Hyperviscosity Syndrome 

Updated: Dec 11, 2019
Author: Thomas J Hemingway, MD, FACEP; Chief Editor: Barry E Brenner, MD, PhD, FACEP 

Overview

Practice Essentials

Hyperviscosity syndrome (HVS) refers to the clinical sequelae of increased blood viscosity. Increased serum viscosity usually results from increased circulating serum immunoglobulins and can be seen in such diseases as Waldenström macroglobulinemia and multiple myeloma.[1] HVS can also result from increased cellular blood components (typically white or red blood cells) in hyperproliferative states such as the leukemias, polycythemia, and the myeloproliferative disorders.

The clinical presentation in HVS consists principally of the triad of mucosal bleeding, visual changes, and neurologic symptoms.[2, 3] Constitutional symptoms and cardiorespiratory symptoms may also occur.

The diagnosis of HVS is confirmed by measurement of elevated serum viscosity in a patient with characteristic clinical manifestations of HVS. No exact diagnostic cut-off exists for serum viscosity, however, as different patients will have symptoms at different values.

Plasmapheresis is the treatment of choice for initial management and stabilization of HVS from elevated immunoglobulin levels.[4] Leukapheresis, plateletpheresis, and phlebotomy are indicated for HVS from leukostasis, thrombocytosis, and polycythemia, respectively.

Definitive treatment of HVS is treatment of the underlying disorder (eg, chemotherapy). If the underlying disease process is left untreated, the hyperviscosity will recur.

Pathophysiology

Viscosity is a property of liquid and is described as the resistance that a liquid exhibits to the flow of one layer over another. As serum proteins or cellular components increase, the blood becomes more viscous. Vascular stasis and resultant hypoperfusion then lead to the clinical symptoms of hyperviscosity syndrome (HVS).

The normal relative serum viscosity ranges from 1.4-1.8 units (reported as Centipoises). Symptoms usually are not seen at viscosities of less than 4 units, and HVS typically requires a viscosity greater than 5 units.

HVS is associated most commonly with plasma cell dyscrasias[5] (the paraproteinemias) and is due to the large size of the excess immunoglobulin M (IgM) paraproteins in these disorders. Waldenström macroglobulinemia is the most common cause and accounts for about 85% of cases of HVS. Less frequently, HVS can occur in multiple myeloma (especially with myeloma proteins of the IgA and IgG3 types) and connective tissue diseases. Chen and colleagues describe seven cases of polyclonal HVS caused by IgG4-related disease.[6]

HVS can also be caused by the bone marrow hyperproliferative states, as follows:

  • Leukemia
  • Polycythemia
  • Essential thrombocytosis
  • Myelodysplastic disorders

Confusion and mental status changes result from the increased viscosity of the blood and decreased cerebral blood flow. This sludging leads to segmental dilatation of retinal veins and retinal hemorrhages. Mucosal bleeding may occur from prolonged bleeding time caused by myeloma proteins interfering with platelet function.

Cardiopulmonary symptoms such as shortness of breath, hypoxemia, acute respiratory failure, and hypotension also result from this sludging of blood and decreased microvascular circulation.

Clinical sequelae of HVS can include congestive heart failure, ischemic acute tubular necrosis, and pulmonary edema with multiorgan system failure and death if treatment is not promptly initiated.[7] Thus, prompt recognition and expeditious treatment are imperative in preventing deterioration.[3]

Epidemiology

Little epidemiologic information is available on hyperviscosity symdrome. One study found that 61% of blood dyscrasias occur in males. Most blood dyscrasias are not diagnosed until the seventh decade of life. Mortality is related to the underlying cause of the hyperviscosity syndrome.

 

Presentation

History

The clinical presentation of hyperviscosity syndrome consists principally of the triad of mucosal bleeding, visual changes, and neurologic symptoms.[3] Constitutional symptoms and cardiorespiratory symptoms also contribute to the clinical presentation.

