Received: 17 December 2021 Revised: 7 March 2022 Accepted: 7 March 2022

DOI: 10.1111/hae.14552

SUPPLEMENT ARTICLE

Low dose prophylaxis and antifibrinolytics: Options to consider

with proven benefits for persons with haemophilia

Manuel Carcao1 Emna Gouider2 Runhui Wu3

1
Haemophilia Clinic and Haemostasis
Program, Division of Haematology/Oncology,
Department of Paediatrics, Hospital for Sick
Children, University of Toronto, Toronto,
Ontario, Canada
2
Hemophilia Treatment Centre, Aziza
Othmana Hospital, University Tunis El Manar,
Tunis, Tunisia
3
Haemophilia Comprehensive Care Centre,
Haematology Centre, Beijing Children’s
Hospital, National Centre for Children’s
Health, Capital Medical University, Beijing,
China
Correspondence
Manuel Carcao, Hospital for Sick Children,
Room 9416, 555 University Av, Toronto,
Ontario M5G 1X8, Canada.
Email: manuel.carcao@sickkids.ca
Abstract
Introduction: Prophylaxis has become standard of care for persons with severe phe-
notype haemophilia (PWsH). However, ‘standard prophylaxis’ with either factor or
non-factor therapies (emicizumab) is prohibitively expensive for much of the world.
We sought to evaluate whether haemophilia care can be provided at a lower cost yet
achieve good results using Lower dose/Lower frequency prophylaxis (LDP) and with
increasing use of antifibrinolytics (Tranexamic acid and Epsilon amino caproic acid).
Methods: We identified 12 studies that collectively included 335 PWsH using LDP.
Additionally, we undertook a literature search regarding the benefits of antifibrinolyt-
ics in haemophilia care.
Results: Identified studies show that LDP is far superior to no prophylaxis (On demand
[OD] therapy) resulting in significant patient benefits. Patients on LDP showed (in com-
parison to patients OD) on average: 72% less total bleeds; 75% less joint bleeds; 91%
less days lost from school; 77% less hospital admission days; and improved quality of
life measures. These benefits come at similar or only slightly higher (< 2-fold greater)
costs than OD therapy. Antifibrinolytics are effective adjunctive agents in managing
bleeds (oral, nasal, intracranial, possibly other) and providing haemostasis for surgeries
(particularly oral surgeries). Antifibrinolytics can substitute for more expensive factor
concentrates or can reduce the use of such concentrates. There is evidence to show
that antifibrinolytics may be used in conjunction with factor concentrates/emicizumab
for more effective/less costly prophylaxis.
Conclusions: The use of LDP along with appropriate and increased use of antifib-
rinolytics offers less resourced countries good options for managing patients with
haemophilia.

KEYWORDS
epsilon amino caproic acid, haemophilia, low dose prophylaxis, tranexamic acid

1 INTRODUCTION replacement therapy (referred to as prophylaxis—the regular replace-

Haemophilia care has generally been very expensive particularly now
that for the most part haemophilia is a lifelong condition that necessi-
tates repeated infusions of costly coagulation factor replacement ther-
apies. Provided that patients with severe haemophilia receive regular
ment of the missing factor given, in anticipation of, and with the intent
to, prevent bleeding) they can be protected from bleeding most, or all
the time.1 Yet prophylaxis has traditionally been very expensive due
to the high cost of haemostatic therapies. In this paper, we discuss the
value of low dose prophylaxis (LDP) as an alternative to traditional dose

