Disease: Von Willebrand Disease (VWD)

Patient(s): Found in 2 families

Variant: VWF NM_000552.5: c.2311A>G, p.(M771V Homozygous variant in exon 18 (VWF D' domain; 8 residues down from proteolytic VWFpp furin cleavage site)

Family: In family 1 there are 4 homozygous patients (2 male and 2 female), and one heterozygous patient (1 female). The affected females are denoted as person 1 and person 4 and the affected males are person 2 and person 3. There are three WT family members (1 female and 2 male), grandparents of these members are of unknown genotype including a daughter of an affected female and a WT male. Note here that in the family a p.R2663P variant has co-segregated with the above-mentioned variant but is not suspected to be the pathogenic driver of resulting bleeding tendency.

In family 2 the parents of the homozygous affected male are of unknown genotype. The affected male is denoted as person 7.

Phenotypes: Person 1- nose bleed, skin bleed, GI bleeding, oral cavity bleeds, Menorrhagia, muscle bleeding, and joint bleeding. Receives on-demand treatment for bleeding.

Person 2-Nose bleed, skin bleed, bleeding from small wounds, oral cavity bleeds, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment, reduced to on-demand treatment after a few years.

Person 3-Nose bleed, skin bleed, oral cavity bleeds, bleeding after tooth extraction, muscle bleeding. Receives on-demand treatment for bleeding phenotype.

Person 4- Nose bleed, bleeding from small wounds, oral cavity bleed, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment that was increased after her menarche.

Person 7- Nose bleed, oral cavity bleeds, bleeding after surgery or trauma, joint bleeding. Previously on prophylaxis, now managing bleeding with on-demand treatment.

Note that both the p.R2663P co-segregated variant and p.M771V variant are reported in NCBI dbSNP database but functional effect not yet established.

NGS confirmed the genotype of all study participants.

Disease: Platelet-type Von-willebrand Disorder (PT-VWD)

Patient: 17 yo, male, adopted

Variant: GP1BA NM_000173.7: c:580C>T p.(P.Leu194Phe), Heterozygous, gain-of-function

Phenotypes: moderate bleeding phenotype, ISTH-BAT bleeding score of 3, recurrent epistaxis, easy bruising, mild thrombocytopenia

Family: Adopted, no other family history mentioned, segregation studies not performed.

Genetic analysis performed: found variant in GP1BA, results obtained by sanger sequencing.

Variant present in gnomAD(rs368111193): low allele frequency, contradictory classifications

Variant is not present in ClinVar, LOVD, or HGMD databases

According to this paper, ACMG guidelines classified this variant as a VUS.

This paper entered it into Clinvar (var ID 1693270)

Disease: mild haemophilia A, influencing VWF levels

Patient: 20 yo, Female

Variant1: F8 NM_000132.3: c.1127T>G: p. Val376Gly (Exon 8, current clinvar interpretation not available)

Variant 2: F8 NM_000132.3: c.3780C>G: p. Asp1260Glu (Exon 14, current ClinVar interpretation is benign)

Variant 3: VWF NM_000552.5: c.1415A>G:p.His484Arg (Exon 13, current ClinVar interpretation is Benign/likely Benign)

Variant 4: VWF NM_000552.5: c.2365A>G:p.Thr789Ala (Exon 18, current ClinVar interpretation is Benign/ likely Benign)

Variant 5: VWF NM_000552.5: c.2771G>A:p.Arg924Gln (Exon 21, current ClinVar interpretation is conflicting interpretations of pathogenicity (VUS-3)(Benign-4)(Likely benign-1))

Variant 6: VWF NM_000552.5: c.4141A>G:p.Thr1381Ala (Exon 28, current ClinVar interpretation is Benign/ Likely Benign)

Variant 7: VWF NM_000552.5: c.6532G>T:p.Ala2178Ser (Exon 37, Conflicting interpretations of pathogenicity: (VUS-1) (Likely Benign-1))

Variant 8: F5 NM_000130.5: c.2773A>G:p.Lys925Glu (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 9: F5 NM_000130.5: c.2594A>G:p.His865Arg (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 10: F5 NM_000130.5: c.2573A>G:p.Lys858Arg (Exon 13, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 11: F5 NM_000130.5: c.5290A>G:p.Met1764Val (Exon 16, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 12: F13A1 NM_000129.4: c.103G>T:p.Val35Leu (Exon 2, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-3))

Variant notes: All are heterozygous

Both variants in F8 are linked to reports associated with haemophilia, though second variant is considered benign.

