Nav: Home

Two blood-clotting disorders with different causes interact synergistically

September 06, 2019

BIRMINGHAM, Ala. - Two rare but potentially deadly blood-clotting diseases, namely thrombotic thrombocytopenic purpura, or TTP, and hemolytic uremic syndrome, or HUS, show similar pathologies -- a multitude of painful blockages in small blood vessels that cause varying degrees of organ injury throughout the body. However, the two disorders have distinctbiological mechanisms.

Now, in a preclinical study published in the journal Blood, researchers have found a synergistic connection, or crosstalk, between the two disorders. Such a linkage between the two thrombotic microangiopathic disorders "may provide a rationale for a more targeted therapeutic intervention in patients with refractory thrombotic microangiopathy," said X. Long Zheng, M.D., Ph.D., who led a team of researchers at the University of Alabama at Birmingham.

At UAB, Zheng is the Robert B. Adams Professor of Pathology and Division Director of Laboratory Medicine in the Department of Pathology, UAB School of Medicine.

TTP is mostly caused by autoimmune antibodies that attack one of the body's own enzymes, ADAMTS13, first identified and cloned by Zheng in 2001. HUS, particularly the atypical form, is caused mostly by improper activation of complement through the alternative complement pathway, a part of the immune system that helps, or "complements," the clearance of infecting microbes or damaged cells from the body.

Some clinical evidence from patients with TTP led Zheng and colleagues at UAB and the University of Pennsylvania to test the hypothesis that there may be a synergy between ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy.

They used two existing mouse lines -- one that completely lacks ADAMTS13 and one that has a heterozygous mutation in complement factor H gene, or cfh, where the mouse has one gene with unmutated cfh and one with the mutated cfh. Mammals like humans and mice have two copies of each chromosome, so there are two copies of the gene cfh.

These two lines are known as Adamts13-/-, which completely lacks the enzyme ADAMTS13, and cfhW/R, where the W indicates the amino acid tryptophan in the normal CFH protein from the unmutated gene, and R indicates that the tryptophan has been replaced by an arginine in the mutant CFH protein. Those two mouse lines remain completely asymptomatic for thrombotic microangiopathy despite the presence of occasional microvascular thrombi in various organ tissues on histology analysis.

To look for interactions between the pathogenic pathways for TTP and atypical HUS, the researchers generated a third strain, which showed the signs and symptoms, and laboratory evidence, of thrombotic microangiopathy.

They found that mice carrying both Adamts13-/- and cfhW/R showed thrombocytopenia, which is low counts of blood platelets because the platelets have left circulating blood to form blood clots. The mice also had low plasma haptoglobin and increased fragmentation of erythrocytes in peripheral blood smears, the signs of red blood cells that were broken trying to squeeze past blood clots. The mice also had increased plasma levels of lactate dehydrogenase activity, blood urea nitrogen and creatinine, signs of general organ damage and kidney damage from clots, and these mice also had an increased mortality rate.

Strains of mice that had the cfh mutation in both genes, known as the homozygous mutation cfhR/R, with or without Adamts13-/-, developed an even more severe thrombotic microangiopathy. The mortality rate in mice with both Adamts13-/-and cfhR/R was significantly higher than that in mice with cfhR/R alone.

All three affected mouse strains had microscopically visible disseminated platelet-rich thrombi in terminal arterioles and capillaries of major organ tissues, including brain, heart, lungs, kidney, liver and intestine.

"Altogether," Zheng said, "our results support the synergistic effects of ADAMTS13 deficiency and complement activation in the pathogenesis of thrombotic microangiopathy. The results may help design a potentially novel strategy to treat the refractory thrombotic microangiopathy in the future."
-end-
Co-authors with Zheng of the report, "Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy," are Liang Zheng, Di Zhang and Wenjing Cao, Division of Laboratory Medicine, UAB Department of Pathology; and Wen-Chao Song, the University of Pennsylvania Perelman School of Medicine, Philadelphia.

Support came from the National Heart, Lung, and Blood Institute grant HL126724, the Answering TTP Foundation, and the American Heart Association postdoctoral fellowship grant 18POST33960098.

University of Alabama at Birmingham

Related Gene Articles:

Gene therapy/gene editing combo could offer hope for some genetic disorders
A hybrid approach that combines elements of gene therapy with gene editing converted an experimental model of a rare genetic disease into a milder form, significantly enhancing survival, shows a multi-institutional study led by the University of Pennsylvania and Children's National Hospital in Washington, D.C.
Unraveling gene expression
EPFL chemists have uncovered the first steps in the process of gene expression by showing how the protein Rap1 pries open the tightly wound, compacted structure of DNA in the cell to gain access to specific genes.
Gene coding error found in rare, inherited gene cof lung-scarring disorder linked to short telomeres
By combing through the entire genetic sequences of a person with a lung scarring disease and 13 of the person's relatives, Johns Hopkins Medicine researchers say they have found a coding error in a single gene that is likely responsible for a rare form of the disease and the abnormally short protective DNA caps on chromosomes long associated with it.
The two faces of the Jekyll gene
Genes which are specific to a species or group of species can reflect important genetic changes within lineages.
Gene therapy vectors carrying the telomerase gene do not increase the risk of cancer
Researchers from the Spanish National Cancer Research Centre (CNIO) have shown in a new study that the gene therapy with telomerase that they have developed, and which has proven to be effective in mice against diseases caused by excessive telomere shortening and ageing, does not cause cancer or increase the risk of developing it, even in a cancer-prone setting.
Blindness gene discovered
Researchers from UNIGE have investigated a recessive genetic disorder that destroys the eyes from developing and results in childhood blindness.
Gene editing just got easier
An international team of researchers has made CRISPR technology more accessible and standardized by simplifying its complex implementation in a way that offers a broad platform for off-the shelf genome engineering.
Gene regulation: Risk-free gene reactivation
Chemical modification of DNA subunits contribute to the regulation of gene expression.
No gene is an island
Genes do not exist in isolation. Like beads on a string, they sit next to each other on the chromosomes.
New disease gene for axon degeneration identified through international gene matching
Research group from the University of Helsinki, Finland, has identified a new disease gene for early-onset axonal neuropathy and mild intellectual disability through an international research network, which was brought together by 'Tinder for geneticists'.
More Gene News and Gene Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

TED Radio Wow-er
School's out, but many kids–and their parents–are still stuck at home. Let's keep learning together. Special guest Guy Raz joins Manoush for an hour packed with TED science lessons for everyone.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.