26 © 2022 John Wiley & Sons Ltd. wileyonlinelibrary.com/journal/hae Haemophilia. 2022;28(Suppl. 4):26–34.
CARCAO ET AL .
prophylaxis and discuss the use of antifibrinolytic agents to reduce the
usage of much more expensive clotting factor concentrates (CFC) when
treating bleeds.
Prophylaxis in haemophilia began in several European centres in
the 1960s and 70s.2,3 Those early prophylaxis regimens, in com-
parison to today’s regimens, used relatively lower doses given less
frequently. Over the decades in more affluent countries prophy-
laxis regimens gradually shifted towards using larger and more fre-
quent doses to reduce the annual number of bleeds per patient
(annual bleeding rates, ABR) to as close as possible to ZERO. Part
of the stimulus for this were several studies showing that the longer
a person with severe haemophilia had a factor level of < 1% the
higher their risk of bleeding.4 Yet studies in different European coun-
tries comparing more intense prophylaxis regimens (full dose; in
haemophilia A this generally involves administering 25–40 U/kg three
times/week [≈4000–6000 U/kg/year]) to intermediate prophylaxis
regimens (generally involves administering 15–25 U/kg 2–3X/week
[≈1600–3900 U/kg/year]) only showed minor reductions in bleed rates
but no improvement in quality of life with the full dose regimen.5
Unfortunately, these prophylaxis regimens still involve administer-
ing relatively frequent and high doses of factor and consequently
have traditionally been perceived as being too expensive and hence
unattainable for less affluent countries such as China, India, Indonesia,
Thailand and Iran with vast populations and consequently huge num-
bers of persons with haemophilia (PWH).
Consequently, most of the world’s population of PWH have tradi-
tionally either not been receiving any therapy whatsoever or at most
have been receiving haemostatic therapy (factor concentrates) episod-
ically (meaning on demand—OD) simply to stop bleeding when bleed-
ing occurs. The problem with this approach is that by not preventing
bleeds patients managed episodically continue to experience 15–35
bleeds annually and this very quickly results in such patients develop-
ing joint disease as children and becoming quite disabled later in life or
in many cases dying of intracranial haemorrhages at early ages.6
Fortunately beginning in the late 1990s and continuing into this cen-
tury it began to be appreciated that even low dose/low frequency pro-
phylaxis (LDP; generally defined as the administration of 10–15 IU/kg
once or twice/week for haemophilia A and 10-20 IU/kg once per week
for haemophilia B) could achieve significant benefits over OD therapy.
An increasing number of publications have come out showing benefits
of LDP; reduced bleeds and better preservation of joint health, over
OD therapy without a dramatic increase in cost (see Table 1A and 1B).
The superiority of LDP to OD therapy led the World Federation of
Haemophilia (WFH), in their most recent guidelines, to recommend
prophylaxis as standard of care for all regions of the world. The WFH,
however, recognizes that in less affluent (more resource constrained)
countries that LDP should be considered and accepted as being prefer-
able to OD therapy. The more recent introduction of extended half-
life (EHL) factor concentrates has also enabled more patients (in more
affluent countries and in some less affluent countries through Humani-
tarian Aid program donations) to benefit from lower frequency prophy-
laxis regimens.
27
2 RATIONALE BEHIND LOW DOSE
PROPHYLAXIS
The rationale behind LDP is encompassed by the statement that ‘a
little bit goes a long way’. This was first noted in a small, yet ele-
gant study by Shimpf in the 1970s.7 Shimpf and colleagues showed
that if patients with severe haemophilia A received 36 U/kg once
per week they still experienced a significant number of bleeds but if
instead they received the same weekly dose but divided into three
doses/week each dose being 12 U/kg that the same patients demon-
strated a marked reduction in bleeding rates. This showed that even
small doses of factor if given frequently could be very effective in lead-
ing to marked reductions in bleeding rates. Other studies since have
shown the effectiveness of small doses of factor given frequently—
potentially even daily at maintaining low bleeding rates whilst reducing
the use (and hence cost) of CFC.8 A recent modelling study compared
the cost of various LDP regimens in comparison to a standard 40 U/kg
three times/wk (total: 120 U/kg/wk) regimen. Modelling showed that if
patients receive 10 U/kg three times/wk (total: 30 U/kg/wk) that this
would lead to a 75% cost savings with only an 11% increase in bleed-
ing risk while a regimen of 15 U/kg twice/wk (total: 30 U/kg/wk) would
similarly lead to a 75% cost savings but with a 27% increase in bleeding.
The same modelling study predicted that five U/kg three times/week
(total: 15 U/kg/wk) would lead to an 87% reduction in cost and would
only increase the risk of bleeding by 27% while 10 U/kg two twice/wk
(total: 20 U/kg/wk) would reduce costs by 83% while incurring a 34%
increased risk in bleeding.9
In the clinical development process of CFCs manufacturers have not
conducted pivotal clinical trials using their product as part of LDP reg-
imens and consequently LDP regimens tend to be regimens that are
developed post-hoc often out of necessity and usually in less affluent
countries. However, recently in the development of an EHL FIX one
company (Novo Nordisk) ended up doing what was an essentially LDP
arm with their EHL FIX (N9-GP; Refixia, Rebinyn). They compared a
very low dose of N9-GP (10 U/kg) given once per week to a standard
dose of 40 U/kg given once per week in a randomized double blinded
study.10 The results showed that even the very low dose regimen, using
75% less concentrate than the standard regimen, still led to a very
acceptable rate of bleeding (ABR = 2.93). For most patients in less afflu-
ent countries this would be far superior to being left on demand and
experiencing in most cases 20 or more bleeds. The results of this study
are very much in keeping with the concept that ‘a little prophylaxis goes
a long way’ and ‘a lot of prophylaxis only goes a little bit further’.
A widely held argument as to why prophylaxis has not been an
option for poorer countries was the assumption that it would be signif-
icantly more costly than OD therapy. Yet published experiences of LDP
presented in this paper seem to refute this as they show that patients
on LDP regimens (who primarily use CFCs to prevent bleeds) end up
using similar amounts of CFCs (or only slightly more) as do patients
managed OD who use factor primarily to treat bleeds.
Although resource constrained countries will seek to use LDP reg-
imens they still seek to achieve better treatment results (reducing
 28

