Factor VII Padua: a systematic review of reported cases, diagnosis, clinical manifestations, and management strategies

Abstract

Factor VII (FVII) Padua is a rare inherited disorder caused by a missense variant in the F7 gene (Arg364Gln), resulting in variable FVII activity depending on the thromboplastin source used in assays. Although often linked to a hypercoagulable state, critical gaps remain in understanding its diagnosis, clinical manifestations, and geographic distribution. Following PRISMA guidelines, a systematic search of PubMed, Scopus, and Web of Science was conducted through February 2026 to identify studies reporting FVII Padua. Data on demographics, laboratory findings, and bleeding or thrombotic events were extracted from eligible publications. Thirty-six studies comprising 75 patients were identified. Most cases originated from Italy (22.6%), Iran (20%), the USA (17.3%), France (12%), and Brazil (9.3%). Ages ranged from 5 to 79 years. Sex information was available for 50 patients, of whom 27 (54%) were female and 23 (46%) were male. Prolonged prothrombin time and markedly reduced FVII activity using rabbit-brain thromboplastins were key diagnostic features, while human or recombinant thromboplastins showed milder reductions. Nearly half of the patients (n = 28; 49%) were asymptomatic; however, some experienced severe bleeding, including postpartum hemorrhage (n = 1; 1.7%) and gastrointestinal bleeding (GIB) (n = 3; ~5%). Thrombotic events were reported in six patients out of 13 (46%), including deep vein thrombosis (DVT) in two patients (33.3%) and pulmonary embolism (PE) in one patient (16.6%). This study demonstrates the global distribution and clinical heterogeneity of FVII Padua, emphasizing the need for thromboplastin-specific diagnostic evaluation and individualized management. Further research is essential to address existing diagnostic and therapeutic gaps.

Introduction

Factor VII deficiency (FVIID), is a genetic bleeding disorder that is inherited in an autosomal recessive manner. Its global prevalence is estimated to be around 1 in 300,000 to 500,000 people. The condition was initially identified in 1951 by Alexander et al., with the first documented case describing a 4-year-old girl who experienced significant bleeding from her umbilical cord at birth [1]. FVIID, though rare, is recognized as the most common among rare bleeding disorders. It is a global condition, but it shows a higher prevalence in certain regions, such as the United Kingdom, the United States, Brazil, Turkey, Italy, the Slovak Republic, and Iran [2–4]. It can be classified into two types based on the nature of the defect in the F7 gene; Type I deficiency is characterized by a decrease in both Factor VII coagulant activity (FVII: C) and Factor VII antigen levels (FVII: Ag), indicating a quantitative defect with reduced production or availability of the FVII protein. Conversely, type II deficiency involves qualitative defects, in which FVII: C is impaired despite normal or near-normal levels of FVII: Ag, suggesting structural or functional abnormalities that compromise the protein’s effectiveness [5, 6]. The abnormal FVII observed in these cases could exhibit varying degrees of activity depending on the specific type of thromboplastin utilized in the assay system [7].

A rare genetic variant, FVII Padua (NM_000131.3:c.1091G > A), has been identified as a type II deficiency, with a minor allele frequency (MAF) of 0.0004, according to the European Association for Hemophilia and Allied Disorders (EAHAD) [8]. This variant is associated with a specific missense mutation in exon 9 of the F7 gene, resulting in a nucleotide substitution from CGG to CAG at position 1091, leading to the amino acid change p.Arg364Gln, which occurs within a CpG dinucleotide. It was first described and diagnosed by Girolami et al. [9]. Historically, this variant was reported as g.10828G > A or p.Arg304Gln [9, 10]; However, in alignment with the most recent EAHAD recommendations for standardized variant nomenclature, it is now designated as p.Arg364Gln [8]. FVII Padua is characterized by a marked discrepancy in activity levels depending on the source of tissue thromboplastins utilized in laboratory assays. Specifically, when rabbit brain-derived thromboplastin is used, FVII activity is notably reduced, typically ranging from 4% to 10% of normal levels. In contrast, assays using ox-brain thromboplastin demonstrate activity levels within the normal range. Thromboplastins derived from human sources, such as placental tissue, or recombinant human thromboplastins yield intermediate activity levels, approximately 30% to 40% of normal [9, 10]. Patients harboring the FVII Padua variant generally exhibit normal plasma FVII antigen levels, indicating preserved quantitative expression of the protein. However, despite normal antigen concentrations, the coagulant activity is characteristically diminished due to a qualitative functional defect in the protein. Patients with this variant usually exhibit symptoms like mild-to-moderate bleeding, which can present as easy bruising, nosebleeds, gum bleeding, or bleeding after surgical procedures such as dental extractions or tonsillectomy [11]. However, some people may remain asymptomatic and have no notable history of bleeding episodes [12]. Although FVIID is traditionally considered a bleeding disorder, some researchers propose that the FVII Padua variant may be associated with a greater risk of venous thromboembolism (VTE), suggesting complex contributions to thrombotic risk beyond deficiency alone [7, 13]. In particular, studies by Girolami et al. suggest that individuals carrying this genetic variant exhibit elevated levels of activated FVII (FVIIa), which may contribute to increased thrombotic risk [7]. Several studies have revisited families and patient cohorts carrying this variant and have shown increased susceptibility to both venous and arterial thrombosis, particularly in individuals who are either homozygous or compound heterozygous for this variant [13] Additionally, individuals carrying this variant tend to exhibit elevated FVII levels and enhanced thrombin generation, both of which contribute to a heightened risk of thrombosis [7, 14].

Given the diagnostic complexity, phenotypic heterogeneity, and potential thrombotic risk associated with this variant, a consolidated review of all reported FVII Padua cases is warranted. The primary objective of this systematic review is to characterize the diagnostic and clinical spectrum of FVII Padua by assessing thromboplastin-dependent variability in PT/FVII activity, genotype–phenotype correlations according to zygosity, the frequency and pattern of bleeding and thrombotic manifestations and the geographic distribution of reported cases.

