Treatment of Three Cats with Hyperviscosity Syndrome and Congestive Heart Failure Using Plasmapheresis
Three cats were evaluated at a veterinary teaching hospital for congestive heart failure (CHF) secondary to hyperviscosity syndrome from plasma cell neoplasia. All cats had severe hyperproteinemia due to hyperglobulinemia. Multiple myeloma or plasma cell neoplasia was diagnosed based on cytopathology and post mortem examination. The cats presented with signs of CHF including acute collapse, tachypnea, increased respiratory effort, and pulmonary crackles. All cats had heart murmurs and echocardiographic signs consistent with hypertrophic cardiomyopathy. An enlarged left atrium was found in all cats and two of three cats also had spontaneous echocardiographic contrast. Plasmapheresis (centrifugal plasma exchange) was performed on all three cats by the removal of whole blood and the infusion of a balanced electrolyte solution while the whole blood was centrifuged and separated. The RBCs were then washed before being readministered to the patient. Plasmapheresis alleviated the clinical signs of CHF (tachypnea) in all three cats. Plasmapheresis should be considered in cases of CHF secondary to hyperviscosity syndrome to rapidly alleviate clinical signs associated with heart failure while diagnosis of the underlying cause is made and appropriate therapy implemented.
Introduction
Hyperviscosity syndrome (HVS) consists of a collection of clinical signs that occur due to an increase in blood viscosity. In cats, HVS is most commonly due to hyperglobulinemia associated with neoplasia such as plasma cell tumors or lymphoma. Signs of HVS are typically manifest in the cardiovascular, renal, neurologic, coagulation, and ocular systems.1–5 In some cases, elevated blood viscosity causes increased resistance to blood flow and an increased cardiac workload required to pump the viscous blood. This increased resistance combined with an expanded plasma volume and systemic hypertension can result in hypertrophy of the myocardium and eventual decompensation of cardiac function with subsequent congestive heart failure (CHF).
Treatment of HVS in people includes management of the underlying disease and either intermittent or continuous plasmapheresis to control clinical signs associated with hyperviscosity.1–4 Although plasmapheresis has been reported in the veterinary literature for the treatment of HVS, to the authors’ knowledge, plasmapheresis has not been documented as a treatment specifically for CHF associated with HVS. The purpose of this report is to outline the presentation, diagnosis, management, and outcome of three cats with CHF secondary to HVS and plasma cell neoplasia whose signs of heart failure were successfully alleviated with plasmapheresis.
Case Report
Case 1
An 8 yr old, 4.3 kg, male castrated domestic shorthair presented for evaluation following collapse. The owner described that the cat's eyes became fixed and glazed, the cat then vocalized and fell over. The cat had been previously diagnosed with asymptomatic hypertrophic obstructive cardiomyopathy based on echocardiography approximately 3 yr prior. During the physical examination, the cat was alert and responsive; however, tachypnea (70 breaths/min), tachycardia (240 beats/min), and a grade 4/6 left parasternal systolic murmur was noted. Electrocardiography showed sinus tachycardia with increased amplitude R waves consistent with left ventricular hypertrophy. Echocardiographic findings were consistent with severe hypertrophic obstructive cardiomyopathy. There was asymmetric hypertrophy of the left ventricle and the left atrium was severely enlarged with spontaneous echocardiographic contrast (“smoke”) present. The initial assessment was that the cat most likely sustained an embolic event to the brain as a result of heart disease. Treatment of the cat was initiated with dalteparina (100 IU/kg subcutaneously [SC] q 24 hr) indefinitely and furosemideb (2.3 mg/kg SC as needed) as needed for tachypnea.