TA B L E 1 A Low dose prophylaxis studies (showing regimens and factor consumption) (all numbers refer to means unless otherwise indicated)

Annualized Factor consumption

Cohort size (on Duration of (U/kg/y); fold increase in
Author (y) Country prophylaxis) Age of patients (y) prophylaxis Prophylaxis regimens consumption (OD to P)
44
Chuansumrit (1995) Thailand 6 (all HA) 12 (median) 1y FVIII: 8–10 U/kg 2X/wk Range: 832–1040
45
Wu (2011) China 34 (HA: 28; HB: 6) 7.8 (median) 12 wk FVIII: 10 U/kg 2X/wk ≈ FVIII = 1040
FIX: 20 U/kg 1X/wk ≈ FIX = 1040
Tang (2013)46 China 66 (all HA) 8.6 6–12 wk FVIII: 10 U/kg 2X/wk 1235 (OD) versus 1238 (P)
(1.0-fold)
Verma (2016)47 – India 11 (P) versus 10 (OD) 4.3 11.5 mo FVIII: 10 U/kg 2X/wk 676 (OD) versus 1044 (P);
randomized study (all HA) (1.5-fold)
Gouider (2017)48 – Tunisia 51 (all HA) 5.3 (median age at 5 y (median) FVIII: 10–15 U/kg 1, 2 or 3X/wk 1612 (median)
escalating dose cohort start) By study end: 31% 1X/wk; 51%
study 2X/wk; 18% 3X/wk
FIX: 25-35 1X or 2X/wk
Sidharthan (2017)49 India 14 (11 HA; 3 HB) 7.6 6 mo OD than FVIII: 10–20 U/kg 2X/wk 1078 (OD) versus 968 (P)
6 mo P FIX: 25–40 U/kg 1X/wk (medians); (.9-fold)
Chuansumrit (2018)50 Thailand 15 (P) versus 35 (OD) 20.4 (median) 3 mo FVIII: 8-10 U/kg 1X-2X/wk NR
versus 15 P (All HA)
Eshghi (2018)12 –escalating Iran 25 (20 HA; 5 HB) Mean age at start of 6 mo FVIII: 25 U/kg 1X/wk (n = 15), 2X/wk 853 (OD) versus 1754 (P);
dose prophylaxis P = 19.8 mo; (n = 5) (2.1-fold)
all < 15 y FIX: 30-50 U/kg 1X/wk (n = 4) or
2X/wk (n = 1)
Chozie (2019)51 –escalating Indonesia 25 (P) versus 25 (OD) 12.1 (OD); 11.8 y (P) 12.8 mo FVIII: 10-15 U/kg 2X/wk 786 (OD) versus 1293 (P);
dose randomized study (all HA) (1.5-fold)
Gulshan (2020)52 India 30 (all HA) 6.5 y median; range: 6 mo (OD) then EHL-FVIII: 10 U/kg 2X/wk 2044 (OD) versus 1866 (P);
EHL-FVIII 2-12 y 12 mo (P) (.9-fold)
Lambert (2020)17 Ivory Coast 25 (21 HA; 4 HB) 5.6 y 17 mo EHL FVIII: 20 U/kg 1X/wk ≈ 1040 (FVIII)
EHL FVIII; EHL FIX EHL FIX: 20 U/kg q10d ≈ 730 (FIX)
Wu (2021)13 –escalating China 33 (all HA) 4.8 y (median) 3 mo OD than For pts ≥4 y: by study end 4 on 1118 (OD) versus 2040 (last
dose 1 y (P) 10-15 U/kg 2X/wk; 8 on 10-15 quarter of P) (medians)
U/kg 3X/wk; 15 on 15-20 U/kg (1.8-fold)
3X/wk; 1 on 20-25 U/kg 3X/wk
For pts < 4 y: 2 on 20-30 IU/kg
1X/wk; 3 on 15-20 IU/kg 2X/wk

Abbreviations: OD, on demand; P, prophylaxis; y, year; mo, month; wk, week; HA, haemophilia A, HB, haemophilia B.
CARCAO ET AL .
TA B L E 1 B Low dose prophylaxis studies (showing outcome data–where available) (all numbers refer to means unless otherwise indicated)

School absent days Hospital admission days

CARCAO ET AL .

