Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation

Abstract

Waldenström macroglobulinemia (WM) is a rare, incurable, low-grade, B cell lymphoma. Symptomatic disease commonly results from marrow or organ infiltration and hyperviscosity secondary to immunoglobulin M paraprotein, manifesting as anemia, bleeding and neurological symptoms among others. The causes of the bleeding phenotype in WM are complex and involve several intersecting mechanisms. Evidence of defects in platelet function is lacking in the literature, but factors impacting platelet function and coagulation pathways such as acquired von Willebrand factor syndrome, hyperviscosity, abnormal hematopoiesis, cryoglobulinemia and amyloidosis may contribute to bleeding. Understanding the pathophysiological mechanisms behind bleeding is important, as common WM therapies, including chemo-immunotherapy and Bruton's tyrosine kinase inhibitors, carry attendant bleeding risks. Furthermore, due to the relatively indolent nature of this lymphoma, most patients diagnosed with WM are often older and have one or more comorbidities, requiring treatment with anticoagulant or antiplatelet drugs. It is thus important to understand the origin of the WM bleeding phenotype, to better stratify patients according to their bleeding risk, and enhance confidence in clinical decisions regarding treatment management. In this review, we detail the evidence for various contributing factors to the bleeding phenotype in WM and focus on current and emerging diagnostic tools that will aid evaluation and management of bleeding in these patients.

Fig. 1

Pathways of development of lymphoplasmacytoid B cells in healthy individuals and in WM patients. In WM patients, mutations and loss of DNA methylation occur to the lymphoplasmacytoid cells, with enrichment in B memory cells at an earlier stage of differentiation. The most common mutation, MYD88 ^L265P , results in increased BTK phosphorylation and faster MYD88 complexing with IRAK1/4 in response to low or absent TLR or IL-1R stimulus, which results in increased NF-κB translocation to the nucleus, increased target gene transcription, uncontrolled proliferation of WM lymphoplasmacytoid cells and overproduction of IgM. BTK, Bruton's tyrosine kinase; IgM, immunoglobulin M; IL-1R, interleukin-1 receptor; IRAK, IL-1 receptor-associated kinase; MYD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TLR, toll-like receptor; WM, Waldenström macroglobulinemia.

Fig. 2

Simplified hemostasis. ( A ) Platelet plug formation. Following an injury, GPIb-IX-V and GPVI bind exposed extracellular matrix ligands such as von Willebrand factor (vWF) and collagen respectively to enable platelet adhesion to the endothelium. Engagement of these receptors triggers platelet signaling, and platelets undergo changes to the cytoskeleton and release granules. The platelet-specific integrin, αIIbβ3, becomes active and binds fibrinogen, bridging adjacent platelets. Platelets aggregate forming a platelet plug at the site of the injury. ( B ) Blood coagulation and the securing of the platelet plug. Tissue factor (TF) is exposed at the site of the injury triggering the extrinsic coagulation cascade, resulting in thrombin production. Thrombin converts fibrinogen into insoluble fibrin which secures the platelet plug in place. Blood hyperviscosity and high levels of IgM are likely to interfere with these hemostatic pathways, and potentially underpin bleeding events. GPVI, glycoprotein VI; IgM, immunoglobulin M.

Fig. 3

Platelets and B lymphocytes utilize common signaling pathways. BTK is differentially involved in the downstream signaling pathways triggered by ligand engagement of the major platelet adhesion/signaling receptors (αIIbβ3, GPVI, and GPIbα of the GPIb-IX-V complex) and the BCR. In receptors with ITAMs, following ligand binding and receptor clustering, phosphorylation of the cytoplasmic ITAMs and recruitment of SFKs ensue, resulting in phosphorylation of Syk and activation of PI3K. PI3K mediates the conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate, which engages BTK, resulting in phosphorylation of PLCγ. In platelets, this leads to activation and aggregation. In B cells, activation of MAPKs, NF-κB, and NFAT leads to B cell proliferation, development, and survival. BCR and GPVI ITAM signaling are more reliant on the BTK pathway compared with GPIbα and αIIbβ3, thus signaling downstream of these receptors is more sensitive to BTK inhibition. BCR, B cell receptor; BTK, Bruton's tyrosine kinase; GP, glycoprotein; ITAM, immunoreceptor tyrosine-based activation motif; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; NFAT, nuclear factor of activated T cells ; PI3K, phosphoinositide 3-kinase; PLCγ, phospholipase C γ; SFK, Src-family kinases.

Fig. 4

Recommended pathway to evaluate bleeding phenotypes in Waldenström macroglobulinemia, with treatment options. Blue: asymptomatic WM; red: symptomatic WM; green: therapy recommendations (Castillo et al 2019). ADAM10, a disintegrin and metalloproteinase 10; Ag, antigen; aPTT, activated partial thromboplastin time; BM, bone marrow; CBA, collagen binding assay; DOAC, direct oral anticoagulant; FBC, full blood count; FVIII, factor VIII; IgM, immunoglobulin M; LTA, light transmission aggregometry; PFA, platelet function analyzer; PT, prothrombin time; RBC, red blood cell; R:Co: ristocetin cofactor assay; ROTEM, rotational thromboelastometry; SE, side effect; sGPVI, soluble glycoprotein VI; TEG, thromboelastography; TKI, tyrosine kinase inhibitor; VWD, von Willebrand disease; VWF, von Willebrand factor.