Subsequent evaluation 2 days later revealed continued lethargy, anorexia, and tachypnea. Diagnostic evaluation included a CBC, chemistry panel, thoracic radiographs, and abdominal ultrasound. The most significant laboratory finding was severe hyperproteinemia (14.6 g/dL; reference range, 5.4–8.9 g/dL) characterized by a hyperglobulinemia (12.8 g/dL; reference range, 2.8–5.3 g/dL). The cat was also anemic (PCV was 28%; reference range, 28%–45%). Interpretation of thoracic radiographs revealed cardiomegaly, mild pleural effusion, congested pulmonary vessels, and pulmonary opacities consistent with pulmonary edema and CHF. An abdominal ultrasound examination revealed a mild anechoic peritoneal effusion, mild hepatomegaly, and mild bilateral renomegaly. Bilateral multifocal retinal hemorrhages were observed on fundic examination. Fine-needle aspiration of the liver was performed and cytopathology was consistent with plasma cell neoplasia. Serum protein electrophoresis revealed a monoclonal gammopathy (gamma globulin was 10.6 g/dL; reference range, 0.3–2.5 g/dL). Congestive heart failure, plasma cell neoplasia, and HVS were diagnosed.
Medical management of the CHF and plasma cell tumor were initiated with enalaprile (0.6 mg/kg per os [PO] q 24 hr), buprenorphinef (0.01 mg/kg IV q 6 hr), prednisoloneg (1.8 mg/kg PO q 24 hr), and melphalanh (0.12 mg/kg PO q 24 hr). Dalteparin was continued and cyclophosphamidei (13 mg/kg IV once) was administered. To facilitate a rapid reduction in the serum globulin concentration and alleviate signs of CHF, plasmapheresis (centrifugal plasma exchange) was performed. Approximately 53 mL of blood was removed from the jugular vein into a 60 mL syringe containing 7 mL of anticoagulantj. The blood was then separated into RBCs and plasma by centrifugation and the plasma was discarded. The red cells were washed twice with saline and the red cells were returned to the cat in 5 mL of crystalloid fluidsk. Following the procedure, the cat improved dramatically: the cat's respiratory rate and effort decreased and the total protein decreased to 10 g/dL. The cat was discharged 2 days later on enalapril, prednisolone, melphalan, and dalteparin.
The cat returned for reevaluation 1 wk later. The serum total protein was 9.6 g/dL (globulin was 6.9 g/dL) and a PCV of 24%. Repeat echocardiography showed decreased left atrial size and resolution of the spontaneous echocardiographic contrast. The oral prednisone was discontinued and methylprednisolone acetatel (4.6 mg/kg SC q 1 mo) was prescribed instead due to owner's difficulties with oral administration of the medication. The cat did well at home following the initial diagnosis until he represented for bilateral hind limb paralysis and vocalization 6 mo later. During the physical examination, hind limb paraplegia was noted and both hind limbs were cold with absent femoral pulses. A gallop rhythm was noted on cardiac auscultation and there was evidence of bilateral epistaxis. The cat was diagnosed with presumptive aortic thromboembolism and the owner elected humane euthanasia. Post mortem examination was performed and revealed multiple myeloma of the bone marrow, liver, and spleen with no evidence of osteolytic lesions in the long bones or ribs. Left ventricular myocardial hypertrophy with left atrial dilatation and a distal aortic thromboembolism were also found. No evidence of neoplastic infiltration of the myocardium was noted.
Case 2
A 14 yr old, 4.2 kg, male castrated domestic shorthair presented with a 1 day history of tachypnea. The physical examination revealed tachypnea (respiratory rate 78 breaths/min) and hypothermia (rectal temperature was 35°C). Thoracic auscultation indicated a heart rate of 150 beats/min and a gallop rhythm. Coarse crackles were also present in all lung fields. During abdominal palpation, both kidneys were small and slightly irregular. A palpable thyroid nodule was not noted. The cat had a body condition score of 3/9. Interpretation of thoracic radiographs taken by the referring veterinarian revealed cardiomegaly, mild pleural effusion, and an alveolar pattern in the ventral lung fields. Echocardiography revealed marked asymmetric left ventricular hypertrophy, a hyperechoic and irregular endocardium, moderate left atrial enlargement, scant pericardial effusion, and a small amount of pleural effusion. A diagnosis of CHF secondary to HCM was made.
