Abstract
Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large‐scale genetic association studies have not been performed. The aim of the study was to systematically review variants in LV patients and to analyse the available clinical data. A systematic search of the literature in PubMed and Embase databases was performed to identify articles investigating genetic variation in LV patients. Thirty studies or case reports were identified that reported 265 LV patients tested for at least one out of six genetic variations. Among them, PAI‐1 ‐675 4G/5G was the most common, accounting for 85.26% (81/95). Heterozygous 4G/5G was the major genotype. PAI‐1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Prothrombin G20210A and Factor V G1691A were mainly present in LV patients from Europe, North America, and South America. This review highlights the associations between LV and genetic variants. The distribution of variants may be geographically or ethnicity dependent; however, large sample case‐control studies are needed to clarify associations.
Keywords: genotype, plasminogen activator inhibitor‐1, single‐nucleotide polymorphism, variants, vascular disease
1. INTRODUCTION
Livedoid vasculopathy (LV) was first described by Milian in 1929 and was also named atrophie blanche, segmental hyalinising vasculitis, and livedo reticularis with summer ulcerations.1 LV mainly affects young and middle‐aged women with an incidence of 1:1000002 and presents with erythema, macules, painful ulcers, white satellite scars on both lower extremities. Hypercoagulability and thromboembolism in dermal vessels are the major causes of its pathogenesis. Therefore, the term LV is now frequently used to distinguish thrombo‐occlusive vasculopathy from traditional cutaneous small vessel vasculitis.
A variety of hereditary and acquired coagulation abnormalities have been detected in LV patients, including polymorphisms in Methylenetetrahydrofolate reductase (MTHFR), Plasminogen activator inhibitor‐1 (PAI‐1), Prothrombin, and Factor V.3 The variants, including single‐nucleotide polymorphisms, in the coagulation‐related genes mentioned earlier change or influence their expression and increase the risk of thrombosis, which contributes to the onset of LV. Furthermore, several case reports, case series, and other studies indicate the relationship between LV and certain genetic variants. However, no large‐scale analyses have been conducted concerning genetic variants in LV. Here, we carried out a systematic review of the published literature, focusing on the polymorphisms C677T and A1298C in MTHFR, ‐675 4G/5G and A844G in PAI‐1, G20210A in Prothrombin and G1691A in Factor V (the Leiden mutation), which have been reported in LV patients.
2. METHODS
2.1. Literature search
We screened PubMed and Embase databases on 14 September 2020 for articles concerning LV patients and genetic mutations (Figure 1). LV has a diversity of historic names and associated genes; therefore, the following broad search terms were applied: “livedoid vasculopathy”, “livedoid vasculitis”, “livedo vasculitis”, “atrophie blanche”, “white atrophy”, “segmental hyalinizing vasculitis”, “mutation”, “polymorphism”, “genotype”, “methylenetetrahydrofolate reductase”, “MTHFR”, “Plasminogen activator inhibitor‐1”, “PAI‐1”, “Prothrombin”, “Factor V”, and “Leiden”. Only studies, case series, and case reports published in English from inception of the databases to September 2020 were included. No other filters or restrictions were applied to the search.
FIGURE 1.
PRISMA flow figure of the literature review
2.2. Eligibility criteria
Inclusion criteria are as follows: (a) clinically and histologically confirmed LV diagnosis. Patients clinically presented as recurrent livedo reticularis, erythema, macules, painful ulcers, and white satellite scars on both lower extremities with intraluminal thrombosis, endothelial proliferation, and segmental hyalinisation in dermal vessels on histology. (b) At least one of the following variants were tested: MTHFR C677T and A1298C, PAI‐1‐675 4G/5G and A844G, Prothrombin G20210A and Factor V G1691A (the Leiden mutation). If patients were tested for several variants in an article, and heterozygosity or homozygosity were not clearly presented, then only the clearly recorded genotypes were enrolled. (c) Articles published in the English language. (d) Article types including case‐control studies, case series, and case reports were enrolled.
Exclusion criteria are as follows: (a) the diagnosis of LV was uncertain; (b) heterozygosity or homozygosity of variants tested were not clearly recorded; (c) articles written in languages other than English; (d) review articles or editorial articles.
3. RESULTS
After the extensive literature search, 53 articles were found in PubMed and Embase databases that concern genetic variants in LV patients. By carefully reviewing the full texts of these 53 articles, 30 were enrolled that complied with the inclusion and exclusion criteria (Table 1)4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. A total of 265 patients, of whom 78 were male (29.43%) and 187 were female (70.57%) giving a female to male ratio of 2.4:1, were tested for at least one out of the following six genetic variants, MTHFR C677T and A1298C, PAI‐1 ‐675 4G/5G and A844G, and Prothrombin G20210A and Factor V G1691A. The mean patient age was 35.74 years (range: 12–87 years). Single nucleotide polymorphisms (SNPs) were assessed by polymerase chain reaction (PCR), Hind III restriction fragment length polymorphism (RFLP), or sequencing. The ref SNP ID, location, and affected function are summarised in Table 2.
