowane jako ważne podstawowe wyniki oczekiwane przez pacjentów. ¹⁷

Przewidywanie ciężkości hemofilii

Metody uczenia maszynowego w prognozowaniu

Hemofilia A to stosunkowo rzadkie dziedziczne zaburzenie krzepnięcia spowodowane wadliwym genem F8, co prowadzi do dysfunkcjonalnego białka czynnika VIII (FVIII). Kombinacja analizy struktury białka i uczenia maszynowego (ML) stanowi potężne podejście do przewidywania i zrozumienia wpływu mutacji na wynik choroby. ¹⁸

Badania wykazały bliską zgodność między danymi in silico, in vitro i klinicznymi. Przewidziano ciężkość wszystkich możliwych mutacji w strukturze FVIII, w tym tych, które nie zostały jeszcze zgłoszone w literaturze medycznej. ¹⁹

Wyniki wskazują, że nawet przy ograniczonych danych wejściowych możliwe było zbudowanie struktury ML, która miała bliską zgodność z danymi in vitro i klinicznymi. Możliwość dostosowania progów wskaźnika ciężkości (Severity Score) dodała elastyczności ramie badania i stworzyła kompromis między mniejszą dokładnością a większą liczbą sklasyfikowanych przypadków lub mniejszą liczbą sklasyfikowanych przypadków, ale z większą pewnością. ²⁰

Zweryfikowano bliską zgodność między wynikami in silico i in vitro, co potwierdza fakt, że najbardziej dramatycznemu zmniejszeniu aktywności chromogennej i wydzielniczej białka FVIII towarzyszyły wysokie wskaźniki ciężkości. Jednak zgodność między przewidywaniami Hema-Class a raportami in vitro i klinicznymi nie jest doskonała. ²¹

Zastosowanie nowych technologii w prognozowaniu

Przewiduje się, że badania wykorzystujące uczenie maszynowe umożliwią innym rzadkim chorobom korzystanie z ML i przyczynią się do opracowania lepszych terapii rekombinowanego FVIII. ²²

Chociaż oczekiwana długość życia i jakość życia osób z hemofilią A (PwHA) znacznie poprawiły się w ostatnich dziesięcioleciach, obecne opcje leczenia wciąż mają problemy do rozwiązania. Na przykład konieczne jest poprawienie okresu półtrwania rekombinowanych białek FVIII, a także ich profili immunogennych, aby uniknąć rozwoju przeciwciał neutralizujących. ²³

Niestety, brak aktualnych danych pokazujących, jak valoctocogene roxaparvovec-rvox (terapia genowa) może wydłużyć oczekiwaną długość życia u osób z ciężką hemofilią A. Potrzebne są dalsze długoterminowe badania, aby ocenić, czy leczenie terapią genową może poprawić rokowanie. ²⁴

Aktualny stan wiedzy na temat rokowania w hemofilii

Dziś jest ekscytujący czas w dziedzinie hemofilii. Wraz z wprowadzaniem nowych zaawansowanych terapii potrzebujemy długoterminowego planu, aby naprawdę uchwycić bezpieczeństwo i skuteczność w sposób istotny dla pacjenta. ²⁵

Środki zapobiegawcze i wczesne leczenie znacznie poprawiły długoterminowe perspektywy, czyli rokowanie, dla osób z ciężką hemofilią. Dzięki postępom w leczeniu hemofilii prognoza znacząco się poprawiła, a nowe metody leczenia mogą kontynuować ten trend. ²⁶²⁷

Podsumowując, częstość krwawień u osób z ciężką hemofilią leczonych standardowymi koncentratami o krótkim okresie półtrwania była wysoka w rzeczywistych kohortach, podobnie jak odsetek terapii na żądanie u osób z ciężką hemofilią A. Zwiększenie liczby osób objętych profilaktyką i ustanowienie zindywidualizowanych koncepcji leczenia może dodatkowo zmniejszyć roczne wskaźniki krwawień i poprawić funkcję stawów oraz jakość życia. ²⁸