Strategy of search

We conducted a thorough search of PubMed (n = 158), Scopus (n = 154), and Web of Science (n = 30) up to February 2026, following PRISMA guidelines [15]. We utilized specialized search techniques, incorporating MeSH terms, specific keywords, and their variations, including ‘Factor VII’, ‘Factor VII Padua’, ‘Factor VII deficiency’, ‘Arg364Gln’, and ‘Arg304Gln’. Furthermore, references cited in the retrieved articles were systematically reviewed to identify additional pertinent studies. The details of the search strategy are illustrated in Fig. 1.

Fig. 1.

The search strategy, based on the PRISMA

Eligibility criteria

Two reviewers independently assessed the eligibility of the studies. Any disagreements or discrepancies were resolved through discussion with the study supervisor (A.D) when necessary. Studies were included if they involved patients carrying the FVII Padua variant in the simple heterozygous, homozygous, or compound heterozygous state, as confirmed by clinical and laboratory methods.

Exclusion criteria

A total of 342 papers were initially identified, of which 85 were removed due to duplication. After screening titles and abstracts, 195 additional papers were excluded. Subsequently, 43 papers were excluded for specific reasons: 11 were letters to the editor, 8 were review articles, 2 were written in languages other than English, 16 did not report any FVII Padua, 1 pertained to FVII Padua 2, identical cases 3, and 2 were inaccessible. Additionally, 17 articles were identified through a review of the reference lists of retrieved papers. In total, 36 papers were included in the study.

Data extraction

Data were meticulously extracted by two independent reviewers, focusing on key study characteristics and outcomes. Extracted information included authorship, country of study, publication date, zygosity category (simple heterozygous, homozygous, or compound heterozygous), occurrences of bleeding and thrombotic events, presence of co-morbidities, prothrombin time (PT) results, FVII activity measured using various thromboplastin reagents, and FVII antigen levels.

Results

A comprehensive analysis of 36 publications, comprising 20 case reports and 16 case series, was conducted to evaluate diagnostic methodologies, clinical features, and therapeutic strategies associated with FVII Padua. Detailed findings are summarized in Table 1, providing an overview of the current evidence base and insights into the management of this condition.

Table 1.