TABLE 1.
LV patients tested for MTHFR C677T, MTHFR A1298C, PAI‐1 ‐675 4G/5G, PAI‐1 A844G, prothrombin G20210A, and Factor V G1691A genotype polymorphisms
| No. | Authors | Year | Patients (M/F) | Mean Age | Country | MTHFR C677T | MTHFR A1298C | PAI‐1 ‐675 4G/5G | PAI‐1 A844G | Prothrombin G20210A | Factor V G1691A | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (year) | CC | CT | TT | AA | AC | CC | 4G/4G | 4G/5G | 5G/5G | AA | AG | GG | GG | GA | AA | GG | GA | AA | |||||
| 1 | Tsai et al4 | 2009 | 56 (18/38) | 29.79 | China | 37/56 | 14/56 | 5/56 | 32/56 | 20/56 | 4/56 | 17/56 | 30/56 | 9/56 | NA | NA | NA | 56/56 | 0/56 | 0/56 | 56/56 | 0/56 | 0/56 |
| 2 | Marsch et al5 | 2019 | 42 (15/27) | NA | Germany | 10/25 | 8/25 | 7/25 | 14/25 | 8/25 | 3/25 | 4/17 | 12/17 | 1/17 | 7/17 | 9/17 | 1/17 | 15/16 | 1/16 | 0/16 | 14/17 | 3/17 | 0/17 |
| 3 | Lee et al6 | 2020 | 28 (8/20) | 45.6 | Korea | 4/24 | 13/24 | 7/24 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 4 | Agirbasli et al7 | 2011 | 20 (7/13) | 26 | Turkey | NA | NA | NA | NA | NA | NA | 5/20 | 11/20 | 4/20 | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 5 | Hairston et al8 | 2006 | 45 (13/32) | 45 | America | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NS | NS | NS | 7/9 | 2/9 | 0/9 |
| 6 | Di Giacomo et al9 | 2010 | 34 (10/24) | 45 | Brazil | NS | NS | NS | NS | NS | NS | NA | NA | NA | NA | NA | NA | NS | NS | NS | 28/34 | 6/34 | 0/34 |
| 7 | Da Costa Franca et al10 | 2009 | 14 (1/13) | 41.5 | Brazil | 5/14 | 6/14 | 3/14 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NS | NS | NS | NS | NS | NS |
| 8 | Nakamura et al11 | 2011 | 3 (1/2) | 36 | Japan | 1/3 | 2/3 | 0/3 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 9 | Yong et al12 | 2012 | 2 (0/2) | 33.5 | Singapore | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/2 | 2/2 | 0/2 |
| 10 | Biedermann et al13 | 2000 | 1 (0/1) | 56 | Germany | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 |
| 11 | Mirrakhimov et al14 | 2012 | 1 (0/1) | 87 | America | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 12 | Abou Rahal et al15 | 2012 | 1 (0/1) | 21 | Lebanon | 0/1 | 0/1 | 1/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 13 | Irani‐Hakime et al16 | 2008 | 1 (0/1) | 34 | Lebanon | 0/1 | 0/1 | 1/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 |
| 14 | Deng et al17 | 2006 | 1 (0/1) | 33 | America | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 |
| 15 | Khenifer et al18 | 2009 | 1 (1/0) | 54 | France | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 |
| 16 | Calamia et al19 | 2002 | 1 (0/1) | 44 | America | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 |
| 17 | Kavala et al20 | 2008 | 1 (1/0) | 19 | Turkey | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 |
| 18 | Criado et al21 | 2013 | 1 (1/0) | 13 | Brazil | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 19 | Anavekar et al22 | 2007 | 1 (0/1) | 53 | Australia | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 20 | Cardoso et al23 | 2007 | 1 (0/1) | 31 | Portugal | 0/1 | 0/1 | 1/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 21 | Antunes et al24 | 2010 | 1 (0/1) | 25 | Portugal | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | NA | NA | NA | 0/1 | 1/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 22 | Castillo‐Martínez et al25 | 2014 | 1 (0/1) | 12 | Mexico | 1/1 | 0/1 | 0/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 23 | Shankar et al26 | 2013 | 1 (0/1) | 23 | India | 0/1 | 1/1 | 0/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 24 | Davis et al27 | 2008 | 1 (0/1) | 50 | America | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 |
| 25 | Gotlib et al28 | 2003 | 1 (0/1) | 30 | America | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 0/1 | 1/1 | 0/1 | NA | NA | NA |
| 26 | Brockley et al29 | 2013 | 1 (1/0) | 17 | Afghan | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | NA | NA | NA |
| 27 | Morais et al30 | 2010 | 1 (0/1) | 19 | Portugal | 0/1 | 1/1 | 0/1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 28 | Sahin et al31 | 2017 | 1 (0/1) | 15 | Turkey | NA | NA | NA | 0/1 | 1/1 | 0/1 | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 |
| 29 | Vázquez et al32 | 2018 | 1 (1/0) | 64 | Spain | 0/1 | 0/1 | 1/1 | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 | NA | NA | NA | 1/1 | 0/1 | 0/1 |
| 30 | Wong et al33 | 2011 | 1 (0/1) | 34 | Britain | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1/1 | 0/1 | 0/1 |
Abbreviations: F, female; LV, livedoid vasculopathy; NA, not available; NS, not stated (heterozygosity or homozygosity of mutations not stated clearly); M, male.