The tendency to bleed is the most common manifestation of hyperviscosity syndrome. Patients may present with any of the following:

  • Spontaneous gum bleeding
  • Epistaxis
  • Rectal bleeding
  • Menorrhagia
  • Persistent bleeding after minor procedures

Visual changes range from blurred vision to vision loss. Neurologic manifestations are frequent and varied, and may include the following:

  • Vertigo
  • Hearing loss
  • Paresthesias
  • Ataxia
  • Headaches
  • Seizures
  • Somnolence progressing to stupor and coma

Other manifestations may include heart failure, shortness of breath, hypoxia, fatigue, and anorexia. In fact, the clinician should have a high index of suspicion for hyperviscosity syndrome in patients with unexplained coma/altered mental status or unexplained shortness of breath, especially in those with an underlying hematologic disorder. 

Blood hyperviscosity plays a role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis,and the metabolic syndrome.[8]

Physical

Physical findings are related to the major organ systems involved, as follows:

  • Bruises, epistaxis, or gum bleeding may be noted

  • Ophthalmic examination may reveal decreased visual acuity, dilated retinal veins, "sausage-linked" or "boxcar segmentation" of the retinal veins, or retinal hemorrhages[9]

  • Neurologic examination may reveal various abnormalities, including diminished mental status, confusion, ataxia, or nystagmus

  • Cardiopulmonary examination may reveal signs of congestive heart failure with volume overload (rales, lower extremity edema, elevated jugular venous pressure, and hypoxia)

Causes

Increased serum viscosity usually results from increased circulating serum immunoglobulins and can be seen in Waldenström macroglobulinemia, multiple myeloma, cryoglobulinemia, and Sjögren syndrome.[10, 11]

Less commonly, the hyperproliferative blood cell disorders such as the leukemias, myeloproliferative diseases, polycythemia, or thrombocytosis may be implicated for the increased viscosity caused by proliferation of their respective cellular components.

 

DDx

Diagnostic Considerations

Underlying disorders to consider in patients with hyperviscosity syndrome include the following:

  • Multiple myeloma

  • Waldenström macroglobulinemia

  • Leukostasis (see the Medscape Reference article Oncologic Emergencies, under Hyperleukocytosis)

  • Polycythemia

  • Thrombocytosis

In patients with Waldenström macroglobulinemia, neurologic manifestations are common and are often due to hyperviscosity syndrome or immune peripheral neuropathy. Very rarely, neurologic signs and symptoms in these patients may result from lymphoproliferative infiltration of the central nervous system, a condition known as Bing-Neel syndrome.[12]

The diagnosis of Bing-Neel syndrome may be made by magnetic resonance imaging and cerebrospinal fluid analysis, which may show may show lymphocytic pleocytosis, elevated protein, and IgM kappa or lambda light chain restriction. Treatment is with cranial irradiation and/or intrathecal chemotherapy.

Differential Diagnoses

 

Workup

Laboratory Studies

The diagnosis of hyperviscosity syndrome (HVS) is confirmed by measurement of elevated serum viscosity in a patient with characteristic clinical manifestations of HVS. No exact diagnostic cut-off exists for serum viscosity, as different patients will have symptoms at different values. A clue to the need for measurement of serum viscosity may be that the laboratory has difficulty performing chemical tests, because hyperviscous blood can clog analyzers.

The normal reference range for serum viscosity is 1.4-1.8 Centipoises (1.0 being the viscosity of water). Symptoms usually are not seen before the viscosity reaches 4 Centipoises, and patients with HVS usually present with a serum viscosity greater than 5 Centipoises. Typically, the higher the viscosity, the worse the symptoms.

Other laboratory testing is as follows:

  • Obtain a peripheral blood smear with the complete blood count (CBC); rouleaux formation is often present with increased serum viscosity

  • The white blood cell count (WBC) is typically 100,000/μL or greater in leukostasis causing HVS, but it may be lower in the blast crises of the leukemias

  • Consider measuring total protein (TP) and albumin, as in the paraproteinemias; a globulin gap (TP – albumin = 4 or greater) may exist

  • Consider adding a metabolic panel and electrolytes, as derangements such as hypercalcemia, hyperphosphatemia, and hyperkalemia are common and may require specific treatment (be sure not to contribute to pseudohyperkalemia secondary to the increased cellular lysis through poor venipuncture technique; use a larger needle, withdraw slowly and, if in doubt, order a plasma rather than serum potassium level, which will be more reliable)