Available data of patients with factor VII Padua variant

Author (Ref)	Year	Country	Age, Gender	PT test (seconds)				FVII Activity (%)					FVII antigen (%)	Associated Risks	Zygosity status *	Comments
				Rabbit brain	Human placenta	Ox brain		Rabbit brain	Human placenta		rHu	Ox brain
Safdari [16]	2025	Iran	18, M	57.3	44.4	NA		4	NA		NA	NA	NA	NA	Simple heterozygote
			30, M	87	23.5	NA		28	NA		NA	NA	NA	NA	Simple heterozygote
Shams [11]	2023	Iran	39, M	17	NA	NA		27	NA		69	NA	NA	NA	Simple heterozygote
			14, F	16	NA	NA		31	NA		61	NA	NA	NA	Simple heterozygote
			40, F	16.5	NA	NA		38	NA		81	NA	NA	NA	Simple heterozygote
			18, M	17	NA	NA		29	NA		46	NA	NA	NA	Simple heterozygote
			18, M	16	NA	NA		33	NA		53	NA	NA	NA	Simple heterozygote
Pollak [12]	2006	USA: African-American	14, M	15.6	NA	NA		33	NA		61	NA	57	NA	Simple heterozygote
			27, F	prolonged				26	n.r.		54	NA	67	NA	Compound heterozygote	Compound heterozygote for p.Arg364Gln and p.Arg315Trp
			52, F	14.5	NA	NA		21	NA		69	NA	NA	Diabetes mellitus	Simple heterozygote
Girolami [7]	1978–2002	Italy	NA	30.2 a				8	36		30	105	95	NA	homozygote
			NA	30.0 a				9	32		20	110	110	NA	homozygote
			18, F	32.5 a				10	36		32	100	105	NA	homozygote
			NA	34.0 a				11	34		29	100	110	NA	homozygote
			NA	31.0 a				8	33		30	90	120	NA	homozygote
			64, F	31.6 a				7	29		25	95	100	NA	homozygote
Sabharwal [17]	1992	USA	50, F	NA				NA	14		NA	NA	120	NA	homozygote
Triplett [14]	1985	USA	45, F	> 17 a				< 3	16		NA	NA	113	NA	homozygote	Black e
			NA, F	> 17 a				8	56		NA	NA	100	NA	homozygote	Black e
			24, M	> 17 a				< 3	20		NA	NA	75	NA	homozygote	Black e
			23, M	> 17 a				7	94		NA	NA	90	NA	homozygote	Black e
Shurafa [18]	1993	USA	26, F	NA				14	21		NA	124	100	NA	homozygote
Kirkel [19]	2009	USA African- American	46, F	prolonged				7	NA		77	NA	121	NA	Simple heterozygote
Peyvandi [20]	1997	Iran (Belonged to the same kindred)	51, F	NA				< 1	NA		37	normal	240	NA	homozygote
			45, F	NA				< 1	NA		27	normal	224	NA	homozygote
			55, M	NA				< 1	NA		24	normal	156	NA	homozygote
			30, F	NA				< 1	NA		17	normal	106	NA	homozygote
			21, F	NA				< 1	NA		22	normal	130	NA	homozygote
Marty [21]	2008	France	34, F	NA				NA	NA		10	NA	86	NA	homozygote
			57, F	NA				NA	NA		9	NA	73	Post-surgical (knee hygroma)	Compound heterozygote	Compound heterozygote for p.Cys195Arg and p.Arg364Gln
Marchetti [22]	1991	Italy	9, M	NA				40	NA		NA	100	70	VWD	Simple heterozygote
Croze [23]	1982	France	70, M	Prolonged				10	45		NA	120	80	Gastrointestinal cancer	homozygote	Polypectomy without complications
Girolami [24]	1982	Italy	11, F	34	NA		NA	11	38	NA	105	NA	NA		NA	preparation for tonsillectomy
Rabelo [25]	2015	Brazil	18, M	15 a				29	NA		30	NA	NA	NA	Simple heterozygote
			50, F	29 a				< 1	NA		15	NA	NA	NA	homozygote
			68, F	40 a				3.17	NA		29.94	NA	NA	NA	homozygote
			73, F	37 a				3.32	NA		40.03	NA	NA	NA	homozygote
O’Brien [26]	1991	England	47, M	NA				< 1	30		NA	NA	100	NA	homozygote	Carried out on purified material
Takamiya [27]	1993	Japan	NA	NA				< 1	NA		NA	NA	100	NA	homozygote
Giansily-Blaizot [28]	2001	France	Male	NA				2	NA		NA	NA	72	NA	homozygote	Unspecified Tissue thromboplastin
			Male	NA				5	NA		NA	NA	54	NA	Compound heterozygote	Unspecified Tissue thromboplastin
			Female	NA				< 5	NA		NA	NA	55	NA	Compound heterozygote
			Female	NA				< 5	NA		NA	NA	NA	NA	homozygote
			Male	NA				3	NA		NA	NA	23	NA	Compound heterozygote
			NA	NA				21	NA .		NA	NA	71	NA	Simple heterozygote	Asymptomatic
Fromovich-Amit [29]	2004	Israel	NA	NA				7	NA		NA	NA	60	NA	homozygote	Unspecified thromboplastin
			NA	NA				21	NA		NA	NA	71	NA	Simple heterozygote	Asymptomatic
Fromovich [30]	2005	Tunisia	NA	NA				1	NA		NA	NA	80	NA	homozygote	Unspecified thromboplastin
			Female	NA				5	NA		NA	NA	NA	NA	homozygote	Unspecified thromboplastin
Elmahmoudi [31]	2012	Tunisia	20, M	NA				NA	NA		NA	NA	NA	NA	homozygote
Tahatahary [32]	2007	Iran	NA	NA				30	NA		NA	NA	NA	NA	homozygote	tissue thromboplastin unspecified
Girolami [33]	2016	Argentina	64, F	35.9 b 83.6 c 55.8 d	17.3		40	1	29	39–53	96	105	NA		homozygote	Asymptomatic
Girolami [34]	2018	Argentina	79, M	NA				3	60		60	100	Normal	NA	homozygote
Shahbazi [35]	2017	Iran	67, M	34a				16	NA		NA	NA	NA	NA	homozygote
			31, M	NA				25	NA		NA	NA	NA	NA	Compound heterozygote	Compound heterozygote for p.Arg364Gln and c.IVS7 + 7 A > G
Girolami [36]	2020	Argentina	45, M	54	NA		NA	1	49	100	100	102	Down Syndrome		homozygote
Rodrigues [37]	2003	Brazil	NA	NA				26	38		NA	NA	70	NA	Simple heterozygote
			NA	NA				44	45		NA	NA	60	NA	Simple heterozygote
			NA	NA				NA	40		NA	NA	26	NA	Simple heterozygote
Bernardi [38]	1994	Italy	NA	Prolonged				NA	16		NA	NA	82	NA	Simple heterozygote
			NA	Prolonged				NA	46		NA	NA	75	NA	Simple heterozygote
			NA	Prolonged				NA	44		NA	NA	88	NA	Simple heterozygote
			NA	Prolonged				NA	33		NA	NA	70	NA	Simple heterozygote
			NA	Prolonged				NA	54		NA	NA	73	NA	Simple heterozygote
Horellou [39]	2007	USA: African-American	NA	NA				2–5	25–89		25–89	NA	Normal	NA	homozygote
			NA	NA				2–5	25–89		25–89	NA	Normal	NA	homozygote
Kuppuswamy [40]	1993	USA	NA	NA				4	NA		NA	NA	NA	NA	Compound heterozygote
Bernardi [41]	1996	Italy	NA	Prolonged				NA	31		NA	NA	113	NA	homozygote
Gallardo [42]	2022	Singapore	60, M	27.9	18.4		NA	4	28	21	NA	87	hypertension, hyperlipidemia and coronary artery disease		Compound heterozygote	Compound heterozygote for p.Arg364Gln and p.Ala65Gly
Girolami [43]	1983	Italy	70, M	prolonged				7	NA		NA	105	Normal	NA	homozygote
Girolami [44]	1979	Italy	18, F	33	19.4	37.5		9	19.4		NA	100	Normal	NA	homozygote
Tidd [45]	2005	NA	NA	15.6 a				36	NA		33	NA	61	NA	Simple heterozygote
			NA	prolonged				26	NA		54	NA	67	NA	Simple heterozygote	African American
			NA	14.5 a				21	NA		64	NA	n.r.	NA	Simple heterozygote	African American
Girolami [46]	1992	Italy	9, NA	71a				26	NA		NA	100	70	VWD	Simple heterozygote

M Male, F Female, NA Not available, FVII Factor VII, PT Prothrombin Time, VWD Von Willebrand disease

a) The type of PT reagent was not determined

b) PT with rabbit brain thromboplastin with STA Neoplastin Plus (Stago Laboratory) kit

c) PT with rabbit brain thromboplastin with PT-Fibrinogen HSPlus kit

d) PT with rabbit brain thromboplastin with Tromboplastina S kit

e) Considered as African American

Study population

Since the FVII Padua variant was first identified by Girolami et al. in 1978 [9], a total of 75 patients with this variant have been reported in 36 studies published up to February 1, 2026. Gender information was available for 50 individuals (66.6%), comprising 23 males (46%) and 27 females (54%). Age demographics revealed that the disorder has been identified in individuals ranging from 5 to 79 years of age, with a mean age at diagnosis of 38.02 ± 20.84 years. This wide age range highlights the necessity for clinical vigilance across diverse age groups when evaluating for this rare bleeding disorder.

Genotypic analysis was conducted for 74 patients (98.6%), providing detailed insights into the genetic basis of this condition. Among these, 40 individuals (~ 54%) were homozygous for the FVII Padua variant, 26 (~ 35%) were simple heterozygotes, and 8 (~ 11%) were compound heterozygotes carrying an additional pathogenic F7 variant (Information regarding zygosity in one patient was unavailable [24]). This distinction is clinically relevant because the accompanying allelic state may modify both laboratory findings and the severity of bleeding or thrombotic manifestations. These findings emphasize the genetic heterogeneity associated with the FVII Padua variant and underscore the importance of comprehensive genetic testing to inform diagnosis and management strategies (Table 1).