TABLE 2.
Summary of background information about SNPs discussed in LV
| Genotypes | Ref SNP ID | Location | Chromosome | Mutation | Alter in function |
|---|---|---|---|---|---|
| MTHFR C677T | rs1801133 | Nucleotide 677 of exon 4 | 1p36.3 | C>T | To reduce 60% in MTHFR enzyme activity and to rise 20% in homocysteine levels34 |
| MTHFR A1298C | rs1801131 | Nucleotide 1298 of exon 7 | 1p36.3 | A>C | A mild form of MTHFR deficiency with hyperhomocysteinemia35 |
| PAI‐1 ‐675 4G/5G | rs1799889 | Promoter‐675 region | 7q21.3‐q22 | G deletion or insertion | PAI‐1 levels in the 4G/4G genotype were approximately 25% higher than those in the 5G/5G genotype36 |
| PAI‐1 A844G | rs2227631 | Promoter‐844 region | 7q21.3‐q22 | A>G | Together with PAI‐1 ‐675 4G/5G to affect transcriptional activity of the PAI‐1 gene37 |
| Prothrombin G20210A | rs1799963 | Position 20 210 in the 3′‐untranslated region | 11p11‐q12 | G>A | Increased level of prothrombin mRNA and protein with a more effective poly(A) site38 |
| Factor V G1691A | rs6025 | Nucleotide 1691 of exon 10 | 1q23 | G>A | Poor anticoagulant response to activated Protein C that inactivates Factors Va and VIIIa39 |
Abbreviations: A, adenine; C, cytosine; G, guanine; LV, livedoid vasculopathy; and T, thymine.
3.1. SNPs
3.1.1. MTHFR C677T
Thirteen articles presented LV patients that were examined for MTHFR C677T,4, 5, 6, 9, 10, 11, 15, 16, 23, 25, 26, 30, 32 although one article referred vaguely to its heterozygosity or homozygosity.9 A total of 129 patients were tested for MTHFR C677T, of which 46 had the heterozygous CT genotype (35.66%) and 25 had the homozygous TT genotype (19.38%). Thus, the total carrier rate of MTHFR C677T was 55.04% (71/129).
3.1.2. MTHFR A1298C
There were only two studies and one case report concerning MTHFR A1298C in LV patients.4, 5, 31 In all, 82 LV patients were tested for MTHFR A1298C. Twenty‐nine patients had the AC genotype (a heterozygous carrier rate of 35.67%) and seven had the CC genotype (a homozygous carrier rate of 8.54%). The carrier rate of MTHFR A1298C was 43.90% (36/82).
3.1.3. PAI‐1 ‐675 4G/5G
Three studies and two case reports presented assessment of PAI‐1 ‐675 4G/5G in a total of 95 LV patients.4, 5, 7, 17, 24 Twenty‐eight of 95 LV patients (29.47%) displayed the homozygous 4G/4G genotype, whereas 53 of 95 LV patients (55.79%) showed the heterozygous 4G/5G genotype. The total carrier rate of PAI‐1 ‐675 4G/5G was 85.26% (81/95), which was the highest carrier rate among the assessed SNPs.
3.1.4. PAI‐1 A844G
Compared to PAI‐1 ‐675 4G/5G, the variant PAI‐1 A844G has been rarely assessed in LV patients. Only two articles, including one study and one case report, have reported a total of 18 LV patients tested for PAI‐1 A844G.5, 32 Fifty percent of tested LV patients (9/18) had the heterozygous AG genotype, while only one tested LV patient (5.56%) was homozygous for the GG genotype. The carrier rate of PAI‐1 A844G was 55.56% (10/18).
3.1.5. Prothrombin G20210A
Eighty‐five LV patients from 15 studies or case reports were evaluated for Prothrombin G20210A,4, 5, 14, 15, 16, 18, 21, 22, 23, 24, 25, 27, 28, 29, 31 while patients from another three studies were excluded because of vague descriptions of heterozygosity or homozygosity.8, 9, 10 The total carrier rate of Prothrombin G20210A was 10.59% (9/85), which was the lowest carrier rate of the six SNPs assessed. All the LV patients with Prothrombin G20210A displayed a heterozygous GA genotype (9/85); no homozygous AA carrier was identified (0/85).
3.1.6. Factor V G1691A
The total carrier rate of Factor V G1691A (14.07%) in LV patients was the second lowest among the tested SNPs. From 23 articles,4, 5, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 31, 32, 33 135 LV patients were tested. In one study10 heterozygosity or homozygosity was not clearly stated; however, the remaining studies showed 19 patients to have the heterozygous GA genotype and no patients to have the homozygous AA genotype (0/135).