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Materiały źródłowe

#1 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Hemophilia is classified as mild, moderate, or severe, depending on the level of clotting factor in the blood. About 70% of those with hemophilia have the severe form. […] The most important life-threatening complications of the disease are bleeding in the skull and hemorrhages in soft tissue around airways or other internal organs. […] About 10% of those with severe hemophilia have bleeding in the skull, and 30% with the condition die. There is an up to 8% risk that a person with the disease will develop what doctors call intracranial bleeding during their lifetime. And a third of all hemophilia deaths is due to bleeding in the skull. […] A patientâs prognosis may vary somewhat depending on the severity of disease, but today even children with severe hemophilia are generally expected to have a normal life expectancy, if they are started on treatment early.
#2 Hemophilia A Prognosis: What Is the Life Expectancy? | MyHemophiliaTeam
https://www.myhemophiliateam.com/resources/hemophilia-a-prognosis-what-is-the-life-expectancy
Life expectancy with hemophilia A has increased from 20 to 30 years in the 1960s to over age 70 in recent years. […] The severity of someone’s hemophilia is an important factor in their prognosis (outlook). […] Advances in hemophilia treatment have contributed to the improved prognosis, and new treatments may continue this trend. […] The mortality (death) rate for men with hemophilia is twice that of healthy men in the general population and for those with severe forms of hemophilia, it’s four to six times higher. […] The study conducted in the Netherlands found that men with severe hemophilia had a lower median life expectancy than those with mild or moderate hemophilia. […] However, it increased to 73 years between 2001 and 2018. […] This means that half of the men with severe hemophilia studied between 2001 and 2018 lived at least 73 years. […] Unfortunately, no current data shows how valoctocogene roxaparvovec-rvox may lengthen life expectancy in people with severe hemophilia A. More long-term studies are needed to measure whether gene therapy treatment can improve prognosis.
#3 Hemophilia A Prognosis: What Is the Life Expectancy? | MyHemophiliaTeam
https://www.myhemophiliateam.com/resources/hemophilia-a-prognosis-what-is-the-life-expectancy
Life expectancy with hemophilia A has increased from 20 to 30 years in the 1960s to over age 70 in recent years. […] The severity of someone’s hemophilia is an important factor in their prognosis (outlook). […] Advances in hemophilia treatment have contributed to the improved prognosis, and new treatments may continue this trend. […] The mortality (death) rate for men with hemophilia is twice that of healthy men in the general population and for those with severe forms of hemophilia, it’s four to six times higher. […] The study conducted in the Netherlands found that men with severe hemophilia had a lower median life expectancy than those with mild or moderate hemophilia. […] However, it increased to 73 years between 2001 and 2018. […] This means that half of the men with severe hemophilia studied between 2001 and 2018 lived at least 73 years. […] Unfortunately, no current data shows how valoctocogene roxaparvovec-rvox may lengthen life expectancy in people with severe hemophilia A. More long-term studies are needed to measure whether gene therapy treatment can improve prognosis.
#4 Hemophilia A Prognosis: What Is the Life Expectancy? | MyHemophiliaTeam
https://www.myhemophiliateam.com/resources/hemophilia-a-prognosis-what-is-the-life-expectancy
Life expectancy with hemophilia A has increased from 20 to 30 years in the 1960s to over age 70 in recent years. […] The severity of someone’s hemophilia is an important factor in their prognosis (outlook). […] Advances in hemophilia treatment have contributed to the improved prognosis, and new treatments may continue this trend. […] The mortality (death) rate for men with hemophilia is twice that of healthy men in the general population and for those with severe forms of hemophilia, it’s four to six times higher. […] The study conducted in the Netherlands found that men with severe hemophilia had a lower median life expectancy than those with mild or moderate hemophilia. […] However, it increased to 73 years between 2001 and 2018. […] This means that half of the men with severe hemophilia studied between 2001 and 2018 lived at least 73 years. […] Unfortunately, no current data shows how valoctocogene roxaparvovec-rvox may lengthen life expectancy in people with severe hemophilia A. More long-term studies are needed to measure whether gene therapy treatment can improve prognosis.
#5 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Based on the same WFH estimates, the life expectancy for men already living with hemophilia is about 10 years shorter than that for men without hemophilia. […] With modern screening techniques, the risk of getting an infection from hemophilia treatments nowadays is slim to none, which has helped to improve outcomes for patients diagnosed and treated in the 21st century. […] Preventive measures and early treatment have significantly improved the long-term outlook, or prognosis, for people with severe hemophilia. […] Two major developments have contributed to a longer life expectancy in patients. One is clotting-promotion medicines known as antihemophilic factor concentrates, which prevent serious bleeding. The other is comprehensive care. […] Although joint deterioration remains a chronic complication in hemophilia, prompt and proper treatment can greatly reduce the risk of life-threatening bleeding episodes and the severity of long-term damage to joints.
