10.4081/btvb.2022.52
The year 1222 has traditionally been accepted as the University of Padua’s founding date. The University of Padua is a prestigious center for learning and research, and over the centuries, it has produced luminaries in the most significant disciplines, including medicine, law, philosophy, theology, literature, engineering, astronomy, physics, politics, and religion. The Studium of the teaching of Medicine began around 1250 with the establishment of the Collegium of Medical and Arts Doctors. The history of Medicine at Padua University is extraordinarily rich and counts on the contribution of masters such as Vesalius, Falloppia, Girolamo Fabrici d’Acquapendente, William Harvey, Vallisneri, Ramazzini, Morgagni and many others including Galileo Galilei himself. This year marks the 800th anniversary of the University of Padua, and to commemorate this historic event, the Editor has asked the three of us to summarize the university’s most significant contributions to the fields of hemostasis and thrombosis over the past eight decades. Among all, it should be mentioned the relevant contribution of Prof. Antonio Girolami, who was the founder of the group of Thrombosis and Hemostasis in Padua and one of the Italian and international leaders in the field of the diagnosis and treatment of congenital bleeding disorders. However, due to the large number of outstanding scientists and significant research conducted in these fields at Padua University, it was extremely difficult for us to provide a concise summary of the university’s numerous contributions. Eventually, we concluded that it would be more useful to share with the Readers the experiences we have had over the past several decades, focusing on specific aspects of our research, work, and life at Padua University, and attempting to highlight the aspects that we believe have contributed most to the advancement of knowledge in the fields of thrombosis and hemostasis. Therefore, three topics have been selected and presented separately in a narrative format as pieces of our lives and of the history of our university.
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Bleeding, Thrombosis and Vascular Biology
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Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history
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Bleed Thromb Vascul Biol
Paolo Prandoni
2022/11/07
10.4081/btvb.2022.52
Arianna Foundation on Anticoagulation, Bologna, Italy; Department of Cardio-Thoracic-Vascular Sciences and Public Health, University of Padua
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de la Morena-Barrio ME, Suchon P, Jacobsen EM et al. Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays. Blood 2022;140:140-51
Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history
https://www.btvb.org/btvb/article/download/52/46
1
                                                                                          INVITED NARRATIVE REVIEW

Thrombosis and hemostasis at the University of Padua:
a reappraisal on the occasion of its 800th year of history
Paolo Simioni,1 Vittorio Pengo,2,3 Paolo Prandoni3,4
1
 General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital
and University of Padua Medical School, Padua, Italy; 2Thrombosis Research Laboratory, Department of Cardio-Thoracic-Vascular
Sciences and Public Health, University of Padua, Italy; 3Arianna Foundation on Anticoagulation, Bologna, Italy; 4Department of
Cardio-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy



ABSTRACT
     The year 1222 has traditionally been accepted as the University of Padua’s founding date. The University of Padua is a prestigious
center for learning and research, and over the centuries, it has produced luminaries in the most significant disciplines, including medicine,
law, philosophy, theology, literature, engineering, astronomy, physics, politics, and religion. The Studium of the teaching of Medicine began
around 1250 with the establishment of the Collegium of Medical and Arts Doctors. The history of Medicine at Padua University is extraor-
dinarily rich and counts on the contribution of masters such as Vesalius, Falloppia, Girolamo Fabrici d’Acquapendente, William Harvey,




                                                                                                       ly
Vallisneri, Ramazzini, Morgagni and many others including Galileo Galilei himself. This year marks the 800th anniversary of the University
of Padua, and to commemorate this historic event, the Editor has asked the three of us to summarize the university’s most significant con-




                                                                                               on
tributions to the fields of hemostasis and thrombosis over the past eight decades. Among all, it should be mentioned the relevant contribution
of Prof. Antonio Girolami, who was the founder of the group of Thrombosis and Hemostasis in Padua and one of the Italian and international
leaders in the field of the diagnosis and treatment of congenital bleeding disorders. However, due to the large number of outstanding