  • Consider coagulopathy workup (eg, blood count, type and screen, prothrombin time, activated partial thromboplastin time, platelet count) if the patient presents with hemorrhage

  • Tailor additional workup (eg, chest radiography, brain computed tomography or magnetic resonance imaging) to the patient's presentation

  • Consider panculture and urinalysis; multiple myeloma is complicated frequently by infections; in nonneutropenic patients, infections are usually secondary to Streptococcus pneumoniae or Haemophilus influenzae

  • If the patient has not been diagnosed with an underlying pathologic process that could have caused the HVS (eg, multiple myeloma, Waldenström macroglobulinemia, hyperproliferative blood cell dysplasias), consider adding serum and urine electrophoresis to search for such disorders

Imaging Studies

A computed tomography (CT) scan of the head is indicated for patients who present with altered level of consciousness, seizures, or focal neurologic deficits. Contrast dye is contraindicated in patients with multiple myeloma because of the increased risk of renal failure.

A chest radiograph may be indicated to rule out infection. It also may reveal congestive heart failure (CHF). High-output failure can be caused by hyperviscosity or anemia.

 

Treatment

Prehospital Care

No specific prehospital care is indicated for patients with hyperviscosity syndrome. Emergency medical services personnel should be attentive to airway, breathing, and circulation (the ABCs) and provide symptomatic support.[13]

Emergency Department Care

Plasmapheresis is the treatment of choice for initial management and stabilization of hyperviscosity syndrome (HVS) caused by the paraproteinemias (the majority of cases). Plasmapheresis is usually well tolerated and safe. Leukapheresis, plateletpheresis, and phlebotomy are indicated for HVS from leukostasis, thrombocytosis, and polycythemia, respectively.[14]

As plasmapheresis removes the circulating paraproteins, the serum viscosity decreases and symptoms improve. This procedure remains effective short-term treatment for HVS in the paraproteinemias because of the demonstrated correlation of paraprotein levels and serum viscosity and the 80% intravascular location of paraproteins, especially immunoglobulins (eg, in Waldenström macroglobulinemia). As such, a relatively small reduction in the paraprotein concentration has a significant effect on lowering serum viscosity.[11]

Because bleeding is the most common sign of HVS, urgent plasmapheresis using a cell separator should be carried out for patients experiencing visual symptoms, to reduce the likelihood of blindness from retinal hemorrhages/retinal detachment. Plasmapheresis can also reverse HVS-induced retinal changes promptly, including reducing retinal venous diameter and increased venous blood viscosity.[15]

In similar fashion leukapheresis, plateletpheresis, and phlebotomy also decrease the serum viscosity by decreasing the existing cellular component in excess. Although these treatments are helpful in the acute phase, they typically do not alter the prognosis of the disease process, which is the underlying etiology. These diseases (eg, multiple myeloma, Waldenström macroglobulinemia, blood dyscrasias) should be definitively treated with the appropriate oncologic therapy, or the HVS will typically recur within a few weeks, requiring further pheresis.

Signs and symptoms of congestive heart failure (CHF) from hyperviscosity may not respond to standard therapies for CHF, and, in fact, can be exacerbated by dehydration from diuresis causing increased viscosity. However, plasmapheresis and/or cellular pheresis reverses these symptoms.

While arranging for plasmapheresis, treat hemorrhage, CHF, and metabolic imbalances with standard therapies. One caveat: Use caution with the decision to proceed with packed red blood cell transfusion (pRBCs) for minor bleeding because a single unit of pRBCs may increase the viscosity enough to cause worsening symptoms and clinical decompensation. If a transfusion is indicated, administer it by slow infusion.

If plasma/cellular pheresis is not readily available and the patient is decompensating, one may try vigorous intravenous hydration coupled with a 2-3 unit phlebotomy in the interim as a temporizing measure.

Upon commencing pheresis (especially leukapheresis) one should prepare for the possibility of tumor lysis syndrome and treat accordingly.

