Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed

Figures & data

Table 1. Cases of prothrombin abnormalities due to mutations of Arg596 that are associated with a gain of function towards antithrombin and that therefore cause a thrombophilic state.

Authors, year	Age, sex	FII act	FII ant	Bleeding	Venous thrombosis (age at first episode)	Associated Risk	Mutation	Genotype	Eponym	Comments
Miyawaki et al. (2012) [6]	17, F	37. 6	63.8	No	Yes (11 Years)	No	Arg596Leu	Het.	Prothrombin Yukuhashi	Patient from Japan
Djordjevic et al. (2013) [8] Fam 1 Fam 2	n.r., F n.r., F	n.r. n.r.	n.r. n.r.	n.r. n.r.	Yes (17 years) Yes (16 years)	No No	Arg596Leu Arg596Leu	Het. Het.	Prothrombin Belgrade	Six patients in two families
Sivasundar et al. (2013) [7]	60, M	n.r.	n.r.	n.r.	Yes	n.r.	Arg596Gln	Het.	Prothrombin Amrita	No founds study
Kishimoto et al. (2016) [9]	23, F	n.r.	n.r.	No	Yes (15 years)	No	Arg596Leu	Het.	Prothrombin Belgrade	Patient from Japan
Bulato et al. (2016) [10] Fam. 1 Fam. 2	47, M 29, F	54 29	80 89	No No	Yes (38 years) Yes (27years)	No No	Arg596Trp Arg596Trp	Het. Het	Prothrombin Padua	Seven patients in two families

Note: Het. = Heterozygote; n.r. = not reported. (a) Data supplied in ‘Correspondence’. N. Engl Med 2012; 367:1069–1070. Only the families with the Arg596 mutations are included.

Table 2. Main features of the prothrombin defect, a dysprothrombinemias due to mutations not involving the Arg596 amino acid but still associated with thrombosis.

Authors, year	Age, sex	FII act	FII ant	Bleeding	Venous thrombosis (age at first episode)	Associated risks	Mutation	Genotype	Eponym	Comments
Ding et al. (2017) [18]	30, F	1	82.9	Yes, severe	30	Pregnancy: Replacement therapy with PCC during most of the pregnancy	Arg382His	Hom	n.r.	A sister similarly affected but without thrombosis

Table 3. Main features of prothrombin defects close to the Arg596 amino acid.

Eponym	Salakta	Greenville	(Naetsved)	(Palermo)	C.Christi	Perija	Yukuhashi, Belgrade, Amrita, Padua 2	Scranton	Quick	(Leiden)
References	[15]	[13]	[18]	[26]	[27]	[17]	[7–11]	[16]	[14]	[25]
Mutation	Glu509Ala	Arg560Gln	Ala563Val + Gln519Stop	Arg581Cys	Gly584Stop + Arg475Cys	Gly591Ala	Arg596Leu Arg596Gln Arg596Trp	Lys599Thr	Gly601Val + Arg425Cys	Trp612Stop + IVS2-25C G
Genotype	Hom	Het	C. Het	Hom	Comp.Het	Hom	All.Het	Het	Comp.Het	Comp.Het
Bleeding	No	No	Mild	Severe	No	Mild	No	No	Severe	Severe
Thrombosis	No	No	No	No	No	No	Yes	No	No	No
Country	Tunisia	U.S.A.	Denmark	Italy	Latin America	Venezuela	Japan, Serbia, India, Italy	U.S.A.	Latin America	Holland
Type of defect	II	II	II	II	II	II	II	II	II	I
	509	550	563	581	541	591	596	599	601	612
Amino acid		Arg	Ala	Arg	Gln	Gly	Arg	Lys	Gly	Trp

Note: No thrombotic event has been reported in any of these patients who are mainly affected by dysprothrombinemias or Type II defects. Only a defect due to a compound heterozygosis between Trp617Stop and a splicing defect is a Type I defect. Amino acid residues numbering includes the 43 residues of the pre-pro-sequence. Eponyms between parentheses have been tentatively supplied, for the sake of completion, by the authors of the present paper.