                                                                                         e
scientists and significant research conducted in these fields at Padua University, it was extremely difficult for us to provide a concise sum-
                                                                                   us
mary of the university’s numerous contributions. Eventually, we concluded that it would be more useful to share with the Readers the ex-
periences we have had over the past several decades, focusing on specific aspects of our research, work, and life at Padua University, and
attempting to highlight the aspects that we believe have contributed most to the advancement of knowledge in the fields of thrombosis and
                                                                              al
                                                                             hemostasis. Therefore, three topics have been selected and pre-
                                                                             sented separately in a narrative format as pieces of our lives and
                                                                    ci

                                                                             of the history of our university.
                                                                  er


    Correspondence: Paolo Simioni, General Internal Medicine and
    Thrombotic and Hemorrhagic Units and Hemophilia Centre De-
                                                                 m



    partment of Medicine - University-Hospital of Padua Medical               DIAGNOSTIC AND THERAPEUTIC
    School, Via Giustiniani 2, 35128 Padua, Italy.
                                                      om




    E-mail: paolo.simioni@unipd.it                                            MANAGEMENT OF DEEP VEIN THROMBOSIS:
                                                                              FROM THE MID ’80 TO THE PRESENT DAY
    Key words: Padua University, history, hemostasis, thrombosis.
                                                                                                                      (by Paolo Prandoni)
                                               -c




    Contributions: The authors contributed equally.
                                      on




                                                                              Diagnosis of deep vein thrombosis
    Conflict of interest: The authors declare no potential conflict of in-
    terest.                                                                       Following the demonstration that the clinical diagnosis
                                N




    Funding: None.
                                                                              of deep vein thrombosis (DVT) is inaccurate, for many
                                                                              years ascending phlebography has constituted the only re-
    Received for publication: 5 September 2022.                               liable method of DVT detection. Because of its invasive-
    Revision received: 20 October 2022.                                       ness, however, in the ‘70s phlebography was replaced by
    Accepted for publication: 20 October 2022.
                                                                              a non-invasive method, impedance plethysmography.
    Publisher’s note: All claims expressed in this article are solely those   When I started addressing the diagnosis of DVT in collab-
    of the authors and do not necessarily represent those of their affili-    oration with a group of young, strongly motivated, collab-
    ated organizations, or those of the publisher, the editors and the re-    orators I decided to test the accuracy of a computerized
    viewers. Any product that may be evaluated in this article or claim
    that may be made by its manufacturer is not guaranteed or endorsed        tool (computerized impedance plethysmography), pro-
    by the publisher.                                                         duced by an Italian engineer, using as reference standard
                                                                              ascending phlebography. At the end of a study encompass-
    ©
     Copyright: the Author(s), 2022                                           ing the recruitment of several hundred patients with sus-
    Licensee PAGEPress, Italy
    Bleeding, Thrombosis and Vascular Biology 2022; 1:52                      pected DVT, we concluded that this procedure is largely
    doi:10.4081/btvb.2022.52                                                  inaccurate.1 Although our results were criticized, they
                                                                              eventually ended up causing the abandonment of this pro-
    This work is licensed under a Creative Commons Attribution-
    NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                              cedure everywhere in the world in favor of an emerging
                                                                              strategy, i.e, ultrasonography of the leg vein system. In

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:52
          Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history    33



1989, in collaboration with a group of Dutch researchers             out the need for laboratory monitoring, home treatment
from the University of Amsterdam, guided by Jan Wouter               of DVT was hypothesized and then persuasively demon-
ten Cate, I published the results of a prospective cohort            strated by a multicenter randomized clinical trial, which
study, in which the diagnostic accuracy of compression ul-           involved my Institution.8
trasonography (CUS) for detection of proximal DVT was
tested.2 The results were impressive, as this simple and             Clinical course of deep vein thrombosis
highly reproducible method of DVT diagnosis was found
                                                                         Since the mid ‘80s, I decided to follow-up prospec-
to possess an accuracy that was comparable to that of phle-
                                                                     tively over time patients after their episode of DVT. In a
bography. In a subsequent prospective cohort study, we
                                                                     prospective cohort study published in 1996 in collabora-
showed that it is safe to label patients as being free from
                                                                     tion with the Dutch group, we showed for the first time
DVT if CUS is negative and remains negative in two fur-
                                                                     that the prognosis of proximal DVT in terms of recurrent
ther determinations to be performed in the subsequent
                                                                     VTE after discontinuing anticoagulation is less benign
days;3 and that this approach can be further simplified by
repeating the CUS in the only patients in whom the D-                than previously thought.9 The rate of recurrent VTE after
dimer is positive despite a baseline negative CUS.4 In ad-           three months of anticoagulation was indeed found to be
dition, in a more recent prospective controlled study we             around 30% over a follow-up period of 5-8 years, this in-