Global distribution of FVII Padua

This review highlighted the worldwide distribution of this rare bleeding disorder, with Italy reporting the highest prevalence of patients affected by the FVII Padua variant. A total of 17 cases (22.6%) have been identified in Italy, as documented across eight separate studies [7, 22, 24, 38, 41, 43, 44, 46]. Iran has the second-highest number of FVII Padua patients, with 15 (20%) patients carrying FVII Padua variants reported across five studies [11, 16, 20, 32, 35]. A total of 13 cases (17.3%) of FVII Padua have been documented in the United States across seven studies [12, 14, 17–19, 39, 40]. Among these cases, eight individuals were identified as African American [12, 17–19, 39]. These cases were initially referred to as FVII Richmond [17] and FVII Detroit [18] in their respective reports. The widespread occurrence of the FVII Padua variant among individuals of African-American ethnicity was recognized as early as 1993 [47]. France accounted for 9 cases (12%) [21, 23, 28], and Brazil for 7 cases (9.3%) [25, 37]. Additional cases were reported from Argentina (n = 3) [33, 34, 36], Tunisia (n = 3) [30, 31], Israel (n = 2) [29], Singapore (n = 1) [42], Japan (n = 1) [27], and England (n = 1) [26]. In 3 patients, the country of origin or study location was not available [45]. These findings reflect the global distribution of the FVII Padua variant (Table 1).

Laboratory findings: PT variability

PT variability according to thromboplastin source

Among a total of 75 patients identified with the FVII Padua, PT results were available for 43 individuals, representing 57.3% of the study population. PT assays utilizing rabbit brain thromboplastin as the reagent were documented in 14 cases, accounting for 32.5% of the reported instances. The PT values in these patients exhibited a wide range, spanning from 14.5 s to 87 s. The mean PT result was 31.2 s, with a standard deviation of ± 22.24 s, reflecting significant variability among cases [11, 12, 16, 24, 33, 36, 42, 44]. Girolami et al. reported substantial variability in PT measurements when using different rabbit brain thromboplastin reagents. In their study, PT values of 35.9 s, 83.6 s, and 55.8 s were obtained with STA Neoplastine Plus, PT-FIB HS PLUS, and Tromboplastina S, respectively, highlighting significant inter-reagent differences despite a shared biological source [33]. Additionally, among the 43 patients for whom PT results were reported, the specific type of thromboplastin reagent used was not indicated in 29 cases (67.4%) [7, 12, 14, 23, 25, 35, 38, 43, 45, 46, 48].

In four studies (~ 11%) involving five patients, PT results obtained with human placenta thromboplastin ranged from 17.3 to 44.4 s, with a mean of 24.6 ± 11.31 s [16, 33, 42, 44]. PT results obtained with ox-brain thromboplastin were reported for two patients and measured 37.5 and 40 s, respectively [33, 44]. Together, these findings show substantial variation in PT across thromboplastin sources and reinforce the need to specify the reagent used when interpreting results.

Co-morbidity in patients with FVII Padua

Of the 36 case series and case report studies, co-morbidity data were reported in 7 studies (19.4%), involving 7 patients (9.3%) [12, 21–23, 36, 42, 46]. An African-American female, heterozygous for the FVII Padua, has been documented with a clinical history of diabetes mellitus [12]. Another patient, a 57-year-old female from France who was compound heterozygous for Cys195Arg/Arg364Gln, had a knee hygroma [21]. Two children with von Willebrand disease (VWD) were reported to be heterozygous for the FVII Padua [22, 46]. Girolami et al. observed homozygous FVII Padua in a man with Down syndrome [36]. Gastrointestinal cancer and homozygote state for FVII Padua was reported in a 70-year-old man from France in 1982 [23]. In a recent clinical study, a 60-year-old male, identified as a compound heterozygote for the Arg364Gln and Ala65Gly variants, presented with a medical history significant for hypertension, hyperlipidemia, and coronary artery disease [42]. Of the total cohort, 68 patients (91%) did not report any information pertaining to comorbidities associated with the FVII Padua variant (Table 1).

Clinical manifestations: bleeding and thrombosis

Bleeding phenotype

Bleeding episodes in patients with the FVII Padua variant were reported in 28 studies, representing 77% of the included reports [3, 7, 11, 12, 14, 16, 20–26, 29–37, 40, 42, 44–46, 48]. Among the 57 patients described in these studies, approximately half were asymptomatic (n = 28; 49%). Most symptomatic patients had mild bleeding manifestations. Easy bruising was reported in 8 patients (~ 14%) [7, 11, 16, 20, 21], and epistaxis in 10 patients (17.5%) [7, 11, 12, 16, 22, 30, 34, 35, 45, 46]. Isolated cases included one patient (1.7%) with post-tonsillectomy bleeding [11] and another with mild vaginal bleeding originating from the uterine stump [7]. Gingival and oral cavity bleeding was observed in 8 patients (10%) [11, 16, 22, 30, 35, 46]. Among a female cohort (n = 27), 4 women (14.8%) reported menorrhagia [7, 20, 25]. More severe bleeding such as gastrointestinal bleeding (n = 3; ~5%) [3, 16, 35], massive bleeding after cesarean section (n = 1; 1.7%) [30], postpartum hemorrhage (n = 1; 1.7%) [21], and excessive bleeding after dental procedures or surgeries (n = 5; 9%) have been reported in 10 patients (17.5%) [11, 20, 34].

Analysis of bleeding cases demonstrated that the relationship between FVII activity and clinical phenotype is inconsistent and highly dependent on assay methodology. In symptomatic simple heterozygotes, FVII activity measured with rabbit-brain thromboplastin was often only moderately reduced, such as 27–38% in the Iranian cohort reported by Shams et al. [11], and 33% in the mildly symptomatic patient described by Pollak et al. [12], while corresponding values obtained with recombinant human thromboplastin were substantially higher (46–81% and 61%, respectively). Similarly, in our previously reported bleeding case, rabbit-brain activity was 28% [16]. In contrast, homozygous or compound heterozygous patients often exhibited markedly reduced activity when measured with rabbit-brain thromboplastin, but parallel assays again demonstrated higher values. For example, Girolami et al. [7] reported 7–10% activity with rabbit-brain thromboplastin compared to 29–36% with human placenta and 20–32% with recombinant human reagents. In the Iranian kindred described by Peyvandi et al. [20], activity was < 1% with rabbit-brain thromboplastin but increased to 22–37% with recombinant human reagents and remained normal with ox-brain thromboplastin. Comparable discrepancies were observed in other bleeding cases, including 3.17% versus 29.94% in a Brazilian patient with menorrhagia [25], and 3% versus 60% in an Argentine patient with post-extraction bleeding [34]. Overall, these findings demonstrate that low FVII activity values—particularly those obtained using rabbit-brain thromboplastin—do not consistently correlate with bleeding severity. Instead, they largely reflect reagent-dependent assay variability. Therefore, interpretation of FVII levels in FVII Padua requires integration of the thromboplastin source, genetic background (zygosity), and clinical presentation, rather than reliance on a single numerical value.

