ADAMTS13 and VWF Genetic Variants: blood clots and thrombocytopenia

When you get a cut, it activates a cascade of events to form a clot. Platelets rush in to join together with the lining of the blood vessel, plugging up the leak. Fibrinogen is activated to shore up the clot, and then a continual breaking down, remodeling, and reforming of the clot happens as the wound heals.

This process of forming a clot and activating platelets involves a number of proteins made by the body. Genetic variants, of course, cause some people to have different clotting factors, which can increase the risk of small blood clots.

This article digs into just two of the genes involved in creating a blood clot. I’ll explain how a low platelet count can be caused by increased platelet activation due to increased von Willebrand factor or decreased ADAMTS13. If you are interested, this may tie in with my article on Adenovirus-vector vaccines, blood clots, and platelets. 

Von Willebrand Factor: essential in clotting

Von Willebrand factor is one component of the blood clotting cascade. Epithelial cells that line the blood vessels release von Willebrand factor, which can bind to platelets. Platelets can also release von Willebrand factor (VWF).

VWF is a protein that can have multiple sizes, such as ultra-large multimeric glycoproteins – meaning that it can be a bigger conglomeration of von Willebrand factor protein, or it can be broken up into smaller molecules.

Size is important here. Ultra-large von Willebrand factor is very reactive and could cause unwanted blood clotting. The body modulates the reactivity by breaking it into smaller fragments, which are less reactive.[ref]

Blood type and VWF:

While von Willebrand factor is being synthesized, it interacts with certain glycans that are also important in your blood type.

People with type O blood have lower average levels of von Willebrand factor.[ref] A rare blood type called Bombay blood group is linked to even lower VWF levels.[ref]

Lower levels of VWF in people with type O blood link to a slightly lower risk of heart disease and strokes due to clots.[ref]

ADAMTS13: preventing too much clotting

The ADAMTS13 gene encodes an enzyme that cleaves or breaks apart von Willebrand factor. This protein is synthesized in the liver, platelets, vascular endothelial cells, and glial cells.[ref]

The amount of ADAMTS13 in the plasma is significantly inhibited by inflammatory cytokines such as TNF-alpha, IL-6, and interferon-gamma.[ref]

Reduced ADAMTS13 results in more ultra-large VWF in circulation.[ref]

A deficiency in ADAMTS13 can increase the risk for small clots to form in small blood vessels, known as platelet microthrombi. Low levels of ADAMTS13 can also increase the risk of heart attacks and strokes caused by blood clots.[ref][ref]

A genetic disease called Upshaw-Schulman Syndrome is caused by mutations in ADAMTS13. It causes the genetic form of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is characterized by a low platelet (thrombocytopenia), and damaged red blood cells (microangiopathic hemolytic anemia).

TPP can either be an autoimmune disease (antibodies against ADAMTS13) or due to rare genetic mutations in ADAMTS13.

The decrease in ADAMTS13 allows for more of the ultra-large von Willebrand factor.

This leads to small blood clots in the smallest blood vessels due to platelet activation and aggregation. After activation, the body doesn’t reuse platelets. Instead, they are destroyed and cleared out in the liver or spleen.[ref]

Thus the decreased ADAMTS13 leads to both blood clots and low platelet levels (thrombocytopenia).

Thrombotic thrombocytopenic purpura due to an ADAMTS13 mutation is a rare genetic disease with a prevalence of 4 in a million. Most cases of TTP are due to an autoimmune cause, and pregnancy is one trigger of TTP.[ref][ref]

There is a higher than normal (but still rare) prevalence in Norway of ADAMTS13 mutations.[ref]


ADAMTS13 and VWF Genotype Reports:

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Genetic variant in the ADAMTS13 gene:

Check your genetic data for rs28647808 Pro618Ala (23andMe v5):

  • C/C: typical
  • C/G: lower ADAMTS13, increased risk of kidney and cardiovascular complications in diabetes
  • G/G: rare, lower ADAMTS13, increased risk of kidney and cardiovascular complications in diabetes[ref][ref]

Members: Your genotype for rs28647808 is .

Check your genetic data for rs685523 A900V (AncestryDNA):

  • C/C: typical
  • C/T: lower ADAMTS13; increased risk of cardiac-related death
  • T/T: lower ADAMTS13; increased risk of cardiac-related death[ref]

Members: Your genotype for rs685523 is .

 

Rare mutations that significantly affect ADAMTS13:  Please note that 23andMe data is not guaranteed to be clinically accurate, so always get another test to double-check the results before making medical decisions.

Check your genetic data for rs142572218 p.R1177Q (23andMe v5; AncestryDNA):

  • C/C: typical
  • C/T: carrier of a pathogenic mutation in ADAMTS13, Upshaw-Schulman syndrome[ref][ref]; linked to pregnancy-induced TTP[ref]

Members: Your genotype for rs142572218 is .

Check your genetic data for rs148312697 D187H (23andMe v5):

  • C/C: reduced ADAMTS13 (really rare)
  • C/G: reduced ADAMTS13[ref][ref][ref]
  • G/G: typical

Members: Your genotype for rs148312697 is .

 

Genetic variants in VWF (von Willebrand factor) gene:

Variants in the VWF gene can increase the amount of von Willebrand factor that is likely to be produced. (There are also variants that decrease VWF, not listed here)

Keep in mind that people with type O blood have slightly lower VWF levels, on average.[ref] Thus, the following genetic variants may not impact people with type O blood as much.

Check your genetic data for rs1063856 (23andMe v4; AncestryDNA):

  • T/T: typical
  • C/T: likely to have slightly higher Von Willebrand factor
  • C/C: likely to have increased Von Willebrand factor, slightly increased risk of blood clots.[ref][ref]

Members: Your genotype for rs1063856 is .

Check your genetic data for rs1063857 (23andMe v4; AncestryDNA):

  • A/A: typical
  • A/G: likely to have slightly higher von Willebrand factor
  • G/G: likely to have increased von Willebrand factor[ref]

Members: Your genotype for rs1063857 is .


Lifehacks:

Take the information about your blood clot genetic risk factors as a ‘heads up’ and seek treatment for symptoms of a blood clot. Symptoms of a blood clot can include heat, swelling, or pain in an arm or leg. Clots can also cause trouble breathing, edema, or chest pain.

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Related Articles and Topics:

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Blood clots, platelets, and adenoviruses
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Your genetic variants shape your immune system and give you superpowers against some pathogens – and perhaps more susceptible to others.

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Roose, Elien, et al. “Anti-ADAMTS13 Antibodies and a Novel Heterozygous p.R1177Q Mutation in a Case of Pregnancy-Onset Immune-Mediated Thrombotic Thrombocytopenic Purpura.” TH Open: Companion Journal to Thrombosis and Haemostasis, vol. 2, no. 1, Jan. 2018, pp. e8–15. PubMed, https://doi.org/10.1055/s-0037-1615252.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.