                                                                                       ly
showed that excluding the presence of DVT in sympto-                 cidence being much higher in patients with unprovoked
                                                                     DVT that in those with thrombosis triggered by remov-




                                                                                on
matic patients with the combination of proximal CUS with
D-dimer is as effective as and safer than performing a               able risk factors. These findings inaugurated the search
whole leg color-Doppler assessment, as long as it obviates           for individually tailored approaches to the length of anti-
                                                                     coagulation after a first DVT episode. The long-term fol-



                                                                          e
the risks of unnecessary treatment of isolated calf DVT.5
                                                                     low-up of patients with DVT, conducted at our Institution,
Finally, according to the results of an Italian prospective
cohort study, designed in collaboration with Walter Ageno
from the University of Insubria, the extensive procedure
                                                                   usled to three additional outstanding findings: the demon-
                                                                     stration that regardless of the type of thrombosis, the per-
                                                            al
was found to be a reasonable diagnostic approach in pa-              sistence of residual vein thrombosis, as shown by
tients who present with a negative CUS and a negative D-             ultrasonography three months after the index episode, in-
                                               ci

dimer in spite of a painful calf, as it has the potential to         creases the rate of recurrent VTE;10 the demonstration that
                                             er


identify those isolated calf-vein thromboses that can ben-           patients with unprovoked DVT exhibit a significantly
efit from anticoagulation, while offering alternative expla-         higher rate of subsequent overt malignancies than those
                                            m




nations for patient’s complaints in those who are free from          with secondary thrombosis;11 and the demonstration of an
                                                                     association between DVT and atherosclerosis.12 In addi-
                                  om




thrombosis.6
                                                                     tion, we showed that under VKA treatment cancer patients
Initial treatment of deep vein thrombosis                            exhibit a remarkably higher risk of both recurrent VTE
                             -c




                                                                     and major bleeding complications than cancer-free pa-
    At the beginning of my activity, intravenous unfrac-             tients:13 this demonstration offered the background for all
                     on




tionated heparin (UFH) in doses adjusted to the aPTT was             subsequent investigations addressing the value of
the standard of treatment of DVT. Because of the need for            LMWHs in place of VKA for the treatment of cancer-as-
intravenous infusion and laboratory monitoring, however,
                 N




                                                                     sociated VTE.
it was progressively replaced by fixed-dose subcutaneous
low-molecular-weight heparin (LMWH) in doses adjusted                Prevention of recurrent venous thromboembolism
to the body weight. In collaboration with the Dutch group,
we decided to embark on a randomized clinical trial ad-                  In an attempt to identify the optimal duration of anti-
dressing the comparison between the two strategies. In               coagulant therapy after a first episode of VTE, two mul-
both groups, the heparin treatment was overlapped with               ticenter Italian studies were performed in the ‘90s in
and followed by vitamin K antagonists (VKA) to be ad-                patients presenting with primary DVT and primary pul-
ministered for at least three months. All patients under-            monary embolism (PE), respectively, in collaboration
went phlebography and perfusion lung scanning at                     with Giancarlo Agnelli from the University of Perugia. In
baseline and after 10 days and were followed up for up to            each of the two randomized clinical trials, we showed that
six months. Surprisingly enough, there was a trend favor-            extending to one year the three-month course of VKA
ing LMWH in terms of recurrent venous thromboem-                     treatment – which was the dominant strategy at the end
bolism (VTE), major bleeding complications, earlier vein             of last century – in patients with unprovoked proximal
recanalization and improvement of lung scanning.7 Based              DVT and PE, respectively, is not associated with long-
on these findings and those from additional, subsequent              standing clinical benefit.14,15 Indeed, prolonging anticoag-
studies LMWH has become the standard of treatment of                 ulation simply delayed the timing of VTE recurrences.
DVT. Because of the administration of fixed doses, with-             The results of these two studies revolutionized the ap-

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:52
34                                                       P. Simioni et al.




