Critical Care Medicine

Hyperviscosity syndrome

Hyperviscosity Syndrome

Related conditions: Waldenstrom's Macroglobulinemia, Hyperleukocytosis, Leukostasis, Multiple Myeloma, Myeloproliferative Disorders

1. Description of the problem

Hyperviscosity syndrome (HVS) is a combination of clinical signs and symptoms related to increased blood viscosity. It can result from abnormal plasma components such as paraproteins (seen in Waldenstrom's macroglobulinemia [WM] and multiple myeloma [MM]) or immune complexes (systemic lupus erythematosis). HVS can also be secondary to increased cellular components due to leukemia or myeloproliferative disorders.

Clinical features

The classic triad of symptoms includes neurologic abnormalities, vision changes and mucocal bleeding.Neurologic abnormalities: headache, syncope, seizure, vertigo, hearing loss, stupor, stroke.

Visual disturbances: diplopia, vision loss. Classic findings on fundoscopic examination are dilated, tortuous, "sausage-link" or "box-car" retinal veins.

Mucosal bleeding: gingival, mucosal, nasal, vaginal.

Other clinical features may include:

  • Dyspnea

  • Chest pain

  • High-output cardiac failure

  • Myocardial infarction

Key management points

Plasmapheresis is the mainstay of treatment for hyperviscosity secondary to increased plasma proteins. Leukapheresis, plateletpheresis and phlebotomy are used to treat leukostasis, thrombocytosis and polycythemia, respectively. These various modalities will only treat the symptoms of HVS. Definitive therapy is needed to address the underlying condition.

2. Emergency Management

Plasmapheresis should be initiated as quickly as possible. Treatment for HVS secondary to excess cellular components should be treated in an analogous manner, with removal of the specific blood component.

Plasmapheresis may not be readily available in every hospital. While waiting for the plasmapheresis team, a dialysis-compatible central catheter should be placed; start supportive therapy to treat bleeding, heart failure and metabolic imbalances. If plasmapheresis is not easily accessible, manual plasma exchange may be performed, in which 1-2 unit phlebotomy is performed with normal saline hydration.

Care should be taken when administering fluids and diuresing these patients because aggressive diuresis will increase blood viscosity. Similarly, though most patients will be anemic, packed red cells should be transfused extremely cautiously, as this will also increase viscosity.

3. Diagnosis

Diagnostic criteria and tests

Hyperviscosity is a clinical manifestation of an underlying oncologic process, usually a plasma cell dyscrasia or acute leukemia, though it can sometimes be caused by immune complexes in patients with systemic lupus erythematosis. It should be suspected in any patient who presents with the classic triad of neurologic abnormalities, vision changes and mucosal bleeding.

There is no single diagnostic test for HVS. As always, a good history and physical are important. Laboratory evaluation includes a complete blood count (CBC), peripheral blood smear, serum electrolytes and serum viscosity.

CBC: patients with HVS are typically anemic due to their underlying disease. However, patients with polycythemia vera often present with elevated hemoglobin ( >16 g/dL) and hematocrit (can be as high as 70-80%). Signs and symptoms of leukostasis causing HVS are seen with white blood cell counts greater than 100,000, but can also be seen with a lower WBC.

Peripheral blood smear: rouleaux formation can be seen in patient's paraproteinemia.

Serum electrolytes: hypercalcemia and hyponatremia are often present in paraproteinemia. The hyponatremia is usually an artifact of the paraproteinemia.

Serum viscosity: clinical signs and symptoms of hyperviscosity usually occur when the viscosity reaches 4-5 cp (normal range is 1.4-1.8 cp).

Other laboratory studies that may be helpful

Coagulation panel: prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio (INR) are important, especially if the patient presents with bleeding.

Serum/urine electrophoresis: the presence of a monoclonal spike confirms an underlying gammopathy, usually multiple myeloma or Waldenstrom's macroglobulinemia

Urinalysis: significant proteinuria suggests a gammopathy.

