Introduction
Recent advancements in treatments for hemophilia such as extended half-life coagulation
factors, non-factor replacement therapies, rebalancing agents, and gene therapies
along with widespread access to prophylaxis have collectively extended the life expectancy
of individuals with hemophilia.[1]
[2]
[3] In general, the risk of thrombotic cardiovascular (CV) events increases with age,[4] especially when patients are exposed to risk factors such as hypertension, diabetes
mellites, smoking, etc.[5] Although this is also true for people with hemophilia, previous reports have suggested
that the risks of thrombotic CV events were lower than those without, even in the
presence of CV risk factors of equal or even worse severity.[6]
[7] However, various antithrombotic therapy may be necessary even in people with hemophilia
when they are at a high risk of thrombosis.
In a prospective multicenter hemophilia registry of ADVANCE Japan, Nagao et al showed
that 13 out of 600 people with hemophilia age >40 experienced thrombotic CV events
requiring antithrombotic therapy at the first year of the 10-year follow-up.[7] These results are reasonable since the important burden of thrombotic disease, such
as atheromatous plaque formation, is not prevented or delayed in the presence of hemophilia.[8] Another report from a European cross-sectional study revealed that the risk of thrombosis
in atrial fibrillation, an important factor contributing to the increased risk of
thrombotic CV events,[9] was not reduced by the presence of hemophilia.[10] Moreover, venous thrombotic events necessitating anticoagulant therapy have also
been documented even in people with hemophilia.[11]
[12] From these findings, it is logical to assume that the number of people with hemophilia
with or at a high risk of thrombosis increases with longer life expectancy through
better hemophilia therapy.
The complicated oversight of bleeding and thrombosis is necessary for treating people
with hemophilia with or at a high risk of thrombosis. Various consensus documents
are published for practice guidance—most notably from EHA (European Hematology Association),
ISTH (International Society for Thrombosis and Haemostasisi), EAHAD (European Association
of Hemophilia and Allied Disorders), and ESO (European Stroke Organization)—and are
emerging to address these critical needs.[13]
[14]
[15]
[16] Although these guidelines are largely expert consensus, the rarity of hemophilia,
particularly in these specific contexts, renders large-scale registry or randomized
studies infeasible. Thus, utilizing available guidance as a strategic framework for
treatment considerations remains essential.
In this review, we aim to focus on hemophilia care, particularly from the perspective
of antiplatelet and anticoagulant therapies, and explore current practices and challenges
in this evolving field.
Evolution of Hemophilia Treatment
The advancements in hemophilia treatment have significantly shifted from mere hemostatic
management to comprehensive care as a chronic disease, improving patient survival
while introducing new clinical challenges. Understanding the evolution of hemophilia
treatment is essential not only for bleeding management but also for developing cardiovascular
disease (CVD) treatment strategies that balance the risk of thrombosis.
Traditionally, hemophilia treatment has been centered on coagulation factor replacement
therapy. This method involves intravenous administration of factor VIII (FVIII) or
factor IX (FIX) to control bleeding, with prophylactic therapy recommended for continuous
management. However, this approach had the limitation of a short half-life, necessitating
frequent intravenous infusions. To overcome these challenges, extended half-life (EHL)
factor products were developed. These formulations utilize technologies such as Fc
fusion, PEGylation, and albumin fusion, enabling a more prolonged and stable supply
of coagulation factors and reducing the frequency of infusions.[17] However, EHL products still require intravenous administration, and FVIII products
are particularly limited in their half-life extension due to interactions with von
Willebrand factor (VWF), making FIX products more favorable in this aspect. One breakthrough
solution to this limitation is efanesoctocog alfa, a revolutionary FVIII product with
a half-life two to three times longer than conventional FVIII formulations. This allows
for once-weekly administration while maintaining sufficient coagulation function.[18]
In contrast to traditional factor replacement therapies, non-factor replacement therapies
offer a novel approach. Emicizumab, a bispecific antibody that mimics FVIII function,
can be administered subcutaneously once a week to once a month, significantly reducing
the burden on patients.[19] Other examples include rebalancing therapies, such as fitusiran, an siRNA therapy
that suppresses antithrombin to enhance coagulation. This treatment is administered
monthly via subcutaneous injection, achieving sufficient hemostatic effects.[20] Additionally, concizumab and marstacimab, both tissue factor pathway inhibitor (TFPI)
inhibitors, offer another new approach to bleeding control.[21]
[22] However, some rebalancing therapies have been associated with an increased risk
of thrombosis, raising concerns about their safety. The implications for CVD management
remain even more uncertain.