A constant rate infusion of furosemide was administered (0.6 mg/kg/hr IV for 6 hr). Additional treatments included nitroglycerine ointment (a one-quarter inch strip applied topically once) and dalteparin (100 IU/kg SC q 24 hr). The cat's respiratory rate decreased to 50 breaths/min; however, increased respiratory effort persisted. The furosemide infusion was repeated and the cat's respiratory rate decreased again to 30 breaths/min but the increased respiratory effort persisted. The cat was also mildly hypertensive: the Doppler-derived systolic blood pressure was 160 mmHg. A chemistry panel performed 12 hr after admission revealed hyperproteinemia marked by hyperglobulinemia. The total protein was 14.9 g/dL, globulin was 12.8 g/dL, albumin was 2.1 g/dL (reference range, 3.0–4.2 g/dL). An elevated creatine kinase (1153 IU/L; reference range, 72–481 IU/L) was also noted. An abdominal ultrasound revealed hepatomegaly, splenomegaly, renal infarcts, and a thickened colonic wall. Liver and splenic aspirates were obtained and cytopathology was consistent with plasma cell neoplasia. Interpretation of appendicular skeletal radiographs showed no evidence of lytic bone lesions. Protein electrophoresis revealed a monoclonal gammopathy (gamma globulin was 10.6 g/dL). A diagnosis of CHF secondary to plasma cell neoplasia with associated HVS was made.
To decrease blood viscosity and help resolve the CHF, plasmapheresis was performed using the same technique described in the first case. The remaining washed RBCs were suspended in 15 mL of a crystalloid solutionk and administered to the patient IV over 30 min. After the procedure, the cat was eupneic and the respiratory rate decreased to 24 breaths/min. The total solids decreased to 12.0 g/dL (reference range, 6.5–8.4 g/dL) and the PCV was 30%. At that time, therapy was initiated with prednisolone (2.4 mg/kg PO q 24 hr) and cyclophosphamide (10 mg/kg IV once). The cat was discharged the following day and prescribed prednisolone (2.4 mg/kg PO q 24 hr), melphalan (0.12 mg/kg PO q 48 hr), enalapril (0.6 mg/kg PO q 24 hr), dalteparin (100 IU/kg SC q 24 hr), and furosemide (1.5 mg/kg PO q 8 hr).
Two days following discharge, the cat returned with tachypnea, anorexia, and lethargy. On physical examination, the cat was quiet but responsive and tachypneic (80 breaths/min). A grade 3/6 left parasternal heart murmur was ausculted and crackles were heard over the right hemithorax. The Doppler-derived systolic blood pressure was 70 mmHg. Interpretation of thoracic radiographs revealed cardiomegaly, pulmonary arterial and venous distention, and cranial and right caudal alveolar pattern with scant pleural effusion suggesting progression of the previously diagnosed cardiogenic pulmonary edema. A serum chemistry panel obtained shortly after admission revealed findings consistent with renal failure including severe azotemia (blood urea nitrogen was 181 mg/dL; reference range, 15–41 mg/dL and creatinine was 10.0 mg/dL; reference range, 1.0–2.1 mg/dL), hyperkalemia (6.7 mmol/L; reference range, 3.5–5.1 mmol/L), hyperphosphatemia (14.4 mg/dL; reference range, 2.5–5.5 mg/dL), hyponatremia (135 mmol/L; reference range, 150–159 mmol/L), and hypochloremia (97 mmol/L; reference range, 113–122 mmol/L). Because of the poor prognosis, the owners elected humane euthanasia. Postmortem examination was declined.
