Hyperviscosity Syndrome

Topic Overview

Summary

Hyperviscosity syndrome (HVS) is a haematological emergency characterised by increased blood viscosity due to elevated paraprotein concentrations or cellular elements. It presents with a classic triad of neurological symptoms (confusion, headache, stroke), visual disturbances (blurred vision, retinal haemorrhages with characteristic "sausage-link" retinal veins), and bleeding manifestations (mucosal, spontaneous). The most common cause is Waldenström macroglobulinaemia (WM) due to IgM paraprotein, accounting for 85% of cases, followed by multiple myeloma (10-15%, usually IgA or IgG3 subclass). Serum viscosity above 4 cP (normal 1.4-1.8 cP) typically produces symptoms, with severe manifestations above 6 cP. Emergency treatment is therapeutic plasma exchange (plasmapheresis), which rapidly reduces viscosity by 30-60% per session, followed by definitive therapy targeting the underlying haematological malignancy. Delayed diagnosis leads to permanent neurological sequelae, retinal vein occlusion with blindness, and mortality. Prompt recognition and urgent plasmapheresis are life-saving.

Key Facts

• Cause: IgM paraprotein (Waldenström's 85%), IgA/IgG3 (myeloma 10-15%), cellular (polycythaemia less than 5%)
• Classic triad: Neurological (70%) + visual (60%) + bleeding (50%) symptoms
• Diagnosis: Serum viscosity > 4 cP symptomatic; > 6 cP severe (normal 1.4-1.8 cP)
• Fundoscopy: Pathognomonic "sausage-link" or "box-car" dilated retinal veins
• Emergency treatment: Urgent therapeutic plasma exchange (plasmapheresis)
• Response: Single plasmapheresis session reduces viscosity 30-60%; symptoms improve within hours
• Mortality: 10-15% if untreated; less than 2% with prompt plasmapheresis
• Why IgM?: Pentameric structure (970 kDa) vs monomeric IgG (150 kDa) causes exponential viscosity increase

Clinical Pearls

IgM molecular size: IgM is pentameric (970 kDa) and remains intravascular — causes hyperviscosity at lower concentrations than IgG or IgA. This explains why Waldenström's (IgM) causes HVS in 10-30% of patients vs only 2-5% in myeloma (IgG/IgA).

Avoid RBC transfusion before plasmapheresis: Increasing haematocrit worsens viscosity exponentially (viscosity ∝ Hct²). If transfusion essential, give slowly after initiating plasmapheresis or with concurrent plasma exchange.

Fundoscopy is diagnostic: "Sausage-link" or "box-car" segmented retinal veins with flame haemorrhages are pathognomonic. This finding mandates urgent viscosity measurement and plasmapheresis referral.

Viscosity measurement: Not widely available; many centres rely on clinical diagnosis (triad + paraprotein > 30 g/L). Don't delay plasmapheresis for viscosity result if classic presentation with WM/myeloma.

Bleeding paradox: Despite high paraprotein, bleeding risk is increased (not thrombosis). Mechanism: paraprotein coating of platelets impairs function; von Willebrand factor (vWF) adsorption to IgM reduces levels.

Relative viscosity matters: Symptomatic threshold varies by individual. Some patients tolerate viscosity 5-6 cP; others symptomatic at 4 cP. Treat based on clinical syndrome, not absolute viscosity number.

Why This Matters Clinically

HVS is a true haematological emergency with high morbidity and mortality if untreated. Delayed recognition leads to irreversible complications: ischaemic stroke with permanent deficit, central retinal vein occlusion causing blindness, intracerebral haemorrhage, and cardiac failure. Plasmapheresis provides rapid, dramatic symptom improvement within hours and reduces mortality from 10-15% to less than 2%. Recognition of the triad in at-risk patients (known WM or myeloma) and urgent haematology referral are life-saving. This is a high-yield emergency medicine and MRCP examination topic.

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Visual Summary

Visual assets to be added:

• Fundoscopic photograph showing sausage-link dilated retinal veins with flame haemorrhages
• Serum protein electrophoresis (SPEP) trace showing monoclonal M-spike (IgM, IgA, IgG)
• Immunofixation electrophoresis confirming paraprotein type
• Blood film showing rouleaux formation (red cell stacking)
• Plasmapheresis circuit schematic diagram
• HVS emergency management algorithm (clinical recognition → viscosity measurement → urgent plasmapheresis → definitive therapy)
• Pathophysiology diagram: paraprotein → increased viscosity → microcirculatory stasis → tissue hypoxia + bleeding
• IgM pentamer structure vs IgG monomer size comparison

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Epidemiology

Incidence and Prevalence

Hyperviscosity syndrome is rare in absolute terms but represents a predictable complication of paraproteinaemia disorders. Incidence depends on the underlying haematological malignancy and paraprotein characteristics.

