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 for 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 glycoprotein – 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:

When 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), 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]


Genetic variants:

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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 have as much of an impact on people with type O blood.

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.

Stop smoking: If you carry the variants that cause lower ADAMTS13, this is a really good reason not to smoke. Cigarette smoking also decreases ADAMTS13, and the combination could increase clot risk.[ref]

Know and act: Important to know that TTP can usually be successfully treated if you seek medical help quickly.

Signs and symptoms of thrombotic thrombocytopenic purpura (TTP) include:[ref]

  • petechiae – pinpoint size dots on the skin caused by bleeding under the skin
  • fatigue
  • paleness
  • fast heart rate
  • purplish bruises on the skin
  • headache, confusion, stroke symptoms
  • fever

 

Learn more:
Here’s a video on how a clot forms, if you are interested:

 


Related Articles and Topics:

Top 10 Genes to Check in Your Genetic Raw Data
Wondering what is actually important in your genetic data? These 10 genes have important variants with a big impact on health. Check your genes (free article).

Blood clots, platelets, and adenoviruses
Platelets are an important part of your immune response. This ties together with a low platelet count (thrombocytopenia) and relates to blood clots (thrombosis) in some instances.  

Viral Immunity: How your genes protect you
Your genetic variants shape your immune system and give you superpowers against some pathogens – and perhaps more susceptible to others.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.