3.2. Regional distribution
Most articles did not refer in detail to the ethnicity or race of patients; therefore, we tried to determine the association between regions and genotypes in LV patients, which may provide clues for relationships between ethnicity and genotypes in LV. Patients were identified from 17 countries and 5 continents involving Asia, Europe, North America, South America, and Oceania (Table 3). The heterozygous, homozygous, and total carrier rates of each SNP are summarised in Table 4.
TABLE 3.
Summary of region and general data of articles enrolled
| No. | Country | Authors | Year | Patients (M/F) | Mean age (year) |
|---|---|---|---|---|---|
| Asia | |||||
| 1 | China | Tsai et al4 | 2009 | 56 (18/38) | 29.79 |
| 2 | Japan | Nakamura et al11 | 2011 | 3 (1/2) | 36 |
| 3 | Singapore | Yong et al12 | 2012 | 2 (0/2) | 33.5 |
| 4 | Lebanon | Abou Rahal et al15 | 2012 | 1 (0/1) | 21 |
| 5 | Lebanon | Irani‐Hakime et al16 | 2008 | 1 (0/1) | 34 |
| 6 | Turkey | Kavala et al20 | 2008 | 1 (1/0) | 19 |
| 7 | India | Shankar et al26 | 2013 | 1 (0/1) | 23 |
| 8 | Turkey | Sahin et al31 | 2017 | 1 (0/1) | 15 |
| 9 | Korea | Lee et al6 | 2020 | 28 (8/20) | 45.6 |
| 10 | Turkey | Agirbasli et al7 | 2011 | 20 (7/13) | 26 |
| 11 | Afghan | Brockley et al29 | 2013 | 1 (1/0) | 17 |
| North America | |||||
| 1 | America | Hairston et al8 | 2006 | 45 (13/32) | 45 |
| 2 | America | Mirrakhimov et al14 | 2012 | 1 (0/1) | 87 |
| 3 | America | Deng et al17 | 2006 | 1 (0/1) | 33 |
| 4 | Mexico | Castillo‐Martínez et al25 | 2014 | 1 (0/1) | 12 |
| 5 | America | Davis et al27 | 2008 | 1 (0/1) | 50 |
| 6 | America | Gotlib et al28 | 2003 | 1 (0/1) | 30 |
| 7 | America | Calamia et al19 | 2002 | 1 (0/1) | 44 |
| Europe | |||||
| 1 | Portugal | Cardoso et al23 | 2007 | 1 (0/1) | 31 |
| 2 | Portugal | Antunes et al24 | 2010 | 1 (0/1) | 25 |
| 3 | Portugal | Morais et al30 | 2010 | 1 (0/1) | 19 |
| 4 | Spain | Vázquez et al32 | 2018 | 1 (1/0) | 64 |
| 5 | Britain | Wong et al33 | 2011 | 1 (0/1) | 34 |
| 6 | Germany | Biedermann et al13 | 2000 | 1 (0/1) | 56 |
| 7 | France | Khenifer et al18 | 2009 | 1 (1/0) | 54 |
| 8 | Germany | Marsch et al5 | 2019 | 42 (15/27) | NA |
| South America | |||||
| 1 | Brazil | Di Giacomo et al9 | 2010 | 34 (10/24) | 45 |
| 2 | Brazil | Da Costa Franca et al10 | 2009 | 14 (1/13) | 41.5 |
| 3 | Brazil | Criado et al21 | 2013 | 1 (1/0) | 13 |
| Oceania | |||||
| 1 | Australia | Anavekar et al22 | 2007 | 1 (0/1) | 53 |
Abbreviations: F, female; M, male; NA, not available.
TABLE 4.
