Pathophysiology

Viscosity is formally defined as the internal frictional resistance of fluid to flow, or in simple terms, the “thickness” of the fluid. Water has a lower viscosity than syrup; it therefore travels faster and easier, especially through small passageways. Similarly, hyperviscous blood creates sludge and stasis in the capillary beds resulting in clinical manifestations at the tissue and circulatory level. Viscosity derives from physical and chemical properties, most notably the concentration, the size, and the shape of the molecules. Centipoise (cp) is the standard unit for measuring dynamic fluid viscosity, named in honor of the French physiologist Jean Louis Marie Poiseuille (who also described Poiseuille’s Law). Water has a viscosity of 1.00 cp at 20°C The large protein IgM pentameters in WM are highly viscous but HVS can also be seen in kappa light chain disease, which tends to form unstable, asymmetric, highly polymerized circulating aggregates. The clinical manifestations of HVS appear when the serum viscosity relative to water is greater than about 3 cp; at higher levels of 4cp and 5cp the prevalence of HVS rises to 67% and 75%, respectively. The underlying physiology of the patient creates significant variability from one patient to another, but for a given patient symptoms will manifest at about the same level of viscosity over time.

Clinical Presentation

HVS should be considered in at least three different Emergency Department (ED) scenarios: the patient presenting with the classic triad of HVS; the ED patient who has a previously established immunoglobulin-producing hematologic diagnosis; and critically ill patients with certain laboratory clues pointing to a concurrent underlying gammopathy.

The classic presentation triad for HVS consists of bleeding, visual disturbances, and focal neurologic signs. However, a variety of end organ damage can be observed. The bleeding typically arises from oozing mucosal surfaces including epistaxis, bleeding gums and gastrointestinal hemorrhage due to a supposed mechanism of impaired platelet function. Retinopathy caused by thrombosis, microhemorrhage, exudates, and papilledema results in the common visual derangements. These findings can be directly observed under fundoscopy with the classic picture of “sausage link” or “boxcar” venous engorgement of the retinal veins. Neurologic complications may present with headache, generalized stupor, and coma, or focal findings including vertigo, hearing impairment, seizures, and stroke syndromes. Not in the diagnostic triad, but often more hazardous, are the cardiopulmonary complications of HVS. Among other mechanisms, the effectively expanded plasma volume seen in HVS may drive demand beyond cardiac reserve resulting in high output cardiac failure, valvular dysfunction, or myocardial infarction.

Physicians should consider the diagnosis of HVS if a patient presents with unexplained neurologic symptoms such as visual change or headache in the setting of a concomitant immunoglobulin-producing hematologic condition. HVS is often the presenting characteristic of dysproteinemias. Renal failure has been reported with HVS but is generally more common in myelomas. One mechanism of renal failure in HVS may be that the glomeruli are exposed to a relative hypoperfused “pre-renal” state. Judicious hydration and avoiding use of diuretics is important to prevent further morbidity. Myeloma patients are notoriously susceptible to radiologic contrast nephropathy, so great caution should be exercised in its administration. HVS is also one cause of symmetric peripheral gangrene of the extremities.

Laboratory evaluation should include a complete blood cell count, full serum chemistries, and coagulation profiles. Significant proteinuria on routine urinalysis and an elevated albumin-protein gap (albumin − protein difference) suggests an underlying gammopathy. Occasionally, the laboratory will report the presence of rouleaux formation on the peripheral blood smear or that they are unable to complete tests because the viscous serum has clogged their analytical instruments. Paraneoplastic signs of multiple myeloma include hypercalcemia and hyponatremia. Confirmatory serum and urine protein electrophoresis with the characteristic monoclonal spike on serum electrophoresis confirms an existing gammopathy; this test can be arranged in conjunction with the admitting physician.

Diagnosis

HVS is a clinical diagnosis made on a combination of the symptoms discussed earlier in conjunction with a viscosity of 4 cp or greater as measured by a viscosimeter (normal viscosity is 1.4–1.8 cp). Controversy exists on whether plasma viscosity or whole blood viscosity is better, but measurement of whole blood viscosity is probably superior to that of serum or plasma viscosity alone. Laboratories report whole blood viscosity as comparable to a sample with a certain hematocrit (a viscosity comparable to that of a patient with a hematocrit of 70%). A relative whole blood viscosity of 55% or greater increases the risk of HVS.

