TR-05253; No of Pages 6

Thrombosis Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Review Article

The history of haemophilia – a short review

Wolfgang Schramm ⁎
Department for Transfusion Medicine and Haemostaseology, Ludwig Maximilian’s University Hospital, Ziemsenstrasse 1, 80338 Munich, Germany

a r t i c l e i n f o a b s t r a c t

Available online xxxx The history of haemophilia dates back to the 2nd century AD, with the first “modern” descriptions of the
condition appearing during the 1800s. At that time, transfusion medicine and haemophilia became closely linked,
Keywords: with blood transfusion being the only possible treatment option. A turning point in the history of haemophilia
Haemophilia A came in the middle of the 20th century when researchers identified an “antihaemophilic globulin” that could
History reduce the clotting time in haemophilic blood, thereby paving the way for the introduction of cryoprecipitate
Beriate® P
and the first clotting factor concentrates for the treatment of haemophilia A, haemophilia B and von Willebrand
Transfusion medicine
Factor VIII
disease. The availability of pasteurized, and therefore virus-safe, plasma-derived, clotting factor concentrates,
Haemate® P such as Haemate P® and Beriate® P in Germany and other countries, dramatically improved the quality of life
and life expectancy of haemophilia patients. These and other treatment advances enabled home treatment,
with many centres introducing prophylaxis to younger patients. Today, thanks to the support from patient
organizations, such as the German Haemophilia Society, which was founded by Prof. Rudolf Marx from Munich,
haemophilia patients can be assured of good bleeding control using products with established efficacy and safety
profiles. Work on improving factor concentrates continues, with efforts directed towards extending their half-
lives using recombinant albumin-fused proteins and other modern technologies. The past 20 years has witnessed
major improvements in almost all aspects of haemophilia treatment. It is hoped the next 20 years will add
promising new chapters to the haemophilia book of history.
© 2013 Published by Elsevier Ltd.

Contents

Early history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Discovery of the antihaemophilic globulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Transfusion medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
A distinct bleeding disorder – von Willebrand disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Early treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Clotting factor concentrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Haemophilia setback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Modern-day haemophilia care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
A tribute to Prof. Rudolf Marx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Future development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Early history

Early references to a bleeding condition highly suggestive of

Abbreviations: AHG, antihaemophilic globulin; AIDS, acquired immune deficiency haemophilia date back to the 2nd century AD [1,2]. The Babylonian
syndrome; FVIII, factor VIII; HCV, hepatitis C virus; HIV, human immunodeficiency virus;
VWD, von Willebrand disease; VWF, von Willebrand factor.
Talmud indicates that if a woman has lost her first two sons after
⁎ Tel.: +49 89 5160 2226; fax: +49 89 5160 2148. circumcision she is exempt from the obligation to have the third
E-mail address: w.schramm@med.uni-muenchen.de. son circumcised [2]. Rabbi Simon ben Gamaliel forbade a boy to be

0049-3848/$ – see front matter © 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.thromres.2013.10.020