Case 3
An 8 yr old, 6.8 kg, male castrated domestic shorthair presented for evaluation of increased respiratory effort, lethargy, and inappetence of 2 days’ duration. The cat was taken to an emergency clinic the previous evening where a physical examination revealed tachypnea (60 breaths/min) and a gallop rhythm. A CBC was performed that revealed a severe anemia (PCV was 12.9%), thrombocytopenia (manual platelet count was 73,500/μL; reference range, 200,000–500,000/μL), and RBC agglutination. A chemistry panel showed hyperglycemia (glucose was 202 mg/dL; reference range, 71–159 mg/dL) and markedly elevated total protein (>12.0 g/dL). Interpretation of the thoracic radiographs revealed mild left atrial enlargement, slightly attenuated pulmonary vessels, and no evidence of pulmonary edema. The cat was hospitalized in an oxygen cage and administered doxycyclinem (7.4 mg/kg PO q 12 hr) and famotidinec (0.5 mg/kg SC q 24 hr). The cat was premedicated with dexamethasonen (0.2 mg/kg IV once) and diphenhydramineo (1.2 mg/kg IV once) and a transfusion of fresh whole blood was administered (2.2 mL/kg/hr IV) over 4 hr. By the end of the transfusion, the tachypnea had worsened (104 breaths/min) and the respiratory effort was further increased. Furosemide (2.2 mg/kg IV once) was subsequently administered. A brief echocardiogram was performed and revealed moderate pericardial effusion, an enlarged left atrium (1.8 cm; normal, 0.89 cm to 1.17 cm), and mild mitral insufficiency. Results were consistent with CHF secondary to HVS and fluid overload following the blood transfusion. The cat was subsequently referred for further diagnostics and treatment.
On admission, the physical examination revealed tachycardia (220 beats/min), tachypnea (140 breaths/min), and increased respiratory effort. A Doppler blood pressure was 165 mmHg. The cat was administered flow-by oxygen, buprenorphine (0.01 mg/kg IV once), and midazolamp (0.2 mg/kg IV once) for sedation to facilitate placement of an indwelling jugular catheter. Sedation and oxygen therapy reduced the respiratory rate to 70 breaths/min. A chemistry panel was repeated and confirmed a severe hyperproteinemia (total protein was 16.0 g/dL) characterized by a severe hyperglobulinemia (14.1 g/dL). Following the previous veterinarian's whole blood transfusion, the anemia was improved (PCV was 26.9%; reference range, 32.8–49.8%) and red cell autoagglutination and marked rouleaux formation were observed. A platelet count could not be determined due to excessive clumping.
Plasmapheresis was performed immediately after the jugular catheter was placed using the same technique described for the first case. A balanced electrolyte solutiond (60 mL) was administered to the cat IV while the whole blood was centrifuged and separated. Following the procedure, the cat's respiratory rate decreased to 40 breaths/min and he appeared eupneic. The serum total solids measured by refractometer was >12 g/dL. Six hours later, the cat's respiratory rate increased to 60 breaths/min and plasmapheresis was repeated. Again, the respiratory rate decreased to 40 breaths/min and the total solids decreased to 12.0 g/dL (measured via refractometer). Thoracic radiographs were performed the following morning and interpretation showed moderate pulmonary edema, mild pleural effusion, generalized cardiomegaly, and enlargement of the pulmonary arteries and veins. Shortly thereafter, the owner elected euthanasia due to the cat's poor long-term prognosis. Post mortem examination revealed disseminated plasma cell neoplasia in the liver, spleen, lymph nodes, and bone marrow, in addition to severe diffuse pulmonary edema and mild hemorrhage. No neoplastic infiltrate in the cardiac muscle was noted.
Discussion
HVS consists of a collection of clinical signs that occur due to an increase in blood viscosity. The change in viscosity may be secondary to an increase in any of the blood components including RBCs (polycythemia), white cells (leukemia), or serum protein (paraproteinemia).1–5 Paraproteinemia refers to an increase in the proliferation of a single clone of B lymphocytes that produce excessive monoclonal immunoglobulin. In cats, HVS is most commonly secondary to a monoclonal gammopathy as seen with multiple myeloma, lymphoproliferative tumors (i.e., lymphoma, plasma cell or chronic lymphocytic leukemia), primary (Waldenstrom's) macroglobulinemia, or chronic infectious disease (Ehrlichia infection, feline infectious peritonitis).6,7 Autoimmune diseases and graft-versus-host disease can also be a cause of monoclonal gammopathy.8 Idiopathic paraproteinemias as well as heavy or light chain disease (as opposed to whole immunoglobulin molecules) have also been reported in dogs and cats.6 Hyperviscosity may result from the large size of the protein molecule (e.g., immunoglobulin [Ig] M, polymeric IgA) and also from the shape, concentration, positive charge, or ability of the molecule to form polymers within the serum.4,5 Although IgG-associated hyperviscosity is reported to be rare based on its relatively low molecular weight, two cats in a previous case report had monoclonal IgG-associated HVS due to multiple myeloma.9 Increased concentration, abnormal shape, or aggregates of IgG are suspected to contribute to IgG-associated hyperviscosity.9 All three cats in the report described herein were determined to have HVS secondary to plasma cell neoplasia.