#6 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Hemophilia is classified as mild, moderate, or severe, depending on the level of clotting factor in the blood. About 70% of those with hemophilia have the severe form. […] The most important life-threatening complications of the disease are bleeding in the skull and hemorrhages in soft tissue around airways or other internal organs. […] About 10% of those with severe hemophilia have bleeding in the skull, and 30% with the condition die. There is an up to 8% risk that a person with the disease will develop what doctors call intracranial bleeding during their lifetime. And a third of all hemophilia deaths is due to bleeding in the skull. […] A patientâs prognosis may vary somewhat depending on the severity of disease, but today even children with severe hemophilia are generally expected to have a normal life expectancy, if they are started on treatment early.
#7 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Based on the same WFH estimates, the life expectancy for men already living with hemophilia is about 10 years shorter than that for men without hemophilia. […] With modern screening techniques, the risk of getting an infection from hemophilia treatments nowadays is slim to none, which has helped to improve outcomes for patients diagnosed and treated in the 21st century. […] Preventive measures and early treatment have significantly improved the long-term outlook, or prognosis, for people with severe hemophilia. […] Two major developments have contributed to a longer life expectancy in patients. One is clotting-promotion medicines known as antihemophilic factor concentrates, which prevent serious bleeding. The other is comprehensive care. […] Although joint deterioration remains a chronic complication in hemophilia, prompt and proper treatment can greatly reduce the risk of life-threatening bleeding episodes and the severity of long-term damage to joints.
#8
https://link.springer.com/article/10.1007/s00277-020-04250-9
The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. […] The advantage of prophylaxis in reducing bleeding rates has been documented repeatedly in clinical trials. […] The median ABR in subjects with SHA and SHB on prophylaxis was 4.9 and 3.0, respectively. […] Our study provides data on bleeding outcomes, expressed as ABR, in persons treated with standard half-life products in a real-world setting. […] We also investigated factors associated with ABR and found only a significant association of higher ABRs with active or history of hepatitis B and C. […] In summary, bleeding rates in persons with severe hemophilia treated with standard half-life concentrates were high in our real-world cohort, as was the proportion of on-demand therapy in those with SHA. Increasing the number of persons on prophylaxis and establishing individualized treatment concepts, especially for those with a history of hepatitis, may further reduce ABRs and improve joint function and quality of life.
#9
https://link.springer.com/article/10.1007/s00277-020-04250-9
The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. […] The advantage of prophylaxis in reducing bleeding rates has been documented repeatedly in clinical trials. […] The median ABR in subjects with SHA and SHB on prophylaxis was 4.9 and 3.0, respectively. […] Our study provides data on bleeding outcomes, expressed as ABR, in persons treated with standard half-life products in a real-world setting. […] We also investigated factors associated with ABR and found only a significant association of higher ABRs with active or history of hepatitis B and C. […] In summary, bleeding rates in persons with severe hemophilia treated with standard half-life concentrates were high in our real-world cohort, as was the proportion of on-demand therapy in those with SHA. Increasing the number of persons on prophylaxis and establishing individualized treatment concepts, especially for those with a history of hepatitis, may further reduce ABRs and improve joint function and quality of life.
#10 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Based on the same WFH estimates, the life expectancy for men already living with hemophilia is about 10 years shorter than that for men without hemophilia. […] With modern screening techniques, the risk of getting an infection from hemophilia treatments nowadays is slim to none, which has helped to improve outcomes for patients diagnosed and treated in the 21st century. […] Preventive measures and early treatment have significantly improved the long-term outlook, or prognosis, for people with severe hemophilia. […] Two major developments have contributed to a longer life expectancy in patients. One is clotting-promotion medicines known as antihemophilic factor concentrates, which prevent serious bleeding. The other is comprehensive care. […] Although joint deterioration remains a chronic complication in hemophilia, prompt and proper treatment can greatly reduce the risk of life-threatening bleeding episodes and the severity of long-term damage to joints.
#11 Hemophilia trials in the twentyâfirst century: Defining patient important outcomes
https://pmc.ncbi.nlm.nih.gov/articles/PMC6462740/