Please cite this article as: Schramm W, The history of haemophilia – a short review, Thromb Res (2014), http://dx.doi.org/10.1016/
j.thromres.2013.10.020
2 W. Schramm / Thrombosis Research xxx (2014) xxx–xxx
circumcised because the sons of his mother’s three older sisters had
died after circumcision [3].
Potential haemophilia cases were subsequently described in the
10th century by Albucasis. Maimonides also applied the rules of a Jewish
Rabbi (which resembled the rules in the Babylonian Talmud) to the sons
of a woman who was married twice [3].
It is believed that the first modern description of haemophilia
appeared many centuries later, in 1803, when the American physician,
Dr John Conrad Otto [4], described an inheritable bleeding disorder in
several families in which only males – who he called “bleeders”– were
affected, and in which transmission occurred via unaffected females.
Some years before Otto’s publication, a report in the Salem Gazette
(a weekly newspaper located in Salem, MA, USA) had described a
19-year-old man, Isaac Zoll, who, like his five brothers, died from
exsanguination [5]. Additionally, G. W. Consbruch of Bielefeld, Germany,
writing in 1793, had described a bleeding disease very similar to
haemophilia [6].
The word “haemophilia” appears to have been documented for the
first time in 1828 by the German physician, Johann Lukas Schönlein
and his student Friedrich Hopff, who described the condition in
his dissertation, “Über die Hämophilie oder die erbliche Anlage
zu tödtlichen Blutungen” (“About haemophilia or the hereditary
predisposition to fatal bleeding”) at the University of Zurich,
Switzerland [7].
As Brinkhous explains in his 1970s essay on the history of haemophilia
[1], the term “haemophilia” actually means “affinity to blood”, which is
not how we would describe the condition today. Although mentioned
by Hopff, Schönlein was probably not in favour of the term “haemophilia”
as he himself preferred to use the term “haemorraphilia” (“affinity
to bleed”) [8]. Afterwards, however, the two terms were eventually used
synonymously. Interestingly, during the 1850s, the term “haemorraphilia”
appears to have fallen from favour and “haemophilia” became the
preferred descriptor [7], probably as a result of the publication of
Grandidier’s monograph in 1855 (see references [1,3]).
The first analysis of a haemophilia family tree was published by Hay
in 1813, and this was followed by analyses from Osler (1885), Pratt
(1908), Koller and his group (1954), the latter of whom focused on
the extensive pedigree of “bleeders” in the Swiss mountain village of
Tenna – traced back from the mid-17th century – and McKusick and
Rapaport (1962) (see reference [3]).
The first descriptions of the genetics of haemophilia were published
in 1820 by Nasse [9] and culminated in Nasse’s law, which states
that haemophilia is transmitted entirely by unaffected females to
their sons [1]. This paper prompted further scientific debate, with
publications by Grandidier (1855), Legg (1872) and Immermann
(1879) [3]. In 1890, König described for the first time the link between
haemophilia and the development of joint disease (see reference [3]).
A detailed description of the early history of haemophilia was
published by Bulloch and Fildes in 1912 and the interested reader is
referred to this review [10]. Another recommended early review in
the field of haemophilia, including discussions relating to inheritance,
detailed descriptions of the clinical presentation and natural course of
the condition, and early treatments was published by Schloessmann in
1930 [11].
Haemophilia has often been called “the disease of kings” or “the
royal disease”, as several members of the European royal family were
affected by the condition. The famous Queen of England, Queen
Victoria (1837–1901), was a carrier of haemophilia and passed it onto
her son, Leopold, who had frequent bleeds and died of a brain
haemorrhage at the age of 31 years. The condition spread to other
royal families in Germany, Spain and Russia through Queen Victoria’s
two daughters. Perhaps the best known case of “the royal disease”
was Tsarevich Alexei, the son of the Russian Czar Nicholas II. Today,
we know that the “royal disease” in Europe was in fact haemophilia B
[12]. The impact of this disease on the royal family is discussed by
Ingram in his review of the history of haemophilia [3].
Please cite this article as: Schramm W, The history of haemophilia – a short review, Thromb Res (2014), http://dx.doi.org/10.1016/
j.thromres.2013.10.020
Discovery of the antihaemophilic globulin
Problems associated with coagulation have been described in
haemophilia patients since the 1830s, with Wright being the first to
document the prolonged clotting time of haemophilic blood in a
capillary tube in 1893 [13].
The clotting deficiency associated with haemophilia was first
thought to be the result of a calcium deficiency [13]. This was