ABR (OD vs. P) AJBR (OD vs. P) (OD vs. P) (OD vs. P)
(% reduction with (% reduction with (% reduction with (% reduction with
Author (y) prophylaxis) prophylaxis) prophylaxis) prophylaxis) Other outcome measures
44
Chuansumrit (1995) Medians: 12 (OD) versus NA 12.5 (OD) median versus
2.5 (P) (79% reduction) O (P) (100% reduction)
Wu (2011)45 NR 43 (OD) versus 7.4 (P); 20.4 (OD) versus 1.4 (P); ∙ Gilbert score improved in 67% of diseased joints
(83% reduction) (93% reduction) ∙ 64% improvement in DAS

Tang (2013)46 69% reduction in severe 28.8 (OD) versus 6 (P); ∙ FISH score: 60% improvement (16 (OD) versus 25 (P))
bleeds (79% reduction) ∙ BCH score: improved in 31%

Verma (2016)47 9.4 (OD) versus 2.2 (P); 5.8 (OD) versus .96 (P); 25 (OD) versus 3 (P); ∙ HJHS remained stable for P group; worsened for OD group
(77% reduction) (83% reduction) (88% reduction) ∙ Less emergency visits: 9 (OD) versus 1 (P)

Gouider (2017)48 7(OD) versus .5 (P); ∙ HJHS and FISH scores remained stable on P
(93% reduction)
Sidharthan (2017)49 23 (OD) versus 1.8 (P); 11.3 (OD) versus .9 (P); 43 (OD) versus 1.3 (P); 12.5 (OD) versus 2.4 (P) ∙ HJHS: 4.2 (OD) versus 1.2 (P)
(91% reduction) (92% reduction) (97% reduction) (81% reduction) ∙ FISH: 29 (OD) versus 31.6 (P)

Chuansumrit (2018)50 ∙ Less target joints 74% (OD) versus 40% (P)
12
Eshghi (2018) 5.6 (OD) versus 1.9 (P); 2.1 (OD) versus .9 (P); .64 (OD) versus .24 (P) ∙ Mean Gilbert scores: 5.8 (OD) versus 3.7 (P) (36%
(67% reduction) (57% reduction) (63% reduction) reduction)

Chozie (2019)51 25 (OD) versus 8 (P); 9 (OD) versus 3 (P); ∙ ΔHJHS (from mo 0 to 12): +2 (OD) versus +1(P)
(68% reduction) (67% reduction) ∙ No significant change in HEAD-US score

Gulshan (2020)52 14.5 (OD) versus 2.2 (P); 17.4 d/mo (OD) versus 8.7 (OD) versus 1.1 (P); ∙ HJHS: 8.3 (OD) versus .5 (P); (94% better with P)
(85% reduction) 2.4 d/mo (P); (87% reduction) ∙ Most showed moderate improvement (43%) in DAS
(86% reduction) ∙ Improvement in SAPS: mild in 57% of pts; moderate in 38%

Lambert (2020)17 87.6% reduction in ASJBR ∙ Slight decrease in HJHS (p = .047)

13
Wu (2021) 43% reduction 53% reduction; increase in ∙ Reduction in median HJHS score from 8 to 5 (after 1 yr of
% of boys with ZERO P); 40% resolution of target joints
bleeds from 52% to 82% ∙ No change in Pettersson Xray scores during 1 yr of P