Overall Incidence:

• HVS complicates approximately 4-5% of all plasma cell disorders at presentation
• Annual incidence estimated at 0.5-1.0 per 100,000 population (reflects underlying WM/myeloma incidence)
• Emergency department presentations: less than 0.1% of haematological emergencies

Disease-Specific Rates:

Concentration Thresholds:

• IgM: Symptomatic HVS typically occurs when IgM > 30-40 g/L (viscosity > 4 cP)
• IgA: Requires higher concentrations (> 50-60 g/L) due to dimeric (not pentameric) structure
• IgG3: Requires > 40-50 g/L; other IgG subclasses rarely cause HVS even at very high levels

Demographics

Age:

• Median age at HVS presentation: 60-70 years (reflects age distribution of WM and myeloma)
• Waldenström macroglobulinaemia: median age 63-68 years
• Multiple myeloma: median age 65-70 years
• Rare in patients less than 40 years unless aggressive lymphoplasmacytic disorder

Sex:

• Male predominance: M:F ratio approximately 1.5-2:1 (reflects WM male predominance)
• Waldenström macroglobulinaemia: 2:1 male predominance
• Multiple myeloma: slight male predominance (1.4:1)

Ethnicity:

• Waldenström macroglobulinaemia: more common in Caucasians; rare in Africans and Asians
• Multiple myeloma: twice as common in individuals of African descent vs Caucasians, but HVS frequency similar once myeloma develops
• No ethnicity-specific HVS risk once paraprotein disorder established

Geographical Variation:

• Higher incidence in Western Europe and North America (reflects WM epidemiology)
• Lower incidence in Asia and Africa (lower WM prevalence)

Risk Factors for HVS in Paraprotein Disorders

Paraprotein Characteristics:

• IgM isotype (85% of HVS cases)
• High paraprotein concentration (IgM > 30 g/L, IgA > 50 g/L)
• IgG3 subclass (tendency to polymerise and aggregate)
• Paraprotein with intrinsic high viscosity properties (varies by clone)

Patient Factors:

• Dehydration (reduces plasma volume, increases relative paraprotein concentration)
• Concurrent high haematocrit (polycythaemia, dehydration)
• Renal impairment (reduced paraprotein clearance)
• Acute infection or inflammatory state (can precipitate symptoms)

Disease Factors:

• High tumour burden in WM or myeloma
• Rapid disease progression with rising paraprotein
• Relapsed or refractory disease with escalating paraprotein despite treatment

Natural History

• HVS typically develops gradually over weeks to months as paraprotein accumulates
• Acute decompensation can occur with dehydration, infection, or RBC transfusion
• Without treatment, progressive neurological deterioration, stroke, blindness, and death occur within days to weeks
• With plasmapheresis and disease-directed therapy, symptoms resolve rapidly and prognosis depends on underlying malignancy control

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Pathophysiology

Normal Blood Viscosity

Viscosity Fundamentals: Blood viscosity is a measure of blood's resistance to flow. It is determined by:

1. Plasma viscosity: Protein content (albumin, globulins, fibrinogen)
2. Cellular components: Haematocrit (Hct), white cell count (WCC), platelet count
3. Rheological properties: Red cell deformability, aggregation (rouleaux)

Normal Values:

• Serum viscosity: 1.4-1.8 centipoise (cP) relative to water
• Whole blood viscosity: 3-4 cP (higher than serum due to cellular elements)
• Plasma protein contribution: Albumin 35-50 g/L, globulins 20-35 g/L, fibrinogen 2-4 g/L

Viscosity Determinants:

• Viscosity increases exponentially (not linearly) with haematocrit: viscosity ∝ Hct²
• At Hct 40%, viscosity ~3 cP; at Hct 60%, viscosity ~6 cP (doubling Hct more than doubles viscosity)
• Plasma protein contribution: normally 15-20% of total blood viscosity

Mechanisms of Hyperviscosity

Paraprotein-Mediated Hyperviscosity (Waldenström's, Myeloma):

1. Molecular Size and Shape:

   • IgM: Pentameric structure (5 IgG-like units linked by J-chain); molecular weight 970 kDa
   • IgA: Dimeric or monomeric; IgA dimer 320 kDa (more viscous than monomer 160 kDa)
   • IgG: Monomeric; 150 kDa (least viscous per molecule)
   • Larger molecules cause greater viscosity increase per unit concentration

2. Concentration-Viscosity Relationship:

   • Viscosity increases exponentially with paraprotein concentration
   • IgM: Symptomatic HVS typically at 30-50 g/L (viscosity > 4 cP)
   • IgA: Requires 50-70 g/L due to smaller size
   • IgG: Rarely causes HVS unless > 60-80 g/L (exception: IgG3 polymerisation)

3. IgM-Specific Factors:

   • IgM is exclusively intravascular (cannot cross endothelial barrier due to size)
   • Pentameric structure increases hydrodynamic volume disproportionately
   • IgM can form polymers and aggregates, further increasing viscosity
   • Half-life ~5 days (slower turnover than IgG ~21 days)

4. IgG3 Subclass:

   • IgG3 has tendency to polymerise via Fc-Fc interactions
   • Forms high-molecular-weight aggregates
   • Can cause HVS at lower concentrations than other IgG subclasses (IgG1, IgG2, IgG4)