subsequently disproved, with Morawitz and Lossen (1908) proposing
a deficiency in thrombokinase [14]. In 1911, Addis investigated several
blood and tissue factors, including fibrinogen, thrombin, anti-thrombin,
a potential clotting inhibitor, calcium, thrombokinase and prothrombin
in haemophilia patients and healthy controls [15]. His main conclusion
was that the prothrombin in haemophilic blood was defective [15]. In
a later publication in 1916, he reported on the shortening of the
coagulation time of haemophilic blood after the intravenous infusion
of fresh human serum [16].
At around that time, the debate began over the extent to which the
coagulation deficiency was located within the platelets (see reference
[17]). Govaerts and Gratia showed, in 1931, that haemophilic platelets
reacted normally when transferred to normal plasma and shifted the
focus of the “deficiency” towards the plasma [18]. As an extension to
some of these experiments, van Creveld in 1934 demonstrated that a
“dispersed protein” fraction obtained from serum reduced the clotting
time of haemophilic blood [19]. One year later, Bendien and van Creveld
published their attempts to isolate this “coagulation-promoting”
substance and to administer it to haemophilia patients intravenously or
intramuscularly [20]. They concluded that the coagulating-promoting
substance, which was low in protein, was able to reduce the coagulation
time of haemophilic blood to within normal values [20]. In 1936,
Patek and Taylor, with their short publication in Science, showed
that, in normal blood and in citrated normal plasma rendered free
from platelets by Berkefeld filtration, a substance was identified
that, in small quantities, effectively reduced the clotting time of
haemophilic blood [21]. Subsequently, a large number of papers
were published by this research group between 1936 and 1946 that
supported their initial hypothesis (see reference [17]). This group
extended the work of Addis in that they identified a globulin, initially
called “globulin substance”, which later was specified as “antihaemophilic
globulin” (AHG) [22].
The long-standing debate over whether the missing or deficient
factor in haemophilia was prothrombin or one of its derivatives was
resolved with the development by Quick and his co-workers of the
one-stage prothrombin time test in 1935 [23]. This enabled Quick
et al. to demonstrate that the prothrombin content in haemophilic
plasma was normal. This was subsequently confirmed by Brinkhous
et al. who, in 1939, showed that the prothrombin content was
also normal, but that the rate of prothrombin conversion was delayed
[24].
In 1947, Quick [25] and Brinkhous [26] demonstrated independently
that AHG and platelets reacted together in some way to generate
thromboplastin, and that a deficiency in AHG caused defective
coagulation due to defects in the generation of thromboplastin.
While the pathophysiological basis of haemophilia was becoming
increasingly clear, concerns were raised as to whether haemophilia
was a single entity. Pavlovsky in 1947 observed that transfusion of a
haemophiliac H1, with blood from another haemophiliac H2, temporarily,
but completely, normalized the clotting time of the recipient [27].
Following a series of additional observations, eventually Biggs et al. from
Oxford established a disease entity that was different to haemophilia A,
which they called “Christmas disease” [28]. With the discovery of the
two types of sex-linked haemophilia, the term “haemophilia A” was
proposed for the more common or classical haemophilia associated
with factor VIII (FVIII) deficiency and the term “haemophilia B” was
proposed for the less common type associated with factor IX deficiency
[see 17].
 W. Schramm / Thrombosis Research xxx (2014) xxx–xxx
Transfusion medicine
As haemophilia was often associated with fatal bleeding before
effective treatments were available, it is unsurprising that transfusion
medicine and haemophilia became closely linked. Although the use of
blood transfusion was first proposed by Schönlein in 1832 [29], the
earliest record of its use is probably that by Samuel Armstrong Lane in
1840 [30] (Table 1). Lane gave an account of the direct transfusion of
12 ounces of blood from a “stout young woman” to an 11-year-old
boy who had bled for 6 days after an operation for a squint. After the
transfusion, the bleeding stopped and the boy recovered. Another
publication makes reference to the transfusion of lamb’s blood into
humans in Germany in 1874 [11].
Blood transfusion at that point in history – which was often
conducted using lamb’s blood – proved fatal in around half of all
cases [34]. Even allogeneic blood transfusions were reported to have
“disadvantageous outcomes” in about half of recipients and, by the
beginning of the 20th century, references to the use of blood transfusion
in haemophilia patients had disappeared from the literature [34].
As an alternative to blood transfusion, the renowned surgeon Ernst