Phenotypes: History of bleeding (Heavy mentrual bleeding since menarche)(Treated with transdermal oestrogen and Levonorgestel), iron deficiency anaemia. High Janssen score for pictorial blood assessment. Gum bleeding lasting longer than 10 minutes(Treated with local application of tranexamic acid), recurrent nosebleeds, high score for ISTH and BAT assessments. Decrease in VWF:Ag ratio, VWF:CB ratio decreased, VWF: GPIbR ratio decreased

Family: Maternal grandfather possibly haemophiliac, mother asymptomatic

Disease: Von Willebrand Disease (VWD) Type 2A

Patient: 31 yo, Female

Variant1: VWF NC_000012.12: c.875-5T>Gdel, p.(Ser292_Glu333delinsLys) Causes complete exon 8 skipping

Variant2: VWF NM_000552.5: c.813C>G, p.(Tyr271*)

Phenotypes: History of bleeding (epistaxis, uncontrollable by conventional hemostatic treatment), Easy bruising, gum bleeding, excessive menstrual bleeding, mild decrease in plasma VWF:Ag, severe impairment in VWF function, VWF:Ab/VWF:Ag ratio decreased, VWF:CB/VWF:Ag ratio decreased, FVIII:C lvs slighly below normal range

Family: Son had bleeding diathesis and spontaneous epistaxis (less severe than proband), normal parents

In silico data available: SpliceAI delta score of 0.51 for loss of splice acceptor caused by variant 1

Alamut showed small to moderate effects of the variant on normal splicing of VWF

NetGene2 showed weak strength of 3' splice sites in exon 8

SpliceAid2 showed TIA-1 and TIAL 1, which bind to U-rich motifs and facilitate 5' splice site recognition where destroyed in the mutated sequence

Disease: Von-willebrand Disorder

Patient: 21 yo, female, Italian descent

Variant: VWF NM_000552.5 c:C3379 > T p.(P1127S), homozygous

Heterozygous and Homozygous polymorphic variant in exon 25

Phenotypes: Bleeding Score System (BSS) = 3 minor bruising normal menstrual bleeding

Family: (father paternity confirmed) Father suffered from rectorrhagia for rectal polyps Mother (same variant, heterozygous) has heavy menstrual bleeding, epistaxis events up to age 30, BBS= 2

Present in dbSNP (rs139579968) MAF in European pop = 0.0001-0.0004

Present in gnomAD, said to be present in 2 transcripts in VWF 40 alleles are present

Predictions: listed with PolyPhen-2 and SIFT = probably damaging to protein expression/function

CADD (score =33) and REVEL(score = 0.748) suggest deleterious effect of pathogenic variant

I-TASSER showed large difference in 3D configuration of sequences differing by a single amino acid.

Patient phenotypes listed: mild bleeding history normal platelet number increased mean platelet volume increased RIPA (les than typical PT-VWD) enhanced binding of VWF to platelets (assessed by flow cytometry)

Has functional and HXMS data to support classification to pathogenic

for - example - social media platforms bleeding content producers - Meta - Facebook - Instagram

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via 1949 April 06, Naugatuck Daily News, Walter Winchell In New York, Page 4, Column 5, Naugatuck, Connecticut. (NewspaperArchive)

https://quoteinvestigator.com/2011/09/14/writing-bleed/

• for:holistic medicine - example - oral microbiome and colon cancer, oral microbiome - colon cancer, bleeding gums - colon cancer, gingivitus - colon cancer, periodontitis - colon cancer, bloodstream translocation, complexity - example - human body - colon cancer - oral microbiome

• comment

  • colon cancer starts in the mouth!