Management

Physicians should base treatment decisions primarily on the severity of signs and symptoms rather than the measured degree of hyperviscosity. HVS therapy can be viewed in 4 phases: supportive therapy, plasma exchange, plasmapheresis, and chemotherapy for the underlying hematologic condition. Specific chemotherapy is generally applied after the ED course by hematology/oncology consultants and is therefore beyond the scope of this article.

Supportive Therapy

Paradoxically, these patients may be dehydrated yet present with high output cardiac failure. Judicious fluid resuscitation is usually necessary and diuretics should be avoided. Electrolyte derangements should be corrected with the foreknowledge that sodium derangements are often spurious. Antibiotics should be administered if any suspicion of infection exists. Although fluid compartment shifts may result in a measured anemia, these patients generally have a normal or supernormal red blood cell mass. Because packed red blood cell transfusions increase blood viscosity and thereby accelerate the HVS, they should be withheld until the viscosity can be measured and lowered appropriately.

Plasma Exchange

In the ED, one temporizing measure in a patient with severe HVS is to perform an emergency plasma exchange. The procedure involves phlebotomizing between 1 and 2 units of blood from the patient while simultaneously replacing the volume with normal saline. This therapy is of proven benefit and some experts believe it is more effective than plasmapheresis in decreasing serum viscosity in patients with WM. However, aggressive plasma exchange can deplete platelets, clotting factors, and albumin. Emergency plasma exchange is indicated in the presence of severe neurologic findings (seizure or coma). Measuring quantitative immunoglobulins before and after plasma exchange can help guide further hospital therapy but does not influence the ED course. IgA and IgG molecules have a higher volume of distribution (compared with the IgM of WM) and therefore plasma exchange may need to be performed more aggressively in these myelomas.

Plasmapheresis

Plasmapheresis is the definitive treatment for HVS. The ED physician should establish large-bore central venous access while awaiting the plasmapheresis team, preferably with a dialysis catheter. As noted, IgG- or IgA-related HVS will require longer and more frequent plasmapheresis treatments. The IgM found in WM is mostly intravascular and therefore is cleared more readily. The major complication of plasmapheresis is hypocalcemia related to citrate binding from automated plasmapheresis systems.

Pathophysiology

Hematopoiesis exists in a homeostatic balance between the body’s requirements for particular blood cell lines and loss or destruction of those cells. In the red cell line this balance is maintained by a feedback mechanism primarily involving the hormone erythropoietin. Erythropoietin is primarily produced in the renal cortex, accounting for 90% of this circulating protein. Secondary sites of production consist of liver, spleen, lung, testis, brain, and erythroprogenitor cells. Erythropoietin stimulation results in the production of 2 × 10 ¹¹ red blood cells per day. All blood cell lines arise from a common hematopoetic stem cell. These stem cells begin their initial differentiation onto erythrocyte progenitors when stimulated by one of several cytokine factors.

Erythrocytosis is the proper term for a state of increase in circulating red cells. Specifically, PCV possesses these additional features and has potential for progression to advanced disease. Erythrocytosis is initially identified by the increased in hematocrit and red blood cell count, but it is important to remember that these indices are dependent on red blood cell mass and plasma volume. Thus, a relative erythrocytosis occurs in cases of dehydration and low volume due to hemoconcentration. Correction in these cases can be accomplished by volume replacement and the condition may be short-lived.

An absolute erythrocytosis is associated with an increase in red cell production and mass. These patients are euvolemic with an increased hematocrit. Absolute erythrocytosis has been classified as either primary or secondary. Secondary erythrocytosis consists of congenital and acquired disorders. Congenital conditions are related to high oxygen affinity hemoglobinopathies and gene mutations (eg, 2,3-diphosphoglycerate deficiency). Acquired conditions are associated with erythropoietin-mediated erythrocyte production. This erythropoietin response may be hypoxia in patients living in high altitudes, those with chronic lung disease, or from paraneoplastic effects.