von Bergmann proposed using a modified saline solution [35]. The
administration of saline was introduced in 1879 by Kronecker and
Sander [36], and it was improved by Sidney Ringer [37] with the
addition of electrolytes. Unfortunately, “Ringer’s solution” had only a
limited ability to maintain colloid-osmotic pressure and, in light of the
findings of Ernest Henry Starling, gelatine and albumin were eventually
added [38].
The administration of haemoglobin solutions was studied with
enormous enthusiasm, but studies were terminated prematurely due
to unforeseen safety issues [34,39]; a similar situation has arisen
recently with registration studies of artificial haemoglobin solutions
[40].
A major turning point in transfusion medicine came with the findings
of Karl Landsteiner [41,42], who discovered the human blood groups,
and published the seminal paper, “Über Agglutinationserscheinungen
normalen menschlichen Blutes” (The agglutination phenomenon of
normal human blood) [42]. For his scientific achievements, Karl
Landsteiner was awarded the Nobel Prize in 1930.
The first practical application of the findings of Landsteiner came
from Schulz, who cross-matched blood before he transfused it and
noted that agglutination and subsequent transfusion resulted in a
severe collapse, while a negative cross-matching without agglutination
did not [43,44]. Ottenberg and Kaliski subsequently improved the cross-
matching of Schulz and introduced the major and minor test [45],
thereby avoiding transfusion-related adverse reactions.
Table 1
Early therapies for the treatment of haemophilia A.
Year Therapy
1840 First successful transfusion of whole blood is performed [30]
1911 Preparation of a globulin fraction from normal plasma that
shortens the coagulation time of haemophilic blood [15]
1916 Intravenous injection of fresh human serum reduces clotting
time of haemophilic blood [16]
1934 Russell’s viper venom (“Stypen”) first used for the local treatment
of bleeding in patients with haemophilia A, in those with a
bleeding diathesis, and in healthy controls [31]
1935 A “coagulation-promoting” substance prepared from normal
plasma was able to reduce the coagulation time of haemophilic
blood to within normal values when administered intravenously
or intramuscularly [20]
1936 A precipitate of whole blood plasma first shown to correct bleeding
time of haemophilic blood [21]
1946 Introduction of the term “antihemophilic globulin” [22]
1953 First prothrombin complex concentrate (ACC 76®) is marketed by
Behringwerke AG
1958 Prophylaxis for haemophilia A begins in Sweden [32]
1965 Cryoprecipitate revolutionizes the treatment of haemophilia [33]
Please cite this article as: Schramm W, The history of haemophilia – a short review, Thromb Res (2014), http://dx.doi.org/10.1016/
j.thromres.2013.10.020
3
A distinct bleeding disorder – von Willebrand disease
von Willebrand disease (VWD) was first described by von
Willebrand in 1926 as a hereditary bleeding disorder affecting both
sexes among the inhabitants of the Åland Islands [46]. At that time,
the disease appeared quite different from that of haemophilia due to
its distinct genetic features and long bleeding time, which was seldom
found in classical haemophilia. However, in the 1950s, it was shown
that a reduction in FVIII, which was characteristic of haemophilia, also
occurred in VWD [47]. It was not until the 1970s that a clearer
distinction between the two bleeding disorders was made: persons
with VWD, but not haemophilia, were found to have reduced
“FVIII-related antigen”. It was shown that FVIII was the clotting protein
deficient in haemophilia and that von Willebrand factor (VWF) was a
separate FVIII carrier protein that was deficient in VWD [48]. As a result,
it was suggested that patients with VWD should be treated with VWF
containing concentrates, similar to those with haemophilia A. In 1987,
Ruggeri and Zimmerman made the first official attempt to further
classify VWD into two subtypes [49,50].
Early treatments
Development of the first “antihaemophilic factor” preparation can
be dated to the year 1911, when Addis prepared a very crude fraction
by acidification of plasma [15] (Table 1). Later, in 1916, he described a
shortening of the coagulation time of haemophilic blood following
intravenous administration of fresh human serum [16]. In 1934, Robert
Macfarlane, a British pathologist, described the haemostatic effects of
the Russell’s viper venom when applied locally following surgical
procedures, dental extractions, epistaxis and wound haemorrhages in
haemophilic patients, those with a haemorrhagic diathesis, and in
healthy controls [31]. The prepared venom became commercially
available as “Stypen” and is still used today.
In 1946, Cohn et al described the Cohn Fraction I [51], which was
found to possess, besides fibrinogen, antihaemophilic activity [52].
However, its potency was too low to become a valuable medication
for the management of haemophilia [53]. Following the work of Cohn