5. Red Cell Interactions:

   • Paraproteins coat red blood cells
   • Promote rouleaux formation (red cells stack like coins)
   • Reduces red cell deformability
   • Impairs passage through capillaries (7-10 μm diameter)

Cellular Hyperviscosity (Polycythaemia, Leukaemia):

1. Haematocrit-Dependent:

   • Normal Hct 40-45%; viscosity increases exponentially above 50%
   • Polycythaemia vera: Hct can reach 60-70% (viscosity > 6 cP)
   • Viscosity ∝ Hct² relationship

2. Leukostasis (Hyperleukocytosis):

   • WCC > 100 × 10⁹/L in acute leukaemia (AML, ALL, CML blast crisis)
   • Immature blasts are larger and less deformable than mature WBC
   • Cause microvascular occlusion (cerebral, pulmonary)
   • Distinct syndrome from paraprotein HVS but overlapping clinical features

Microcirculatory Consequences

Blood Flow Impairment:

• Poiseuille's law: Flow = (ΔP × r⁴) / (8 × η × L), where η = viscosity
• Doubling viscosity halves blood flow for same pressure gradient
• Microcirculation (capillaries 7-10 μm) most affected
• Larger vessels (arteries, veins) less affected

Tissue Hypoxia:

1. Reduced oxygen delivery: Flow = Cardiac output × O₂ content; reduced flow reduces O₂ delivery
2. Increased oxygen extraction: Tissues compensate by extracting more O₂ from each unit of blood
3. Tissue ischaemia: When O₂ delivery < O₂ demand, ischaemia occurs
4. Vulnerable organs: Brain (high metabolic rate), retina (end-artery circulation), mucosa (fragile vasculature)

Organs Most Affected:

Bleeding Mechanisms

Despite elevated paraprotein, HVS paradoxically causes bleeding (not thrombosis). Mechanisms include:

1. Platelet Dysfunction:

   • Paraprotein (especially IgM) coats platelet surface
   • Impairs platelet adhesion and aggregation
   • Reduces platelet-endothelial interaction
   • Prolonged bleeding time despite normal platelet count

2. von Willebrand Factor (vWF) Depletion:

   • IgM binds and adsorbs vWF
   • Reduces functional vWF levels (acquired von Willebrand syndrome)
   • Impairs platelet adhesion to damaged endothelium

3. Coagulation Factor Interference:

   • Paraprotein can interfere with fibrin polymerisation
   • Rarely, paraprotein has intrinsic anticoagulant activity (e.g., anti-thrombin, anti-factor VIII)

4. Vascular Fragility:

   • Hyperviscosity causes vascular engorgement and increased transmural pressure
   • Venules and capillaries dilate and rupture
   • Retinal vessels particularly vulnerable (thin-walled, end-artery circulation)

5. Acquired Coagulation Defects:

   • Prolonged APTT or PT in some cases (factor inhibition or consumption)
   • Hypofibrinogenaemia rare but described

Cardiovascular Compensation and Failure

Compensatory Mechanisms:

1. Increased cardiac output: Heart pumps harder to maintain tissue perfusion despite increased viscosity
2. Expanded plasma volume: Attempted dilution of paraprotein (often ineffective)
3. Tachycardia: Increased heart rate to maintain cardiac output

Decompensation:

• High-output cardiac failure develops when compensation exhausted
• Increased afterload (resistance) causes left ventricular strain
• Pulmonary congestion and oedema
• Cardiogenic shock in severe cases

Haemodynamic Effects:

• Increased systemic vascular resistance (SVR)
• Reduced venous return (venous engorgement)
• Increased central venous pressure (CVP)
• Pulmonary hypertension (increased pulmonary vascular resistance)

Summary Pathophysiology Chain

Paraprotein accumulation → Exponential viscosity increase → Microcirculatory stasis → Tissue hypoxia (brain, retina) + Bleeding (platelet dysfunction, vWF depletion, vascular fragility) + Cardiac strain (high afterload) → Clinical triad: Neurological + Visual + Bleeding

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Clinical Presentation

Classic Triad

The classic triad of hyperviscosity syndrome consists of neurological, visual, and bleeding manifestations. While all three features are present in only 30-40% of patients, the presence of any two features in a patient with known WM or myeloma should prompt urgent viscosity assessment.