Weighted averages 72% reduction 75% reduction 91% reduction 77% reduction

Abbreviations: ABR, annual bleeding rate; ASJBR, Annual spontaneous joint bleeding rate; OD, on demand; P, prophylaxis; mo, month.
DAS, daily activity scores45 ; Scored: 0- worst –4 best–negative change indicates deterioration.
FISH, Functional independence score in hemophilia53 ; Scored: 0 worst–32 best–negative change indicates deterioration.
BCH, Beijing Children’s Hospital assessment scale46 ; Scored: 0- worst –4 best–negative change indicates deterioration.
HJHS, haemophilia joint health score54 ; Scored: 0 best-124 worst–positive change indicates deterioration.
SAPS, School Activity Participation score45 ; Scored: 0- worst –4 best–negative change indicates deterioration.
Haemophilia early arthropathy detection ultrasound (HEAD-US) score55 ; Scored: 0 best -8 worst–negative change indicates deterioration.
29
30
bleeds, preventing, or delaying arthropathy, and improving patient
quality of life) while balancing this with reduced costs. To achieve this
some clinicians using LDP (see Table 1A, 1B) have instituted individual-
ized prophylaxis (where prophylaxis is adjusted according to bleeding
or according to pharmacokinetics). The outcomes of LDP regimens are
shown in Tables 1A and 1B.
3 SHORT- AND LONG-TERM OUTCOMES OF
LOW DOSE PROPHYLAXIS
An increasing number of studies of LDP from centres in China, India,
Indonesia, Thailand, Tunisia, Iran, and the Ivory Coast have provided
greater evidence of the significant benefits (less bleeds, less joint dam-
age, and improved quality of life measures) of LDP over OD therapy.
These studies (n = 12; shown in Tables 1A and 1B) collectively
have enrolled 335 mainly boys with haemophilia (most with severe
haemophilia A) on secondary or tertiary prophylaxis. Most of these
studies share certain similarities in their conduct and findings. For
the most part they involve relatively few patients (range: 6–66; mean:
28/study). They are also for the most part relatively short-term pro-
phylaxis studies (generally between six and 12 months of prophylaxis).
The subjects in most of these studies have tended to be children and
adolescents. At these young ages it is still possible with LDP to prevent
target joint development which is crucial to reduce long-term prophy-
laxis needs and the lower weights of children over adults means that
lower (absolute) doses can be used. The most common prophylactic
regimen has involved administering standard half-life (SHL) (either
recombinant or plasma derived) FVIII 10 U/kg twice/week. In most
cases the annualized factor consumption in these studies has been
between 1000 and 1500 U/kg (≈20–30 U/kg/wk). When switching
patients from OD therapy to LDP most experiences have reported that
consumption of FVIII either stays unchanged or rises generally by no
more than 1.5 to 2.1-fold (see Table 1A).
These studies have tended to show similar yet significant ben-
efits of LDP over OD treatment. These include a significant
reduction of 72% (weighted average; range: 43–93% reduction in
different studies) in all bleeds and a 75% overall reduction (range:
53–92% reduction) in joint bleeds. These reductions in bleeding rates
are associated with significant decreases in days lost from school—an
overall drop of 91% (range: 86–97%) and in hospital admission days
(median reduction of 77%; range 63–87% reduction). As well patients
on LDP in these studies show stable or improved physical examination
scores (either Haemophilia joint health score (HJHS) or Gilbert’s),
improved functional scores (FISH, Functional independence score in
haemophilia) and improvements in other activity scores (Daily activity
scores, DAS; School Activity Participation scores, SAPS; and Beijing
Children’s Hospital assessment scale, BCH]. Based on the report of
Andersson et al showing that patients on partial prophylaxis (receiving
only one prophylaxis dose/week or twice per week prophylaxis dosing
with < 20 IU/kg/week—a regimen similar to LDP) showed a 2.5-fold
reduction in ICH versus patients treated OD it is reasonable to assume
that LDP would similarly reduce rates of ICH.11
CARCAO ET AL .
The studies of LDP summarized in this paper show that patients on
LDP regimens (who primarily use CFCs to prevent bleeds) end up using
similar amounts of CFCs (or only slightly more) as do patients managed
OD who use CFCs primarily to treat bleeds. Of course, these are short
term costs, and it has been appreciated that if PWH are simply allowed
to bleed, and bleeds are treated on demand that they will develop sig-
nificant joint disease and will incur additional costs later in life from
increased bleeding rates due to damaged joints and eventually due to
the need for costly orthopaedic joint surgeries. Hence the long-term
cost of OD therapy is most likely much higher than that of LDP.
Some of the experiences with LDP have used escalating dose
prophylaxis where patients begin on a very low dose of factor (usually
10 U/kg) given infrequently (usually once per week) but then escalate
both in dose and in frequency over time should they experience unac-
ceptable rates of bleeding.12,13 This is akin to the approach of Canadian
treaters beginning in the 1990s of using escalating dose prophylaxis