Miyawaki Y, Suzuki A, Fujita J, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med. 2012;366:2390–2396. doi: 10.1056/NEJMoa1201994

 PubMed Web of Science ®Google Scholar

Djordjevic V, Kovac M, Miljic P, et al. A novel prothrombin mutation in two families with prominent thrombophilia – the first cases of antithrombin resistance in a Caucasian population. J Thromb Haemost. 2013;11:1936–1939.

 PubMed Web of Science ®Google Scholar

Sivasundar S, Oommen AT, Prakash O, et al. Molecular defect of ‘Prothrombin Amrita’: substitution of arginine by glutamine (Arg553 to Gln) near the Na(+) binding loop of prothrombin. Blood Cells Mol Dis. 2013;50:182–183. doi: 10.1016/j.bcmd.2012.11.008

 PubMed Web of Science ®Google Scholar

Kishimoto M, Suzuki N, Murata M, et al. The first case of antithrombin-resistant prothrombin Belgrade mutation in Japanese. Ann Hematol. 2016;95:541–542. doi: 10.1007/s00277-015-2533-6

 PubMed Web of Science ®Google Scholar

Bulato C, Radu CM, Campello E, et al. New prothrombin mutation (Arg596Trp, prothrombin Padua 2) associated with venous thromboembolism significance. Arterioscler Thromb Vasc Biol. 2016;36:1022–1029. doi: 10.1161/ATVBAHA.115.306914

 PubMed Web of Science ®Google Scholar

Ding Q, Yang L, Zhao X, et al. Paradoxical bleeding and thrombotic episodes of dysprothrombinaemia due to a homozygous Arg382His mutation. Thromb Haemost. 2017;117:479–490. doi: 10.1160/TH16-10-0750

 PubMed Web of Science ®Google Scholar

Sun WY, Smirnow D, Jenkins ML, et al. Prothrombin Scranton: substitution of an amino acid residue involved in the binding of Na+ (LYS-556 to THR) leads to dysprothrombinemia. Thromb Haemost. 2001;85:651–654.

 PubMed Web of Science ®Google Scholar

Henriksen RA, Owen WG, Nesheim ME, et al. Identification of a congenital dysthrombin, thrombin quick. J Clin Invest. 1980;66:934–940. doi: 10.1172/JCI109961

 PubMed Web of Science ®Google Scholar

O’Marcaigh AS, Nichols WL, Hassinger NL, et al. Genetic analysis and functional characterization of prothrombins Corpus Christi (Arg382-Cys), Dhahran (Arg271-His), and hypoprothrombinemia. Blood. 1996;88:2611–2618.

 PubMed Web of Science ®Google Scholar

Girolami A, Candeo N, Vettore S, et al. The clinical significance of the lack of arterial or venous thrombosis in patients with congenital prothrombin or FX deficiency. J Thromb Thrombolysis. 2010;29:299–302. doi: 10.1007/s11239-009-0342-2

 PubMed Web of Science ®Google Scholar

Stanchev H, Philips M, Villoutreix BO, et al. Prothrombin deficiency caused by compound heterozygosity for two novel mutations in the prothrombin gene associated with a bleeding tendency. Thromb Haemost. 2006;95:195–198.

 PubMed Web of Science ®Google Scholar

Sekine O, Sugo T, Ebisawa K, et al. Substitution of Gly-548 to Ala in the substrate binding pocket of prothrombin Perijá leads to the loss of thrombin proteolytic activity. Thromb Haemost. 2002;87:282–287.

 PubMed Web of Science ®Google Scholar

Miyata T, Aruya R, Umeyama H, et al. Prothrombin Salakta: substitution of glutamic acid 466 by alanina residues the fibrinogen clotting activity and the esterase activity. Biochem. 1992;31:7457–7462. doi: 10.1021/bi00148a005

 PubMed Web of Science ®Google Scholar

Akhavan S, Mannucci PM, Lak M, et al. Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency. Thromb Haemost. 2000;84:989–997.

 PubMed Web of Science ®Google Scholar