Abstract
Heparin-induced thrombocytopenia (HIT) represents a complex pathologic syndrome including all components of the hemostatic system and inflammatory response. ADAMTS-13 is a metalloprotease which mediates the cleavage of von Willebrand factor (vWF) multimers. A deficiency or decreased activity of this protease may result in a TTP-related syndrome manifested by the development of intravascular platelet aggregates, thrombocytopenia, endothelial dysfunction and the deposition of vWF at thrombotic sites. Several recent reports have described decreased functionality of ADAMTS-13 in patients with HIV. This may be due to antibodies than inhibit ADAMTS-13. HIT is characterized by the generation of heparin-induced anti-heparin platelet factor 4 antibodies which are molecularly and functionally heterogeneous. No data is available on the effect of these antibodies on ADAMTS-13. However, increased vWF levels and the generation of ultrahigh molecular weight vWF multimers have been reported in HIT patients. This study was designed to determine the ADAMTS-13 antigen levels in HIT patient plasma samples (n=30) prior to and after treatment with the direct anti-thrombin agent argatroban (ARG 911 study). Plasma samples from normal healthy volunteers (n=30) were used as controls for comparison purposes. ADAMTS-13 antigen levels were quantitated using a newly developed ELISA method from American Diagnostica (Stamford, CT). vWF antigen levels were also measured using an ELISA-based method. The levels of ADAMTS-13 and vWF antigen were reported as percent normal based on the results obtained with the samples from healthy volunteers. The baseline ADAMTS-13 antigen levels varied widely among the HIT patients enrolled in the ARG 911 trial (30–180% NHP) with a mean of 62 ± 24% NHP. On treatment day 1, no significant changes were noted in the ADAMTS-13 levels in HIT patients. However, on the third and 5th-7th day following initiation of argatroban treatment, ADAMTS-13 levels were increased to 81 ± 6% NHP and 86 ± 24% NHP, respectively. The HIT patient group also exhibited higher levels of vWF antigen at baseline (170 ± 27% NHP) which were marginally decreased following treatment with argatroban. During argatroban treatment, a decrease in anti-heparin platelet factor 4 antibody titer and an improvement in platelet count were noted. These results are highly suggestive of a pathogenic role of vWF multimers in HIT syndrome. Furthermore, a decreased ADAMTS-13 antigen level indicates that its regulation in HIT patients may be altered. Additional results on ADAMTS-13 functionality, ADAMTS-13-factor XI complexes and autoantibodies to the metalloprotease may provide additional insights into the pathogenesis of HIT and the pathologic role of vWF related proteins.
Platelet factor 4 inhibits ADAMTS13 activity and regulates the multimeric distribution of von Willebrand factor