Clinical manifestations of HVS include abnormalities of the cardiovascular, renal, neurologic, coagulation, and ocular systems.1–5,7–9 Signs consistent with CHF, including pulmonary edema, pleural effusion, and tachypnea, were present upon admission in all three cats in this report. Elevated blood viscosity causes increased resistance to blood flow thereby decreasing perfusion and causing hypoxia and tissue ischemia. The increased cardiac workload required to pump the viscous blood against increased resistance may result in hypertrophy of the myocardium and eventual decompensation of cardiac function with subsequent CHF.10 Patients with plasma cell neoplasia may also develop heart disease and CHF due to reasons other than HVS. Invasion of the myocardium with neoplastic cells was not documented in two of the cats that had post mortem examinations in this report, but plasma cell invasion of the myocardium has been reported in people leading to CHF.11 High-output heart failure also occurs in people with plasma cell neoplasia because of a decrease in systemic vascular resistance.11,12 This decreases the arterial blood pressure and activates neurohormones causing retention of salt and water by the kidneys. In these cases, the heart itself remains normal and is capable of normal to increased output; however, there is an increase in circulating blood volume and subsequent CHF.11,12 Hyperproteinemia also leads to an expanded plasma volume secondary to the increased plasma oncotic pressure leading to hypervolemia and possible subsequent systemic hypertension.6,9 In patients with HVS who are treated with plasmapheresis, the removal of serum proteins subsequently decreases plasma oncotic pressure and reduces preload.12
In a case series of 24 cats with myeloma-related disorders, 30% of the cats had cardiac hypertrophy identified by thoracic imaging.13 All three cats in the report presented here had cardiomegaly on thoracic radiographs and an enlarged left atrium on echocardiogram consistent with CHF from HCM and concurrent HVS. Decreased vascular perfusion from HVS may have contributed to myocardial hypoxia. Together with the increased workload from the hypervolemia and hypertrophy from systemic hypertension, these factors may have played a role in the development of CHF.1–10,14,15 While systemic hypertension may occur with HVS, none of the three cats described in the present report had a noticeably elevated systemic blood pressure and several previous case studies fail to document systemic blood pressure measurements.12,16–18
Hyperviscosity may also contribute to decreased vascular perfusion and subsequent tissue hypoxia due to sludging of the RBCs through the microvasculature.7 Tissue hypoxia can lead to renal damage, which may have contributed to the renal failure documented in one cat in this report. Increased protein in the glomerular ultrafiltrate and obstruction of the tubules by proteinaceous casts also contribute to progressive tubular damage.6,9,16 Other possible causes of the documented renal failure include prerenal azotemia and treatment with medications known to potentially exacerbate renal disease such as furosemide, enalapril, cyclophosphamide, and prednisolone.
Neurologic dysfunction in HVS may be the result of cerebral hypoxia, thromboembolic disease, or bleeding diathesis.6,8,19,20 One cat in this report had an episode of collapse and several days of lethargy that could have been neurologic manifestation of HVS. The signs of lethargy resolved completely following plasmapheresis and a second episode of collapse was not observed.