Bone marrow biopsy: may reveal underlying disorder (plasma cell dyscrasia, leukemia, myeloproliferative disorder)

Normal lab values

Viscosity 1.4-1.8 centipoise (cp)

How do I know this is what the patient has?

HVS should be strongly suspected in any patient with who presents with the classic triad with or without a known diagnosis of plasma cell dyscrasia, leukemia or myeloproliferative disorder.

What else could it be?

Differential diagnoses will depend on the patient's presenting symptoms, but include coagulopathy, hemorrhagic or ischemic stroke, congestive heart failure, pulmonary edema and diabetic ketoacidosis.

Are there specific confirmatory tests that I should perform?

There is no specific diagnostic test for hyperviscosity syndrome. The diagnosis is based on clinical symptoms and laboratory findings, as described above.

4. Specific Treatment

Plasmapheresis or cytapheresis is first line therapy and should be initiated as quickly as possible. It is very effective in quickly lowering blood viscosity. However, long-term management is necessary to control the underlying disease.

Hyperviscosity syndrome secondary to monoclonal gammopathies

The efficiency of plasmapheresis at removing paraproteins is dependent on the vascular distribution of the proteins. IgM protein is predominantly (70-80%) intravascular, thus a single plasmapheresis procedure can result in a dramatic response. Conversely, IgG and IgA proteins have a large extravascular volume, and several plasmapheresis procedures may be necessary to see the same effect.

In general, daily or every other day single volume plasmapheresis with 5% albumin replacement fluid is performed until symptoms improve. At the same time, disease-specific drug therapy can be started. Treatment options for Waldenstrom's macroglobulinemia and multiple myeloma include alkylating agents, thalidomide-based therapy, rituximab, bortezomib and nucleoside analogs.

Hyperviscosity syndrome secondary tol eukemias and/or myeloproliferative disorders

These conditions include acute and chronic leukemias, polycythemia vera (PV), and essential thrombocytosis (ET).

Hyperleukocytosis: Prompt leukocytoreduction is the mainstay of treatment for hyperleukocytosis and is achieved with a combination of leukapheresis, hydroxyurea, and induction chemotherapy. Leukapheresis is usually performed when the WBC is greater than 100,000, or less if the patient is symptomatic. A single leaukapheresis can lower the white blood cell (WBC) count by 20-60% and can be performed daily until the WBC count is less than 50,000/mm3. Hydroxyurea should also be given concomitantly at a dose of 50-100 mg/kg/day. This dose has been shown to reduce the WBC by 50-60% in 24-48 hours.

Induction chemotherapy should be initiated as soon as possible. Supportive measures include hydration with careful monitoring of fluid balance, especially in patients with cardiac symptoms or comorbidities. It is important that hyperleukocytosis causing leukastasis be recognized and treated promptly, as the mortality rate, if untreated, is as high as 40%.

Erythrocytosis/thrombocytosis: Low-dose aspirin is recommended for all patients with PV and ET. It is recommended that all PV patients be phlebotomized to a target hemacrit of 45%. Hydroxurea may be added for high-risk patients. Plateletpheresis is indicated in patients with ET for acute thromboembolism or hemorrhage. The goal is normalization of the platelet count.

Hyperviscosity syndrome secondary to monoclonal gammopathies

Maintenance plasmapheresis can be performed every 1-4 weeks for treatment of hyperviscosity that is not responsive to chemotherapy.

Hyperviscosity syndrome secondary to leukemias and/or myeloproliferative disorders

Hyperleukocytosis: repeat leukapheresis can be performed, but induction chemotherapy is the definitive treatment.