proach to patients with unprovoked VTE. Indeed, an im-               run the risk of being considered ‘Martians’ within our
pressive series of subsequent studies have conclusively              clinic. In fact, for those of us who wanted to take an in-
demonstrated the advantage of an indefinite anticoagula-             terest in platelets and coagulation factors considered ex-
tion in patients with unprovoked VTE, provided they are              traneous to cardiology, someone affectionately but with a
not perceived as being at a high risk of bleeding. The re-           hint of derision immediately coined the term ‘tilers’.
placement of VKA with the current direct oral anticoagu-                  In 1973 the first nucleus was formed under the lead-
lants, characterized by a more favorable therapeutic                 ership of Professor Antonio Girolami to establish a service
profile, has streamlined this therapeutic conduct. Among             that would provide qualified assistance to patients under-
the several investigations conducted in this field, I cannot         going anticoagulant therapy. Patients received an OAT
help mentioning the Einstein Choice study I had the priv-            control booklet where we recorded the date, percentage
ilege to coordinate in collaboration with Jeff Weitz from            of prothrombin activity and dose of anticoagulant at each
the McMaster University in Canada.16 In a randomized                 check-up. Soon our interest expanded to patients with ve-
controlled clinical trial, involving hundred centers world-          nous thromboembolic disease.
wide we showed that preventive doses of rivaroxaban are                  In the meantime, I was attending postgraduate school
as effective as and safer than therapeutic doses for pro-            in Internal Medicine (1975-1980) and had been assigned
tection against recurrent VTE in patients with a first               to a laboratory on the fourth floor of the polyclinic that




                                                                                             ly
episode of unprovoked or weakly provoked VTE, both                   dealt with coagulation. The subject did not excite me also




                                                                                      on
doses being definitely more effective than aspirin.16                because it had seemed complicated to me during my de-
                                                                     gree course. However, by attending that laboratory I
                                                                     began to appreciate the subject, and this turned into pure




                                                                                 e
THE ESTABLISHMENT OF A THROMBOSIS                                    passion when I happened to catch a congenital alteration
GROUP AND THROMBOSIS SERVICE FOR
PATIENTS ON ANTICOAGULATION THERAPY
AT THE UNIVERSITY OF PADUA
                                                                             us
                                                                     of antithrombin III which led to a publication in an inter-
                                                                     national journal.17 A further turning point in my history as
                                                                     a researcher occurred when I studied the plasma of a pa-
                                                                    al
                                        (by Vittorio Pengo)          tient who had an unexplained lengthening of the activated
                                                      ci

                                                                     partial prothrombin time (aPTT). It was ‘Lupus Antico-
    The idea of setting up specialized care for patients on          agulant’. I became interested in the subject and during a
                                                    er


oral anticoagulant therapy (OAT) in Padua was born in                visit to Padua by Prof Sandor Shapiro of Jefferson Med-
                                                                     ical College in Philadelphia I was offered to go to the
                                                   m



the Institute of Cardiology directed by Professor Sergio
Dalla Volta in the early 1970s. In those years, patients on          United States to study the subject. The visit was very fruit-
                                          om




OAT were predominantly heart patients suffering from                 ful18, 19 and I have not left this topic since.
rheumatic mitral stenosis or wearers of mechanical ball                  After returning from the US, I founded a journal enti-
or swing disc valve prostheses.                                      tled Thrombosis and Atherosclerosis, published by Piccin
                                     -c




    Patients with prosthetic valves for out-of-hospital              in Padua, which had little luck and ceased publication
                                                                     after a few years due to a lack of sponsors following the
                             on




monitoring of OAT often had to rely on doctors without
adequate training, laboratory technicians, or were forced            drug scandals of the early 1990s in Italy.
to resort to self-medication. Patients with mitral stenosis,             The 1980s were characterized by a further expansion
                         N




