Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura.
OBJECTIVE
The metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) regulates the size of von Willebrand factor multimers. A deficiency in ADAMTS13 activity is associated with the life-threatening disease thrombotic thrombocytopenic purpura (TTP). The vast majority of patients have acquired TTP, where circulating anti-ADAMTS13 autoantibodies are causative for the decreased ADAMTS13 activity. Current treatment consists of plasma exchange, but improved therapies are highly warranted.


RESULTS
We have developed a new rat model mimicking various aspects of acquired TTP to investigate the therapeutic efficacy of human recombinant ADAMTS13. A polyclonal antibody against ADAMTS13 completely blocked endogenous rat ADAMTS13 activity in Sprague-Dawley rats. When TTP was triggered using recombinant von Willebrand factor, the animals displayed severe TTP-like symptoms, such as thrombocytopenia, hemolytic anemia, and von Willebrand factor-rich thrombi in the kidneys and brain. Subsequent injection of 400, 800, or 1600 U/kg recombinant ADAMTS13 prevented full development of these symptoms. Analysis of plasma samples confirmed that recombinant ADAMTS13 was able to override circulating anti-ADAMTS13 inhibitory antibodies, resulting in restoration of ADAMTS13 activity and degradation of ultralarge von Willebrand factor multimers.


CONCLUSIONS
Recombinant ADAMTS13 was shown to be effective in averting severe acquired TTP-like symptoms in rats and holds promising value for the treatment of this severe and life-threatening disease in humans.
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Claudia
C
Tersteeg
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Alexandra
A
Schiviz
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Simon F
SF
De Meyer
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Barbara
B
Plaimauer
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Friedrich
F
Scheiflinger
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.). Hanspeter.Rottensteiner@baxalta.com.
Hanspeter
H
Rottensteiner
From the Laboratory for Thrombosis Research, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium (C.T., S.F.D.M., K.V.); and Baxalta Innovations GmbH, Vienna, Austria (A.S., B.P., F.S., H.R.).
Karen
K
Vanhoorelbeke
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D000071120:ADAMTS13 Protein; D000743:Anemia, Hemolytic / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D000906:Antibodies; D004195:Disease Models, Animal; D005240:Feasibility Studies; D006801:Humans; D008297:Male; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index; D013997:Time Factors; D014841:von Willebrand Factor
D000906:Antibodies; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; C512067:Adamts13 protein, rat
ADAMTS13; VWF; acquired TTP; animal model; treatment