Hyperviscosity Syndrome: Rapid Bedside Recognition and Intervention

A Critical Care Review for Postgraduate Medical Education

Dr Neeraj Manikath, Claude.ai

Abstract

Hyperviscosity syndrome (HVS) represents a hematologic emergency requiring immediate recognition and intervention. This comprehensive review addresses the pathophysiology, clinical presentation, diagnostic approaches, and management strategies essential for critical care practitioners. With mortality rates approaching 40% when untreated, early identification and prompt therapeutic plasma exchange can be life-saving. This article provides evidence-based guidance for postgraduate physicians managing this complex condition in the critical care setting.

Keywords: Hyperviscosity syndrome, plasma exchange, multiple myeloma, Waldenström's macroglobulinemia, critical care

Introduction

Hyperviscosity syndrome occurs when blood viscosity increases sufficiently to impair microcirculation, leading to neurological, ophthalmologic, and hemorrhagic complications. First described by Bing and Plum in 1937, HVS remains a diagnostic and therapeutic challenge in modern critical care practice. The syndrome predominantly affects patients with hematologic malignancies, particularly those with elevated serum proteins or cellular components that alter blood rheology.

The critical care physician must maintain high clinical suspicion, as HVS can present with nonspecific symptoms that mimic other neurological emergencies. Early recognition and intervention with therapeutic plasma exchange (TPE) can prevent irreversible complications and reduce mortality from this otherwise fatal condition.

Pathophysiology

Blood viscosity depends on multiple factors: hematocrit, plasma protein concentration, cellular deformability, and flow characteristics. Normal blood viscosity ranges from 1.4-1.8 centipoise (cP) at body temperature. HVS typically manifests when viscosity exceeds 4-5 cP, though symptoms can occur at lower levels in susceptible patients.

Mechanisms of Hyperviscosity

Protein-Related Hyperviscosity:

Monoclonal gammopathies increase plasma viscosity through protein-protein interactions
Immunoglobulin M (IgM) molecules are particularly viscogenic due to their large molecular size (900 kDa)
IgG and IgA can also cause HVS, especially when present in high concentrations or with abnormal polymerization

Cellular Hyperviscosity:

Leukostasis from extreme leukocytosis (typically >100,000/μL)
Increased red cell mass in polycythemia vera
Abnormal cellular rheology in sickle cell disease

The resultant microcirculatory impairment leads to tissue hypoxia, particularly affecting organs with high metabolic demands and terminal circulation patterns, such as the brain, retina, and mucous membranes.

Etiology and Risk Factors

Primary Causes

Hematologic Malignancies (85-90% of cases):

Waldenström's Macroglobulinemia
- Most common cause of protein-related HVS
- IgM levels typically >30 g/L when symptoms develop
- Accounts for 15% of all HVS cases
Multiple Myeloma
- Second most common cause
- Usually associated with IgG or IgA paraproteins
- HVS occurs in 2-6% of myeloma patients
Acute Leukemias
- Primarily acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
- Leukostasis syndrome when blast count >100,000/μL
- Accounts for 10-15% of HVS cases

Secondary Causes

Polycythemia vera (hematocrit >65%)
Essential thrombocythemia (platelet count >1,000,000/μL)
Chronic lymphocytic leukemia with extreme lymphocytosis
Cryoglobulinemia
Systemic lupus erythematosus with hypergammaglobulinemia

Risk Factors for HVS Development

Advanced age (>65 years)
Dehydration
Concurrent infections
Renal insufficiency
Diabetes mellitus
Smoking history

Clinical Presentation

The Classic Triad (Present in 60-70% of cases)

1. Neurological Manifestations

Headache (most common symptom, 84% of cases)
Altered mental status ranging from confusion to coma
Dizziness and vertigo
Seizures (focal or generalized)
Focal neurological deficits mimicking stroke
Ataxia and coordination difficulties

2. Ophthalmologic Changes

Retinal hemorrhages (flame-shaped or dot-blot)
Papilledema
Retinal vein engorgement and tortuosity
Visual field defects
Diplopia
Acute vision loss (medical emergency)

3. Mucosal Bleeding

Epistaxis (nosebleeds)
Gingival bleeding
Gastrointestinal bleeding
Prolonged bleeding from venipuncture sites
Petechiae and ecchymoses

Additional Clinical Features

Cardiovascular:

Congestive heart failure
Hypotension
Arrhythmias

Respiratory:

Dyspnea
Pulmonary edema

Dermatologic:

Livedo reticularis
Digital ischemia
Raynaud's phenomenon

Diagnostic Approach

Laboratory Investigations

Immediate (Stat) Laboratory Studies:

Complete Blood Count with Differential
- Evaluate for leukocytosis, thrombocytosis, or polycythemia
- Look for circulating blasts or abnormal cells
Serum Protein Studies
- Total protein (often >100 g/L in HVS)
- Serum protein electrophoresis (SPEP)
- Immunofixation electrophoresis
- Quantitative immunoglobulins (IgG, IgA, IgM)
Blood Viscosity Measurement
- Serum viscosity >1.8 cP (normal <1.4 cP)
- Whole blood viscosity if available
Peripheral Blood Smear
- Rouleaux formation (pathognomonic finding)
- Blast cells in leukemia
- Abnormal protein precipitates

Pearls for Laboratory Interpretation

🔍 Pearl 1: Rouleaux formation on blood smear is virtually diagnostic of protein-related HVS - red cells stack like coins due to altered surface charge from excess proteins. This finding may be seen alongside other CBC abnormalities.