Thrombotic manifestations

Regarding thrombotic events, data were available from eight studies (n = 13; 22.2%) [7, 14, 16–18, 21, 33, 36]. The remaining studies did not report patients’ thrombotic history. Among the 13 patients, no thrombotic episodes were observed in seven cases (~ 54%) [14, 16, 33, 36]. Documented events included deep vein thrombosis (DVT) in two patients (33.3%) [18, 21] and pulmonary embolism (PE) in one patient (16.6%) [17]. One patient who developed DVT was a 34-year-old woman with a history of postpartum bleeding and central retinal vein thrombosis [21]. In another patient with FVII Padua, the type of thrombosis was not exactly specified [14].

The homozygous patient reported by Shurafa et al. who developed DVT had FVII activity of 14% with rabbit-brain thromboplastin and 21% with human placenta thromboplastin, with preserved antigen (124%) [18]. The homozygous patient reported by Sabharwal et al. with DVT and PE had an activity value of 14% with human placenta thromboplastin and FVII antigen of 120% [17]. In the French patients reported by Marty et al., the homozygous patient with postpartum hemorrhage who subsequently developed central retinal vein thrombosis, lower-limb DVT, and PE had 10% FVII activity with recombinant human thromboplastin and antigen of 86%, whereas the compound heterozygous patient with lower-limb DVT had 9% recombinant-human activity and antigen of 73% [21]. The probable thrombotic case reported by Triplett et al. had < 3% activity with rabbit-brain thromboplastin and 16% with human placenta thromboplastin, with antigen of 113% [14]. One additional homozygous patient in Girolami et al. developed great saphenous phlebitis within a cohort showing rabbit-brain activity of 7–11%, human placenta activity of 29–36%, recombinant human activity of 20–32%, and normal antigen levels, although patient-level assignment of these laboratory results was not possible [7]. Across these reported thrombotic cases, none of the reviewed studies provided information regarding the management of thrombotic events, including use of FVII replacement, anticoagulation, perioperative care, or detailed clinical outcomes. (Table 2.)

Table 2.

Bleeding and Thrombotic events associated with Factor VII Padua variant (corresponding reagent-specific FVII activity for bleeding cases is summarized in the text)

Author (Ref)	Year	Country	Age, Gender	Bleeding event	Thrombotic event
Safdari [16]	2025	Iran	18, M	Asymptomatic	None
			30, M	Easy bruising, Epistaxis, Gum bleeding, GIB	None
Shams [11]	2023	Iran	39, M	Minor childhood epistaxis	NA
			14, F	Easy bruising, bleeding after tonsillectomy	NA
			40, F	Easy bruising	NA
			18, M	Easy bruising, gum bleeding, bleeding after dental surgery	NA
			18, M	Easy bruising, gum bleeding, bleeding after dental surgery	NA
Pollak [12]	2006	USA African- American	14, M	Minor occasional epistaxis	NA
			27, F	Asymptomatic	NA
			52, F	Asymptomatic	NA
Girolami [7]	1978–2002	Italy	NA	Mild	Great saphenous phlebitis
			NA	Mild	NA
			18, F	Easy bruising, epistaxis, menorrhagia	NA
			NA	Mild	NA
			NA	Mild	NA
			64, F	Vaginal bleeding from the uterine stump	NA
Sabharwal [17]	1992	USA	50, F	NA	DVT, PE
Triplett [14]	1985	USA	45, F	Asymptomatic	Thrombosis a
			NA, F	Asymptomatic	None
			24, M	Asymptomatic	None
			23, M	Asymptomatic	None
Shurafa [18]	1993	USA	26, F	NA	DVT
Kirkel [19]	2009	USA	46, F	Asymptomatic	NA
Peyvandi [20]	1997	Iran	51, F	Easy bruising, post-dental extraction bleeding	NA
			45, F	Menorrhagia	NA
			55, M	NA	NA
			30, F	NA	NA
			21, F	Menorrhagia, post-extraction bleeding	NA
Marty [21]	2008	France	34, F	Postpartum hemorrhage	Central retinal vein thrombosis, lower limb DVT, and PE
			57, F	Easy bruising	Lower limb DVT
Marchetti [22]	1991	Italy	9, M	Epistaxis, gum bleeding	NA
Croze [23]	1982	France	70, M	Asymptomatic	NA
Girolami [24]	1982	Italy	11, F	Asymptomatic	NA
Rabelo [25]	2015	Brazil	18, M	Asymptomatic	NA
			50, F	Asymptomatic	NA
			68, F	Menorrhagia	NA
			73, F	Asymptomatic	NA
O’Brien [26]	1991	England	47, M	Asymptomatic	NA
Takamiya [49]	1993	Japan	NA	NA	NA
Giansily-Blaizot [28]	2001	France	Male	NA	NA
			Male	NA	NA
			Female	NA	NA
			Female	NA	NA
			Male	NA	NA
Fromovich-Amit [29]	2004	Israel	NA	Asymptomatic	NA
			NA	NA	NA
Fromovich-Amit [30]	2005	Tunisia	NA	Epistaxis, gingival bleeding	NA
			Female	Massive bleeding after cesarean section	NA
Tahatahary [32]	2007	Iran	NA.	mild	NA
Girolami [33]	2016	Argentina	64, F	Asymptomatic	None
Girolami [34]	2018	Argentina	79, M	Bleeding after tooth extractions	NA
Shahbazi [35]	2017	Iran	67, M	Epistaxis, oral cavity bleeding, cutaneous symptoms	NA
			31, M	Epistaxis, oral cavity bleeding, cutaneous symptoms, GIB	NA
Elmahmoudi [31]	2012	Tunisia	20, M	Asymptomatic	NA
Girolami [36]	2020	Argentina	45, M	Asymptomatic	None
Rodrigues [37]	2003	Brazil	NA	Minor or absent b	NA
			NA	Minor or absent b	NA
			NA	Minor or absent b	NA
Bernardi [38]	1994	Italy	NA	NA	NA
			NA.	NA	NA
			NA	NA	NA
			NA	NA	NA
			NA	NA	NA
Herrmann [3]	2009	USA	5, F	GIB	NA
Horellou [39]	2007	USA: African-American	NA	Asymptomatic	NA
			NA	Asymptomatic	NA
Kuppuswamy [40]	1993	USA	NA	Asymptomatic	NA
Bernardi [41]	1996	Italy	NA	NA	NA
Gallardo [42]	2022	Singapore	60, M	Asymptomatic	NA
Girolami [43]	1983	Italy	70, M	NA	NA
Girolami [44]	1979	Italy	18, F	Asymptomatic	NA
Tidd [45]	2005	NA	NA	Minor Nose Bleeds	NA
			NA	Asymptomatic	NA
			NA	Asymptomatic	NA
Girolami [46]	199	Italy	9, NA	Epistaxis, gingival bleeding	NA

