A 72-year-old man with recently diagnosed amyloidosis, AL (lambda)-type, based on mass spectrometric molecular typing and bone marrow involvement by 5%-9% clonal plasma cells (lambda-restricted), presented with gross hematuria, prompting a comprehensive bleeding diathesis laboratory evaluation. Findings included elevated von Willebrand factor (VWF) antigen (254%; reference range (RR) 55%-200%) with disproportionally decreased VWF latex immunoassay activity (75%; RR 55%-200%) and a VWF-activity/VWF-antigen ratio of 0.3. Factor X activity was also decreased (37%; RR 70%-150%), consistent with an amyloid-associated adsorptive coagulopathy.
The correct answer is ...
Low ADAMTS-13 antigen.
Prior testing confirmed persistent elevations of VWF antigen and decreased VWF activity, with a low VWF-activity/VWF-antigen ratio of less than 0.5. Further clinical investigations revealed cardiac and peripheral nervous system involvement, manifesting as orthostatic hypotension and peripheral neuropathies.
In one single-center prospective observational study that included 111 consecutively treated patients with a new diagnosis of AL-type amyloidosis, 76% of patients had elevated VWF antigen levels, possibly reflecting endothelial dysfunction. In a multivariate analysis, levels of NTproBNP (either ≥4000 or ≥8500 pg/mL) and low systolic blood pressure (SBP <100 mm Hg) were associated with worse survival.1 Notably, VWF antigen levels above 230% (U/dL) were also associated with a higher probability of early death and worse survival, independent of cardiac biomarker and low SBP.1,2 While low ADAMTS-13 levels correlated with high levels of NTproBNP, the ADAMTS-13 level had no independent prognostic significance.1
Additional points: Even if the VWF-activity and VWF-antigen levels are within the laboratory’s respective reference intervals, a decreased VWF-activity/ VWF-antigen ratio (especially if less than 0.5) should prompt further evaluation for congenital type 2A/2B/2M von Willebrand disease (VWD) or an acquired von Willebrand syndrome (AVWS). Subsequent analysis includes VWF multimer analysis, which, in our laboratory, is performed using high-resolution SDS gel electrophoresis followed by fluorochrome-conjugated antibody detection of VWF.3 A normal VWF multimer distribution from a healthy donor is shown in Figure A, top lane. Compared with the normal pattern, the patient’s sample displayed decreased abundance (intensity) of high and intermediate molecular weight multimers and increased abundance of low molecular weight multimers (Figure A, second lane). The classical triplet band pattern was altered with loss or absence of the central band and enhanced satellite bands, suggestive of enhanced VWF proteolysis (Figure B). A similar VWF multimer pattern was previously reported by Melnyk et. al. in a patient with AL-type amyloidosis (Figure A, lower two lanes, and B).4
Abdulrahman Saadalla, M.B., B.Ch.
Fellow, Special Coagulation
Jansen Seheult, M.B., B.Ch., M.D.
Senior Associate Consultant, Hematopathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science