starting with once per week dosing; however, the Canadian tailored
prophylaxis regimen started patients on a dose of 50 U/kg mainly and
consequently still led to a high average per patient factor consumption
of 3656 IU/kg/year.14,15 In contrast, in the Iranian study by Eshghi
and colleagues the average per patient factor consumption was
1754 IU/kg/year whilst the average patient in the study performed by
Wu and colleagues in China ended up consuming 1872 IU/kg/year.12,13
All these escalating dose prophylaxis approaches stem from the
recognition that prophylaxis needs of patients are different and as
such that prophylaxis can be individualized.
As there has been increasing recognition of the value of LDP this
has coincided with other developments in haemophilia including more
widespread use of EHL CFCs. Fortunately, EHL CFCs are also being
adapted for LDP. EHL CFCs are for now more expensive than tra-
ditional SHL CFCs. Several manufacturers of EHL CFCs have made
substantial donations to the WFH which in turn has provided these
concentrates to PWH in poor countries through its Humanitarian aid
program.16 This is what was done in the Ivory Coast where Eloc-
tate/Elocta (Sanofi/Sobi) was used at very low doses given once per
week and showed far superior results to simply having patients OD.17
As mentioned earlier, the experience of using a low dose of N9-GP
(10 U/kg/once/week) for haemophilia B patients as part of a random-
ized study of prophylaxis demonstrated that such a LDP regimen can
still achieve very good results (median ABR = 2.93) although not sur-
prisingly, slightly inferior to the results of using a high dose regimen
(40 U/kg once/week; median ABR = 1.04).10
Emicizumab has been tested in clinical trials all of which involved
administering 6 mg/kg (over a 4-week period) either as 1.5 mg/kg/week
or 3 mg/kg/every 2 weeks or 6 mg/kg/every 4 weeks. Several studies
have shown that emicizumab when given at this dosage scheme results
in a variable FVIII equivalent steady state level of protection (mean
20%; range: 10% to 40%).18,19 This is a far higher level of protection
than trough levels obtained with CFC prophylaxis regimens. As such
emicizumab has been shown to be an excellent prophylactic agent for
haemophilia A resulting in a very low, but not, zero rate of bleeds.20
Being a new agent there are a lot of unknowns relating to its use—most
importantly whether it will result in better long term joint protection
CARCAO ET AL .
than what has been seen until now with factor prophylaxis. A ques-
tion which has not been addressed is can lower doses of emicizumab
be used as a form of LDP and potentially might this still provide good
prophylaxis at a much more affordable price.
4 ROLE OF ANTI-FIBRINOLYTICS TO REDUCE
USE OF CLOTTING FACTOR CONCENTRATES (CFCS)
Epsilon amino caproic acid (EACA) was discovered in the 1950s whilst
Tranexamic acid (TXA) was discovered in the mid 1960′s.21 Both
antifibrinolytic agents act by binding reversibly to plasminogen and
blocking the interaction of plasminogen with fibrin thus reducing fib-
rinolysis. EACA, in comparison to TXA is 10 times less potent and has a
shorter half-life and so is less widely used.22 TXA is particularly useful
as it can be administered intravenously, orally, topically, or as a mouth
wash. In comparison to CFCs these agents are reasonably inexpensive
(in Canada the cost of 5 days of TXA is < 10% the cost of just one dose
of CFC) and readily available and furthermore do not have much side
effects and hence are easily tolerated by most patients. The usual dose
of oral TXA is 25 mg/kg every 6–8 h (usual maximum of 1500 mg/dose)
whereas intravenous TXA is usually given at a dose of 10 mg/kg every
8 h. TXA, available in 500-mg tablets, can be crushed and dissolved in
liquids for administration to young children. The usual dosage of EACA
is 75 mg/kg every 6 h.
These anti-fibrinolytics have been shown to be effective at treat-
ing and preventing bleeding in a variety of haemostatic challenges
(surgery, oral bleeding, epistaxis, and menorrhagia) in both patients
with, and without, bleeding disorders. For many bleeding disorders
such as haemophilia these agents are usually used as adjunctive ther-
apies as there are specific therapies available for conditions such as
haemophilia, Von Willebrand disease or factor deficiencies. Sometimes
these agents are the only treatment available for certain rare con-
genital bleeding disorders particularly disorders of hyperfibrinolysis,
such as alpha-2 antiplasmin deficiency, PAI-1 deficiency, and Que-
bec Platelet disorder.23 In these disorders and others where no good
prophylactic agent exists (e.g., Glanzmann’s thrombasthenia) antifibri-
nolytics have at times been given for long periods of time to reduce
bleeding risk.24
The effectiveness of these agents is particularly seen in surgical set-
tings where several large placebo-controlled randomized trials have
proven the effectiveness of TXA in reducing postoperative blood loss
and transfusion requirements in cardiac and orthopaedic surgery.25,26
TXA has also been used in the setting of intracranial bleeds (sub-
arachnoid and subdural) in people with, and without, known bleeding
disorders and it has been found that TXA reduces the overall risk of