Complete Triad Present: 30-40% of symptomatic HVS patients

Isolated Features:

• Neurological only: 20-25%
• Visual only: 15-20%
• Bleeding only: 10-15%

Neurological Manifestations

Mechanisms:

• Cerebral hypoperfusion due to increased viscosity
• Microvascular ischaemia (watershed territories)
• Venous stasis and thrombosis
• Intracerebral haemorrhage (less common but more severe)

Clinical Features:

1. Headache (50%):

   • Generalised, persistent, throbbing
   • Often refractory to simple analgesia
   • Worse with dehydration or exertion
   • May be associated with nausea

2. Encephalopathy (40%):

   • Confusion, disorientation, altered consciousness
   • Progressive deterioration over days to weeks
   • Can mimic dementia or metabolic encephalopathy
   • Reversible with plasmapheresis

3. Dizziness and Vertigo (30%):

   • Non-specific lightheadedness
   • True vertigo less common
   • Postural symptoms

4. Focal Neurological Deficits (15-20%):

   • Stroke (ischaemic >> haemorrhagic): Hemiparesis, dysphasia, hemianopia
   • Transient ischaemic attacks (TIAs)
   • Cerebellar signs: Ataxia, dysmetria
   • Cranial nerve palsies (rare)

5. Seizures (5-10%):

   • Generalised tonic-clonic or focal
   • May be presenting feature
   • Can occur without prior epilepsy history

6. Coma (5%):

   • Severe cases with delayed treatment
   • Associated with very high viscosity (> 8 cP)
   • Poor prognosis if prolonged

Red Flags:

• Acute onset confusion or reduced GCS
• Focal neurological signs (suspect stroke)
• Seizures in patient with WM/myeloma
• Progressive encephalopathy despite supportive care

Visual Manifestations

Mechanisms:

• Retinal vein stasis and engorgement
• Retinal hypoxia and ischaemia
• Vascular leakage and haemorrhage
• Optic nerve ischaemia (papilloedema)

Clinical Features:

1. Blurred Vision (50%):

   • Gradual onset over days to weeks
   • Bilateral (usually symmetric)
   • Described as "looking through fog" or "cloudy vision"
   • May fluctuate with hydration status

2. Diplopia (20%):

   • Horizontal or vertical
   • May indicate cranial nerve palsy (III, IV, VI) due to vascular compromise

3. Visual Field Defects (15%):

   • Scotomas (dark spots)
   • Peripheral field loss
   • Altitudinal defects (upper or lower half)

4. Sudden Vision Loss (10%):

   • Central retinal vein occlusion (CRVO)
   • Branch retinal vein occlusion (BRVO)
   • Ischaemic optic neuropathy
   • This is an ophthalmological emergency

5. Photophobia and Visual Discomfort (5-10%):

   • Light sensitivity
   • Eye pain or discomfort
   • Conjunctival injection

Fundoscopic Findings (Pathognomonic):

"Sausage-link" veins: This classic finding results from red blood cell aggregation (rouleaux) within retinal veins, creating segmented appearance. Pathognomonic for hyperviscosity.

Red Flags:

• Sudden vision loss (CRVO, BRVO)
• Fundoscopy showing sausage-link veins + haemorrhages
• Progressive visual deterioration
• Bilateral visual symptoms

Bleeding Manifestations

Mechanisms:

• Platelet dysfunction (paraprotein coating)
• Acquired von Willebrand syndrome (vWF adsorption by IgM)
• Vascular fragility and engorgement
• Rarely, acquired coagulation factor inhibitors

Clinical Features:

1. Mucosal Bleeding (Most Common):

   • Epistaxis (30%): Often severe and recurrent; anterior or posterior bleeds
   • Gum bleeding (25%): Spontaneous or with minor trauma (toothbrushing)
   • Oral mucosal bleeding: Bleeding from tongue, buccal mucosa
   • GI bleeding (10%): Melaena, haematemesis (usually upper GI; oesophageal, gastric varices rare)

2. Cutaneous Bleeding (20%):

   • Purpura: Petechiae (pinpoint) or larger purpura (palpable in cryoglobulinaemia)
   • Ecchymoses: Easy bruising with minimal trauma
   • Bleeding from venepuncture or IV sites (prolonged oozing)

3. Retinal Haemorrhage (40% on fundoscopy):

   • Often asymptomatic unless involving macula
   • Flame-shaped (superficial nerve fibre layer)
   • Dot-blot haemorrhages (deeper retinal layers)
   • Can cause sudden vision loss if large

4. Other Sites (Rare):

   • Haematuria (5%)
   • Intracranial haemorrhage (less than 5% but life-threatening)
   • Post-procedural bleeding (biopsies, surgery)

Laboratory Findings:

• Prolonged bleeding time (platelet function assay abnormal)
• Normal or mildly prolonged APTT/PT (unless acquired factor inhibitor)
• Normal platelet count
• Reduced vWF activity (acquired von Willebrand syndrome)

Red Flags:

• Spontaneous bleeding (without trauma)
• Multiple bleeding sites simultaneously
• Intracranial haemorrhage (headache, vomiting, focal signs)
• Severe or refractory epistaxis

Other Systemic Features

Cardiovascular:

1. Congestive Heart Failure (20-30%):

   • Dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea (PND)
   • Elevated jugular venous pressure (JVP)
   • Peripheral oedema (ankles, sacral)
   • Bibasal crackles on auscultation
   • High-output failure (warm peripheries, bounding pulse)

2. Angina (Rare):

   • Myocardial ischaemia due to reduced coronary perfusion
   • Can occur without coronary artery disease

Respiratory:

• Dyspnoea (multifactorial: heart failure, pulmonary congestion, anaemia)
• Pulmonary oedema (flash pulmonary oedema in severe cases)

Constitutional Symptoms (Underlying Disease):

• Fatigue and lethargy (anaemia, disease burden)
• Weight loss (malignancy)
• Night sweats (B symptoms in lymphoma-like WM)
• Fever (infection, underlying disease)

Raynaud's Phenomenon:

• If associated cryoglobulinaemia (cold-precipitable paraproteins)
• Fingers/toes become white, blue, then red on cold exposure
• Can lead to digital ischaemia and ulceration

Renal Impairment:

• Acute kidney injury (AKI): Reduced renal perfusion, light chain cast nephropathy (myeloma), AL amyloidosis
• Chronic kidney disease (CKD): Paraprotein deposition

Clinical Examination Findings

General Inspection:

• Patient may appear pale (anaemia), dyspnoeic, confused
• Signs of bleeding: Epistaxis, gum bleeding, purpura
• Signs of heart failure: Peripheral oedema, raised JVP

Neurological Examination:

• Focal signs: Hemiparesis, dysphasia, cranial nerve palsies
• Papilloedema (fundoscopy)
• Seizure activity (if witnessed)

Fundoscopy (Critical):

• Sausage-link or box-car retinal veins (pathognomonic)
• Retinal vein engorgement and tortuosity
• Flame-shaped and dot-blot haemorrhages
• Papilloedema (disc swelling, blurred margins)
• Cotton-wool spots (white patches)
• Optic disc hyperaemia

Cardiovascular:

• Tachycardia
• Elevated JVP (↑ CVP)
• Displaced apex beat (cardiomegaly)
• S3 gallop rhythm (heart failure)
• Bibasal fine crackles (pulmonary oedema)
• Peripheral oedema (ankles ± sacrum)

Mucosal Bleeding:

• Active epistaxis or recent epistaxis (crusting)
• Gum bleeding (inspect oral cavity)
• Purpura or petechiae on skin

Lymphadenopathy and Hepatosplenomegaly (Underlying Disease):

• Lymphadenopathy (cervical, axillary, inguinal) in WM
• Splenomegaly (WM, myeloma with extramedullary disease)
• Hepatomegaly (WM, myeloma, amyloidosis)

Precipitating Factors

HVS can develop gradually or be acutely precipitated by:

Red Flags Requiring Urgent Action

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Investigations

Initial Assessment

The diagnosis of hyperviscosity syndrome is primarily clinical (triad + underlying paraprotein disorder), but investigations confirm the diagnosis, quantify viscosity, identify the paraprotein type, and assess complications.

Serum Viscosity Measurement

Principle: Viscosity is measured using a viscometer (Ostwald or cone-and-plate viscometer). Serum viscosity is expressed relative to water (centipoise, cP) or as a ratio to normal serum.

Normal Values:

• Normal serum viscosity: 1.4-1.8 cP (relative to water = 1.0 cP)
• Whole blood viscosity: 3-4 cP (higher due to cellular components)

Symptomatic Thresholds:

Important Notes:

• Viscosity measurement not widely available (specialised haematology labs only)
• Clinical diagnosis often made without viscosity measurement in resource-limited settings
• Do not delay plasmapheresis if classic clinical presentation (triad + WM/myeloma) while awaiting viscosity result
• Symptomatic threshold varies between individuals; some tolerate 5-6 cP, others symptomatic at 4 cP
• Relative viscosity (patient's viscosity / normal viscosity) > 4 indicates significant hyperviscosity

Sample Requirements:

• Fasting serum sample (lipids can interfere)
• Temperature-controlled (cryoglobulins precipitate at low temperature)
• Process within 2 hours if possible

Paraprotein Identification

Serum Protein Electrophoresis (SPEP):

Principle: Separates serum proteins by size and charge using electrophoresis. Produces a graph showing:

• Albumin peak
• α1-globulin, α2-globulin, β-globulin, γ-globulin regions
• Monoclonal band ("M-spike") if paraprotein present

Findings in HVS:

• Monoclonal band (M-spike) in β or γ region (most commonly γ)
• Height and area under M-spike correlate with paraprotein concentration
• IgM: Usually γ region; broad-based peak (pentamer)
• IgA: β-γ region
• IgG: γ region

Quantification:

• Paraprotein concentration estimated from M-spike area
• IgM > 30 g/L typically causes HVS
• IgA > 50 g/L; IgG > 60 g/L (except IgG3 lower threshold)

Immunofixation Electrophoresis (IFE):

Principle: Confirms paraprotein type using specific antisera (anti-IgG, anti-IgA, anti-IgM, anti-κ, anti-λ).