Treatment for hemophilia has advanced dramatically over the past 5 decades. […] The success of prophylactic therapy in preventing bleeding and decreasing the progression of joint disease has established a new standard of care, progressively adopted since early childhood. […] The advent of gene therapy and coagulation mimetics, producing unprecedented results in terms of level and durability of their clotting effect, necessitates a complete reassessment of outcomes measured in hemophilia trials in light of the progress in the science of outcome measurements, to ensure appropriate assessment of the value contributed by these advanced therapies. […] The importance of defining, choosing, measuring, analyzing, and reporting outcomes appropriately has always been at the core of health care practice and research since evidence-based medicine came into play.
#12 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Based on the same WFH estimates, the life expectancy for men already living with hemophilia is about 10 years shorter than that for men without hemophilia. […] With modern screening techniques, the risk of getting an infection from hemophilia treatments nowadays is slim to none, which has helped to improve outcomes for patients diagnosed and treated in the 21st century. […] Preventive measures and early treatment have significantly improved the long-term outlook, or prognosis, for people with severe hemophilia. […] Two major developments have contributed to a longer life expectancy in patients. One is clotting-promotion medicines known as antihemophilic factor concentrates, which prevent serious bleeding. The other is comprehensive care. […] Although joint deterioration remains a chronic complication in hemophilia, prompt and proper treatment can greatly reduce the risk of life-threatening bleeding episodes and the severity of long-term damage to joints.
#13 Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa | Hematology, Transfusion and Cell Therapy
https://www.htct.com.br/en-clinical-outcome-incidence-inhibitor-development-articulo-S2531137922000554
Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa […] The aim of this study was to evaluate clinical outcomes and inhibitor development in people with hemophilia receiving low-dose prophylaxis (LDP) in a sub-Saharan African setting. […] The LDP in Hemophilia improves the clinical outcome without a surplus risk of inhibitor development. […] The occurrence of inhibitors increases the risk of the following adverse outcomes: uncontrolled bleeding and disability due to joint destruction, reduced quality of life and an increased risk of death, as well as difficulty in managing the disease. […] The incidence of inhibitors in our study was within the values reported in the literature, ranging from 15% to 33% in patients with severe HA. […] The study results suggest that LDP is more beneficial than OD treatment in reducing bleeding and improving musculoskeletal health and physical ability, without increasing the incidence of inhibitor development.
#14 Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa | Hematology, Transfusion and Cell Therapy
https://www.htct.com.br/en-clinical-outcome-incidence-inhibitor-development-articulo-S2531137922000554
Clinical outcome and incidence of inhibitor development in severe hemophilia patients receiving low-dose prophylaxis: a 3-year follow-up study in Senegal, West Africa […] The aim of this study was to evaluate clinical outcomes and inhibitor development in people with hemophilia receiving low-dose prophylaxis (LDP) in a sub-Saharan African setting. […] The LDP in Hemophilia improves the clinical outcome without a surplus risk of inhibitor development. […] The occurrence of inhibitors increases the risk of the following adverse outcomes: uncontrolled bleeding and disability due to joint destruction, reduced quality of life and an increased risk of death, as well as difficulty in managing the disease. […] The incidence of inhibitors in our study was within the values reported in the literature, ranging from 15% to 33% in patients with severe HA. […] The study results suggest that LDP is more beneficial than OD treatment in reducing bleeding and improving musculoskeletal health and physical ability, without increasing the incidence of inhibitor development.
#15 Hemophilia trials in the twentyâfirst century: Defining patient important outcomes
https://pmc.ncbi.nlm.nih.gov/articles/PMC6462740/
Treatment for hemophilia has advanced dramatically over the past 5 decades. […] The success of prophylactic therapy in preventing bleeding and decreasing the progression of joint disease has established a new standard of care, progressively adopted since early childhood. […] The advent of gene therapy and coagulation mimetics, producing unprecedented results in terms of level and durability of their clotting effect, necessitates a complete reassessment of outcomes measured in hemophilia trials in light of the progress in the science of outcome measurements, to ensure appropriate assessment of the value contributed by these advanced therapies. […] The importance of defining, choosing, measuring, analyzing, and reporting outcomes appropriately has always been at the core of health care practice and research since evidence-based medicine came into play.
#16 Hemophilia trials in the twentyâfirst century: Defining patient important outcomes
https://pmc.ncbi.nlm.nih.gov/articles/PMC6462740/
The potential impact of patient input is broad. […] The frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use, and mental health were identified as important core outcomes. […] Advanced therapies are demonstrating improved efficacy with decreased disease burden, and the potential for cure. […] Systematic collection of PIOs is critical in this process, as achieving near normal factor activity levels may change the perceived impact of traumatic bleeds. […] It is an exciting time in hemophilia. As new advanced therapies are introduced, we need a long-term plan to truly capture safety and efficacy in a patient relevant manner.
