Nonconventional Management of a Hyperviscosity Syndrome Failing Plasma Exchange

Abstract

Hyperviscosity syndrome (HVS) is a life-threatening haematological emergency. We report a severe HSV case in which extracorporeal plasma polymerization prevented an effective plasma exchange procedure. We elaborated an unconventional successful approach consisted in the manual removal of whole patient blood followed by red blood cells (RBC) and plasma support.

Hyperviscosity syndrome (HVS) is a life-threatening hematological emergency. HVS is usually associated with a reduction in red blood cells (RBC), shape deformity or increased levels of blood cell elements, or a pathological rise of high molecular weight serum protein such as IgM antibodies. ¹ Increased immunoglobulin levels are the most common cause of HVS, and Waldenstrom Macroglobulinemia (WM) is the most frequent etiology of a rise in these levels. ² This pathological occurrence severely affects plasma viscosity through several different mechanisms related to physicochemical properties, nonspecific interactions with other proteins, antibody activity, and tendency of tissue deposition. ³

HVS is characterized by a heterogeneous clinical appearance, and not all patients require aggressive blood viscosity management.^4–6 Typically, skin and mucosal bleeding, visual disturbance, and various neurologic disorders hallmark HVS. ⁵ Thrombotic complications are frequent. ⁵ Congestive heart failure and other cardiovascular manifestations occur but are less common. ¹ Symptomatic HVS warrants emergency treatment, with plasma exchange being the standard of care. ⁵ International apheresis guidelines recommend this procedure with the highest level of evidence.^7,8

Situations in which apheresis procedures are not practicable are critical emergencies. ¹ Here, we report the case of a 68-year-old caucasian woman with severe HVS in which extracorporeal plasma polymerization prevented the conduction of effective plasma exchange procedures.

The Case

A patient was admitted to the emergency department of our hospital for a two-week history of mild fever, asthenia, and dyspnea. A diagnosis of IgM-monoclonal gammopathy of undetermined significance (MGUS) was made six years ago, but the patient refused a regular follow-up as recommended by our clinical practice. Concerning medical history, breast cancer was radically treated 10 years ago, and oncological remission was obtained.

Upon hospital admission, the patient complained of headache and fatigue and showed mild confusion. No visual disturbances were reported. At the physical examination, she was extremely pale, with skin bruising on the arms and mild epistaxis; no signs of vascular injury or enlargement of the lymph nodes, spleen, or liver were found. Vital signs were reported as arterial pressure of 110/70 mm Hg, heart rate of 92 beats per minute, and mild hypoxemia. A body weight of 60 kilograms was also reported. Pulmonary and abdominal examination was normal, and peripheral edema was reported. Neurological examination was negative. A retinal scan was not performed. A blood sample was collected; however, the patient's blood rapidly clogged the laboratory tube machines and only preliminary blood count was obtained. Reports indicated severe anemia (hemoglobin 5.90 g/dL, hematocrit 19%), severe hyper-leukocytosis (white blood cell [WBC] 42.96 × 10*9/L with lymphocytes 17.66 × 10*9/L), and normal platelet (PLT) levels (165 × 10*9/L). A May-Grünwald-Giemsa peripheral blood smear was performed and showed large plasmacellular elements with no evidence of circulating immature blast cells.

A rapid saline intravenous infusion was started and the second laboratory test keeping blood samples at 37 °C was done. This approach enabled an additional laboratory examination showing normal liver enzymes, normal hemolysis markers, and normal renal function. In contrast, total protein values (17.60 g/dL) and serum electrophoresis (19.6% of albumin, 63.4% of immunoglobulins) were markedly abnormal. An IgM-kappa paraprotein was detected (9.7 g/dL). Of note, coagulation evaluation was impossible to perform, and no measurement of serum viscosity was conducted. In consideration of the pandemic phase, SARS-CoV-2 was tested by PCR and found to be negative. A cytofluorimetric examination of peripheral blood showed clonal lymphocyte B-cell population, suggesting an HVS-related chronic lymphoproliferative disorder as lymphoplasmacytic lymphoma (LPL). ⁹

The HVS severity was urgent, requiring an immediate life-saving treatment. A steroid therapy (prednisone 1 mg/kg) was started. Severe anemia was also a major concern, but the potential increase in blood viscosity induced by transfused RBC advised us to attempt an aggressive plasma viscosity reduction before any transfusions. ¹ An urgent therapeutic plasma exchange was attempted to prevent extra-corporeal blood gelling; a number of ambient manipulations were conducted. We opted for Spectria Optia, vers. 11, with ACD-A anticoagulant, ratio 12 to 1, and replacement fluid with albumin 5%.