M Male, F Female, NA Not Available, DVT Deep vein thrombosis, PE Pulmonary Embolism, GIB Gastrointestinal bleeding

a) The exact type and place of thrombosis was not available in the mentioned study

b) We consider these patients as asymptomatic

Discussion

The FVII Padua variant, also known as FVII Arg364Gln, has been extensively characterized. It is classified as a type II variant and exhibits the following features: (1) variable FVII activity levels depending on the thromboplastin reagent used in the assay, (2) normal FVII antigen concentrations, (3) normal FVIIa levels, (4) minimal or absent bleeding tendency, although 17.5% (n = 10) of reported cases demonstrated severe bleeding manifestations, (5) a predisposition to VTE, and (6) no evident association with arterial thrombosis [7, 9]. Regarding the findings in the 75 patients with the FVII Padua variant included in the studies (n = 36), the FVII Padua defect has been identified in individuals aged 9 to 79 years, highlighting the wide age distribution of this disorder. Gender information was available for the majority of patients (n = 50; 66.6%), with an approximately balanced distribution between males (n = 23; 46%) and females (n = 27; 54%). Importantly, the genotype distribution among FVII Padua patients was as follows: 40 individuals (~ 54%) were homozygous, 26 (~ 35%) were simple heterozygotes, and 8 (~ 11%) were compound heterozygotes carrying FVII Padua together with another F7 variant. This three-tier distinction is important when interpreting phenotype.

One key observation is the broad geographic distribution of the FVII Padua, with cases reported across multiple countries. Italy (n = 17; 22.6%) [7, 22, 24, 38, 41, 43, 44, 46] and Iran (n = 15; 20%) [11, 16, 20, 32, 35] accounted for the highest number of reported cases. This pattern may reflect not only a potential founder effect or increased regional prevalence but also greater research activity and diagnostic awareness in these regions. The initial cluster of cases was identified in northeastern Italy, specifically in the Piave River Valley. In the seminal study by Girolami et al., all six original patients, along with approximately 60 heterozygous carriers, originated from this area [9]. Beyond Italy and Iran, the FVII Padua variant has been reported in patients from France (n = 9; 12%) [21, 23, 28], Tunisia (n = 3; 4%) [30, 31], Brazil (n = 7; 9.3%) [25, 37], Argentina (n = 3; 4%) [33, 34, 36], and the United States (n = 13; 16%) [12, 14, 17–19, 39, 40]. The presence of homozygous cases in the United States, predominantly among African-American individuals, indicates that regions outside Europe should also be considered when investigating the geographic and ethnic distribution of this variant. The frequency of the variant varies between North-Central and South America. Although both the United States and Brazil received substantial numbers of individuals of African descent during the forced migration period, homozygous cases are more frequently reported in the United States than in Brazil, despite Brazil having a larger population of African origin. This discrepancy may reflect differences in the prevalence of heterozygotes among ancestral populations, socio-economic factors influencing health outcomes, or disparities in diagnostic capabilities between the two countries [12, 25, 37]. The widespread occurrence of the Padua variant across geographically and ethnically diverse populations may be partially explained by a CpG mutation hotspot. Studies have confirmed CpG sequences as mutation hotspots in this gene and reported that the F7 gene harbors CpG-associated mutations, accounting for a substantial proportion of FVII deficiency variants [50]. Given that the FVII Padua variant involves a CpG dinucleotide, which is inherently prone to mutational events, its wide geographical distribution may reflect either a founder mutation in specific populations or recurrent independent mutational events. Future studies should concentrate more for using haplotype analysis and population-genetic approaches to clarify the variant’s origin, which may also help to understand environmental and genetic factors contributing to its clinical heterogeneity.

Laboratory findings and assay interpretation

Our study underscores the complexity of laboratory assessment for the FVII Padua variant. Although prolonged PT was a consistent finding, the extent of prolongation varied according to the thromboplastin source used in the assay. Specifically, rabbit brain-derived thromboplastins produced the most pronounced PT prolongation, whereas human placenta and recombinant human thromboplastins yielded comparatively milder prolongation. These differences with various thromboplastin sources are not solely attributable to technical variation but also may reflect underlying biological mechanisms. The activity of FVII depends on its interaction with TF, forming the TF–FVIIa complex that initiates coagulation [51]. We can hypothesize that variations in thromboplastin composition, including the source and structure of TF, phospholipid content, and ionic conditions, modulate the efficiency of this interaction and thereby alter assay sensitivity to FVII levels. Furthermore, another hypothesis is that recombinant thromboplastins have been shown to be more sensitive to reductions in FVII activity than tissue-derived reagents, while trace amounts of FVIIa present in some preparations may reduce sensitivity by partially activating the coagulation cascade. These factors may contribute to the differing clotting responses observed across assay systems. Also, variability seen between reagents highlights the critical importance of selecting appropriate thromboplastin sources for accurate diagnosis and patient monitoring in patients with FVII Padua. Consistent with our findings, Girolami et al. demonstrated that the thromboplastin ratio of ox brain to rabbit brain more accurately reflects the characteristic functional differences of the FVII Padua variant than assays using thromboplastins from other tissues [52]. Therefore, it is recommended to perform assays using rabbit brain–derived thromboplastin in conjunction with ox brain thromboplastin to ensure accurate assessment of FVII Padua activity.