Findings:

• Identifies immunoglobulin heavy chain: IgM, IgA, IgG (IgG subtype can be further characterised)
• Identifies light chain: κ or λ (clonality marker)
• Example: "IgM κ paraprotein" (Waldenström's), "IgA λ paraprotein" (myeloma)

Free Light Chains (Serum FLC):

• κ and λ free light chains measured separately
• κ/λ ratio: Normal 0.26-1.65
• Abnormal ratio indicates clonal plasma cell/B-cell disorder
• Useful in monitoring disease and light chain-only myeloma

Haematological Investigations

Full Blood Count (FBC):

Blood Film:

Coagulation Screen:

Platelet Function Testing:

• Platelet aggregation studies: Impaired aggregation with ADP, collagen, arachidonic acid
• PFA-100: Prolonged closure times

von Willebrand Factor (vWF) Assays:

• vWF antigen (vWF:Ag): Normal or ↓
• vWF activity (vWF:RCo): Reduced (acquired von Willebrand syndrome)
• Ratio vWF:RCo/vWF:Ag less than 0.7 suggests acquired vWS

Biochemical Investigations

Urine Tests:

• Urine protein electrophoresis (UPEP): Bence Jones protein (free light chains κ or λ)
• Urine immunofixation: Confirms light chain type
• 24-hour urine protein: Quantifies proteinuria (nephrotic range if AL amyloidosis)

Imaging Investigations

Chest X-Ray:

• Cardiomegaly (heart failure)
• Pulmonary oedema (fluffy alveolar shadowing, Kerley B lines, pleural effusions)
• Exclude infection (pneumonia precipitant)

CT Head (If Neurological Signs):

Indications:

• Acute confusion or reduced GCS
• Focal neurological deficit
• Seizures
• Exclude intracerebral haemorrhage, ischaemic stroke, mass lesion

Findings:

• Ischaemic stroke: Hypodensity in vascular territory (may not be visible acutely)
• Intracerebral haemorrhage: Hyperdense blood
• Cerebral oedema (severe hyperviscosity)
• May be normal if pure hyperviscosity encephalopathy

MRI Brain (If CT Normal but Symptoms Persist):

• More sensitive for small infarcts (DWI sequence)
• Venous sinus thrombosis (rare complication)

Echocardiography (If Heart Failure):

• Left ventricular function (usually preserved or hyperdynamic in high-output failure)
• Valvular abnormalities
• Pericardial effusion (rare)
• Exclude structural heart disease

Bone Marrow Biopsy

Indications:

• Confirm underlying diagnosis (WM vs myeloma vs other lymphoproliferative disorder)
• Assess disease burden
• Prognostic assessment

Findings:

Immunophenotyping (Flow Cytometry):

• Waldenström's: CD19+, CD20+, sIg+ (surface immunoglobulin), CD5-, CD10-, CD23-
• Myeloma: CD138+, CD38+, CD56+ (often), cytoplasmic Ig+ (cIg)

Cytogenetics and Molecular Studies:

• MYD88 L265P mutation: > 90% of WM (diagnostic)
• CXCR4 mutation: 30% of WM (affects ibrutinib response)
• Myeloma: t(11;14), t(4;14), del(17p), gain(1q) (prognostic)

Diagnostic Algorithm

Patient with neurological/visual/bleeding symptoms
                 ↓
Known WM/myeloma or paraprotein disorder?
         ↙              ↘
      YES               NO
       ↓                 ↓
Suspect HVS      Investigate for paraprotein:
                  - SPEP, IFE
                  - Serum FLC
                  - Skeletal survey (myeloma)
       ↓                 ↓
Check serum viscosity    Paraprotein identified?
(if available)                  ↓
       ↓                       YES → Suspect HVS
Viscosity > 4 cP                 ↓
+ clinical triad?         Check serum viscosity
       ↓
      YES
       ↓
Arrange urgent plasmapheresis
       ↓
Investigate complications:
- CT head (if neuro signs)
- Fundoscopy (all patients)
- CXR (if dyspnoea/heart failure)
- Coagulation screen
- Renal function
       ↓
Definitive therapy for underlying disease (WM, myeloma)

Summary of Key Investigations

Do not delay plasmapheresis awaiting investigations if classic clinical presentation.

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Management

Emergency Management: Therapeutic Plasma Exchange (Plasmapheresis)

Therapeutic plasma exchange (TPE, plasmapheresis) is the cornerstone emergency treatment for symptomatic hyperviscosity syndrome. It rapidly reduces paraprotein concentration and viscosity, providing immediate symptom relief and preventing life-threatening complications.

Mechanism of Action:

• Patient's plasma (containing paraprotein) is removed and replaced with albumin or fresh frozen plasma (FFP)
• Typical exchange volume: 1-1.5 plasma volumes (calculated from weight and haematocrit)
• Single session removes 30-60% of paraprotein
• Viscosity reduction correlates with paraprotein removal

Efficacy:

Indications for Urgent Plasmapheresis:

Contraindications (Relative):

• Haemodynamic instability (hypotension): May require vasopressor support during procedure
• Active bleeding (ICH): Relative; TPE may worsen bleeding acutely but benefits outweigh risks
• Vascular access issues: May require central venous catheter (CVC) insertion

Procedure Details:

1. Vascular Access:

   • Large-bore peripheral venous access (if adequate veins) OR
   • Central venous catheter (CVC): Internal jugular, subclavian, or femoral vein
   • Double-lumen apheresis catheter (11-14 French)

2. Exchange Volume:

   • 1-1.5 plasma volumes per session
   • Plasma volume (litres) = 0.065 × Weight (kg) × (1 - Haematocrit)
   • Example: 70 kg patient, Hct 0.35: Plasma volume = 0.065 × 70 × 0.65 = 2.96 L
   • Exchange 3-4 litres per session

3. Replacement Fluid:

   • 4-5% Albumin solution (preferred): No infection risk, cheaper, readily available
   • Fresh frozen plasma (FFP): If active bleeding, coagulopathy, or acquired factor deficiency
   • Ratio: 100% albumin OR 80% albumin + 20% FFP

4. Anticoagulation:

   • Citrate (most common): Binds calcium, prevents clotting in circuit
   • Monitor for hypocalcaemia symptoms (paraesthesia, tetany, prolonged QTc)
   • Heparin (alternative): If citrate contraindicated

5. Frequency:

   • Daily plasmapheresis until symptoms resolve and viscosity less than 4 cP
   • Typically 3-5 sessions required
   • Monitor viscosity after each session (if available)

Response to Plasmapheresis:

Monitoring During Plasmapheresis:

Complications of Plasmapheresis:

Important Precautions:

1. Avoid RBC Transfusion Before Plasmapheresis:

   • Increasing Hct increases viscosity exponentially (viscosity ∝ Hct²)
   • If transfusion essential (symptomatic anaemia, Hb less than 70 g/L), give slowly after starting plasmapheresis or concurrently
   • Consider single-unit transfusions rather than routine 2-unit transfusions

2. Hydration:

   • Dehydration worsens viscosity
   • IV normal saline 1-2 L over 12-24 hours (unless heart failure)
   • Monitor fluid balance (risk of pulmonary oedema if over-resuscitated)

3. Avoid Nephrotoxic Agents:

   • NSAIDs, IV contrast (can precipitate AKI in setting of paraprotein nephropathy)

Supportive Care

Symptomatic Management:

Bleeding Management:

• Avoid antiplatelet agents (aspirin, clopidogrel) and anticoagulants (unless specific indication)
• Tranexamic acid 1 g TDS IV/PO if severe mucosal bleeding (theoretical risk of thrombosis)
• Platelet transfusion if less than 20 × 10⁹/L + active bleeding (relative indication; platelets dysfunctional)
• FFP if coagulopathy (prolonged PT/APTT) + bleeding

Renal Support:

• IV hydration (avoid dehydration)
• Avoid nephrotoxins (NSAIDs, aminoglycosides, IV contrast)
• Treat hypercalcaemia if present (myeloma): IV fluids, bisphosphonates, calcitonin
• Renal replacement therapy (RRT) if severe AKI (rare indication in HVS alone)

Definitive Treatment: Disease-Directed Therapy

Plasmapheresis provides temporary relief (paraprotein rebounds in 7-14 days). Definitive treatment targets the underlying clonal B-cell or plasma cell disorder.

Waldenström Macroglobulinaemia (WM):

First-Line Therapy (Treatment-Naïve):

Rituximab-Based Chemotherapy (DRC or BR):

• Rituximab 375 mg/m² IV weekly × 4-8 doses (or monthly in maintenance)
• Cyclophosphamide 100 mg/m² PO daily × 5 days every 21 days OR bendamustine 90 mg/m² IV days 1-2 every 28 days
• Dexamethasone 20-40 mg PO weekly
• IgM flare: Rituximab can transiently increase IgM (first 4-12 weeks); monitor viscosity; may need additional plasmapheresis

BTK Inhibitors (Ibrutinib, Zanubrutinib):

• Ibrutinib 420 mg PO daily continuously
• Zanubrutinib 160 mg PO BD continuously
• Advantages: Oral, rapid IgM reduction, high response rate, no IgM flare
• Disadvantages: Bleeding risk (impairs platelet function), atrial fibrillation (ibrutinib 5-10%), expensive
• Avoid if CXCR4 mutation (associated with lower response rate)

Relapsed/Refractory WM:

• Alternative BTK inhibitor if relapsed on chemotherapy
• Alternative chemotherapy if relapsed on BTK inhibitor
• Clinical trials (BCL2 inhibitors, proteasome inhibitors)

Multiple Myeloma:

First-Line Therapy (Transplant-Eligible, Age less than 70, Fit):

• Induction: 4-6 cycles VRd
• ASCT (autologous stem cell transplant): Melphalan 200 mg/m² conditioning
• Maintenance: Lenalidomide 10-15 mg daily until progression

First-Line Therapy (Transplant-Ineligible, Age > 70, Frail):

Emergency Myeloma Therapy for HVS:

• Bortezomib-based regimens preferred (rapid paraprotein reduction)
• Bortezomib 1.3 mg/m² SC/IV days 1, 4, 8, 11 every 21 days
• Dexamethasone 40 mg PO weekly
• Cyclophosphamide 500 mg PO weekly (if VCD regimen)