However, the procedure was immediately and prematurely interrupted for extensive precipitation in the first centimeters of the apheresis tube, and no other plasma exchange attempts were performed. Given the impossibility of obtaining a successful therapeutic apheresis, we decided to carry out an unconventional procedure consisting of a phlebotomy followed by RBC and plasma support. During the procedure, 1000 mL of whole blood (2 aliquots) were removed and replenished with 3 units of concentrated RBC and 450 mL of fresh frozen plasma. ⁹ Patient remained stable and tolerated this approach well.

After the first procedure, we were able to perform all laboratory tests to obtain a complete evaluation of coagulation (prothrombin time [PT] 1.25; partial thromboplastin time [aPTT] 0.83; fibrinogen 565 mg/dL; antithrombin III [ATIII] 77%) and a sufficient reduction of the monoclonal component amount (Figure 1). Blood count electrolytes were also tested, with no significant modifications.

Figure 1.

Legend: Blood test evolution after procedures.

A second urgent phlebotomy with RBC/plasma replacement was conducted, achieving a further reduction of the IgM-kappa paraprotein. The diagnosis of lymphoplasmacytic lymphoma was made by histological bone marrow examination and according to WHO criteria. ¹⁰ MYD88 mutation was not available. Abdominal computer tomography (CT) showed modest spleen enlargement with no pathological findings of the lymph nodes or liver. A debulkying strategy with VCD (Bortezomib 1.3 mg/m² day [D] 1,4,8,11; cyclophosphamide 1500 mg D1; 800 mg D11; dexamethasone 20 mg D 1,2,4,5,8,9,11,12) was started, and a final phlebotomy course was performed gaining stable and safe control of HVS ¹¹ (Figure 1). After two VCD cycles, the patient was lost to follow up.

Discussion

HVS is an oncological emergency requiring timely treatment to prevent complications. In this case, we faced a severe HVS clinical presentation that could not be managed with the standard plasma-exchange approach due to extreme gelling caused by a serum cryo-precipitable protein. Therefore, we elaborated an unconventional approach that was based on physiological premises but had not yet been reported in scientific literature. The approach consisted of whole manual removal of the patient's blood followed by concurrent replacement with an approximately 50% RBC/plasma mix mimicking the physiological hematocrit. ⁹ This strategy was repeated, making it possible to overcome the clinical emergency, resolve HVS symptoms, complete the diagnostic work-up, and safely initiate the cytoreductive treatment. Instead of purified human plasma proteins (“Plasmagrade® Kedrion SpA, Italy”) or other blood products, solvent/detergent inactivated fresh frozen plasma was selected for replacement to adhere as much as possible to the physiological blood composition, and because no information was available about the coagulation state.

Several additional issues are worth consideration. First, severe anemia is a life-threatening risk factor and an RBC transfusion is a life-saving treatment. On the other hand, RBC supports can increase blood viscosity and worsen HVS.^4,5 For these reasons, we decided to perform RBC transfusion only after a careful blood viscosity reduction was achieved.^1,5

Second, we observed a rapid clinical improvement even when RBC/plasma mix replaced a relatively small amount of plasma (approximately 700 mL in the first procedure and 1000 in the second) because there was a concurrent beneficial effect on anemia and HVS during the early high-risk phase of the clinical history of the patient.

Third, rapid-acting systemic chemotherapy can reduce serum viscosity and overcome the need for plasma exchange. Bortezomib-based triplet regimens result in the fastest decline of protein levels and are recommended in WM- and multiple myeloma-related HVS. ⁵ Our patient started a steroid-, bortezomib and cyclophosphamide-triple combination that has undoubtably contributed to clinical improvement and HVS resolution. ⁵ A rituximab-containing regimen was avoided to reduce IgM flair risk. ¹¹ However, pharmacological treatment is never considered as an alternative to plasma exchange for immediate hyper-viscosity reduction. ⁵ This case reinforces the importance of periodic monitoring of the M-component to prevent the occurrence of life-threatening emergencies such as HVS. ¹² Our patient had a previously known M-component, but she preferred not to undergo periodic evaluations either at the hematology clinic or under the supervision of her general practitioner, which is usually recommended for these patients, even if it is debated at least for M-components <1.5 g/dL. ¹²

Conclusion

Our data indicate that phlebotomy replenished by an appropriate RBC/plasma mix could be considered an effective and safe alternative for emergency situations in which a plasma exchange procedure cannot be performed to correct hyper-viscosity.