Defects in Primary Hemostasis and Acquired Von Willebrand Disease As Cause of Bleeding in Patients with Multiple Myeloma
Authors: Hinterleitner Clemens , Kreisselmeier Klaus Peter , Pecher Ann Christin , Weisel Katja C. , Kanz Lothar , Kopp Hans Georg , Jaschonek Karl G. 
Published: October 2019

Abstract
Introduction. Paraproteinemia has been associated with both thromboembolic and bleeding complications. Previous retrospective analyses and case reports report on a direct correlation of serum immunoglobulin levels (especially IgM and IgA) with critical bleeding events. Underlying mechanisms include interference with platelet function, immune thrombocytopenia, clotting factor deficiencies, and acquired von Willebrand disease (AVWD).
Methods. Laboratory data, including qualitative and quantitative analyses of von Willebrand Factor (vWF), collagen binding assay (CBA) and PFA-100 closure time from 132 patients with diagnosis of multiple myeloma between 2003 and 2015 were retrieved, and cases were retrospectively evaluated for bleeding complications. Coagulation abnormalities were correlated with clinical history and disease parameters.
Results. 70 out of 132 patients (53%) displayed bleeding complications including multiple hematomas (n=41), epistaxis (n=10), or perioperative bleeding (n=9). Bleeding vs. non-bleeding patients showed no differences regarding age, gender, previous chemotherapy, or immunoglobulin isotypes. Special coagulation lab results of patients with bleeding events are shown in table 1.
Table 1. Pathological coag labs in 70 patients with bleeding Normal Abnormal Sensitivity(95% CI) Specificity(95% CI) PPV*(95% CI) NPV*(95% CI) PLT (<50x103/µl) 70 0 0 1 0 0.47 (0.38-0.56) PT, aPTT 68 2 0.06 (0.02-0.1) 0.95 (0.85-0.99) 0.57 (0.2-0.88) 0.47 (0.38-0.56) vWF:Ag or RCoF 64 6 0.09 (0.04-0.18) 0.95 (0.86-0.99) 0.67 (0.3-0.9) 0.48 (0.39-0.9) PFA-100 27 43 0.61 (0.49-0.73) 0.97 (0.88-0.99) 0.96 (0.84-99) 0.69 (0.58-0.78) CBA/vWF 45 25 0.35 (0.25-0.48) 0.98 (0.9-0.99) 0.96 (0.78-1) 0.58 (0.48-0.67) PFA-100 or CBA/vWF 52 18 0.74 (0.62-0.84) 0.95 (0.86-0.99) 0.94 (0.84-1) 0.76 (0.65-0.85) *PPV = positive predictive value, NPV = negative predictive value Serum free light-chain, but not complete Ig paraprotein levels were significantly associated with bleeding events (p<0.001), prolonged PFA-100 closure time (p<0.001), and pathological CBA/vWF-ratio (p<0.05).
Conclusions. Bleeding events were most commonly due to defects of primary hemostasis. Global coagulation tests as well as vWF:Ag and RCo were insufficient in predicting bleeding. When the results of both PFA-100 and CBA/vWF-ratio were considered, 74% of the bleeding patients could be detected. We suggest that both PFA-100 and CBA/vWF-ratio should be determined in patients with multiple myeloma and signs of bleeding in order to rule out AVWD with sufficient sensitivity. Serum free light-chain levels were correlated with hemorrhage and detectable AVWD. Therefore, free Ig light-chains may play a role in the pathophysiology of bleeding.

Disclosures
Weisel: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Noxxon: Consultancy; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support.