What is Waldenstrom (Waldenstrom's macroglobulinemia) syndrome and can it cause blood clots?

Waldenstrom's Macroglobulinemia and Its Relationship to Blood Clots

Waldenstrom's macroglobulinemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by the overproduction of monoclonal IgM protein, which can cause hyperviscosity syndrome that may lead to blood clots and other complications. 1, 2

Definition and Pathophysiology

• WM is defined by the presence of IgM monoclonal protein in the serum associated with ≥10% clonal lymphoplasmacytic cells in the bone marrow 3
• Over 90% of WM patients have the L265P mutation in MYD88, which helps distinguish it from other lymphoid neoplasms 1, 3
• WM is considered a distinct pathological entity, not merely a clinical syndrome 4

Clinical Manifestations

• Common clinical features include:
  • Anemia (normochromic, normocytic) with median hemoglobin of 10 g/dl at diagnosis 2
  • Hepatomegaly (20% of patients) 2
  • Splenomegaly (15% of patients) 2
  • Lymphadenopathy (15% of patients) 2
  • Fatigue, which is often related to anemia 2

Hyperviscosity and Blood Clots

• Hyperviscosity syndrome is a significant complication of WM that can lead to blood flow abnormalities and clotting issues 1
• Symptoms of hyperviscosity include:
  • Headaches, blurry vision or visual loss 1
  • Confusion and neurological symptoms 1, 2
  • Oronasal bleeding 2
  • Retinal hemorrhages and venous engorgement ("sausaging" of retinal veins) 1
• Severe hyperviscosity can lead to somnolence or coma in advanced cases 2
• Thrombocytopenia (low platelet count) may occur in WM patients, which can affect clotting function 3

Other WM-Related Complications That Can Affect Blood Flow and Clotting

• Cryoglobulinemia: IgM proteins that precipitate at cold temperatures can cause Raynaud-like symptoms, acrocyanosis, and ulcerations of extremities 1
• Cold agglutinin disease: can lead to hemolytic anemia 1
• Acquired von Willebrand disease: can cause bleeding diathesis 1
• Amyloidosis: can affect multiple organs including the heart, which may impact circulation 1

Diagnosis and Assessment

• Diagnostic workup should include:
  • Complete blood count with differential 1
  • Serum protein electrophoresis and immunofixation 1
  • Quantification of immunoglobulins 1
  • Bone marrow biopsy 3
  • Testing for MYD88 L265P mutation 1, 3
• For hyperviscosity assessment:
  • Fundoscopic examination is more reliable than serum viscosity measurements 1
  • Testing for cold agglutinins and cryoglobulins in symptomatic patients 1

Risk Stratification

• Prognostic factors include:
  • Age (≥65 years) 1, 3
  • Hemoglobin level (≤11.5 g/dl) 1, 3
  • Platelet count (≤100,000 × 10⁹/l) 1, 3
  • Beta-2 microglobulin (>3 mg/l) 1, 3
  • IgM concentration (>70 g/l) 1, 3
  • LDH levels 3

Management Considerations for Hyperviscosity and Clotting Issues

• Asymptomatic patients should be observed without treatment (watch and wait approach) 1, 3
• Treatment is indicated for symptomatic patients, particularly those with:
  • Hyperviscosity syndrome 1
  • Symptomatic cryoglobulinemia 1
  • Hemoglobin <10 g/dl or platelet count <100 × 10⁹/l 1
• Plasmapheresis may be required for acute management of severe hyperviscosity 1
• Definitive treatment options include:
  • Rituximab-based combination therapies 1, 3
  • Bendamustine plus rituximab 1, 3
  • Bruton tyrosine kinase inhibitors 3, 5
  • Proteasome inhibitors like bortezomib 1, 3

Important Caveats

• Monoclonal IgM alone is not a reason to initiate treatment without symptoms 1
• Serum viscosity measurements do not always correlate well with clinical hyperviscosity 1
• The presence of cold agglutinins or cryoglobulins may affect the accurate determination of IgM levels 1
• Treatment selection should consider toxicity reduction given WM's indolent nature 3, 5