🔍 Pearl 2: The "reverse albumin-globulin ratio" - when globulin exceeds albumin significantly (>2:1), suspect HVS. Look for total protein >100 g/L as a red flag.

🔍 Pearl 3: Serum monoclonal component concentration >15 g/L warrants hyperviscosity assessment, even in asymptomatic patients.

🔍 Pearl 4: Asymptomatic patients with elevated serum viscosity do not require plasma exchange - treat symptoms, not just numbers.

🔍 Pearl 5: Additional metabolic abnormalities may include hypercalcemia, hypophosphatemia, and hyperkalemia - check comprehensive metabolic panel.

Advanced Diagnostic Studies

Imaging:

Non-contrast head CT to exclude intracranial hemorrhage
MRI brain for subtle ischemic changes
Echocardiography if heart failure suspected

Specialized Tests:

Bone marrow biopsy (when clinically stable)
Flow cytometry for leukemia/lymphoma workup
Cryoglobulin studies if indicated

Management Strategies

Immediate Interventions (First Hour)

1. Airway, Breathing, Circulation Assessment

Secure airway if altered mental status
Supplemental oxygen for respiratory distress
IV access with caution (bleeding risk)

2. Symptom-Directed Supportive Care

Seizure management with benzodiazepines
Blood pressure support if hypotensive
Avoid excessive fluid resuscitation (may worsen viscosity)

3. Emergency Therapeutic Plasma Exchange (TPE)

DO NOT DELAY for definitive diagnosis
Asymptomatic patients with elevated serum viscosity do not require plasma exchange - treat symptomatic patients first
Initiate within 6 hours of recognition when possible
Remove 1-1.5 plasma volumes per session
Replace with normal saline or 5% albumin
Remove approximately 25% of patient's plasma volume per session - done gradually

Therapeutic Plasma Exchange Protocol

Indications for Emergency TPE:

Clinical triad with laboratory support
Serum viscosity >4.0 cP
Neurological symptoms with paraproteinemia
Visual changes with retinal findings

TPE Technical Specifications:

Vascular access: Large-bore central venous catheter
Anticoagulation: Citrate preferred over heparin (bleeding risk)
Replacement fluid: Normal saline or 5% albumin
Volume processed: 1-1.5 total plasma volumes
Frequency: Daily until clinical improvement

Hacks for Optimal TPE Management

🎯 Hack 1: Start TPE before hematology consultation if clinical suspicion is high - time is tissue in HVS. There is no specific diagnostic test - base decision on clinical symptoms and laboratory findings.

🎯 Hack 2: Use the "vision test" - if visual symptoms improve within 4-6 hours post-TPE, you've confirmed the diagnosis and effectiveness.

🎯 Hack 3: Monitor ionized calcium closely during TPE - citrate anticoagulation can cause severe hypocalcemia requiring calcium replacement.

🎯 Hack 4: In resource-limited settings, judicious phlebotomy with concurrent crystalloid/blood product replacement can be a temporizing measure.

🎯 Hack 5: Different apheresis techniques for different causes: Plasmapheresis for elevated immunoglobulins, leukapheresis for leukostasis, plateletpheresis for thrombocytosis, phlebotomy for polycythemia.

Adjunctive Therapies

Immediate (0-24 hours):

Hydration with normal saline (cautiously)
Avoid aspirin and anticoagulants
Platelet transfusion if severe thrombocytopenia with bleeding

Intermediate (24-72 hours):

Chemotherapy for underlying malignancy (after TPE initiation)
Rituximab for Waldenström's macroglobulinemia
Hydroxyurea for leukostasis syndrome

Long-term:

Disease-specific treatment protocols
Maintenance TPE if refractory to chemotherapy

Monitoring and Complications

Key Monitoring Parameters

Clinical Monitoring:

Neurological status (hourly initially)
Visual acuity and fundoscopic exam
Bleeding assessment
Vital signs and urine output

Laboratory Monitoring:

Serum viscosity (pre/post TPE)
Total protein and paraprotein levels
Complete blood count
Electrolytes (especially calcium)
Coagulation studies

Complications of HVS

Untreated HVS:

Cerebral infarction
Retinal detachment and blindness
Congestive heart failure
Gastrointestinal bleeding
Death (mortality 20-40%)

Treatment-Related Complications:

TPE complications (catheter-related, hypocalcemia, allergic reactions)
Tumor lysis syndrome from chemotherapy
Bleeding from anticoagulation

Oysters (Diagnostic Pitfalls)

🦪 Oyster 1: Not all neurological symptoms in hematologic malignancy patients are due to CNS involvement - consider HVS, especially with concurrent visual or bleeding symptoms.