et al, human preparations of FVIII were produced in Britain by Kekwick
and Wolf [54], in France by Soulier et al. [55], and in Sweden by
Blombäck et al. [56]. This led, in 1958, to the development of the
“Swedish model” (Malmö protocol) of prophylaxis [57].
One of the most noteworthy early developments in the field at that
time was the observation in the New England Journal of Medicine by
Judith Pool in 1965 that, on slowly thawing frozen plasma, much of
the FVIII activity remained within the fibrinogen “sludge” that was
slow to re-dissolve [33]. This so-called “cryoprecipitate” revolutionized
the treatment of haemophilia and today it remains the only treatment
option in some countries.
Clotting factor concentrates
The introduction, in the mid-1960s, of FVIII concentrates derived
from plasma finally made possible clotting factor replacement therapy,
resulting in a dramatic increase in both the quality of life and life
expectancy of individuals with haemophilia A [2]. While non-virus-
inactivated FVIII concentrates emerged at the end of the 1970s,
Behringwerke AG, the predecessor of CSL Behring, was the first
manufacturer to introduce a pasteurized, virus-inactivated FVIII
product, Haemate® P, in 1981 in Germany (Haemate® P was developed
by Prof. Norbert Heimburger) (Table 2). This was subsequently followed
by the introduction, in 1990, of the high-purity pasteurized FVIII
product Beriate® P.
As a result of highly refined donor selection and manufacturing
processes, plasma-derived clotting factor concentrates can now be
regarded as state-of-the-art products in terms of their efficacy and
long-term safety for haemophilia A and VWD patients.
4 W. Schramm / Thrombosis Research xxx (2014) xxx–xxx
Table 2
Availability of modern haemophilia A treatment.
Year Therapy
1981 First pasteurized factor VIII (FVIII) concentrate (Haemate® P)
available in Germany
1990 The highly purified pasteurized FVIII concentrate Beriate®
P registered in Germany
1992 First recombinant FVIII product is registered
Since 2004 Further developments of recombinant FVIII products
Haemophilia setback
Prior to 1986, much of the non-virus-inactivated clotting factor
concentrates made from multiple human blood donations had been
unknowingly contaminated by blood-borne viruses and, in 1982,
infections related to acquired immune deficiency syndrome (AIDS)
claimed the life of a patient with haemophilia for the first time [58].
Sadly, thousands of haemophilia patients were subsequently infected
with the human immunodeficiency virus (HIV). In 1989, the hepatitis
C virus (HCV) was first identified [59] and it soon became apparent
that an even higher proportion of patients with haemophilia had also
been exposed to this virus.
After having their life expectancy and quality of life increased by
new factor concentrates and the availability of home treatment and
prophylaxis, patients with haemophilia now saw both drastically
reduced. It was a real breakthrough when, in 1981, the pasteurized
FVIII/VWF concentrate Haemate® P was introduced into the German
market. Pasteurization was shown to effectively inactivate not only
HIV, but also HCV [60,61]. Later, the introduction of other virus-
inactivation techniques for plasma-derived clotting factors, such as heat
treatment or solvent-detergent treatment, were also effective in
inactivating HIV as well as hepatitis B and C viruses. However, these latter
treatments almost always required the use of a combination of methods
to effectively inactivate the viruses, in contrast to pasteurization, which
alone was sufficient to inactivate both enveloped and non-enveloped
viruses. By the end of the decade, all plasma-derived products were
manufactured using virus-inactivation technologies.
Modern-day haemophilia care
The introduction of clotting factor concentrates such as Haemate® P,
Beriate® P and later recombinant FVIII products, radically changed
the way haemophilia could be managed and laid the foundation for
a more modern approach to haemophilia care [62] (Table 3).
Cryoprecipitate and low-purity products could be used only in the
hospital setting because slow intravenous infusions were required,
and they frequently caused anaphylaxis [62]. The newer products
required less diluent and could be injected easily with syringes, making
it possible for patients to treat themselves at home – a treatment
advance that was introduced by Rabiner and Telfer in the USA [66]
and Egli and Brackmann in Germany [63]. Early treatment of bleeding
became feasible, and many centres started to introduce prophylaxis in
younger patients.
Table 3
Advances in haemophilia treatment.
Year Therapy
1968 First commercial factor VIII (FVIII) concentrates developed
1972 Medically controlled home therapy commences in Germany [63]
1977 Desmopressin is recognized to boost FVIII and VWF levels [64]
1977 Introduction of immune tolerance therapy [65]
VWF, von Willebrand factor.