Diagnosis

The diagnosis begins with determining the red cell mass/body surface area in patients presenting with a persistently increased hematocrit in the absence of secondary causes of erythrocytosis. The Polycythemia Vera Study Group and the World Health Organization (WHO) have issued criteria for the diagnosis of PCV ( Box 1 ). New, proposed WHO criteria incorporate the presence of erythrocytosis or increased red cell mass and the presence of a known PCV molecular lesion.

Treatment

Phlebotomy and low-dose aspirin are the mainstays of PCV treatment. The current recommendations are phlebotomy to a hematocrit of ≤45% in men and ≤42% in women. However, no evidence exists for this goal of phlebotomy other than correlation between increased risk of thrombosis and a hematocrit >45% in these patients. Low-dose aspirin (either 81 or 100 mg daily) is recommended unless there are specific contraindications. More recent studies support initiation of aspirin therapy even in those patients with a previous history of gastric bleeding in the setting of concurrent use of a proton pump inhibitor. Further treatment is individualized based on the patient’s risk for thrombotic complications. A history of thrombosis, age more than 60 years, and associated thrombocytosis are indications for more aggressive treatment.

The next step in the management of higher risk patients is the addition of cytoreductive therapy. Options include hydroxyurea, chlorambucil, or intravenous radioactive phosphorus-32. Recombinant interferon alpha is another option in myelosuppressive management. Secondary erythrocytosis may be managed initially with phlebotomy. However, definitive management will require the primary cause to be addressed. Malignancy, hypoxia, and extrinsic sources of erythropoietin should be addressed and managed accordingly. These patients are also at risk for neurologic sequelae.

Pathophysiology

Hematopoiesis exists in a homeostatic balance between the body’s requirements for particular blood cell lines and loss or destruction of those cells. In the red cell line this balance is maintained by a feedback mechanism primarily involving the hormone erythropoietin. Erythropoietin is primarily produced in the renal cortex, accounting for 90% of this circulating protein. Secondary sites of production consist of liver, spleen, lung, testis, brain, and erythroprogenitor cells. Erythropoietin stimulation results in the production of 2 × 10 ¹¹ red blood cells per day. All blood cell lines arise from a common hematopoetic stem cell. These stem cells begin their initial differentiation onto erythrocyte progenitors when stimulated by one of several cytokine factors.

Erythrocytosis is the proper term for a state of increase in circulating red cells. Specifically, PCV possesses these additional features and has potential for progression to advanced disease. Erythrocytosis is initially identified by the increased in hematocrit and red blood cell count, but it is important to remember that these indices are dependent on red blood cell mass and plasma volume. Thus, a relative erythrocytosis occurs in cases of dehydration and low volume due to hemoconcentration. Correction in these cases can be accomplished by volume replacement and the condition may be short-lived.

An absolute erythrocytosis is associated with an increase in red cell production and mass. These patients are euvolemic with an increased hematocrit. Absolute erythrocytosis has been classified as either primary or secondary. Secondary erythrocytosis consists of congenital and acquired disorders. Congenital conditions are related to high oxygen affinity hemoglobinopathies and gene mutations (eg, 2,3-diphosphoglycerate deficiency). Acquired conditions are associated with erythropoietin-mediated erythrocyte production. This erythropoietin response may be hypoxia in patients living in high altitudes, those with chronic lung disease, or from paraneoplastic effects.

Diagnosis

The diagnosis begins with determining the red cell mass/body surface area in patients presenting with a persistently increased hematocrit in the absence of secondary causes of erythrocytosis. The Polycythemia Vera Study Group and the World Health Organization (WHO) have issued criteria for the diagnosis of PCV ( Box 1 ). New, proposed WHO criteria incorporate the presence of erythrocytosis or increased red cell mass and the presence of a known PCV molecular lesion.

Treatment

Phlebotomy and low-dose aspirin are the mainstays of PCV treatment. The current recommendations are phlebotomy to a hematocrit of ≤45% in men and ≤42% in women. However, no evidence exists for this goal of phlebotomy other than correlation between increased risk of thrombosis and a hematocrit >45% in these patients. Low-dose aspirin (either 81 or 100 mg daily) is recommended unless there are specific contraindications. More recent studies support initiation of aspirin therapy even in those patients with a previous history of gastric bleeding in the setting of concurrent use of a proton pump inhibitor. Further treatment is individualized based on the patient’s risk for thrombotic complications. A history of thrombosis, age more than 60 years, and associated thrombocytosis are indications for more aggressive treatment.

