Cosi, E.

Ferrari, S.

Girolami, A.

Randi, M. L.

English

Girolami A.

Ferrari S.

Cosi E.

Randi M. L.

Archivio istituzionale della ricerca - Università di Padova

Letter to the EditorThe Dysprothrombinemias due toArg596 Mutations: A Conundrum WithNo Bleeding Tendency and VenousThrombosis due to AntithrombinResistanceAntonio Girolami, MD1, Silvia Ferrari, PhD1, Elisabetta Cosi, MD1,and Maria Luigia Randi, MD1Keywordsprothrombin, mutations, dysprothrombinemias, thrombosisDate received: 25 January 2019; revised: 06 March 2019; accepted: 11 March 2019.The transformation of a bleeding disorder into a prothromboticone is an extraordinary event in blood coagulation. This is whatoccurred recently with the description of 3 dysprothrombine-mias, prothrombin Yukuhashi, prothrombin Belgrade, and pro-thrombin Padua 2 which do not cause bleeding but, instead,show antithrombin resistance with consequent thrombosis.1-4 Itis now of paramount importance to verify if the Arg596 muta-tions are the only ones responsible for the shift from a hemor-rhagic condition to a thrombophilic one or if other amino acidsof the same area of the prothrombin molecule encoded by exon14 might also be associated with the change.Two approaches are available, namely (1) the restudy ofcases of prothrombin defect with mutations encoded aroundthe Arg596 residue and (2) chimeric studies in vitro. The3 prothrombin defects close to the Arg596 residue areprothrombin Scranton (Lys399Thr) downstream and pro-thrombin Perija (Gly591Ala) and prothrombin Saint Denis(Asp395Glu), upstream.5-8The relation with prothrombin Scranton is interesting. Thisfamily had a Lys599Thr mutation, the patients were all hetero-zygotes and also neither a bleeding tendency nor thrombosis,namely, probably, no antithrombin resistance.5Prothrombin Perija (Gly591Ala) is upstream to Arg596. Thepatient is homozygote for the defect and shows a mild bleedingtendency despite a prothrombin level of 2% of normal but nothrombosis.6,7 Prothrombin Saint Denis (Asp595Glu) has nobleeding and no thrombosis and is also upstream (Figure 1).8Mutation involving amino acids: 592, 593, and 594 of theprothrombin molecule, upstream to the Arg596, unfortunately,have not been yet demonstrated in patients. The same is true forthe amino acids 597 and 598, downstream of Arg596.9,10However, chimeric studies in vitro have shown that theGlu592Gln mutation causes antithrombin resistance.11The mutations seen in the dysprothrombinemias associatedwith venous thrombosis are Arg596Leu, Arg596Gln, andArg596Trp. These mutations confer to the prothrombin mole-cule a resistance to antithrombin. This indicates that theArg596 is crucial since the antithrombin resistance occursregardless of the replacing amino acid Leu, Gln, or Trp. It isworth noting that a delayed or defective binding to antithrom-bin had been suspected to exist also for prothrombin Perija(Arg591Ala) and prothrombin Saint Denis (Asp595Glu). How-ever, since the carriers of these mutation showed no thromboticevent, the finding was not pursued.7,8It would be interesting to know if the patient with prothrom-bin Saint Denis (Asp595Glu) which is a mutation attached toArg596 has ever developed thrombosis. Since the patient wasreported as a new born and followed for only about 2.5 years(30 months), the occurrence of a thrombotic event could not beexcluded.8 Unfortunately, no further information is available.The mean age for the occurrence of thrombosis, for all theArg596mutated patients, excluding prothrombin Amritaanother case of Arg596Gln mutation seen in India,12 is about20 years.1Department of Medicine, University of Padua Medical School, Padua, ItalyCorresponding Author:Antonio Girolami, Department of Medicine, University of Padua MedicalSchool, Via Ospedale 105, Padua 35128, Italy.Email: antonio.girolami@unipd.itClinical and AppliedThrombosis/HemostasisVolume 25: 1-3ª The Author(s) 2019Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/1076029619841701journals.sagepub.com/home/catCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative CommonsAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Accesspages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Chimeric studies in vitro have shown that mutationLys599Arg and mutation Glu592Gln show antithrombinresistance similar to that seen in prothrombin Yukuhashi(Arg596Leu) and prothrombin Belgrade (Arg596Gln).9 Amutation similar to Lys599Arg has been found, clinically,in prothrombin Scranton (Lys599Thr), whereas the othermutation (Glu592Gln) so far has no clinical counterpart orconfirmation.Granting the differences that may be present between chi-meric in vitro studies and clinical observations, it would seemthat the substitution of amino acid Lys599 either with Arg(chimeric studies) or with Thr (Prothrombin Scranton) maycause resistance to antithrombin.5,9 However, antithrombinresistance has not been searched for in the original paper deal-ing with in prothrombin Scranton.5These clinical observations and chimeric studies, taken