#17 Hemophilia trials in the twentyâfirst century: Defining patient important outcomes
https://pmc.ncbi.nlm.nih.gov/articles/PMC6462740/
The potential impact of patient input is broad. […] The frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use, and mental health were identified as important core outcomes. […] Advanced therapies are demonstrating improved efficacy with decreased disease burden, and the potential for cure. […] Systematic collection of PIOs is critical in this process, as achieving near normal factor activity levels may change the perceived impact of traumatic bleeds. […] It is an exciting time in hemophilia. As new advanced therapies are introduced, we need a long-term plan to truly capture safety and efficacy in a patient relevant manner.
#18 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
Hemophilia A is a relatively rare hereditary coagulation disorder caused by a defective F8 gene resulting in a dysfunctional Factor VIII protein (FVIII). […] We verified a close agreement between in silico, in vitro and clinical data. Finally, we predicted the severity of all possible mutations in the FVIII structure including those not yet reported in the medical literature. […] The combination of protein structure analysis and machine learning is a powerful approach to predict and understand the effects of mutations on the disease outcome. […] Although the life expectancy and the quality of life of PwHA improved considerably in the last decades, current treatment options still have issues to be addressed; for instance, it is necessary to improve the half-life of recombinant FVIII proteins, as well as its immunogenic profiles to avoid the development of neutralizing antibodies.
#19 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
Hemophilia A is a relatively rare hereditary coagulation disorder caused by a defective F8 gene resulting in a dysfunctional Factor VIII protein (FVIII). […] We verified a close agreement between in silico, in vitro and clinical data. Finally, we predicted the severity of all possible mutations in the FVIII structure including those not yet reported in the medical literature. […] The combination of protein structure analysis and machine learning is a powerful approach to predict and understand the effects of mutations on the disease outcome. […] Although the life expectancy and the quality of life of PwHA improved considerably in the last decades, current treatment options still have issues to be addressed; for instance, it is necessary to improve the half-life of recombinant FVIII proteins, as well as its immunogenic profiles to avoid the development of neutralizing antibodies.
#20 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
We anticipate that this study will enable other rare diseases to benefit from ML and will contribute to the engineering of better recombinant FVIII therapeutics. […] Taken together, our results indicate that in addition to the properties inferred directly from the protein structure, properties derived from the RIN offer a distinct perspective on the importance of the residues in FVIII and their relation to HA phenotypes. […] Our results indicate that even with limited input data, it was possible to build a ML framework that had a close agreement with in vitro and clinical data. […] The ability to adjust the Severity Score thresholds added flexibility to the framework and created a trade-off between a smaller accuracy and more instances classified, or fewer instances classified but with more certainty.
#21 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
We verified a close agreement between the in silico and in vitro results, as evidenced by the fact that the most dramatic reductions in the chromogenic and secretion activities of the FVIII protein were accompanied by high Severity Scores. […] The agreement between Hema-Class predictions and the in vitro and clinical reports is not perfect.
#22 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
We anticipate that this study will enable other rare diseases to benefit from ML and will contribute to the engineering of better recombinant FVIII therapeutics. […] Taken together, our results indicate that in addition to the properties inferred directly from the protein structure, properties derived from the RIN offer a distinct perspective on the importance of the residues in FVIII and their relation to HA phenotypes. […] Our results indicate that even with limited input data, it was possible to build a ML framework that had a close agreement with in vitro and clinical data. […] The ability to adjust the Severity Score thresholds added flexibility to the framework and created a trade-off between a smaller accuracy and more instances classified, or fewer instances classified but with more certainty.
#23 Prediction of hemophilia A severity using a small-input machine-learning framework | npj Systems Biology and Applications
https://www.nature.com/articles/s41540-021-00183-9
Hemophilia A is a relatively rare hereditary coagulation disorder caused by a defective F8 gene resulting in a dysfunctional Factor VIII protein (FVIII). […] We verified a close agreement between in silico, in vitro and clinical data. Finally, we predicted the severity of all possible mutations in the FVIII structure including those not yet reported in the medical literature. […] The combination of protein structure analysis and machine learning is a powerful approach to predict and understand the effects of mutations on the disease outcome. […] Although the life expectancy and the quality of life of PwHA improved considerably in the last decades, current treatment options still have issues to be addressed; for instance, it is necessary to improve the half-life of recombinant FVIII proteins, as well as its immunogenic profiles to avoid the development of neutralizing antibodies.