many of them young women with previous rheumatic dis-                of Prof. Schivazappa’s initial group, which was joined by
ease, often did not receive anticoagulant treatment despite          Prof. Paolo Prandoni and me.
the fact that this valvular heart disease carried a high                 The first resource was the acquisition of a room in the
thromboembolic risk. Professor Luciano Schivazappa,                  kitchen wing of the hospital, which we converted into a
then consultant cardiologist in cardiac surgery and respon-          laboratory, equipping it with a counter and the minimum
sible for the follow-up of patients with valvular heart dis-         necessary for routine coagulation tests. The method used
eases and cardiac valve prosthesis wearers, was fully                for measuring Quick’s time was manual and the value was
aware of these problems.                                             expressed as a percentage of prothrombin activity. In the
    The solution was obvious: it was necessary for us car-           absence of technicians to carry out the tests and maintain
diologists to learn the theory and practice of how to han-           the laboratory, help was sought from students and cardi-
dle anticoagulant drugs properly, and then set up an                 ology residents. In the meantime, Prof Prandoni was
outpatient clinic to monitor the OAT of so many patients             working on instrumental diagnostics of venous throm-
left dangerously to their own devices.                               boembolism.
    This was not an easy task, as it involved, in an ultra-              The first step for me was to put order in the cramped
specialist era, going beyond the strictly cardiological field        kitchen room used as a laboratory and to plan the neces-
and acquiring skills considered to belong to other disci-            sary equipment for proper laboratory control of anticoag-
plines such as hematology or internal medicine. We could             ulated patients and for research activities. An archive of

                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:52
          Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history    35



patients was created by numbering the booklets for the                  The systematic follow up of patients with pulmonary
OAT control. Checks were only carried out one afternoon              embolism led to an important publication in 2004 on the
per week: blood samples and therapy prescriptions were               course of disease ending in Chronic Thromboembolic Pul-
taken in the cardiology outpatient clinic on the ground              monary Hypertension (CTEPH).20
floor of the polyclinic, coagulation tests were performed               Despite the introduction of new anticoagulants, the
in the laboratory attached to the kitchens.                          Service continues to be the point of reference for treat-
    By this time, the group had found its autonomy as there          ment with oral anticoagulants, which always pose prob-
was both clinical and laboratory expertise within it. One            lems that can only be dealt with by a Service with
thousand nine hundred eighty-four was an important year              personnel competent in the issue.
because the first results concerning the activity of our lab-
oratory were published and the first attempt was made to
express the level of anticoagulation more correctly by in-           FROM INHERITED HYPERCOAGULABLE
troducing the Corrected Prothrombin Ratio (CPR). This in-            STATES TO FACTOR IX PADUA: A FASCINATING
novation was the result of my visit to the Thrombosis                STORY ON HOW THROMBOPHILIA HAS
Service in Leiden headed by Prof Broekman. The CPR                   HELPED HEMOPHILIA
value had to be kept between 1.8 and 3 in all patients.                                                        (by Paolo Simioni)




                                                                                       ly
    In 1986, a further decisive step was taken in the stan-




                                                                                on
dardization of laboratory tests for monitoring OAT with                  In the early ‘80s when I defended my thesis in Medi-
the introduction of the INR (International Normalized                cine and Surgery entitled “The hypercoagulable states:
Ratio). The INR makes it possible to standardize the lev-            laboratory diagnosis and clinical implications” at Padua




                                                                          e
els of anticoagulation obtained in laboratories using dif-           University Medical School, the concept of inherited hy-
ferent reagents and thus to compare the quality of therapy
and the risk of hemorrhage in different centers based on
                                                                   uspercoagulability was still associated with a limited num-
                                                                     ber of families with a predisposition to thrombosis whose
the actual level of anticoagulation.                                 members were carriers of heterozygous antithrombin (AT)
                                                            al
    A further development for the monitoring of our OAT              defects. Actually, some of these patients with the so-called
                                               ci

patients came from the introduction of a computer pro-               “heparin binding defects” were not at all prone to throm-
gram whose name is PARMA, an acronym for Anticoag-                   bosis or only mildly prone to it even though they showed
                                             er


ulated Monitoring Reporting Archiving Program. The                   similar activity levels as those found in patients with true
program was purchased by me in Modena while the com-
                                            m



                                                                     AT defects and thrombosis.21 I thought then that there was
puter, an Olivetti M24 (20MB!), had been obtained on                 no end to the strange things that may happen in the world
                                  om




loan as compensation for a study on thrombosis.                      of inherited coagulation defects and thrombosis. In those
    At the suggestion of a patient who had a mechanical              years protein C (PC) and protein S (PS) were discovered,
valve prosthesis, and at my suggestion, an association was           and inherited defects of these physiological clotting in-
                             -c




founded in 1987 to deal specifically with patients on OAT.           hibitors were associated with familial thrombosis. Dr An-
At first, it was called APA (Associazione Pazienti Antico-
                      on