Genotypes polymorphisms results in LV patients from five continents
| Continents | Patients (M/F) | Mean age (year) | Countries | Articles | MTHFR C677T | MTHFR A1298C | PAI‐1 ‐675 4G/5G | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Heterozygous | Homozygous | Total | Heterozygous | Homozygous | Total | Heterozygous | Homozygous | Total | |||||
| Asia | 115 (36/79) | 27.26 | 8 | 11 | 34.88% | 16.27% | 51.15% | 36.84% | 7.02% | 43.86% | 53.95% | 28.95% | 82.90% |
| Europe | 49 (17/32) | 40.43 | 5 | 8 | 32.14% | 32.14% | 64.28% | 32% | 12% | 44% | 66.67% | 27.78% | 94.45% |
| North America | 51 (13/38) | 43 | 2 | 7 | 0% | 0% | 0% | NA | NA | NA | 0% | 0% | 0% |
| South America | 49 (12/37) | 33.17 | 1 | 3 | 42.86% | 21.43% | 64.29% | NA | NA | NA | NA | NA | NA |
| Oceania | 1 (0/1) | 53 | 1 | 1 | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Total | 265 (78/187) | 35.74 | 17 | 30 | 35.66% | 19.38% | 50.04% | 35.67% | 8.54% | 43.90% | 55.79% | 29.47% | 85.26% |
| Continents | Patients (M/F) | Mean age (year) | Countries | Articles | PAI‐1 A844G | Prothrombin G20210A | Factor V G1691A | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Heterozygous | Homozygous | Total | Heterozygous | Homozygous | Total | Heterozygous | Homozygous | Total | |||||
| Asia | 115 (36/79) | 27.26 | 8 | 11 | NA | NA | NA | 1.67% | 0% | 1.67% | 6.45% | 0% | 6.45% |
| Europe | 49 (17/32) | 40.43 | 5 | 8 | 50% | 5.56% | 55.56% | 15.79% | 0% | 15.79% | 21.74% | 0% | 21.74% |
| North America | 51 (13/38) | 43 | 2 | 7 | NA | NA | NA | 75% | 0% | 75% | 28.57% | 0% | 28.57% |
| South America | 49 (12/37) | 33.17 | 1 | 3 | NA | NA | NA | 100% | 0% | 100% | 17.14% | 0% | 17.14% |
| Oceania | 1 (0/1) | 53 | 1 | 1 | NA | NA | NA | 100% | 0% | 100% | 0% | 0% | 0% |
| Total | 265 (78/187) | 35.74 | 17 | 30 | 50% | 5.56% | 55.56% | 10.59% | 0% | 10.59% | 14.07% | 0% | 14.07% |
Abbreviations: F, female; M, male; and NA, not available.
3.2.1. Asia
In Asia, there were 11 studies or case reports from eight countries including China,4 Japan,11 Singapore,12 Lebanon,15, 16 Turkey,7, 20, 31 India,26 South Korea,6 and Afghanistan.29 A total of 115 LV patients, of whom 36 were male (31.30%) and 79 were female (68.70%), with a mean age of 27.26 years were evaluated. The variant carriers were for 51.15% for MTHFR C677T, 43.86% for MTHFR A1298C, 82.9% for PAI‐1 ‐675 4G/5G, 1.67% for Prothrombin G20210A, and 6.45% in Factor V G1691A. The PAI‐1 A844G polymorphism has not yet been tested in Asian populations.
3.2.2. Europe
In Europe, there were eight articles involving 49 LV patients from five countries, including Portugal,23, 24, 30 Spain,32 Britain,33 Germany,5, 13 and France.18 The female to male ratio was 1.88:1, and the mean age of these LV patients was 40.43 years. The variant carrier rates were 64.28% for MTHFR C677T, 44% for MTHFR A1298C, 94.45% for PAI‐1 ‐675 4G/5G, 55.56% for PAI‐1 A844G, 15.79% for Prothrombin G20210A, and 21.74% for Factor V G1691A.
3.2.3. North America
In North America, seven studies or case reports were enrolled; one article was partially excluded because of a lack of description of heterozygosity or homozygosity.8 Six out of the seven articles were conducted in America,8, 14, 17, 19, 27, 28 the other was from Mexico.25 A total of 51 LV patients from North America, 13 males and 38 females with a mean age of 43 years, were tested for genetic variation. The total mutation carrier rates were 75% for Prothrombin G20210A and 28.57% for Factor V G1691A. There were only case reports for carriers of wild‐type MTHFR C677T and PAI‐1 ‐675 4G/5G. MTHFR A1298C and PAI‐1 A844G have not yet been tested in North America.
3.2.4. South America
There were three studies conducted in South America, all in Brazil,9, 10, 21 and two of them only vaguely described mutations in MTHFR, Prothrombin G20210A, and Factor V G1691A, was and so were partially ignored.9, 10 There were a total of 49 LV patients consisting of 12 males and 37 females, with a mean age of 33.17 years. The carrier rate of MTHFR C677T and Factor V G1691A was 64.29% and 17.14%, respectively.
3.2.5. Oceania
In Oceania, only one case report from Australia was identified. A 53‐year‐old female LV patient was tested for Prothrombin G20210A and Factor V G1691A and showed a heterozygous GA genotype for Prothrombin G20210A.22
4. DISCUSSION
LV mainly affects female patients with a female to male ratio of 2.4:1. The mean age ranges from 27.26 to 53 years in the five continents, with an earlier disease onset in Asian populations compared to LV patients in Europe, South America, and North America. Feng et al emphasised that the peak age at disease onset was much younger in Chinese LV patients than that in the published literature.40 Our review findings of the demographic data are consistent with the results of Feng et al and also provide the clinical characteristics of early onset in Asian LV patients.