🦪 Oyster 2: Normal hematocrit doesn't exclude HVS - protein-related hyperviscosity can occur with normal cellular elements.

🦪 Oyster 3: Mild symptoms can progress rapidly - a patient with "just a headache" and paraproteinemia may develop coma within hours.

🦪 Oyster 4: TPE can temporarily worsen bleeding by removing clotting factors - balance risk vs. benefit carefully.

🦪 Oyster 5: Don't mistake leukostasis for sepsis - both can present with altered mental status and elevated WBC, but treatments differ dramatically.

Prognosis and Outcomes

Factors Affecting Prognosis

Favorable Prognostic Factors:

Early recognition and treatment
Younger age (<65 years)
Absence of neurological complications at presentation
Underlying disease responsiveness to treatment

Poor Prognostic Factors:

Delayed diagnosis (>24 hours)
Coma at presentation
Concurrent infections
Refractory underlying malignancy

Outcome Data

Recent studies demonstrate significant improvement in HVS outcomes with early TPE:

Mortality reduced from 40% to <10% with prompt intervention
Complete neurological recovery in 85% when treated within 12 hours
Visual recovery in 70% of patients with retinal complications

Future Directions and Research

Emerging Therapies

Novel Approaches:

Selective plasma filtration techniques
Monoclonal antibody therapies targeting specific paraproteins
Advanced cytoreduction strategies for leukostasis

Biomarker Development:

Point-of-care viscosity measurement devices
Rapid paraprotein quantification assays
Predictive models for HVS risk stratification

Areas for Investigation

Optimal TPE protocols for different etiologies
Combination therapies to reduce TPE requirements
Long-term neurological outcomes following HVS

Conclusion

Hyperviscosity syndrome represents a true hematologic emergency requiring immediate recognition and intervention. The critical care physician must maintain high clinical suspicion when encountering the classic triad of neurological symptoms, visual changes, and mucosal bleeding in patients with known or suspected hematologic malignancies. Laboratory clues including elevated serum proteins, rouleaux formation, and increased plasma viscosity support the diagnosis, but treatment should not be delayed pending confirmatory testing.

Therapeutic plasma exchange remains the cornerstone of acute management and should be initiated emergently when clinical suspicion is high. Early intervention with TPE, combined with appropriate supportive care and treatment of the underlying condition, can prevent irreversible complications and significantly improve patient outcomes.

The key to successful HVS management lies in rapid bedside recognition, immediate initiation of TPE, and coordinated multidisciplinary care involving critical care, hematology, and apheresis specialists. With proper recognition and treatment, this previously fatal condition can have excellent outcomes, emphasizing the critical importance of early diagnosis and intervention.

References

Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018;132(13):1379-1385. doi:10.1182/blood-2018-06-846816
Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119(10):2205-2208. doi:10.1182/blood-2011-10-384115
Perez-Rogers A, Estes M. Hyperviscosity Syndrome. StatPearls. 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518963/
Sidiqi MH, Gertz MA. Therapeutic plasma exchange for hyperviscosity syndrome in IgA multiple myeloma. Transfus Apher Sci. 2024;63(4):103916. doi:10.1016/j.transci.2024.103916
Green J, Strahm B, Millward K, et al. The utility of therapeutic plasma exchange in Hyperviscosity syndrome associated with juvenile rheumatoid arthritis: A case report. J Clin Apher. 2021;36(5):736-739. doi:10.1002/jca.21903
Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost. 1999;25(2):199-208. doi:10.1055/s-2007-994920
ACEP Critical Care Medicine Section. Hyperviscosity Syndrome. January 2025. Available from: https://www.acep.org/criticalcare/newsroom/newsroom-articles/january-2025/hyperviscosity-syndrome
Porcu P, Cripe LD, Ng EW, et al. Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management. Leuk Lymphoma. 2000;39(1-2):1-18. doi:10.3109/10428190009053534
Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29(5):467-471. doi:10.1055/s-2003-44555
Schwab PJ, Fahey JL. Treatment of Waldenstrom's macroglobulinemia by plasmapheresis. N Engl J Med. 1960;263:574-579. doi:10.1056/NEJM196009222631202
Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98(5):1614-1615. doi:10.1182/blood.v98.5.1614
Somer T. Hyperviscosity syndrome in plasma cell dyscrasias. Adv Exp Med Biol. 1975;63:89-133. doi:10.1007/978-1-4613-9387-2_8
Adams BD, Baker R, Lopez JA, Spencer S. Myeloproliferative disorders and the hyperviscosity syndrome. Emerg Med Clin North Am. 2009;27(3):459-476. doi:10.1016/j.emc.2009.04.001
Bloch KJ, Maki DG. Hyperviscosity syndromes associated with immunoglobulin abnormalities. Semin Hematol. 1973;10(2):113-124.
Rosenstein ED, Itzkowitz SH, Jacobson IM, et al. Hyperviscosity syndrome in multiple myeloma: clinical correlates and response to plasmapheresis. Am J Med. 1982;73(1):141-145. doi:10.1016/0002-9343(82)90939-3

Wednesday, June 25, 2025