                                                                     tonio Girolami, a scientist in the field of hemostasis and
agulati) but when it was founded, in order to give the ini-          thrombosis mainly involved in the characterization of rare
tiative a national scope, I preferred to call it A.I.P.A.            bleeding defects (i.e., hemophilia, Factor X Friuli and oth-
                 N




(Associazione Italiana Pazienti Anticoagulati).                      ers), was the chief of a coagulation lab at Padua Univer-
    The official foundation of the A.I.P.A. took place in            sity Hospital. He was my mentor and suggested that I
December 1987. Writing the statute and finding a notary              focus on patients with inherited PC and PS defects. My
and the funds to pay for it was no easy task. In 1989, the           work dealt with young patients, with personal and family
center was included in the 1989-91 regional health and               history of thrombosis often resulting from minor risk fac-
social plan (annex to Regional Law No. 21 of 20 July                 tors such as surgery, oral contraceptive treatment, or preg-
1989) as a Thrombosis Prevention and Therapy Service,                nancy. Again, my curiosity was aroused by the
a name it still retains today. In the same year, at the pro-         discrepancies between antigen and activity PC levels (to
posal of our center and eight other Italian centers, the Fed-        my surprise, chromogenic was normal and coagulometric
eration of Anticoagulated Surveillance Centers (FCSA)                activity reduced!) found in one family. This led me in
was founded.                                                         1993 to intern at Dr Rogier Bertina’s coagulation lab in
    From that moment on, an uninterrupted growth in                  Leiden, where I learnt how to isolate PC from plasma and
skills and in technical and human resources began, leading           study its properties. Actually, the above-mentioned vari-
to the establishment of the Thrombosis Prevention and                ant, named “Protein C Padua 2” because of a Cys substi-
Therapy Service, which over time reached a peak of                   tution     at    position Arg-1        was     bound      to
around 5,000 users being treated with warfarin or                    alpha-1-microglobulin, which strongly impaired its func-
acenocumarol.                                                        tional activity (dysfunction in the GLA-domain) and

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:52
36                                                        P. Simioni et al.




caused thrombosis in carriers.22 I was strongly attracted             proband’s plasma. Sequencing of the F9 gene led to the
to both the perfection of nature as well as it flaws in mat-          discovery of Factor IX Padua, a gain-of-function mutation
ters related to coagulation. In the same lab in Leiden, I             in the F9 gene (R338L) responsible for a hyper-functional
had the pleasure of meeting Dr Valder Arruda from Brazil              FIX molecule. The expression in vitro of recombinant
and discuss with him a number of topics concerning he-                Factor IX Padua confirmed the properties of the hyper-
mostasis. Valder was actively involved in research on he-             functional molecule and, particularly, an 8 to 10-fold in-
mophilia but very open to discussing any other topics.                creased functional procoagulant activity. This discovery
When I came back to Padua in early 1994, something had                also sparked off the idea of a potential use of this variant
become absolutely clear in my mind: I was keenly inter-               for the gene therapy of hemophilia B. It was at that time
ested in discovering new “mistakes” in nature causing in-             in 2008 that I contacted my old friend Dr Valder Arruda,
herited thrombophilia and, as a physician, I proposed to              who was involved in the field of the gene therapy of he-
take care of these patients. I was positively surprised when          mophilia B in Philadelphia. He fully confirmed the char-
late in 1994 and then in 1996, respectively, Factor V Lei-            acteristics of the FIX Padua variant and contributed to the
den (Activated Protein C, APC, resistance) 23 and pro-                publication of the data.33 This discovery had the potential
thrombin G20210A mutations 24 were identified in many                 to help the development of the gene therapy of hemophilia
patients with thrombosis in Dr Bertina’s laboratory in Lei-           B in humans. As a matter of fact, many already terminated




                                                                                              ly
den, where I had worked.                                              or still ongoing clinical trials of gene therapy for hemo-




                                                                                       on
     The contribution to thrombophilia from Padua Throm-              philia B using the FIX Padua provide a clear demonstra-
bosis and Haemostasias Center during the following years              tion of a successful and stable cure for many hemophilia
was mainly related to several large cohort studies in                 B patients.34 “Nature does nothing uselessly” (Aristotle,