Currently, hypercoagulability and abnormalities in coagulation function are considered the main mechanisms of pathogenesis in LV. Platelets, coagulation and anticoagulation system, and fibrinolysis system maintain dynamic balance and participate in physiological haemostasis and removal of abnormal blood clots. The six variants examined in this review are known to participate in the development of hypercoagulability and thrombophilia by acting on different pathways. MTHFR C677T and A1298C promote the prethrombotic state by affecting homocysteine levels through folate metabolism,41 the metabolites of which cause damage to vascular endothelial cells, whereas PAI‐1 ‐675 4G/5G and A844G, Prothrombin G20210A and Factor V G1691A influence the endogenous fibrinolytic system and coagulation function, increasing the risk of hypercoagulability. In this review, we found that PAI‐1 ‐675 4G/5G was the most common variant in LV patients, accounting for 85.26%. PAI‐1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most commonly existing variants in LV patients. The carrier rates of Prothrombin G20210A and Factor V G1691A were at relatively lower percentages.
The epidemiology of theses variants may vary depending on geography and ethnicity. Grouped by continents, LV patients from Asia and Europe demonstrated higher rates of PAI‐1 ‐675 4G/5G, with heterozygous 4G/5G being the major genotype that accounted for over 50% of variants. Although the total carrier rate of PAI‐1 A844G was more than 50% in European LV patients, up to now PAI‐1 A844G has only been detected in LV patients from Europe. PAI‐1 A844G has not been detected in LV patients from continents other than Europe. The carrier rate of MTHFR C677T was slightly higher in LV patients from Europe and South America. However, there was no significant difference in the MTHFR A1298C rate between LV patients in Asia and Europe. Prothrombin G20210A and Factor V G1691A showed relatively lower carrier rates; however, compared with LV patients from Asia, rates in LV patients from Europe, North America and South America were higher.
In this review, PAI‐1 ‐675 4G/5G was the most frequently detected variant and by influencing the expression of PAI‐1 it is involved in the pathogenesis of LV. The 4G allele results in a higher PAI‐1 expression level.36 Even though overexpression and enhanced activity of PAI‐1 have been detected in LV patients, its role in pathogenesis remains unclear.7, 42 PAI‐1 is probably involved in far more processes than just thrombosis; it may play roles in other pathophysiological processes and activities, such as cell adhesion, migration, and angiogenesis.43 Tissue‐type plasminogen activator (tPA) treatment targeting PAI‐1 is regarded as a promising therapy for LV.44 The tPA therapy was reported to be effective in LV patients with PAI‐1 ‐675 4G/4G homozygous genotype.17, 24 Therefore, PAI‐1 in LV pathogenesis warrants further study.
This review has explored the association between LV and genetic variation. However, few case control studies were enrolled, with case series and case reports being the main resource. Ideally, a large scale case‐control study of genetic variation in LV patients should be performed. And the multilocus effects by multifactor dimensionality reduction indicating gene‐gene interaction and gene‐environmental interactions may probably provide new insight into LV in further case‐control study.
5. CONCLUSIONS
In this review of six variants in LV patients, PAI‐1 ‐675 4G/5G was the most common and accounted for 85.26% (81/95) with heterozygous 4G/5G the major genotype; PAI‐1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Because the cause of LV is still unknown and no large sample case‐control study has been performed, our review of LV and its association with genetic variants may facilitate further basic research and clinical treatment. In particular, our regional analysis may enable further research to be targeted according to geography and ethnicity.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
Gao Y, Jin H. Livedoid vasculopathy and its association with genetic variants: A systematic review. Int Wound J. 2021;18:616–625. 10.1111/iwj.13563
DATA AVAILABILITY STATEMENT
Data sharing not applicable ‐ no new data generated
REFERENCES
- 1.Feldaker M, Hines EA Jr, Kierland RR. Livedo reticularis with summer ulcerations. AMA Arch Derm. 1955;72(1):31‐42. [DOI] [PubMed] [Google Scholar]
- 2.Pulido‐Pérez A, Avilés‐Izquierdo JA, Suárez‐Fernández R. Cutaneous vasculitis. Actas Dermosifiliogr. 2012;103(3):179‐191. [DOI] [PubMed] [Google Scholar]