rebleeding following nontraumatic SAH.27
TXA is often used in conjunction with other systemic (e.g., CFCs
or DDAVP) or local therapies (e.g., fibrin sealants) to reduce blood
loss. In haemophilia, both antifibrinolytic agents (TXA and EACA) are
extensively used usually in combination with minimal factor support
during surgical procedures. Much of the evidence for this use comes
from studies conducted in the early 1970s. Two double-blind, placebo-
31
controlled trials (one randomized, one quasi-randomized) evaluated
the role of antifibrinolytic agents as haemostatic support to the initial
replacement treatment in 59 PWH (either haemophilia A or B) under-
going 63 dental extractions.
In the first trial 28 PWH received an intravenous infusion of 6 g of
EACA (experimental group) or isotonic saline (placebo group), imme-
diately after a preoperative loading dose of plasma derived FVIII (or
cryoprecipitate) or FIX concentrate.28 Participants who received EACA
continued oral EACA every 6 h whilst the placebo group continued to
receive a placebo every 6 h; in both cases for 7–10 days
In the second trial, 31 PWH were randomised to either oral TXA (1 g
given every 8 h) or placebo starting 2 h before extraction and continu-
ing for 5 days. All participants also received a dose of FVIII or FIX pre-
extraction.29
Both trials showed the efficacy of the addition of antifibri-
nolytic agents (TXA or EACA) resulting in reduced bleeding, less
blood loss, and consequently less need for additional therapeutic
CFC/cryoprecipitate. Furthermore, there were no substantial side
effects.
There have been many further studies on the use of TXA in den-
tal procedures. Hewson and colleagues reported the outcomes in 113
dental extractions (31 surgical and 82 simple extractions) carried out in
50 persons with either haemophilia [n = 37; severe (n = 10), moderate
(n = 6) or mild (n = 21)] or Von Willebrand Disease (VWD; n = 13). Pro-
cedures were performed using 5% TXA solution, as well as placement
of surgical and careful suturing of the socket(s). Importantly patients
did not receive pre-procedure factor replacement therapy. Despite not
getting preoperative haemostatic replacement therapy 41/50 patients
reported no bleeding during the 8 day postoperative period and no
patient reported severe bleeding; only four PWH required postoper-
ative factor replacement therapy by day 8 post-op.30
Lewandaski and colleagues, in a retrospective study of 19 patients
with bleeding disorders (17 mild haemophilia and two VWD) reported
tooth extraction without CFC replacement therapy using a single initial
intravenous infusion of TXA 25 mg/kg (30 min pre dental extraction)
which continued orally (frequency not specified) post-procedures until
wound healing. The authors indicated that only three of the 19 patients
(15.7%) reported any bleeding.31
Ramos and colleagues published the results of using TXA in conjunc-
tion with low doses of factor replacement in a series of 23 patients who
underwent 30 minor oral surgical procedures. Apart from one mild case
of bleeding (in a patient who did not show good compliance with post-
operative instructions) all patients did very well.32
TXA has been widely used in orthopaedic surgeries in PWH. Huang
et al. reported 18 total hip and 24 knee arthroplasties performed
in PWH with, or without, TXA, and concluded that with TXA there
were significant benefits: less perioperative blood loss, less overall
blood loss, lower transfusion rate, a lower rate of postoperative knee
swelling, less postoperative joint pain, lower levels of inflammatory
biomarkers and better joint function.33
Rodriguez-Merchan undertook a retrospective case-control study
of 30 cases of total knee arthroplasty in persons with severe
haemophilia and showed that the addition of intraarticular TXA
32
(2500 mg/25 ml diluted with 10 ml of sodium chloride) reduced the
rates of blood transfusion.34 In the 15 procedures performed using
intraarticular TXA no patient needed a transfusion whereas in the 15
procedures performed without it seven patients needed a transfusion.
TXA has been used in other surgical settings, including
circumcision.35,36 The use of fibrin glue in this procedure is also a
useful adjuvant therapy.
Hence the data is quite strong that the addition of TXA during vari-
ous surgical procedures results in less intra and postoperative bleeding
thus resulting in a reduction in the use of expensive CFCs (FVIII or FIX)
and as well to less need for blood transfusion and to less time in hospital
and all of this can lead to substantial cost savings.
TXA also has been found to be quite useful in certain bleeds (e.g.,
nose bleeds) as many of these can potentially be treated only with
antifibrinolytics alone without needing to receive CFC. As a result of
this in the 3rd edition of the WFH Guidelines for the management of
haemophilia, the WFH recommends the use of antifibrinolytic drugs
(e.g., TXA, or EACA) alone or as adjuvant treatment, particularly in con-
trolling mucosal bleeds and for invasive dental procedures.37 In addi-
tion to the above benefits antifibrinolytics as they can be administered
orally or as a mouth wash or topically applied to injured tissue offer