                                                                                  e
thrombophilic families for the assessment of the risk of              384-322 A.C.), which seems to be perfectly true of the
first (and recurrent) VTE in carriers of inherited defects.25-
29
   In addition, peculiar and rare coagulation factor variants
                                                                              us
                                                                      FIX Padua. I have no words to express my deep sorrow
                                                                      for the recent news that Valder has prematurely passed
such as pseudo-homozygous APC resistance 30-31 were                   away. It was a great privilege for me to work with him.
                                                                     al
characterized and some unique PC defects were identified                  In 2012 a novel gain-of-function polymorphism in the
                                                       ci

(for example, in thrombosis patients with only the beta-              prothrombin molecule leading to resistance to AT was
form of PC in blood).32 Due to my personal feeling and                identified in Japan (Prothrombin Yukuhashi,
                                                     er


the previous positive cooperation experiences, many of                Arg596Leu).35 The molecular basis of this defect is a mis-
these studies were performed thanks to many scientists                sense mutation of the prothrombin Arg596 residue (exon
                                                    m




from different countries around the world. At the same                14) resulting in impaired thrombin–AT binding and de-
                                           om




time thousands of inherited patients with thrombophilia               fective inhibition of the mutated thrombin by AT. A unique
belonging to hundreds of families were - and still are! -             prothrombin variant Arg596Trp, named prothrombin
identified and followed on a clinical and laboratory                  Padua 2, with the same mechanism of resistance to AT
                                     -c




ground at Padua University Hospital.                                  was identified in two families from the Veneto area.36
     Let me move on to a few years later, when I was in                   The story of inherited thrombophilic defects found in
                              on




charge of the lab and clinical research on thrombophilia              Padua has recently been enriched by the discovery of the
at Padua University Hospital looking for new inherited                first defect in the F8 gene (FVIII Padua) associated with
                         N




thrombophilic conditions based on clinical manifestations             markedly elevated FVIII levels and severe thrombophilia,
of patients and their coagulation lab phenotypes. Surpris-            the so-called Factor VIII Padua.37 Genetic analysis re-
ingly enough, most of the information available for clin-             vealed a 23.4-kb tandem duplication of the proximal por-
ical management of thrombophilic patients was based on                tion of the F8 gene (promoter, exon 1 and a large part of
the results of old studies only dealing with thrombophilia            intron 1), which co-segregated with high FVIII levels
defects discovered years before. In contrast, it was com-             across the family. The identification and characterization
monly seen that in a large number of families (almost                 of this gene defect in two families from the North-East of
50%) symptomatic for thrombophilia, none of those de-                 Italy was the result of a fruitful and prolonged cooperation
fects could be identified.                                            with a Dutch group of scientists at Maastricht University
     Within this context, the year 2007 saw the casual and            and, in particular, with Dr Jan Rosing, Dr Tilman Hackeng
fortunate finding of a young boy who had experienced                  and Dr Elisabetta Castoldi. Whether also the mechanism
deep vein thrombosis and presented such a high level of               underlying the expression of FVIII Padua can be helpful
coagulation FIX activity (772%!) that my first thought                for the gene therapy of hemophilia A is currently under
was that it could only be a lab mistake or a typo error in            investigation.
reporting the data. The test was repeated several times and               The large number of newly discovered inherited de-
the data confirmed, but the real surprise came when we                fects in the last decades both in Padua and all over the
also detected a normal FIX antigen level (92%) in the                 world 38 and their clinical impact seems to justify why

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:52
           Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history          37



testing for thrombophilia patients belonging to families              14. Agnelli G, Prandoni P, Santamaria MG, et al. Three months
with VTE should not be abandoned.                                         versus one year of oral anticoagulant therapy for idiopathic
    I have no doubt that the University of Padua will con-                deep venous thrombosis. N Engl J Med 2001;345:165-9.
tinue to make contribution to the research fields of throm-           15. Agnelli G, Prandoni P, Becattini C, et al. Extended oral an-
                                                                          ticoagulant therapy after a first episode of pulmonary em-
bophilia and hemophilia gene therapy in the years to come.
                                                                          bolism. Ann Intern Med 2003;139:19-25.
                                                                      16. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or as-
                                                                          pirin for extended treatment of venous thromboembolism.
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