Erythrocytosis/thrombocytosis: patients with PV or ET who are resistant to hydroxyurea may be treated with interferon-alpha or busulfan.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Hyperviscosity syndrome secondary to monoclonal gammopathies

Plasmapheresis is very effective at removing paraproteins from the circulation, particularly IgM proteins. Because viscosity is logarithmically related to paraprotein levels, even small reductions can reduce viscosity and improve symptoms. Patients with Waldenstrom's macroglobulinemia (WM) tend to respond better than patients with multiple myeloma (MM).

Hyperviscosity syndrome secondary to leukemias and/or myeloproliferative disorders

Hyperleukocytosis: Though leukapheresis is very effective at lowering the blast count in acute leukemias, there appears to be no improvement in survival. Early death due to leukostasis may still occur. Predictors of poor prognosis are renal failure, respiratory distress, neurologic symptoms or coagulopathy.

Erythrocytosis/Thrombocytosis: Rapid improvement in clinical symptoms can be seen after one procedure.

If patients do not respond after 2-3 plasmapheresis/leukapheresis procedures, other causes for their symptoms should be investigated.

What follow-up should this patient receive?

HVS is a medical emergency, and most patients will remain hospitalized until their symptoms have resolved and their condition is stable. Additional follow-up will depend on the underlying disease.

Pathophysiology

Viscosity is defined as the internal frictional resistance of fluid to flow, or more simply, the "thickness" of the fluid. Water has a lower viscosity than honey, thus it travels faster. Blood viscosity varies as a function of hematocrit, red blood cell aggregation, plasma proteins, and interactions between blood and the blood vessel wall. In hyperviscosity syndrome, excessive plasma or cellular components cause inpaired transit through the microcirculation, which leads to stasis and hypoperfusion of tissues, resulting in end organ damage.

Centipoise (cp) is the standard unit for measuring biological fluids (the viscosity of water is 1.00 cp). The normal range is 1.4-1.8 cp. Symptoms of hyperviscosity generally appear between 4.0-5.0 cp. HVS usually is seen at levels higher than 5.0 cp.

Hyperviscosity syndrome secondary to monoclonal gammopathies

Increased viscosity in patients with multiple myeloma and Waldenstrom's macroglobulinemia is secondary to excessive amounts of circulating immunoglobulins. IgM is responsible for the majority of cases, as it is the largest immunoglobulin, but IgG and IgA can also cause HVS.

As the concentration of immunoglobulins increases, aggregate formation and binding to water via their carbohydrate content occurs. This increases osmotic pressure and increases resistance to blood flow. In addition, immunoglobulins interact with red cells and reduce their ability to travel through microvasculature, eventually leading to impaired transit of red blood cells, decreased tissue perfusion and tissue damage.

Hyperviscosity syndrome secondary to leukemias and/or myeloproliferative disorders

Emerging evidence suggests that activation of adhesion molecules on leukemic blasts and interactions between these blasts and endothelial cells enhances aggregation of the blasts. Increased production of cytokines and expression of adhesion molecules by endothelial cells results in the recruitment of additional blasts.

Epidemiology

Hyperviscosity syndrome secondary to monoclonal gammopathies

The most common cause of hyperviscosity syndrome due to increased paraproteins is Waldenstrom's macroglobulinemia. HVS has been reported in 10-30% of these patients. Conversely, HVS is a rare complication of multiple myeloma and is seen in only 2-6% of myeloma patients.

Hyperviscosity syndrome secondary to leukemias and/or myeloproliferative disorders

HVS and hyperleukocytosis occur in 5-30% of adult leukemias.

Prognosis

Prognosis depends on the underlying cause of the hyperviscosity. For example, hyperviscosity secondary to an acute leukemia or multiple myeloma has a worse prognosis than that due to polycythemia vera or essential thrombocythemia.

What's the evidence?

Behl, D, Hendrickson, A, Moynihan, TJ. "Oncologic emergencies". Crit Care Clin. vol. 26. 2010. pp. 181-205.

(Excellent in-depth review of emergency management of numerous high-risk situations in cancer patients.)