Furthermore, gene therapy has been introduced in Western countries, using adeno-associated
virus (AAV) vectors to deliver FVIII or FIX genes into liver cells to promote endogenous
factor production.[23]
[24]
[25] This one-time treatment has attracted attention as a new therapeutic option. The
major advantage of gene therapy is its potential for long-term factor production,
theoretically offering a “functional cure.” However, significant individual variability
exists in post-treatment factor levels, and some patients may not achieve sufficient
factor production. Additionally, concerns such as a decline in factor production over
time and liver toxicity require careful monitoring.
The emergence of these new treatments is altering the coagulation profile of hemophilia
patients compared to the past. At the same time, the available therapeutic options
for hemophilia have expanded when antiplatelet or anticoagulant therapy is required
following the onset of CVD.
Antiplatelet Therapy in Hemophilia
Antiplatelet Therapy
Antiplatelet therapy with aspirin and P2Y12 inhibitors is the standard of care in patients with acute coronary syndrome (ACS)
including acute myocardial infarction.[26]
[27]
[28] Even in stable coronary artery disease, antiplatelet therapy is widely used after
percutaneous coronary intervention (PCI).[29] Moreover, dual antiplatelet therapy (DAPT) of aspirin and P2Y12 receptor antagonists showed a reduction of fatal or non-fatal stent thrombosis.[30]
The use of P2Y12 inhibitors in DAPT for ACS shifted from clopidogrel to a newer generation of agents
in patients with ACS.[31]
[32] Initially, DAPT was considered for at least 12 months after the onset of ACS.[19] Initially, the newer P2Y12 inhibitors were also tested for 12-month therapy.[33]
[34] Obviously, strong antiplatelet therapy by DAPT reduced the risk of thrombosis, but
increased the risk of serious bleeding complications. To achieve the best balance
between thrombosis and bleeding both longer and shorter DAPT strategies were tested
as compared to the initially established 12-month DAPT. A longer DAPT strategy achieved
a further reduction of thrombotic events but with an increased risk of serious bleeding
complications.[35]
[36] On the other hand, shorter DAPT or de-escalation of DAPT from aspirin plus potent
P2Y12 inhibitors to aspirin plus a low-dose potent P2Y12 inhibitor or clopidogrel strategy at 1 month resulted in reduced risk of serious
bleeding complication without increasing the risk of thrombotic events.[37] A similar short DAPT strategy for only 1 month also resulted in better clinical
outcome as compared to longer DAPT after stenting, even in the absence of ACS.[38] Accordingly, the shorter DAPT strategy also became a standard of care in stable
coronary artery disease patients who undergo PCI treatment.[39]
DAPT provides strong antiplatelet therapy to reduce the risk of thrombotic major cardiovascular
events (MACE) including myocardial infarction after ACS and endothelial damage by
PCI ([Fig. 1]). Platelet thrombus formation is induced by endothelial damage. Thus, only 1-month
DAPT should be sufficient in theory since the endothelial damage by PCI should be
recovered by then. The MACE events become symptomatic when the thrombi become large
enough to reduce organ perfusion. The large thrombi are mostly caused by fibrin. The
activated platelet provides procoagulant surfaces to initiate fibrin formation, but
coagulation factors should play more direct roles than platelets for expanding fibrin
thrombi (right part of [Fig. 1]). In other words, antiplatelet therapy may prevent initiation of coagulation cascade
by preventing the formation of prothrombinase complex, but its role for fibrin thrombus
growth is limited. Indeed, a few case reports suggested that antiplatelet agents could
be used even in people with hemophilia in certain conditions of ACS.[40]
[41] Thus, shorter DAPT in those with ACS and after PCI until endothelial recovery may
be possible for the hemophilia population.