- 3.Kerk N, Goerge T. Livedoid vasculopathy—current aspects of diagnosis and treatment of cutaneous infarction. J German Soc Dermatol. 2013;11(5):407‐410. [DOI] [PubMed] [Google Scholar]
- 4.Tsai TF, Yang CH, Chu CY, Liou YH, Hsiao WC, Lin CT, Wu LS. Polymorphisms of MTHFR gene associated with livedoid vasculopathy in Taiwanese population. J Dermatol Sci. 2009;54(3):214‐216. [DOI] [PubMed] [Google Scholar]
- 5.Marsch WC, Komatsuzaki S, Mueller A, Hagemann M, Lange D, Maemecke L, Villavicencio‐Lorini P, Hoffmann K. Livedoid vasculopathy: does hyperhomocysteinaemia play an aetiological role?. Eur J Dermatol. 2019;29(3):287‐293. [DOI] [PubMed] [Google Scholar]
- 6.Lee JS, Cho S. Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism in Korean livedoid vasculopathy patients. J Am Acad Dermatol. 2020. 10.1016/j.jaad.2020.05.158. [DOI] [PubMed] [Google Scholar]
- 7.Agirbasli M, Eren M, Eren F, Murphy SB, Serdar ZA, Seckin D, Zara T, Cem Mat M, Demirkesen C, Vaughan DE. Enhanced functional stability of plasminogen activator inhibitor‐1 in patients with livedoid vasculopathy. J Thromb Thrombolysis. 2011;32(1):59‐63. [DOI] [PubMed] [Google Scholar]
- 8.Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol. 2006;142(11):1413‐1418. [DOI] [PubMed] [Google Scholar]
- 9.Di Giacomo TB, Hussein TP, Souza DG, Criado PR. Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs—a prospective study. J Eur Acad Dermatol Venereol. 2010;24(11):1340‐1346. [DOI] [PubMed] [Google Scholar]
- 10.Da Costa Franca AFE, De Moraes Mazetto B, Orsi FA, De Paula EV, Machado TFGS, Souza EM, Annichino‐Bizzacchi JM. Adamts13 activity and von willebrand factor levels in patients with livedoid vasculopathy. Blood. 2009;114:22. [Google Scholar]
- 11.Nakamura S, Kishibe M, Nishi K, Hashimoto Y, Takeda K, Mizumoto T, Iizuka H. Livedoid vasculopathy; favorable clinical response with low dose warfarin. Eur J Dermatol. 2011;21(6):1011‐1012. [DOI] [PubMed] [Google Scholar]
- 12.Yong AA, Tan AW, Giam YC, Tang MB. Livedoid vasculopathy and its association with factor V Leiden mutation. Singapore Med J. 2012;53(12):e258‐e260. [PubMed] [Google Scholar]
- 13.Biedermann T, Flaig MJ, Sander CA. Livedoid vasculopathy in a patient with factor V mutation (Leiden). J Cutan Pathol. 2000;27(8):410‐412. [DOI] [PubMed] [Google Scholar]
- 14.Mirrakhimov AE, Velasquez Kho E, Ali A. Painless Livedoid vasculopathy in a patient with G20210A Prothrombin gene mutation. Case Rep Med. 2012;2012:910231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Abou Rahal J, Ishak RS, Otrock ZK, Kibbi AG, Taher AT. Livedoid vasculopathy in a patient with lupus anticoagulant and MTHFR mutation: treatment with low‐molecular‐weight heparin. J Thromb Thrombolysis. 2012;34(4):541‐544. [DOI] [PubMed] [Google Scholar]
- 16.Irani‐Hakime NA, Stephan F, Kreidy R, Jureidini I, Almawi WY. Livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity. J Thromb Thrombolysis. 2008;26(1):31‐34. [DOI] [PubMed] [Google Scholar]
- 17.Deng A, Gocke CD, Hess J, Heyman M, Paltiel M, Gaspari A. Livedoid vasculopathy associated with plasminogen activator inhibitor‐1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator. Arch Dermatol. 2006;142(11):1466‐1469. [DOI] [PubMed] [Google Scholar]
- 18.Khenifer S, Thomas L, Balme B, Dalle S. Livedoid vasculiltis associated with a double heterozygous Factor V Leiden and prothrombin G20210A gene mutations. Clin Exp Dermatol. 2009;34(8):e811‐e813. [DOI] [PubMed] [Google Scholar]
- 19.Calamia KT, Balabanova M, Perniciaro C, Walsh JS. Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation. J Am Acad Dermatol. 2002;46(1):133‐137. [DOI] [PubMed] [Google Scholar]
- 20.Kavala M, Kocaturk E, Zindanci I, Turkoglu Z, Altintas S. A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin. J Dermatolog Treat. 2008;19(2):121‐123. [DOI] [PubMed] [Google Scholar]
- 21.Criado PR, Alavi A, Halpern I, Sotto MN, Kirsner RS. Unilateral livedoid vasculopathy associated with involutional phase of cutaneous infantile hemangioma: the connection to coagulation disorders. Int J Low Extrem Wounds. 2013;12(4):306‐309. [DOI] [PubMed] [Google Scholar]
- 22.Anavekar NS, Kelly R. Heterozygous prothrombin gene mutation associated with livedoid vasculopathy. Australas J Dermatol. 2007;48(2):120‐123. [DOI] [PubMed] [Google Scholar]
- 23.Cardoso R, Gonçalo M, Tellechea O, Maia R, Borges C, Silva JA, Figueiredo A. Livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren's syndrome. Int J Dermatol. 2007;46(4):431‐434. [DOI] [PubMed] [Google Scholar]