alltogether, would seem to indicate that the area of prothrombinencoded by exon 14, from Gly591 to Lys599 are associatedwith impaired or delayed binding to antithrombin and to antith-rombin resistance. It is not clear yet whether such featuresextend to amino acids downstream from Arg596, for example,to prothrombin Scranton (Lys599Thr).It seems therefore that the area of prothrombin associatedwith antithrombin resistance spans at least from residue Gly591(prothrombin Perija) to residue Lys599 (prothrombin Scran-ton), regardless of the amino acid substitution. Since onlypatients with the Arg substitutions with Leu, Gln, or Trp areassociated with venous thrombosis, it would seem that the lackof Arg, regardless of the substitution, Leu, Gln, or Trp, isresponsible for the occurrence of the antithrombin resistance.Alternatively, it could be that these abnormal prothrombinsArg596Leu, Arg596Gln, or Arg596Trp could be the cause ofthe appearance of antithrombin resistance.This seem very unlikely because of the great structural dif-ferences existing among leucine, glutamine, and tryptophan.Defects in the amino acid 592, 593, 594, and 597, 598 havenot been reported yet in patients.10,11The discovery of these patients could be useful in definingthe area of the prothrombin molecule encoded by exon 14associated with antithrombin resistance and the appearanceof thrombosis.Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect tothe research, authorship, and/or publication of this article.FundingThe author(s) received no financial support for the research, author-ship, and/or publication of this article.References1. Miyawaki Y, Suzuki A, Fujita J, et al. Thrombosis from a pro-thrombin mutation conveying antithrombin resistance. N Engl JMed. 2012;366(25):2390-2396.2. Djordjevic V, Kovac M, Miljic P, et al. A novel prothrombinmutation in two families with prominent thrombophilia—the firstcases of antithrombin resistance in a Caucasian population.J Thromb Haemost. 2013;11(10):1936-1939.3. Bulato C, Radu CM, Campello E, et al. New prothrombin muta-tion (Arg596Trp, prothrombin Padua 2) associated with venousthromboembolism. Arterioscler Thromb Vasc Biol. 2016;36(5):1022-1029.PerijaHom.Gly591AlaBleedingNo Thromb.DecreasedSaint DenisYukuhashiBelgradePadua2Hom. Het.Asp Arg LysScrantonHet.595 596 599ThrLeu, Gln, TrpGluNo BleedingNo Thromb.No BleedingVenousThromb.No BleedingNo Thromb.Decreased Resistant ProbablydecreasedEPONYMPROTHROMBINBINDING TO ATA.A. SUBSTITUTIONCLINICAL ASPECTSFigure 1. Schematic representation of the main features of the dysprothrombinemias due to Arg596 substitution and of other closedysprothrombinemias, all encoded by exon 14. The probable decreased binding to antithrombin for prothrombin Scranton is inferred fromchimeric in vitro studies. A.A. indicates amino acid; AT, antithrombin; tromb, thrombosis.2 Clinical and Applied Thrombosis/Hemostasis4. Miljic P, Gvozdenov M, Takagi Y, et al. Clinical and bio-chemical characterization of the prothrombin Belgrade muta-tion in a large Serbian pedigree: new insights into theantithrombin resistance mechanism. J Thromb Haemost.2017;15(4):670-677.5. SunWY, Smirnow D, Jenkins ML, Degen SJ. Prothrombin Scran-ton: substitution of an amino acid residue involved in the bindingof Naþ (LYS-556 to THR) leads to dysprothrombinemia. ThrombHaemost. 2001;85(4):651-654.6. Ruiz-Sa´ez A, Luengo J, Rodriguez A, Ojeda A, Go´mez O, Acur-ero Z. Prothrombin Perija: a new congenital dysprothrombinemiain an Indian family. Thromb Res. 1986;44(5):587-598.7. Sekine O, Sugo T, Ebisawa K, et al. Substitution of Gly-548 to alain the substrate binding pocket of prothrombin Perija´ leads to theloss of thrombin proteolytic activity. Thromb Haemost. 2002;87(2):282-287.8. Rouy S, Vidaud D, Alessandri JL, et al. Prothrombin Saint-Denis:a natural variant with a point mutation resulting in Asp to Glusubstitution at position 552 in prothrombin. Br J Haematol. 2006;132(6):770-773.9. Girolami A, Scandellari R, Scapin M, Vettore S. Congenitalbleeding disorders of the vitamin K-dependent clotting factors.Vitam Horm. 2008;78:281-374.10. Lancellotti S, Basso M, De Cristofaro R. Congenital prothrombindeficiency: an update. Semin ThrombHemost. 2013;39(6):596-606.11. Tamura S, Murata-Kawakami M, Takagi Y, et al. In vitro explo-ration of latent prothrombin mutants conveying antithrombinresistance. Thromb Res. 2017;159:33-38.12. Sivasundar S, Oommen AT, Prakash O, et al. Molecular defect of‘Prothrombin Amrita’: substitution of arginine by glutamine(Arg553 to Gln) near the Na(þ) binding loop of prothrombin.Blood Cells Mol Dis. 2013;50(3):182-183.Girolami et al 3

The Dysprothrombinemias due to Arg596 Mutations: A Conundrum With No Bleeding Tendency and Venous Thrombosis due to Antithrombin Resistance

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The Dysprothrombinemias due to Arg596 Mutations: A Conundrum With No Bleeding Tendency and Venous Thrombosis due to Antithrombin Resistance

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