Fig. 1 Role of Platelets and Coagulation Factors in Thrombus Formation. Platelets adhere
promptly at sites of endothelial damage. Initial adhesion is mediated by platelet
glycoprotein Iba binding with von Willebrand factor (VWF) expressed at the damaged
endothelium. Then, adhered platelets are activated. Negatively charged phospholipids
such as phosphatidyl serine (POPS) are expressed on the activated platelet membrane.
Coagulation factors with the gla domain bind with POPS, and those without the gla
domain contribute to the formation of prothrombinase complex. Various antiplatelet
agents prevent thrombosis by inhibiting platelet activation and procoagulant activity.
Symptomatic thrombosis, such as myocardial infarction, occurs when blood perfusion
is disturbed by large thrombi mostly caused by fibrin. Essential coagulation factor(s)
such as factor VIII or factor IX is lacking in individuals with hemophilia. However,
a minimal amount(s) of these essential coagulation factor(s) is necessary for hemostatic
thrombus formation. DAPT, dual antiplatelet therapy; POPC, phosphatidyl serine.
The most frequently used agents in single antiplatelet therapy (SAPT) are aspirin
and clopidogrel, with ticagrelor used in some cases. Prasugrel, however, is rarely
used as monotherapy due to its high bleeding risk.[42] In patients with high bleeding risk, clopidogrel is often preferred over aspirin
due to its lower risk of bleeding.[43]
In contrast, real-world data from France (69,911 patients) suggest that low-dose aspirin
carries a lower bleeding risk than clopidogrel and high-dose aspirin, particularly
for gastrointestinal and intracranial bleeding.[44] Therefore, the choice of SAPT should be individualized based on patient-specific
thrombotic and bleeding risks.
Maintenance of Coagulation Factor during Antiplatelet Therapy
To prevent serious bleeding complications in hemophilia patient requiring antiplatelet
therapy, maintaining a deficient coagulation factor in various levels is recommended
by EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.[14] When patients need DAPT with aspirin and P2Y12 receptor antagonist, the maintenance of FVIII/IX level over 20 IU/dL is recommended
while FVIII/IX level of 1 to 5 IU/dL may be fine with an SAPT using either aspirin
or clopidogrel.[14] It is likely that relatively small amount of essential coagulation factors is necessary
to stop bleeding ([Fig. 1]).
It is of note that the practice recommendation by EHA-ISTH-EAHAD-ESO is not based
on strong clinical evidence provided by randomized clinical trials. Careful consideration
of the risk of thrombosis and bleeding in individual patients is necessary to achieve
the best personalized outcomes. In practice, maintaining a factor VIII trough level
above 20% using currently available FVIII products may need frequent intravenous infusions.
More recent anti-hemophilia agents, such as emicizumab, may be a good alternative.
The action of emicizumab to stop bleeding is much more complex compared to simple
supplemental therapy. However, clinical data on the use of emicizumab remains limited,
and existing case reports suggest that severe hemophilia patients were successfully
managed during 1 month of DAPT with emicizumab alone without serious bleeding complications.[7]
[45] Although no bleeding complications were observed in these cases, the small number
of patients raises questions about whether this was due to other factors being fortuitously
favorable or if emicizumab alone is sufficient for adequate management. Further evidence
from larger clinical studies is needed. [Table 1] summarizes the necessary maintenance therapy in hemophilia if they need antiplatelet
therapy. More clinical evidence with the use of emicizumab alone is expected.
Table 1
Maintenance therapy in people with hemophilia requiring antiplatelet therapy
|
Maintenance therapy in people with hemophilia require antiplatelet therapy
|
|
Single antiplatelet therapy (SAPT)
|
FVIII/IX level of 1–5 IU/dL for SAPT (aspirin or clopidogrel)
|
|
Dual antiplatelet therapy (DAPT)
|
FVIII/IX level of 20 IU/dL for DAPT
|
|
Single and dual antiplatelet therapy
|
Different parameter may be necessary when using emicizumab
|
Oral Anticoagulants in Hemophilia
Choice of Oral Anticoagulant
Vitamin K antagonists (VKAs) were the only available oral anticoagulants for a long
period of time. Recently developed orally available specific inhibitor of coagulation
factor Xa, namely, direct oral anticoagulants (DOACs), became a standard of care in
various conditions such as stroke prevention in patients with non-valvular cause of
atrial fibrillation (AF).[46]
[47]
[48] The global registry of AF at risk of stroke showed the evolving changes in the use
of DOAC in stroke prevention in newly diagnosed AF patients at risk of stoke around
the globe.[49] Similar rapid transition from VKA to DOACs were observed in various registry mostly
due to safe profile of DOACs as compared to VKA with no need for monitoring.[50]
[51]
[52] VKA is still necessary but only in those patients with high thrombotic risk such
as AF with mechanical heart valve[53] and hemodynamically overt mitral stenosis.