a tremendous advantage of convenience over CFCs which must be
administered intravenously.38 TXA should not be used in the setting of
haematuria where TXA might result in the formation of clots in the uri-
nary tract potentially leading to urinary obstruction. Other relatively
minor side effects reported with use of TXA include headaches, sinus
and nasal symptoms, back pain, abdominal pain, musculoskeletal pain,
joint pain, muscle cramps, migraine, anaemia and fatigue.
Several laboratory-based studies over the years have shown that
simultaneous treatment with TXA and CFC (FVIII or FIX concen-
trates or bypassing agents) improves clot stability in patients with
haemophilia thus raising the possibility that perhaps prophylaxis reg-
imens can be made more effective by simultaneously having patients
on regular doses of TXA.39–41 Anti-fibrinolytics have been perceived to
be safe in combination with rFVIIa whilst their safety in combination
with aPCC has been questioned yet some data suggest that they may
also be safe in combination with aPCC.42
There is now some very recently reported basic laboratory exper-
imental data to suggest that adding TXA to patients on emicizumab
may reduce bleeding rates. Using a FVIII-KO mice model investiga-
tors showed that if such mice were on both emicizumab and TXA that
they showed less trauma induced knee joint bleeding than if they were
receiving only emicizumab.43
5 CONCLUSIONS
Prophylaxis is now accepted as standard of care for patients with
haemophilia with a severe phenotype (includes all severe haemophilia
and many moderate haemophilia patients).37 Unfortunately, due to its
expense it was believed to not be possible in resource constrained
countries. The multitude of experiences with LDP described in this
CARCAO ET AL .
paper have made haemophilia treaters and the WFH recognize the
value of LDP regimens. However, it should not be inferred that patients
currently on high or intermediate dose prophylaxis should simply be
deescalated to a LDP regimen. Although LDP is far superior to OD ther-
apy it still does lead to slightly more bleeds and more joint damage than
what would be seen with higher dose prophylaxis regimens.
As such LDP should not be considered an alternative to high dose
prophylaxis but instead should be appreciated as an alternative to OD
therapy. It is a way of utilizing expensive treatments in a prophylactic
fashion (to prevent all types of bleeds) rather than reactively (to stop
bleeds when they occur but allowing them to occur).
There has been a movement to recognize that all forms of prophy-
laxis can be tailored and should not be considered a one size fits all
strategy. There is much evidence that even when commencing patients
on a LDP regimen that some patients will do reasonably well on such a
regimen, but others will not and will need more.
As indicated LDP is certainly a good option when the alternative is
OD therapy. It is a cost-effective way of managing patients. Neverthe-
less, in many poor countries often things are not set up for patients
to be on prophylaxis. Ideally PWH on prophylaxis with CFC need to
be taught how to do venous infusions rather than having to come to a
clinic regularly to receive these. Additionally, for effective and sustain-
able prophylaxis regimens they should have a steady supply of factor so
that they are not periodically having to stop prophylaxis which would
defeat the value of being on continuous prophylaxis. Emicizumab and
potentially other non-factor therapies all of which are designed to be
administered subcutaneously may be particularly useful in countries
without good established home care intravenous administration pro-
grams. Lastly PWH need to be appropriately educated on the impor-
tance of prophylaxis as a way of maintaining good health while they
perhaps wait for curative gene therapy treatments in the future.
In a similar fashion to how the use of LDP regimens can provide sub-
stantial benefits to patients at much lower cost than traditional prophy-
laxis regimens used in more affluent countries the use of antifibrinolyt-
ics in perioperative settings, in bleed management settings and perhaps
in conjunction with long-term LDP can also help to reduce the cost of
haemophilia care while providing patients with significant benefits.
CONFLICT OF INTEREST
Manuel Carcao: Having received research support from Bayer, Biover-
ativ/Sanofi, CSL-Behring, Novo Nordisk, Octapharma, Pfizer, Roche
and Shire/Takeda.
Having received honoraria for speaking/participating in advisory
boards from Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo
Nordisk, Pfizer, Roche and Shire/Takeda. He has no stocks or any equity
in any pharmaceutical company and is not part of any company board.
Emna Gouider: Reports no conflict of interests. Runhui Wu: Reports no
conflict of interests.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author on reasonable request.
CARCAO ET AL .
ORCID
Manuel Carcao https://orcid.org/0000-0001-5350-1763
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How to cite this article: Carcao M, Gouider E, Wu R. Low dose
prophylaxis and antifibrinolytics: Options to consider with
proven benefits for persons with haemophilia. Haemophilia.
2022;28(Suppl. 4):26–34. https://doi.org/10.1111/hae.14552