Defects in Primary Hemostasis and Acquired Von Willebrand Disease As Cause of Bleeding in Patients with Multiple Myeloma

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.