The risk–benefit balance with the use of DOAC in hemophilia population is more complicated
than that with the use of antiplatelet agents because the bleeding risk with the use
of oral anticoagulants is much higher than antiplatelets. Indeed, the annual risk
of serious bleeding with the use of aspirin of approximately 0.2%/year is substantially
lower as compared to that of approximately 2 to 3%/year with the use of DOACs.[46]
[47]
[48] Aspirin could be recommended for almost all secondary prevention cohort patients
because the merit of reducing thrombosis in these population is usually much higher
than the increased risk of bleeding.[54] For the DOACs, the selection of high-risk patients is necessary. Simple risk calculation
based on the CHA2DS2-VASc score is widely accepted. The bleeding risk was previously
assessed using the HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly and Drugs or alcohol) score. In the era of DOAC, a few bleeding risk scores have been developed
so far.[55] However, the bleeding risk stratification in people with hemophilia requiring oral
anticoagulants is still to be elucidated.
A trough FVIII/IX level of 20 IU/dL is recommended when anticoagulants are considered
in people with hemophilia by EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.[14] A precise and personalized risk stratification is necessary to avoid bleeding complications
in people with hemophilia when using DOACs.
Risk Stratification When Using Anticoagulants
Risk stratification using clinical parameters such as CHA2DS2-VASc and HAS-BLED is
easy. For further precise risk clarification, biomarker-based risk stratification
may be helpful. ABC risk stratification is widely accepted for risk prediction of
stroke/systemic embolization[56] and serious bleeding.[57] However, their role in people with hemophilia is unclear. Of the biomarkers, thrombin
generation assay (TG) was investigated deeply to select high bleeding risk patients
in the VKA era. The quantitative relationship between TG assay and PT-INR was investigated.
TG levels below 10% aligned well with the therapeutic INR range for VKAs: 10 to 20%
with an INR range of 1.5 to 1.9, and above 20% begin to overlap with normal controls.
Maintenance of 20% or higher factor VIII/IV levels recommended by EHA-ISTH-EAHAD-ESO
Clinical Practice Guidance for using DOACs is based on TG assay data.[14]
The potential role of TG in understanding the effects of DOACs in people with hemophilia
was investigated in a small clinical study.[58] The authors showed that endogenous thrombin potential was higher in anti-Xa treated
patients compared to those with mild hemophilia. TG may be useful for assessing hemophilia
therapy because people with severe hemophilia express significantly improved TG parameter
if they are treated with emicizumab.[58] If the TG parameters precisely reflect the thrombotic and bleeding risk in hemophilia
patients on DOACs treatment, they can be used to make individualized decisions such
as no need for DOACs if the TG parameters were low enough in the hemophilia patients
even if they have other risk factors that puts them at high risk of thrombosis. Similarly,
DOAC may be recommended when TG parameters are higher than the values in patients
who are maintain factor level above 20%. [Table 2] summarizes the clinical condition when anticoagulant therapy is necessary, even
in hemophilia.
Table 2
Anticoagulation therapy in people with hemophilia with or at a risk of thrombosis
|
Anticoagulant therapy in people with hemophilia
|
|
DOAC
|
● Stroke prevention in patients with atrial fibrillation with a trough FVIII/IX level
of 20 IU/dL
|
|
Risk stratification
|
● Clinical risk stratification with CHA2DS2-VASc, CHA2DS2, and HAS-BLED should not
strong enough
● Thrombin generation (TG) assay may provide necessary level of FVIII/IX
|
|
Monitoring
|
● Serially measured PT-INR may be helpful in patients treated by VKA.