• references

  • Oral-Intestinal Microbiota in Colorectal Cancer: Inflammation and Immunosuppression (2022)

    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8824753/
    • Abstract
      • It is widely recognized that microbial disorders are involved in the pathogenesis of many malignant tumors.
      • The oral and intestinal tract are two of the overriding microbial habitats in the human body. Although they are anatomically and physiologically continuous, belonging to the openings at both ends of the digestive tract, the oral and intestinal microbiome do not cross talk with each other due to a variety of reasons, including
        • intestinal microbial colonization resistance and
        • chemical barriers in the upper digestive tract.
      • However, this balance can be upset in certain circumstances, such as
        • disruption of colonization resistance of gut microbes,
        • intestinal inflammation, and
        • disruption of the digestive tract chemical barrier.
      • Evidence is now accruing to suggest that the oral microbiome can colonize the gut, leading to dysregulation of the gut microbes.
      • Furthermore, the oral-gut microbes create an
        • intestinal inflammatory and
        • immunosuppressive microenvironment
      • conducive to
        • tumorigenesis and
        • progression of colorectal cancer (CRC).
      • Here, we review
        • the oral to intestinal microbial transmission and
        • the inflammatory and immunosuppressive microenvironment, induced by oral-gut axis microbes in the gut.
      • A superior comprehension of the contribution of the oral-intestinal microbes to CRC provides new insights into the prevention and treatment of CRC in the future.

  • Insights into oral microbiome and colorectal cancer – on the way of searching new perspectives (2023)

    • https://www.frontiersin.org/articles/10.3389/fcimb.2023.1159822/full
    • Abstract
      • Microbiome is a keystone polymicrobial community that coexist with human body in a beneficial relationship.
      • These microorganisms enable the human body to maintain homeostasis and take part in mechanisms of defense against infection and in the absorption of nutrients.
      • Even though microbiome is involved in physiologic processes that are beneficial to host health, it may also cause serious detrimental issues.
      • Additionally, it has been proven that bacteria can migrate to other human body compartments and colonize them even although significant structural differences with the area of origin exist.
      • Such migrations have been clearly observed when the causes of genesis and progression of colorectal cancer (CRC) have been investigated.
      • It has been demonstrated that the oral microbiome is capable of penetrating into the large intestine and cause impairments leading to dysbiosis and stimulation of cancerogenic processes.
      • The main actors of such events seem to be oral pathogenic bacteria belonging to the red and orange complex (regarding classification of bacteria in the context of periodontal diseases), such as
        • Porphyromonas gingivalis and
        • Fusobacterium nucleatum respectively,
      • which are characterized by significant amount of cancerogenic virulence factors.
      • Further examination of oral microbiome and its impact on CRC may be crucial on early detection of this disease and would allow its use as a precise non-invasive biomarker.

Male, Victoria. ‘Menstrual Changes after Covid-19 Vaccination’. BMJ 374 (16 September 2021): n2211. https://doi.org/10.1136/bmj.n2211.

Association, N. S. and P. (n.d.). AstraZeneca covid-19 vaccine may hinder blood clotting in rare cases. New Scientist. Retrieved 18 June 2021, from https://www.newscientist.com/article/2280446-astrazeneca-covid-19-vaccine-may-hinder-blood-clotting-in-rare-cases/

ReconfigBehSci. ‘@sarahflecke “Reports Emerging of Rare Types of Multiple Thrombosis, Bleeding, and Thrombocytopenia .. Similar to Disseminated Intravasc. Coagulation ... in Otherwise Healthy Individuals Shortly after Receiving ..AstraZeneca ..Vaccine. These Outcomes Are Not Included in the Present Analysis.”’ Tweet. @SciBeh (blog), 2 April 2021. https://twitter.com/SciBeh/status/1377984798422077446.

I kind of like this term for it's visceral nature, but it doesn't seem as fitting as "bleeding"

So could this also be formulated as "matter comes to matter" through the +s or through "bleeding"?