#24 Hemophilia A Prognosis: What Is the Life Expectancy? | MyHemophiliaTeam
https://www.myhemophiliateam.com/resources/hemophilia-a-prognosis-what-is-the-life-expectancy
Life expectancy with hemophilia A has increased from 20 to 30 years in the 1960s to over age 70 in recent years. […] The severity of someone’s hemophilia is an important factor in their prognosis (outlook). […] Advances in hemophilia treatment have contributed to the improved prognosis, and new treatments may continue this trend. […] The mortality (death) rate for men with hemophilia is twice that of healthy men in the general population and for those with severe forms of hemophilia, it’s four to six times higher. […] The study conducted in the Netherlands found that men with severe hemophilia had a lower median life expectancy than those with mild or moderate hemophilia. […] However, it increased to 73 years between 2001 and 2018. […] This means that half of the men with severe hemophilia studied between 2001 and 2018 lived at least 73 years. […] Unfortunately, no current data shows how valoctocogene roxaparvovec-rvox may lengthen life expectancy in people with severe hemophilia A. More long-term studies are needed to measure whether gene therapy treatment can improve prognosis.
#25 Hemophilia trials in the twentyâfirst century: Defining patient important outcomes
https://pmc.ncbi.nlm.nih.gov/articles/PMC6462740/
The potential impact of patient input is broad. […] The frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use, and mental health were identified as important core outcomes. […] Advanced therapies are demonstrating improved efficacy with decreased disease burden, and the potential for cure. […] Systematic collection of PIOs is critical in this process, as achieving near normal factor activity levels may change the perceived impact of traumatic bleeds. […] It is an exciting time in hemophilia. As new advanced therapies are introduced, we need a long-term plan to truly capture safety and efficacy in a patient relevant manner.
#26 Hemophilia Prognosis and Life Expectancy – Hemophilia News TodayEnvelope icon
https://hemophilianewstoday.com/hemophilia-prognosis-life-expectancy/
Based on the same WFH estimates, the life expectancy for men already living with hemophilia is about 10 years shorter than that for men without hemophilia. […] With modern screening techniques, the risk of getting an infection from hemophilia treatments nowadays is slim to none, which has helped to improve outcomes for patients diagnosed and treated in the 21st century. […] Preventive measures and early treatment have significantly improved the long-term outlook, or prognosis, for people with severe hemophilia. […] Two major developments have contributed to a longer life expectancy in patients. One is clotting-promotion medicines known as antihemophilic factor concentrates, which prevent serious bleeding. The other is comprehensive care. […] Although joint deterioration remains a chronic complication in hemophilia, prompt and proper treatment can greatly reduce the risk of life-threatening bleeding episodes and the severity of long-term damage to joints.
#27 Hemophilia A Prognosis: What Is the Life Expectancy? | MyHemophiliaTeam
https://www.myhemophiliateam.com/resources/hemophilia-a-prognosis-what-is-the-life-expectancy
Life expectancy with hemophilia A has increased from 20 to 30 years in the 1960s to over age 70 in recent years. […] The severity of someone’s hemophilia is an important factor in their prognosis (outlook). […] Advances in hemophilia treatment have contributed to the improved prognosis, and new treatments may continue this trend. […] The mortality (death) rate for men with hemophilia is twice that of healthy men in the general population and for those with severe forms of hemophilia, it’s four to six times higher. […] The study conducted in the Netherlands found that men with severe hemophilia had a lower median life expectancy than those with mild or moderate hemophilia. […] However, it increased to 73 years between 2001 and 2018. […] This means that half of the men with severe hemophilia studied between 2001 and 2018 lived at least 73 years. […] Unfortunately, no current data shows how valoctocogene roxaparvovec-rvox may lengthen life expectancy in people with severe hemophilia A. More long-term studies are needed to measure whether gene therapy treatment can improve prognosis.
#28
https://link.springer.com/article/10.1007/s00277-020-04250-9
The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. […] The advantage of prophylaxis in reducing bleeding rates has been documented repeatedly in clinical trials. […] The median ABR in subjects with SHA and SHB on prophylaxis was 4.9 and 3.0, respectively. […] Our study provides data on bleeding outcomes, expressed as ABR, in persons treated with standard half-life products in a real-world setting. […] We also investigated factors associated with ABR and found only a significant association of higher ABRs with active or history of hepatitis B and C. […] In summary, bleeding rates in persons with severe hemophilia treated with standard half-life concentrates were high in our real-world cohort, as was the proportion of on-demand therapy in those with SHA. Increasing the number of persons on prophylaxis and establishing individualized treatment concepts, especially for those with a history of hepatitis, may further reduce ABRs and improve joint function and quality of life.