When FVII activity in FVII Padua was interpreted according to the thromboplastin reagent used, a consistent assay-dependent pattern was observed. Very low activity measured with rabbit-brain thromboplastin often coexisted with substantially higher values obtained using human placenta, recombinant human, or ox-brain reagents in the same patient. It should be mentioned that very low rabbit-brain values were also reported in some asymptomatic individuals, whereas several symptomatic patients had only moderate reductions. These findings indicate that the apparent severity of FVII deficiency in FVII Padua is strongly influenced by the assay method and that a single reported FVII activity level, especially when the thromboplastin source is not specified, cannot be considered a reliable predictor of bleeding risk. Rather, the laboratory phenotype may reflect assay variability more than the clinical phenotype. Consistent with this, low FVII activity measured with rabbit-brain thromboplastin alone should be regarded as clinically meaningful for raising suspicion of FVII Padua, but not as sufficient evidence of severe bleeding tendency by itself [7, 10–12, 16, 20, 25, 34]. This distinction is particularly important because many laboratories do not have access to multiple thromboplastin reagents. In such settings, an isolated prolonged PT and low FVII activity should be interpreted as a screening result and integrated with the patient’s personal and family bleeding history, previous surgical or obstetric hemostatic challenges, and, when available, zygosity or molecular findings, as well as the bleeding risk of the planned procedure [4, 6]. For asymptomatic or mildly symptomatic patients whose laboratory findings appear discordant with the clinical picture, repeat testing, referral for confirmatory testing with an alternative reagent, or molecular analysis may be more appropriate than immediate replacement therapy [4, 52]. In low-resource settings, where access to additional reagents or molecular testing may be limited, practical management should focus on careful clinical assessment, local hemostatic measures, and antifibrinolytic therapy for minor procedures when appropriate, while reserving replacement therapy mainly for active major bleeding, previous procedure-related bleeding, or high-risk surgery and childbirth.

Clinical phenotype: bleeding and thrombosis

Our findings demonstrate a broad spectrum of bleeding phenotypes associated with the FVII Padua variant. While the majority of patients were asymptomatic or exhibited only mild bleeding tendencies (n = 33; 57.8%), more severe hemorrhagic events, including gastrointestinal bleeding, excessive postoperative bleeding, and postpartum hemorrhage, were observed in a subset of patients (n = 10; 17.5%). Regarding phenotypic interpretation according to zygosity status, the available literature supports separate interpretation of simple heterozygous, homozygous, and compound heterozygous FVII Padua cases. Simple heterozygous individuals (n = 26) were predominantly asymptomatic or had mild mucocutaneous bleeding, and several had relatively higher FVII activity when human or recombinant thromboplastins were used. In contrast, homozygous individuals (n = 40) more often demonstrated markedly reduced activity with rabbit-brain thromboplastin and a wider clinical spectrum, ranging from asymptomatic status to clinically relevant bleeding and venous thrombosis. Compound heterozygotes (n = 8) constituted the most phenotypically heterogeneous subgroup because the accompanying F7 variant likely modified expression; reported manifestations in this subgroup ranged from asymptomatic presentation to postpartum hemorrhage, lower-limb DVT, and other procedure-related bleeding. Nonetheless, because several reports did not provide complete subgroup-specific clinical details, these findings should be interpreted as a structured qualitative synthesis rather than a formal pooled comparison.

Our review underscored the thrombotic risk associated with the FVII Padua variant. Among the 13 patients with FVII Padua evaluated for thrombotic events, documented cases included DVT in two patients (33.3%) and pulmonary embolism in one patient (16.6%). FVII activity levels varied depending on the thromboplastin reagent used (rabbit-brain, ox-brain, human placenta, or recombinant human), as summarized in Table 1. One patient with DVT had a history of postpartum bleeding and central retinal vein thrombosis. None of the reviewed case reports or series provided information regarding the management of thrombotic events. As such, while these reports confirm that thrombotic events can occur in FVII Padua, the literature does not allow conclusions regarding optimal management strategies. This gap highlights the need for future studies to systematically report therapeutic interventions and outcomes for thrombotic complications in this patient population. The occurrence of thrombotic events in FVIID, while paradoxical for a bleeding disorder, is documented in previous studies in homozygous and compound heterozygous individuals, indicating that reduced FVII activity does not always confer protection against thrombosis [13, 21, 53]. Previous publications have underscored that thrombosis in FVIID patients may be linked to specific underlying settings, including the perioperative setting, surgery, or the use of substitutive treatment (e.g., recombinant FVIIa) [21, 53]. Nevertheless, the structural and functional basis of this paradox remains incompletely understood. One possible explanation is altered regulation of FVIIa by endogenous inhibitors such as tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Circulating FVIIa forms complexes with AT, and variations in this interaction are associated with cardiovascular risk, suggesting that dysregulation of FVIIa inhibition might contribute to prothrombotic phenotypes even in the presence of low catalytic activity [54, 55]. While direct experimental data on TFPI or AT resistance for p.Arg364Gln are lacking, this represents a plausible mechanism analogous to that described for prothrombin Arg596 variants in which impaired AT binding leads to antithrombin resistance and increased thrombosis risk [56]. Likewise, the hypothesis that thrombosis in FVII Padua is due to a specific gain-of-function (GOF) property of the Arg364Gln substitution remains unproven. Similarly, elevated FVIIa levels in some patients with FVII Padua [7], altering TF binding characteristics due to the Arg364Gln substitution, and different reactivity with various thromboplastin sources [9, 53] have not completely elucidated this phenomenon. Therefore, the mechanism by which this variant might predispose to thrombosis remains unclear and warrants further investigation. Accordingly, future studies should combine functional investigations (changes in inhibitory interactions with TFPI or AT) with systematic assessment of inherited thrombophilia (FV Leiden, prothrombin G20210A, protein C/S/antithrombin deficiencies), acquired thrombotic risk factors (surgery, immobilization, oral contraceptives, pregnancy), replacement therapy exposure, and other hypercoagulable states (elevated FVIII, antiphospholipid antibodies) to better define the mechanisms and determinants of thrombotic risk in patients with FVII Padua.

