The study find that the 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. But 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; but a part of the immune system that helps, or “complements;” the clearance of infecting microbes or damaged cells from the body. Therefore 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.
Alternative complement pathway
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. Because These two lines are know 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the amino acid tryptophan in the normal CFH protein from the unmutated gene; and R indicates that the tryptophan has been replaced by an arginine in the mutant CFH protein.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. Therefore 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.