Those with alpha-1 antitrypsin deficiency (AATD) caused by 2 copies of the abnormal Z allele of the SERPINA1 gene have a 2.2 fold increase in the risk of venous thromboembolism, according to a new study published in the Journal of Thrombosis and Haemostasis.

Based on this finding, the authors of the study concluded that genetic screening of venous thromboembolism should include Z allele genotyping. Moreover, patients with AATD due to a homozygous ZZ allele should be monitored for venous thromboembolism, the authors suggested.

There are 2 abnormal SERPINA1 alleles that can cause AATD. These are the S and Z alleles. The most common form of AATD is caused by homozygous Z alleles.

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In the present study, a team of researchers in Denmark was led by Shoaib Afzal, MD, PhD. They prospectively analyzed 107,075 people from the Copenhagen General Population Study to test the association between the Z allele and the risk of venous thromboembolism.

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The results showed that during follow-up, venous thromboembolism was diagnosed 6649 times in noncarriers, 436 times in heterozygotes, and 10 times in homozygotes. The authors calculated that the absolute risk of venous thromboembolism associated with the ZZ genotype was 7.8%. 

They proposed that the Z allele may be increasing the risk of venous thromboembolism by causing changes in the hemostatic system.

The Z allele leads to a substitution of the lysine amino acid for glutamic acid at position 342 in the AAT protein. This causes the protein to misfold and accumulate in hepatocytes, causing damage. It also means there is not enough AAT in the plasma.

Since the role of AAT is to inhibit neutrophil elastase, not enough AAT in the plasma means elastin is broken down by elastase in the lungs, which ultimately leads to chronic obstructive pulmonary disease.


Riis J, Nordestgaard BG, Afzal S. α1 -antitrypsin Z allele and risk of venous thromboembolism in the general population. J Thromb Haemost. Published online October 18, 2021. doi:10.1111/jth.15556