Based on the findings of the included studies, five patients with FVII Padua experienced confirmed thrombotic events and one additional patient had a probable thrombotic event [14]. Although the available data are limited, documented events included DVT, PE, central retinal vein thrombosis, and superficial venous thrombosis. Importantly, the reported thrombotic events were concentrated mainly among homozygous patients [17, 18, 21] and in at least one compound heterozygous patient [21], whereas clear thrombotic events were not well documented in simple heterozygotes. This genotype-stratified pattern suggests that zygosity may influence thrombotic risk, although the literature remains too sparse and heterogeneous for firm quantitative inference. Given that other FVIID variants have also been associated with an increased risk of thrombosis [53, 57, 58], it remains unclear whether the incidence of thrombotic events in homozygous individuals carrying the Arg364Gln (FVII Padua) variant exceeds that observed in patients with other variants, such as Ala294Val [21, 53].

Implications for clinical management

FVIID is the most frequently encountered disorder among the rare congenital coagulation defects [3, 4]. Where available, testing with more than one thromboplastin source is clinically useful primarily for diagnostic clarification rather than for routine monitoring in every patient. In FVII Padua, comparison of rabbit-brain with ox-brain, human placenta, or recombinant human thromboplastins can reveal the characteristic assay discrepancy, distinguish this qualitative variant from true quantitative FVII deficiency, and thereby prevent overestimation of disease severity and unnecessary replacement therapy, particularly before surgery or other invasive procedures [10, 16, 52, 59]. However, the absence of multiple reagents should not preclude clinical decision-making, because management must ultimately be based on integrated interpretation of laboratory findings, bleeding history, genotyping (if available), and the nature of the planned hemostatic challenge [4, 6]. It’s noteworthy that, in symptomatic cases (bleeding or thrombosis), a key prerequisite for proper categorization of the thrombosis cause is diligent documentation and confirmation or exclusion of the exact cause of thrombosis. The accurate interpretation of the FVII Padua variant’s contribution to a thrombotic phenotype relies heavily on ruling out or the presence of known or stronger thrombotic risk factors, such as inherited thrombophilia. Additionally, one important fact is that the clinical interpretation of a reported FVII level also differs according to the thromboplastin reagent used and the aspect of function captured by the assay. Rabbit-brain thromboplastin is highly useful for recognizing the characteristic laboratory pattern of FVII Padua; however, as mentioned earlier, a very low value obtained with this reagent may exaggerate the apparent severity of deficiency and should not be interpreted alone as evidence of a severe bleeding phenotype. By contrast, human placenta, recombinant human, or ox-brain thromboplastins often yield higher activity values, suggesting that the variant retains greater functional activity under other assay conditions, but these values likewise do not independently predict bleeding risk. Accordingly, reagent-derived FVII activity should be regarded as an assay-specific functional readout rather than a direct surrogate for true in-vivo hemostatic competence. Clinical decisions should therefore be based on integrated assessment of bleeding history, prior hemostatic challenges, planned interventions, and genotype when available, rather than on any single reagent-specific FVII level.

Although the FVII Padua variant represents one of the more common forms of congenital FVIID, it holds substantial clinical relevance for optimal patient management. In contrast to individuals with other variants of FVIID, patients harboring the FVII Padua variant generally require little to no replacement therapy despite markedly prolonged PT. This highlights the importance of accurate molecular characterization to guide appropriate therapeutic decisions and to avoid unnecessary treatment [59].

Limitation

One of the main objectives of this study is to clarify better the clinical association between FVII Padua and bleeding and thrombotic phenotypes. However, this relation is challenging and must be interpreted with caution. In contrast to individuals with other variants of congenital FVIID, patients harboring the FVII Padua variant generally require little to no replacement therapy despite a markedly prolonged PT. Since both bleeding and thrombotic conditions are also relatively common in the general population independently of FVIID, the true risk estimate derived from studies based on symptomatic or referred cohorts is challenging. In this regard, thrombotic history was available for only a limited subset of patients, and most reports lacked detailed information on concomitant risk factors, management, and clinical outcomes. As a result, the true magnitude of thrombotic risk associated with FVII Padua cannot be estimated reliably from the currently available literature. In addition, subgroup-specific reporting was inconsistent across publications, which limited robust pooled comparisons among homozygous, simple heterozygous, and compound heterozygous individuals. Accordingly, the current findings primarily reflect the reported clinical spectrum rather than precise genotype-specific population risks, which is a recognized limitation of this study.

Conclusion

Despite the established association between the FVII Padua variant and a hypercoagulable state, several questions remain regarding optimal diagnostic methods, the origin of the defect, and its clinical manifestations. The clinical spectrum is highly variable: approximately half of patients are asymptomatic, whereas others experience mild to severe bleeding episodes. Concurrently, the hypercoagulable state is evidenced by thrombotic events, including DVT and PE, reported in a subset of patients. The present review shows that very low FVII activity, particularly when measured with rabbit-brain thromboplastin, does not necessarily predict severe bleeding and should not be interpreted in isolation. Instead, clinical assessment should integrate the thromboplastin source, bleeding history, prior hemostatic challenges, and genetic background, including zygosity status. The available literature also suggests that homozygous and compound heterozygous patients may show broader phenotypic variability, including thrombotic manifestations; however, the current evidence remains insufficient to define the true magnitude or mechanism of this risk. Accordingly, accurate diagnosis of suspected FVII Padua requires thromboplastin-aware interpretation and, where feasible, molecular confirmation. Future studies should report laboratory and clinical findings separately by zygosity and should include standardized documentation of thrombotic risk factors, treatment, and outcomes to improve understanding of this variant and guide patient management. Addition population-genetic studies could clarify whether FVII Padua represents a founder mutation or a recurrent hotspot, which may in turn inform understanding of genotype-phenotype correlations and environmental modifiers.

Author contributions

Conceptualization of the project: AD; Data collection and analysis: SMS, SA, MSH. Discussion and interpretation of results: AD, SMS, SA, MSH; All authors reviewed the final manuscript.

Funding

No funding was received to assist with the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.