Siami, GA, Siami, FS. "Plasmapheresis and paraproteinemia: cryoprotein-induced diseases, monocolonal gammopathy, Waldenstrom's macroglobulinemia, hyperviscosity syndrome, multiple myeloma, light chain disease, and amyloidosis". Ther Apher. vol. 3. 1999. pp. 8-19.

(Comprehensive review of the role of plasmapheresis in paraprotein diseases.)

Mehta, J, Singal, S. "Hyperviscosity syndrome in plasma cell dyscrasias". Sem in Throm and Hem. vol. 29. 2003. pp. 467-71.

(Concise review of pathophysiology, clinical features and management of HVS in plasma cell dyscrasias.)

Mullen, EC, Wang, M. "Recognizing hyperviscosity syndrome in patients with Waldenstrom macroglobulinemia". Clin J Onc Nurs. vol. 11. 2007. pp. 87-95.

(Focuses on clinical symptoms, treatment and nursing implications for WM.)

Mullen, E, Mendez, N. "Hyperviscosity in patients with multiple myeloma". Onc Nurs Forum. vol. 35. 2008. pp. 350-2.

(Interesting case study of MM, followed by concise review of pathophysiology, presentation and treatment.)

Tefferi, A, Vainchenker, W. "Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies". JCO. vol. 29. 2011. pp. 573-82.

(Excellent review of genetic mechanisms, diagnosis and treatment that incorporates investigational modalities.)

Zarkovic, M, Kwaan, H. "Correction of hyperviscosity by apheresis". Sem Throm Hem. vol. 29. 2003. pp. 535-42.

(In-depth review of the principles of apheresis and different techniques in use, as well as its application to HVS.)

Adams, BD, Baker, R, Lopez, JA, Spencer, S. "Myeloproliferative disorders and the hyperviscosity syndrome". Hematol Oncol Clin N Am. vol. 24. 2010. pp. 585-602.

(Reviews symptoms, pathophysiology, diagnosis and treatment related to HVS. Very well organized, data is clearly presented.)

Porcu, P, Farag, S, Marcucci, G. "Leukocytoreduction for acute leukemia". Ther Aph. vol. 6. 2002. pp. 15-23.

(Review of pathophysiology and effect of cytoreduction on prognosis in acute leukemia.)

Porcu, P, Cripe, LD, Ng, EW. "Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management". Leuk Lymph. vol. 391. 2000. pp. 1-18.

(Frequently cited review of several studies and primary data with a focus on prognostic indicators.)

Greist, A. "The role of blood component removal in essential and reactive thrombocytosis". Ther Aph. vol. 6. 2002. pp. 36-44.

(Most up to date review of pathophysiology and role of plateletpheresis in thrombocytosis.)

Kwaan, HC, Wang, j. "Hyperviscosity in polycythemia vera and other red cell abnormalities". Semin Thromb Hemost. vol. 29. 2003. pp. 451-458.

(Detailed review describing the factors that affect thrombosis and management in PV. Excellent clinical images.)

Corrigan, FE, Leventhal, AR, Khan, S. "A rare cause of cardiac ischemia: systemic lupus erythematosus presenting as the hyperviscosity syndrome". Ann Int Med. vol. 153. 2010. pp. 422-4.

(Describes an interesting case that demonstrates a rare cause of hyperviscosity.)

Rosencranz, R, Bogen, S. "Clinical laboratory measurement of serum, plasma, and blood viscosity". Am J Clin Path. vol. 125. 2006. pp. S78-S86.

(Detailed information of the fundamentals for measuring viscosity, including definitions, terminology and laboratory principles.)

Szczepiorkowski, ZM, Winter, JL, Bandarenko, N. "Guidelines on the use of therapeutic apheresis in clinical practice - evidence based approach from the Apheresis Applications Committee of the American Society for Apheresis". J Clin Apher. vol. 25. 2010. pp. 83-177.

(Provides one page fact sheets summarizing evidence for therapeutic apheresis in 59 disease entities.)
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