Benedictus Dhewa, Sartika Riyandhini, Chairunnisa Sitorus, Dessy Esa, Fitrisia Rahma, Fanny, Lady Rovyanda, Meisya Shabrina

April-Mei 2013

Background
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 Waldenstrm macroglobulinemia and multiple myeloma. It 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 complications most commonly associated with

this syndrome include mucous membrane bleeding, neurologic and pulmonary symptoms, and the associated retinopathy.

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, leading to the clinical symptoms of hyperviscosity syndrome secondary to the vascular stasis and resultant hypoperfusion.
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 the hyperviscosity syndrome typically requires a viscosity greater than 5 units.

 Hyperviscosity syndrome (HVS) is associated most

commonly with plasma cell dyscrasias (the paraproteinemias) and is due to the large size of the excess immunoglobulin M (IgM) paraproteins in these disorders. Waldenstrm macroglobulinemia is the most common cause and accounts for about 85% of cases of HVS. Less frequently, the disease can occur in multiple myeloma (especially with myeloma proteins of the IgA and IgG3 types) and connective tissue diseases.

 Hyperviscosity syndrome can also be caused by the

bone marrow hyperproliferative states: the leukemias, polycythemia, essential thrombocytosis, and the myelodysplastic disorders, which also increase serum viscosity.

 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.[1] Thus, prompt recognition and expeditious treatment are imperative in preventing deterioration.[2]

Epidemiology
Mortality/Morbidity Mortality is related to the underlying cause of the hyperviscosity syndrome. Sex While not much information is available regarding the incidence of hyperviscosity syndrome, one study found that 61% of blood dyscrasias occur in males. Age Little information is available regarding the age of patients with hyperviscosity syndrome. Most blood dyscrasias are not diagnosed until the seventh decade of life.

History
Clinical symptoms generally are related to the triad of

mucosal bleeding, visual changes, and neurologic symptoms.[2] Constitutional symptoms and cardiorespiratory symptoms also contribute to the clinical presentation.

 The tendency to bleed is the most common

symptom of hyperviscosity syndrome.

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

Visual changes range from blurred vision to vision

loss.

 Other manifestations may include heart failure,

shortness of breath, hypoxia, fatigue, and anorexia. In fact, one should have a high index of suspicion for HVS in patients with unexplained coma/altered mental status or unexplained shortness of breath especially in those with an underlying hematologic disorder.

Physical Finding
Physical findings are related to the major organ

systems involved.
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.

 Neurologic examination may reveal various findings,

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 JVP, and hypoxia).

 Neurologic manifestations are frequent and varied.

The neurologic symptoms of hyperviscosity have been referred to as the Bing-Neal syndrome.
Vertigo Hearing loss Paresthesias Ataxia Headaches Seizures Somnolence progressing to stupor and coma

Causes
Increased serum viscosity usually results from

increased circulating serum immunoglobulins and can be seen in Waldenstrm macroglobulinemia and multiple myeloma. Less commonly, the hyperproliferative blood cell disorders such as the leukemias, myeloproliferative diseases, polycythemia, and thrombocytosis may be implicated for the increased viscosity caused by proliferation of their respective cellular components.

Differential Diagnoses
Congestive Heart Failure and Pulmonary Edema Stroke, Hemorrhagic Stroke, Ischemic

Laboratory Studies
Determine serum viscosity. Serum viscosity is diagnostic in evaluating hyperviscosity syndrome when the elevated viscosity is concomitant with characteristic symptoms. No exact diagnostic cut-off exists for viscosity as different patients will have symptoms at different values of viscosity. A clue may be that the laboratory may be having difficulty performing chemical tests on the blood due to the serum stasis and increased viscosity, which may clog analyzers. The normal reference range 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 hyperviscosity syndrome usually presents with a serum viscosity greater than 5 Centipoises. Typically, the higher the viscosity, the worse are the symptoms. Obtain a peripheral blood smear with the CBC. Rouleaux formation is often present with increased serum viscosity. WBC count is typically 100,000 or greater in leukostasis causing HVS, but it may be lower in the blast crises of the leukemias. Consider adding total protein (TP) and albumin as in the paraproteinemias; a globulin gap (TP albumin = 4 or greater) may exist.

 Consider adding serum and urine electrophoresis in

new cases without preceding diagnosis for diagnostic purposes. Consider coagulopathy workup (eg, blood count, type and screen, prothrombin time, activated partial thromboplastin time, platelet count) if the patient presents with hemorrhage.

 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 from poor venipuncture technique; use a larger needle, withdraw slowly and, if in doubt, send for a plasma rather than serum potassium level, which will be more reliable).

 Tailor additional workup (eg, chest radiography, brain

CT or MRI) to the patient's presentation. Consider panculture and urinalysis.Multiple myeloma is complicated frequently by infections. In nonneutropenic patients, infections are usually secondary toStreptococcus pneumoniae or Haemophilus influenzae. Search for other disorders. Hyperviscosity syndrome is the result of another pathologic process (eg, multiple myeloma, Waldenstrm macroglobulinemia, hyperproliferative blood cell dysplasias).

Imaging Studies
Head CT scan is indicated if the patient presents with

altered level of consciousness, seizures, or focal neurologic deficits. Contrast dye is contraindicated in multiple myeloma because of the increased risk of renal failure. 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 Be attentive to the ABCs and symptomatic support.

Emergency Department Care Plasmapheresis is the treatment of choice for initial treatment and stabilization of the hyperviscosity syndrome caused by the paraproteinemias (the majority of cases), while leukapheresis, plateletpheresis, and phlebotomy are indicated for leukostasis, and symptomatic thrombocytosis, and polycythemia, respectively.

 As plasmapheresis removes the circulating paraproteins,

the serum viscosity decreases and symptoms improve.

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, Waldenstrm macroglobulinemia, blood dyscrasias) should be definitively treated with the appropriate oncologic therapy, such as chemotherapeutics, for example, or these symptoms will typically recur within a couple weeks requiring further pheresis.

 Although symptoms of CHF from hyperviscosity may

not respond to standard therapies, and, in fact, can be exacerbated due to the resultant dehydration from diuresis causing increased viscosity; plasmapheresis and/or cellular pheresis reverses these symptoms. While arranging for plasmapheresis, treat hemorrhage, CHF, and metabolic imbalances with standard therapies. 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, proceed with caution and 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 these therapies do not control the underlying disease. 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.[1]

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

Further Inpatient Care

Supportive

care should be initiated for the complications of hyperviscosity syndrome pending definitive therapy. Care includes support for blood loss, central nervous system disorders, and cardiovascular effects, and metabolic derangements. Note that the definitive treatment of hyperviscosity syndrome is treatment of the underlying disorder (eg, chemotherapy); as without this, even with treatment by plasmapheresis the hyperviscosity will recur if the underlying disease process is left untreated.

Transfer
Consider

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

Complications
Complications depend upon the underlying cause of

the hyperviscosity

Prognosis
Prognosis depends on the severity of the complications

associated with hyperviscosity syndrome and the underlying cause of the hyperviscosity syndrome and the response of the appropriate definitive treatment. For example, multiple myeloma continues to have a poor long-term prognosis

Patient Education
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).