Paraproteinemia contributes to coagulation abnormalities through direct binding and inactivation of clotting factors of both the intrinsic and extrinsic pathways as well as interference with platelet function.6,8 A bleeding diathesis from HVS secondary to paraproteinemia may cause epistaxis, petechiation, and gingival or intestinal bleeding. In one study, 4 of 24 cats presented with clinical signs of bleeding as a myeloma-related disorder.21 Retinal hemorrhages from thrombocytopenia or a bleeding diathesis may be observed in cats with HVS.6–9 Retinal detachment or tortuous retinal vessels from hyperviscosity or systemic hypertension are also often observed and vision impairment may be a presenting complaint in cases of HVS.6–9 One cat in a case series of two cats diagnosed with multiple myeloma had thrombocytopenia and both cats had perivascular retinal hemorrhages determined to be secondary to HVS.10 One of the three cats presented herein demonstrated bilateral multifocal retinal hemorrhages and experienced bilateral epistaxis as evidence of a hemostatic disorder from the HVS.
Treatment of HVS in people includes management of the underlying disease, correction of dehydration, and either intermittent or continuous plasmapheresis to control clinical signs associated with hyperviscosity.1–4,7 Apheresis involves the removal of whole blood followed by separation of the blood by centrifugation or membrane filtration and removal of the offending cellular or plasma component.22,23 Plasmapheresis, or in this case series, centrifugal plasma exchange, is a form of apheresis that involves the removal of whole blood followed by separation of the blood by centrifugation, removal of the plasma component, and reinfusion of the remaining RBCs with replacement fluid. Therapeutic plasmapheresis may be used in HVS for removal of excessive paraproteins and can also been used for the removal of toxins, lipoproteins, immune complexes, and autoantibodies from the plasma of both human and veterinary patients.22,23 It has been demonstrated in human medicine that the removal of even a small amount of Igs in patients with HVS will exponentially decrease the serum viscosity.7 Plasmapheresis may be either continuous or intermittent depending on the needs of the patient. Automated plasmapheresis may be performed mechanically in clinical settings with advanced technology. Intermittent plasmapheresis may easily be performed by centrifugation (i.e., the centrifugal plasma exchange technique described in this case series) or even sedimentation in the general practice setting.
Plasmapheresis may be a reasonable adjunctive long-term therapy and can be a viable emergency therapy for CHF, neurologic, and ocular manifestations of HVS.1–8,10,11,13,14,17,19–21,24 Although plasmapheresis for HVS has been documented in cats in the literature, to the authors’ knowledge, this is the first known report of plasmapheresis as a treatment of CHF secondary to HVS in cats.9,15 To quickly reduce the increased impedance to ejection of blood and the increased workload on the heart from the increased blood viscosity, plasmapheresis was performed. All cats responded immediately in terms of their respiratory effort and rate and the improvement in two cases was better than that seen following diuretic therapy. Plasmapheresis not only reduces serum paraproteins and viscosity but it may also make neoplastic cells more responsive to chemotherapeutics by altering the cell cycle of myeloma cells.9
While previously documented in dogs,5,6,8,10,23 reports of plasmapheresis in cats9,13,16–18 are few, perhaps due to the poor prognosis of paraproteinemia-related diseases such as multiple myeloma and plasmacytoma. The literature reports that the majority of cats are euthanized within 6 mo of diagnosis.17 One of the cats described in this report was diagnosed with multiple myeloma and seemed to respond relatively well to chemotherapy. He survived for 6 mo with a good quality of life at home and was subsequently diagnosed with plasmacytoma. The cat failed to respond to therapy and was euthanized shortly after diagnosis. In cases of multiple myeloma or plasmacytoma, multidrug therapy is recommended.16–19 Corticosteroid therapy combined with an alkylating agent such as melphalan was administered to the two cats in this report that were treated. Unfortunately, corticosteroids may lead to an increase in plasma volume and this may have contributed to the CHF that developed in the two cats in this report.25 One cat also received cyclophosphamide, a chemotherapeutic with metabolites that also act as alkylating agents. Alternative available therapies not used in these patients include vincristine and chlorambucil.9
Conclusion
CHF can occur in cats secondary to HVS from plasma cell neoplasia or other causes of hypergammaglobulinemia. Therapy for heart failure can be implemented on an emergent basis with plasmapheresis while further diagnostics are performed. Plasmapheresis is easy to perform and successful in alleviating clinical signs of tachypnea and increased respiratory effort due to CHF in cats with HVS.
Contributor Notes