- 24.Antunes J, Filipe P, André M, Fraga A, Miltenyi G, Marques Gomes M. Livedoid vasculopathy associated with plasminogen activator inhibitor‐1 promoter homozygosity (4G/4G) and prothrombin G20210A heterozygosity: response to t‐PA therapy. Acta Derm Venereol. 2010;90(1):91‐92. [DOI] [PubMed] [Google Scholar]
- 25.Castillo‐Martínez C, Moncada B, Valdés‐Rodríguez R, González FJ. Livedoid vasculopathy (LV) associated with sticky platelets syndrome type 3 (SPS type 3) and enhanced activity of plasminogen activator inhibitor (PAI‐1) anomalies. Int J Dermatol. 2014;53(12):1495‐1497. [DOI] [PubMed] [Google Scholar]
- 26.Shankar S, Vasudevan B, Deb P, Langer V, Verma R, Nair V. Livedoid vasculopathy—a vasculitic mimic. Arthritis Rheum. 2013;65(3):791. [DOI] [PubMed] [Google Scholar]
- 27.Davis MD, Wysokinski WE. Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: response to warfarin. J Am Acad Dermatol. 2008;58(3):512‐515. [DOI] [PubMed] [Google Scholar]
- 28.Gotlib J, Kohler S, Reicherter P, Oro AE, Zehnder JL. Heterozygous prothrombin G20210A gene mutation in a patient with livedoid vasculitis. Arch Dermatol. 2003;139(8):1081‐1083. [DOI] [PubMed] [Google Scholar]
- 29.Brockley J, Recica H, Tso S, Ilchyshyn A. Multiple exquisitely painful leg ulcerations in a teenager. Br J Dermatol. 2013;169:28 [Google Scholar]
- 30.Morais P, Mota A, Azevedo F, Almeida M. Livedoid vasculopathy with hyperhomocysteinemia: therapeutic approach. J Am Acad Dermatol. 2010;62(3):AB26. [Google Scholar]
- 31.Sahin N, Kisaarslan AP, Cicek SO, Sözeri B, Akcin ME, Gunduz Z, Dusunsel R, Poyrazoglu MH. Hyperbaric oxygen therapy in a livedoid vasculopathy: A case report. Pediatr Rheumatol. 2017;15(Suppl 2):64‐65. 10.1186/s12969-017-0185-x. [DOI] [Google Scholar]
- 32.Vázquez MS, Nevarez O, Martin RF. Livedoid vasculopathy (LV) associated with hyperhomocysteinemia due to a homozygous methylene tetrahydrofolate reductase (MTHFR) C677T mutation: a case report. J Am Acad Dermatol. 2018;79(3):A178. [Google Scholar]
- 33.Wong M, Ramakrishnan R, Teixeira F, Ali I. A case of livedoid vasculopathy associated with a raised factor VIII level: A case report and review of the literature related to coagulation disorders. Br J Dermatol. 2011;165:13‐14.21919898 [Google Scholar]
- 34.Devlin AM, Clarke R, Birks J, Evans JG, Halsted CH. Interactions among polymorphisms in folate‐metabolizing genes and serum total homocysteine concentrations in a healthy elderly population. Am J Clin Nutr. 2006;83(3):708‐713. [DOI] [PubMed] [Google Scholar]
- 35.Levin BL, Varga E. MTHFR: addressing genetic counseling dilemmas using evidence‐based literature. J Genet Couns. 2016;25(5):901‐911. [DOI] [PubMed] [Google Scholar]
- 36.Eriksson P, Kallin B, van 't Hooft FM, Bavenholm P, Hamsten A. Allele‐specific increase in basal transcription of the plasminogen‐activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995;92(6):1851‐1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Hultman K, Tjarnlund‐Wolf A, Odeberg J, Eriksson P, Jern C. Allele‐specific transcription of the PAI‐1 gene in human astrocytes. Thromb Haemost. 2010;104(5):998‐1008. [DOI] [PubMed] [Google Scholar]
- 38.Ceelie H, Spaargaren‐van Riel CC, Bertina RM, Vos HL. G20210A is a functional mutation in the prothrombin gene; effect on protein levels and 3′‐end formation. J Thromb Haemost. 2004;2(1):119‐127. [DOI] [PubMed] [Google Scholar]
- 39.Kujovich JL. Factor V Leiden thrombophilia. Genetics Med. 2011;13(1):1‐16. [DOI] [PubMed] [Google Scholar]
- 40.Feng S, Su W, Jin P, Shao C. Livedoid vasculopathy: clinical features and treatment in 24 Chinese patients. Acta Derm Venereol. 2014;94(5):574‐578. [DOI] [PubMed] [Google Scholar]
- 41.Liew SC, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015;58(1):1‐10. [DOI] [PubMed] [Google Scholar]
- 42.Agirbasli M, Goktay F, Peker I, Gunes P, Aker FV, Akkiprik M. Enhanced mRNA expression of plasminogen activator inhibitor‐1 in livedoid vasculopathy lesions. Cardiovasc Ther. 2017;35(3):e12255. 10.1111/1755-5922.12255. [DOI] [PubMed] [Google Scholar]
- 43.Gao Y, Jin H. Plasminogen activator inhibitor‐1: a potential etiological role in livedoid vasculopathy. Int Wound J. 2020;17:1902‐1908. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Micieli R, Alavi A. Treatment for Livedoid vasculopathy: a systematic review. JAMA Dermatol. 2018;154(2):193‐202. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable ‐ no new data generated