● In patients treated by DOAC, TGA/TEG/ROTEM may provide better monitoring.
|
Abbreviations: DOAC, direct oral anticoagulant; HAS-BLED, Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly and Drugs or alcohol; TEG, Thromboelastography; TGA, thrombin generation assay; VKA, vitamin
K antagonist.
Management of Bleeding Complication with the Use of DOACs in Hemophilia
During treatment with antiplatelet drugs or DOACs, it is crucial for patients to keep
a detailed record of their bleeding events, which is also necessary for calculating
the annual bleeding rate (ABR). In addition to documenting factor replacement therapy
for typical bleeding episodes, patients should also be educated to record less severe
bleeding events such as subcutaneous hemorrhage, epistaxis, oral cavity bleeding,
and mucosal-related bleeding (like changes in menstrual flow), even when factor replacement
is not required. If a patient's record suggests frequent bleeding episodes, special
caution should be taken for the individual, including adjustment to the antiplatelet/DOAC
therapy. Clinical trial suggests that the extremely low dosage of DOAC still bring
benefit in elderly patients at high risk of bleeding.[59] A similar dose adjustment might be helpful for hemophilia population.
Monitoring of Anticoagulant Therapy in People with Hemophilia
PT-INR is an established monitoring marker for patients treated by VKAs. Typically,
single-measured PT-INR values are used to adjust the dosage of VKA. Multidimensional
data such as serially measured PT-INR should contain more information for predicting
future risks of bleeding and thrombotic events. However, the quantitative relationship
between multidimensional data and clinical events risks is difficult to calculate.
Recently developed neural network on computers enabled reduction of multidimensional
data into single dimension ([Fig. 2]). Computer-based artificial intelligence (AI) models using these neural networks
successfully predict the future risk of thrombosis/bleeding events in patients starting
VKA using serially measured PT-INR dataset obtained from day 1 to 30.[60] These neural network–based AI enables the prediction of various disease risk from
multidimensional data.[61]
[62]
[63]
[64]
[65] Currently, their application to people with hemophilia is still to be elucidated.
Precise monitoring of the individual effects of anticoagulants in people with hemophilia
should be helpful for monitoring the efficacy and safety of the anticoagulant therapy
in individuals with hemophilia.
Fig. 2 Individualized Prediction of Thrombotic and Bleeding Risk in Individuals with Hemophilia
and Anticoagulant Therapy Using Multidimensional Data with Artificial Intelligence.
Typically, various hemostatic parameters such as PT-INR were used to predict the risk
of thrombosis and bleeding by a single-point measurement. Multidimensional data, such
as serially measured data sets, should contain more information than single-day measurements.
However, it was difficult to quantify the relationship between multidimensional data
and the future risk of thrombotic/bleeding events. The neural network enables the
reduction of multidimensional data into a single-dimensional space with an established
mathematical model. The quantitative relationships between the dimension-reduced data
and the risk of thrombosis/bleeding events could be calculated. A multidimensional
data–based personalized approach should improve the quality of care in complicated
antithrombotic therapy in people with hemophilia.
Unlike PT-INR for VKA, classical screening coagulation assays such as single-time
measurements of prothrombin time (PT), activated partial thromboplastin time (APTT),
and thrombin time (TT) are not a suitable marker for evaluating the efficacy and safety
of DOACs. Liquid chromatography–mass spectrometry measurements of DOAC concentration
are considered as the gold standard.[66] So far, the best values for people with hemophilia have not been established. Just
like PT-INR in patients on warfarin, the multidimensional data of serially measured
monitoring values may include precise information to predict the future risks of thrombotic
and bleeding events in individual with hemophilia.
Regarding monitoring during emicizumab treatment, previous reports have shown that
global hemostasis assays such as ROTEM or thrombin generation assay (TGA) may provide
better predictive accuracy for the risk of thrombosis and bleeding in hemophilia patients.[67] Perhaps, future risk of thrombotic/bleeding events could be more precisely predicted
by multidimensional analysis of measured data ([Fig. 2]). Again, the use of multidimensional data may further increase the predictive accuracy
of future clinical events in individual patients.