Ultimately, the underlying dysproteinemia or blood cell dyscrasia needs to be addressed, as plasmapheresis and similar therapies do not alter the underlying disease process. The definitive treatment varies according to the diagnosis but often involves chemotherapeutic agents, such as alkylating agents or nucleoside analogs, which should be addressed with the consulting hematologist/oncologist to prevent further deterioration and possible recurrent episodes.[7]

Consultations

A hematologist should be consulted to arrange plasma/cellular pheresis and plan for interval chemotherapy as indicated.

 

Follow-up

Further Inpatient Care

Supportive care should be initiated for the complications of hyperviscosity syndrome, pending definitive therapy. Complications to address may include blood loss, central nervous system disorders, cardiovascular effects, and metabolic derangements.

Note that the definitive treatment of hyperviscosity syndrome is treatment of the underlying disorder (eg, chemotherapy). If the underlying disease process is left untreated, the hyperviscosity will recur.

Transfer

Consider transfer if hematology/oncology consultation and plasma or cellular pheresis are unavailable at the treating facility.

Prognosis

The prognosis in patients with hyperviscosity syndrome depends on the severity of the associated complications, and on the underlying cause of the syndrome and the response of the appropriate definitive treatment. For example, the long-term prognosis for patients with multiple myeloma continues to be poor.

Patient Education

See the list below:

  • The diseases leading to hyperviscosity are chronic, and this condition may recur.

  • Patients and their families and/or caregivers should be educated about early signs and symptoms (eg, bleeding, visual symptoms, headache, mental status changes, shortness of breath).

 

Questions & Answers

Overview

What is hyperviscosity syndrome (HVS)?

What is the clinical presentation of hyperviscosity syndrome (HVS)?

How is the diagnosis of hyperviscosity syndrome (HVS) confirmed?

What is the initial treatment of hyperviscosity syndrome (HVS) from elevated immunoglobulin levels?

What is the definitive treatment of hyperviscosity syndrome (HVS)?

What is the pathophysiology of hyperviscosity syndrome (HVS)?

What bone marrow conditions cause hyperviscosity syndrome (HVS)?

What are the physiologic causes of the symptoms of hyperviscosity syndrome (HVS)?

What is the epidemiology of hyperviscosity syndrome (HVS)?

Presentation

What is the clinical presentation of hyperviscosity syndrome (HVS)?

What are the most common symptoms of hyperviscosity syndrome (HVS)?

What visual changes are associated with hyperviscosity syndrome (HVS)?

What other symptoms are associated with hyperviscosity syndrome (HVS)?

What are the physical findings of the major organ systems in hyperviscosity syndrome (HVS)?

What causes of hyperviscosity syndrome (HVS)?

DDX

Which neurologic signs and symptoms are associated with hyperviscosity syndrome (HVS)?

What are the diagnostic considerations for hyperviscosity syndrome (HVS)?

What are the differential diagnoses for Hyperviscosity Syndrome?

Workup

Which lab studies can confirm a diagnosis of hyperviscosity syndrome (HVS)?

What other lab testing is done to diagnose hyperviscosity syndrome (HVS)?

Which imaging studies are indicated in the workup of hyperviscosity syndrome (HVS)?

Treatment

What prehospital care is indicated for patients with hyperviscosity syndrome (HVS)?

What is the initial treatment for hyperviscosity syndrome (HVS) caused by paraproteinemia?

What treatment is indicated for patients with visual symptoms in hyperviscosity syndrome (HVS)?

What are the signs and symptoms of congestive heart failure (CHF) from hyperviscosity syndrome (HVS)?

What is the definitive treatment of hyperviscosity syndrome (HVS)?

When should a hematologist be consulted in the treatment of hyperviscosity syndrome (HVS)?

Follow-up

What inpatient care is indicated in the treatment of hyperviscosity syndrome (HVS)?

When is transfer indicated in the treatment of hyperviscosity syndrome (HVS)?

What is the prognosis of hyperviscosity syndrome (HVS)?

How should a patient be educated about hyperviscosity syndrome (HVS)?