Please cite this article as: Schramm W, The history of haemophilia – a short review, Thromb Res (2014), http://dx.doi.org/10.1016/
j.thromres.2013.10.020
The discovery of desmopressin in 1977 provided a new, inexpensive
and safe way of treating patients with certain types of VWD and mild
haemophilia A, many of whom did not require additional treatment [64].
The 1990s witnessed progressive improvements in virus-inactivation
methods leading to impressive outcomes in terms of the safety of
plasma-derived concentrates [62]. Recombinant concentrates were
introduced in 1992, enabling “mass production” of clotting factor
concentrates and bringing greater choice to the clinic. The wider
availability of clotting factor concentrates, and the publication of
randomized controlled trials showing the superiority of prophylaxis
over on-demand treatment, encouraged broader use of prophylaxis
in many countries.
Great progress has also been made in the treatment of haemophilia
patients with inhibitors. Bypassing agents, although not perfect, enable
bleeding control, even in the presence of high-titre inhibitors. The
introduction of immune tolerance therapy by Brackmann and Gormsen
in Germany [65] has led to the possibility of eliminating the inhibitors
in up to 70% of cases, as reported by registries [67–69], and up to 93%,
as reported with the use of plasma-derived FVIII/von Willebrand
factor concentrates at three different sites in Germany (Bonn, Bremen,
Frankfurt) [70].
Today, most individuals with haemophilia are treated in compre-
hensive care centres offering a broad range of services around the
clock. Home treatment with coagulation factor concentrates should be
actively encouraged in all patients with severe haemophilia. Prophylaxis
is recommended for all children with severe haemophilia, with ongoing
prophylaxis in adults highly desirable. Immune tolerance should be
offered to all patients with haemophilia who develop clinically significant
inhibitory antibodies.
A tribute to Prof. Rudolf Marx
This review would not be complete without mentioning some of the
achievements of Prof. Dr. Rudolf Marx from Munich. Prof. Marx, a pioneer
in haemophilia research, discovered in the early 1940s the diminution of
the prothrombin molecule during its conversion to thrombin. In
cooperation with Behringwerke, Prof. Marx initiated the development of
the first prothrombin complex preparation as a coumarin antidote,
which was introduced to the German market as “ACC 76” in 1953.
Prof. Marx was the first to introduce the term “haemostaseology” in
1953. In 1956 he founded the "Deutsche Arbeitsgemeinschaft für
Blutgerinnungsforschung (DAB)", the predecessor of the German
Society for Thrombosis and Haemostasis Research (GTH), and, due to
the commitment to the haemophilia patients, in the same year the
"Deutsche Hämophiliegesellschaft (DHG)". The primary aim of the
DHG (German Haemophilia Society) was to provide general support
to haemophilia patients. Interestingly, the society focused on
establishing individual consultations with each haemophilia patient
and their relatives and specialized haemophilia treatment centres,
working in close contact with eye specialists, orthopaedic surgeons
and gynaecologists/obstetricians. One could argue that this model was
the precursor of today’s haemophilia comprehensive care centres. The
contributions and efforts of Prof. Marx do not end here, but to mention
them all would exceed the scope of this review.
Future development
For the future, within the European Union, there is a commitment to
fostering the development of equitable care in all member states, to
harmonizing and expanding the various guidelines from medical bodies
in different countries, and to raising awareness and improving the
treatment of the rarer bleeding disorders. In order to foster the
cooperation of patient organizations and physicians, it has been
recommended that a formal mechanism be established in each country
to develop best practice in haemophilia care. Work on improving factor
concentrates continues, with efforts directed towards extending their
 W. Schramm / Thrombosis Research xxx (2014) xxx–xxx
half-lives using recombinant albumin-fused proteins and other modern
technologies.
We have come a long way since Lane’s “stout young woman” and
bleeding boy, and the last 20 years have witnessed the greatest progress
towards normalizing life for people with haemophilia. One can only
guess where we will be in 20 years time, but it is hoped that several
promising new chapters will be added to the haemophilia book of
history.
Conflict of interest statement
The author has no conflict of interests.
Acknowledgements
The support of Dr. Mathias Jürs from CSL Behring and editorial
assistance from Swiss Medical Press are highly appreciated.
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Please cite this article as: Schramm W, The history of haemophilia – a short review, Thromb Res (2014), http://dx.doi.org/10.1016/
j.thromres.2013.10.020