The next step in the management of higher risk patients is the addition of cytoreductive therapy. Options include hydroxyurea, chlorambucil, or intravenous radioactive phosphorus-32. Recombinant interferon alpha is another option in myelosuppressive management. Secondary erythrocytosis may be managed initially with phlebotomy. However, definitive management will require the primary cause to be addressed. Malignancy, hypoxia, and extrinsic sources of erythropoietin should be addressed and managed accordingly. These patients are also at risk for neurologic sequelae.

Pathophysiology

The granulocytic and lymphocytic cell lines are routinely measured in the ED. The granulocytic series is primarily involved in phagocytic activities and is derived from a common progenitor cell located in the bone marrow that also gives rise to erythrocytes, megakaryocytes, eosinophils, basophils, and monocytes. Granulocytes are maintained in a series of developmental and storage pools. The most important is the postmitotic storage pool for neutrophils, which represents 15 to 20 times the circulating population and contains metamyelocytes, band neutrophils, and mature neutrophils. The pool can be drawn on as a ready reserve during rapid consumption of granulocytes. Cytokines and complement components release granulocytes from the marrow storage pool into the circulation, which can result in a two- to threefold increase in the granulocyte count within 4 to 5 hours. Circulating neutrophils are subdivided equally into the circulating neutrophil pool and the marginal pool. The marginal pool consists of mature cells adherent to the blood vessel walls, which can rapidly enter the circulating pool and can cause a doubling of the WBC count.

A leukemoid reaction is an excessive leukocytic response in the peripheral blood of the granulocytic cell line. The WBC exceeds 50,000/mm ³ and resembles chronic myeloid leukemia. A leukemoid reaction is characterized by a significant increase in neutrophils in the peripheral blood and a differential demonstrating a left shift. The precursors (myelocytes, metamyelocytes, promyelocytes, and myeloblasts) may occasionally be observed in severe reactions. In contrast to acute leukemia, proliferation and orderly maturation of all normal myeloid elements is observed in the bone marrow and the morphology of the myeloid elements is normal. Diagnosis of a leukemoid reaction should only be made after excluding a hematologic malignancy.

The morbidity of hyperleukocytosis results primarily from the leukostasis syndrome caused by the increased viscosity and sluggish flow of circulating leukemic blasts in tissue microvasculature. A postulated mechanism suggests an increase in blood viscosity and blockade of the microcirculation resulting in organ damage. More recent evidence suggests that interactions between leukemic blasts and the surface of endothelial cells might be responsible for the aggregation in the microcirculation. Increased production of cytokines and expression of adhesion markers such as ICAM-1, VCAM-1, and selectin by endothelial cells enables myeloblasts to recruit additional myeloblasts. This forms a vicious cycle in which increasingly more cells are trapped in the microcirculation.

Diagnosis

A unique problem with white blood cell disorders is the wide variability of normal quantitative values. Total WBC and neutrophil count in neonates younger than 1 week are physiologically higher than those in older children and adults; however, young infants less than 3 months old have smaller storage pools of neutrophils. The proportion of lymphocytes and absolute lymphocyte counts in children are higher than those in adults. Failure to recognize age-specific lymphocytosis may lead to unnecessary investigations.

Clinical Presentation

In general, leukostasis is observed in AML if the WBC is >100 × 10 ⁹ /L and in ALL if the WBC is >400 × 10 ⁹ /L. Leukostasis is usually associated with a high number of circulating blasts but has also been described with blast counts less than 50,000/mm ³ . Hyperleukocytosis is seen in up to 13% of patients with AML, is less common in ALL, and even less common in chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). The frequency of complications is higher in AML than in ALL because the myeloblasts are larger and more adhesive than lymphoblasts. Leukostasis is present in 12% of adult patients with CML and in up to 60% of pediatric cases, but CML represents only 2% to 7% of childhood leukemias.

The manifestations of acute hyperleukocytosis are protean ( Box 2 ). Fever is common, but can be traced to definitive infection in only a small number of these patients. Blood cultures should still be obtained so that infection can be ruled out, because hyperleukocytosis can mimic several viral, bacterial, and fungal syndromes.

Box 2

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