Hyperviscosity syndrome (HVS) is an oncologic emergency that classically presents with the triad of neurological deficits, visual changes, and mucosal bleeding. Elevated blood viscosity is the result of either red blood cell shape deformity or a pathological increase in serum proteins, red blood cells (RBC), white blood cells (WBC), or platelets. The most common cause of HVS is Waldenstrom macroglobulinemia (WM), and therefore, the term HVS is typically used to describe an increase in serum proteins. Management consists of supportive care with intravenous fluids, plasmapheresis, and treatment of the underlying hematological condition.
Any pathologic elevation of the cellular components (erythrocytes, leukocytes, or platelets) or acellular components (protein) of blood can cause hyperviscosity. Conditions responsible for HVS that involve cellular components of blood include polycythemia vera, leukemia, and thrombocytosis. Sickle cell disease and spherocytosis can also contribute to HVS due to deformed red blood cells. The pathologic rise of acellular components can either be monoclonal or polyclonal. Monoclonal diseases include myeloma, Waldenstrom macroglobulinemia (WM), and cryoglobulinemia. Rheumatic conditions such as seropositive rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome compromise polyclonal causes of HVS as well as Castleman disease and HIV infection.
Hypergammaglobulinemia is the most common cause of HVS, specifically the monoclonal condition Waldenstrom macroglobulinemia. More than 30% of all WM patients develop HVS at some point in their life because of the large star-shaped IgM pentamers that are highly viscous. Myelomas are the second leading cause of HVS. About 25% of HVS cases secondary to myelomas are caused by IgA, followed by IgG myelomas at less than 5% of cases.
Viscosity is formally defined as the measurement of the internal resistance of a fluid to flow but can simply be thought of as the "thickness" or "stickiness" of a fluid. When fluid has low viscosity, it travels quickly and without much difficulty. Viscous fluids are thicker and travel more slowly. HVS is the pathological condition in which blood is "thicker" than normal and therefore flow is reduced. An increase in blood viscosity can be caused either by a deformity of the shape of red blood cells (RBCs) which causes RBC aggregation and decreased blood flow or by any pathological elevation of the components of blood. This includes RBC, WBC, platelets, or serum proteins.
This increase in viscosity causes sluggish blood flow, relative decreased microvascular circulation, and hypoperfusion of tissues. An increase in circulating proteins can also affect platelet aggregation and cause prolonged bleeding time. The severity of clinical symptoms is directly related to the increased levels of serum viscosity, with progressively more severe symptoms occurring as the individual patient’s serum viscosity increases. The level of viscosity at which symptoms can initially present is variable from person to person depending on the underlying physiology, but for a given patient, symptoms will typically manifest about the same level of viscosity over time.
A high degree of clinical suspicion is required based on history and physical exam findings to diagnose HVS. During history taking, it is important to note any current or past hematological disorders as well as any family history of such conditions. The clinical triad of mucosal or skin bleeding, neurological deficits, and visual disturbances suggests HVS; however, a variety of end-organ damages can also be observed as the initial presenting symptom.
Bleeding is the most common manifestation and typically arises from impaired platelet function resulting in oozing mucosal surfaces like epistaxis, bleeding gums, or gastrointestinal (GI) bleeding. Neurological findings can include a headache, neuropathic syndromes, generalized stupor, coma, dizziness, ataxia, hearing impairment, seizures, and stroke syndromes. These neurological manifestations are due to decreased blood flow to the central nervous system and deposition of paraproteins within the myelin sheath of peripheral nerves. Retinopathy and visual derangements such as blurred vision or double vision arise because of microvascular changes such as thrombosis or hemorrhage. The classic finding of "sausage link" or "boxcar" engorgement of retinal veins can be seen on the fundoscopic exam as well as papilledema, flame-shaped hemorrhages, or exudates. The eye examination is an important part of the physical exam because it can enable prompt diagnosis and treatment in the appropriate clinical setting. Less commonly seen are cardiopulmonary symptoms such as high output cardiac failure, shortness of breath, valvular dysfunction, or myocardial infarction. HVS can also cause acute kidney injury, likely resulting from a relative hypoperfusion state.
Laboratory evidence of high serum viscosity establishes the diagnosis. There is controversy over whether whole blood viscosity versus serum viscosity is superior, but most clinical laboratories measure the viscosity of the serum component of blood. Viscosity is measured in the unit of centipoise (cp). The viscosity of water is 1 cp. Normal serum viscosity relative to water is 1.4 to 1.8 cp. Symptoms of hyperviscosity can appear with a serum viscosity as low as 3 cp, but usually, arise when it exceeds 4 to 5 cp.
Further testing should include a complete blood count (CBC), full serum chemistries, coagulation profile, and urinalysis. An elevated albumin-protein gap along with significant proteinuria on routine urinalysis suggest an underlying gammopathy. Rouleaux formation on a peripheral blood smear is highly suggestive of serum stasis. Serum stasis can also lead to the malfunction of laboratory testing equipment in which lab samples cannot be analyzed. This should raise suspicion for an underlying increase in serum viscosity. Measuring quantitative immunoglobulins is not necessary to establish a diagnosis of HVS, but can help guide long-term treatment if measured before and after the intervention.
HVS is an oncological emergency, and timely treatment can prevent life-threatening complications such as thromboembolic events, myocardial infarction, and catastrophic ischemia that results in multiple organ failure. Therapy should be based on the severity of signs and symptoms rather than the calculated degree of viscosity. Most signs and symptoms are reversible with prompt treatment. Short-term management is directed at symptom control, whereas long-term management is directed at controlling the underlying hematologic condition. The mainstays of treatment include supportive therapy, plasma exchange or plasmapheresis, and chemotherapy. Dehydration can worsen HVS, and these patients are usually dehydrated. Therefore, judicious fluid administration is advised. It is considered common practice to empirically administer 1 to 2 L of normal saline when HVS is suspected. The more definitive short-term treatment is plasmapheresis. It can promptly reverse most clinical manifestations of HVS and is usually well tolerated and safe. Plasmapheresis can decrease serum viscosity by 20% to 30% and can be done on a daily basis until clinical resolution of symptoms. Patients can present with concurrent anemia or acquire dilutional anemia secondary to fluid resuscitation, and it is important to note that transfusion of packed red blood cells can increase blood viscosity. Therefore, one should wait until after plasmapheresis has reduced serum viscosity before transfusing.
If prompt plasmapheresis cannot be obtained, a temporizing measure that can be performed emergently is intravenous phlebotomy. This involves phlebotomizing about 1 to 2 units of the patient's blood and concurrently replacing it with normal saline. However, this has to be performed with caution because aggressive plasma exchange can cause the elimination of clotting factors, albumin, and platelets. Phlebotomy should only be completed in the presence of severe neurological deficits like seizure or coma.
The definitive treatment of HVS involves chemotherapy for the underlying hematologic condition. Plasmapheresis does not affect the underlying disease, so chemotherapy is often started concomitantly. A hematology/oncology consultant should administer this, and it is strongly recommended to consult with this expert as soon as HVS is identified. Since exchange therapies such as plasmapheresis and leukapheresis are the mainstay of management, these patients may require transfer to a higher level of care facility.