• hyperviscosity syndrome (HVS) is a clinical-laboratory syndrome resulting from increased blood viscosity
  • it is mainly associated with excessive levels of immunoglobulins (noncorpuscular hyperviscosity)
  • less commonly, HVS occurs due to an increase in blood elements, as observed in myeloproliferative diseases (corpuscular hyperviscosity)
  • prompt treatment is key to preventing organ complications, including stroke

Pathophysiology

  • blood flow to the organs depends on t on various factors, including:
    • blood pressure
    • vessels characteristics (stenosis/occlusion, anatomical variants, collaterals, etc.)
    • blood composition and rheological properties  (particularly viscosity)
  • viscosity affects blood flow through the microcirculation (arterioles and capillaries)
  • physiological mechanisms compensate for the reduced flow of hyperviscous blood by increasing blood pressure
    • high viscosity or a simultaneous drop in blood pressure (caused by dehydration or antihypertensives) can lead to the failure of these compensatory mechanisms, resulting in blood stasis within the microcirculation, hypoperfusion, and subsequent organ ischemia
  • the manifestations of HVS are more pronounced in older individuals
    • possibly due to alterations in the vascular component, such as decreased elasticity of the vascular wall and the presence of potential stenoses

HVS and stroke

Pathophysiological mechanisms through which HVS increases stroke risk include:

  • reduced cerebral perfusion (impaired blood flow through the arterioles and capillaries causing chronic hypoperfusion)
  • thrombosis (increased viscosity and abnormal interactions between blood cells and the coagulation cascade can lead to the formation of thrombi, which can occlude cerebral vessels and cause ischemic strokes)
  • embolic events (in conditions associated with HVS, such as myeloproliferative disorders or dysproteinemias, there is often an increased risk of embolization from aggregated cells or pathological proteins)
  • vasculopathy (chronic hyperviscosity can contribute to endothelial dysfunction and promote atherosclerosis)

Etiology

Corpuscular HVS

  • increased blood viscosity is caused by the proliferation of blood elements, particularly observed in myeloproliferative diseases; platelet hyperaggregability may also contribute to HVS
    • most commonly associated with polycythemia vera (PV)  Thrombus in CCA/ICA junction in a patient with polycythemia vera    [Griesshammer, 2021]
    • the blastic phase of chronic myeloid leukemia (where an acute transformation results in a rapid increase in immature white blood cells)
    • hyperleukocytosis in acute myeloid leukemia
    • leukostasis syndrome (microcirculation disorder caused by the accumulation of leukocytes overrepresented in the peripheral blood; notably prevalent in chronic myeloid leukemia)

Noncorpuscular HVS

  • monoclonal gammopathy (disorders characterized by the proliferation of a single clone of B cells)
    • multiple myeloma (MM) is the most prevalent, accounting for 85-90% of cases
      • IgG and IgA molecules are predominantly deposited extracellularly; the relationship between concentration and viscosity is fairly linear
      • symptoms of HVS typically become evident when concentrations of IgA or IgG3 (the IgG class that most significantly affects viscosity) exceed 40-50 g/L or 80-100 g/L for polymerized IgA
      • rarely, cases of HVS due to extreme levels of immunoglobulin light chains have been reported
    • Waldenström macroglobulinemia (WM)
      • involves pathological production of IgM immunoglobulin molecules, with ~80% of them deposited intravascularly
      • the relationship between concentration and viscosity tends to be exponential
      • manifestations of HVS can be observed at concentrations of 40-50 g/L
  • polyclonal hypergammaglobulinemia
    • occurs in non-clonal B-lymphoproliferative conditions (SLE, Sjögren’s syndrome, or rheumatoid arthritis)
    • an increase in various immunoglobulin types is observed due to chronic immune stimulation
  • cryoproteins (proteins that form gel or precipitate in the cold and redissolve when reheated to 37°C)
    • cryoglobulins (immunoglobulins that precipitate at temperatures < 37 °C and dissolve at 37 °C)
      • type I: consists of monoclonal immunoglobulins (most commonly IgM). Precipitation usually occurs place within 24 hours. It is associated with hematological malignancies (Waldenström’s macroglobulinemia, multiple myeloma)
      • type II: the precipitate consists of a monoclonal component (mostly IgM) and a mixture of polyclonal immunoglobulins (mainly IgG). Precipitation usually occurs within 24 hours and is associated with chronic inflammation, infection, and autoimmune disease
      • type III: the precipitate consists of a mixture of one or more classes of polyclonal immunoglobulins and usually takes several days to precipitate. It is associated with systemic diseases (e.g., SLE, RA, or liver disease) and chronic infections (hepatitis C)
    • cryofibrinogen
      • precipitates only in plasma and is formed by fibrinogen-fibrin complexes
      • precipitates with heparin, which may cause skin lesions

 Clinical presentation

Clinical symptoms of HVS result from hypoperfusion and reduced tissue oxygenation due to stasis of hyperviscous blood or thrombosis in the venous/arterial circulation (typically in polycythemia vera). There is no direct correlation between the manifestations of HVS and specific viscosity values. The manifestations of HVS occur when an individual viscosity threshold is exceeded (which varies significantly, ranging from 2 to 12 times the normal plasma or serum viscosity)

Clinical symptoms are attributed to hypoperfusion and reduced tissue oxygenation due to stasis of hyperviscous blood or thrombosis in the venous/arterial circulation

  • neurological symptoms
    • encephalopathy – confusion, headache, disturbance of consciousness, including coma (“paraproteinemic coma”)
    • epileptic seizures
    • TIA/ischemic stroke
    • amaurosis fugax
  • exacerbation of chronic diseases
    • cardiac – angina pectoris, congestive heart failure (CHF), tachycardia
    • respiratory – exacerbation of chronic lung diseases with dyspnoea, pulmonary edema
    • renal – worsening of CKD, acute renal failure (often due to acute tubular necrosis)
  • peripheral ischemia (acrocyanosis, livedo reticularis, limb pain)
  • hemorrhagic manifestations (especially mucosal and cutaneous petechiae) due to interaction with platelets and pathological binding of coagulation factors with immunoglobulin molecules)
  • general symptoms
    • low-grade fever
    • nonspecific manifestations of generalized malignancy (such as anorexia, night sweats, or weight loss)

Diagnostic evaluation

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Therapy

  • the mainstay of management involves reducing blood viscosity and addressing the underlying hematological disease
  • plasma exchange is indicated for non-corpuscular HVS
    • elevated serum viscosity alone is not an indication for PE – careful evaluation of the clinical manifestations of HVS is required (do not delay PE if symptoms indicative of HVS are present)
    • exceptionally, PE can be utilized as a stand-alone palliative measure in the context of symptomatic therapy of malignant disease
  • corpuscular HVS can be managed by therapeutic phlebotomy, leukapheresis, erythrocytapheresis, or thrombocyte apheresis
  • adequate hydration is essential, aiding in the reduction of blood viscosity
  • treatment of hypercalcemia (occurring in up to 30% of patients with malignancies and often worsening HSV symptoms)
  • anticoagulation – consider in patients with a history of thromboembolic events
  • correction of any anemia and/or thrombocytopenia

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Hyperviscosity syndrome
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