Relapsed/Refractory Myeloma:

• Daratumumab (anti-CD38 monoclonal antibody)
• Carfilzomib (proteasome inhibitor)
• Pomalidomide (immunomodulatory drug)
• CAR-T cell therapy (emerging)

Polycythaemia Vera (Cellular Hyperviscosity):

Immediate Management:

• Venesection: Remove 250-500 mL blood every 2-3 days until Hct less than 45% (men) or less than 42% (women)
• Target Hct less than 45% to reduce stroke risk

Long-Term Management:

• Aspirin 75-100 mg daily (antiplatelet; paradoxically reduces thrombosis despite high Hct)
• Hydroxycarbamide (hydroxyurea) 500-1000 mg PO daily (cytoreductive; reduces Hct, platelet count)
• Ruxolitinib (JAK2 inhibitor) if refractory to hydroxycarbamide

Monitoring and Follow-Up

Acute Phase (During Plasmapheresis):

• Daily serum viscosity (if available)
• Daily FBC, U&E, Ca²⁺, coagulation
• Repeat fundoscopy after 3-5 sessions (retinal haemorrhages should improve)
• Neurological examination daily (GCS, focal signs)

Maintenance Phase (After Plasmapheresis, During Definitive Therapy):

• Weekly FBC (monitor for chemotherapy-induced cytopenias)
• Monthly SPEP (track paraprotein response)
• Serum FLC monthly (κ/λ ratio normalisation indicates response)
• Serum viscosity if symptoms recur
• Clinical assessment for disease response and toxicity

Long-Term (Remission/Maintenance):

• 3-monthly SPEP, FLC (detect relapse early)
• 6-monthly bone marrow biopsy (assess disease burden)
• Annual fundoscopy (retinal recovery)
• Monitor for treatment-related toxicities (neuropathy, cytopenias, infections)

Management Algorithm

Suspected HVS (triad + WM/myeloma)
            ↓
Measure serum viscosity (if available)
+ Fundoscopy (sausage-link veins?)
            ↓
Viscosity > 4 cP + symptoms OR classic triad OR sausage-link veins?
            ↓
           YES
            ↓
URGENT PLASMAPHERESIS
- Daily sessions until symptoms resolve + viscosity less than 4 cP
- Avoid RBC transfusion before/during plasmapheresis
- IV hydration (avoid dehydration)
- CVC insertion if needed
- Monitor Ca²⁺, coagulation, BP
            ↓
Concurrent supportive care:
- Treat heart failure (furosemide)
- Seizure control (levetiracetam)
- Analgesia (paracetamol)
            ↓
Initiate definitive therapy:
- WM: DRC, BR, or ibrutinib/zanubrutinib
- Myeloma: VRd, VCD, or bortezomib-based
- PV: Venesection + hydroxycarbamide
            ↓
Monitor response:
- Weekly FBC
- Monthly SPEP, FLC
- Viscosity if symptoms recur
            ↓
Relapse surveillance:
- 3-monthly SPEP, FLC
- Treat relapse promptly

---

Complications

Complications of Hyperviscosity Syndrome

Neurological:

1. Ischaemic stroke: Permanent hemiparesis, dysphasia, cognitive impairment
2. Intracerebral haemorrhage: High mortality; due to vascular fragility + bleeding diathesis
3. Seizures: May persist after HVS resolves; require ongoing anticonvulsants
4. Coma: Prolonged coma associated with poor neurological recovery
5. Permanent cognitive impairment: Vascular dementia from multiple small infarcts

Ophthalmological:

1. Central retinal vein occlusion (CRVO): Sudden painless vision loss; often irreversible
2. Branch retinal vein occlusion (BRVO): Partial visual field loss
3. Vitreous haemorrhage: Requires vitrectomy if severe
4. Retinal detachment: Rare complication of severe haemorrhage
5. Permanent blindness: In 5-10% if treatment delayed

Haemorrhagic:

1. Intracranial haemorrhage: Mortality 30-50%
2. GI bleeding: May require endoscopy, transfusion
3. Severe epistaxis: May require ENT intervention (nasal packing, cautery)

Cardiovascular:

1. Congestive heart failure: High-output failure; may become chronic
2. Myocardial infarction: Coronary hypoperfusion
3. Arrhythmias: Atrial fibrillation, ventricular arrhythmias

Renal:

1. Acute kidney injury: Cast nephropathy (myeloma), hypoperfusion
2. Chronic kidney disease: Light chain deposition, AL amyloidosis
3. Dialysis-dependent renal failure: 5-10% of myeloma patients

Mortality:

• Untreated HVS: 10-15% mortality
• Treated with plasmapheresis: less than 2% mortality
• Death usually due to ICH, stroke, or cardiac failure

Complications of Treatment

Plasmapheresis Complications: (See Management section above)

Chemotherapy Complications:

1. Myelosuppression: Neutropenia (infection risk), thrombocytopenia (bleeding), anaemia
2. Peripheral neuropathy: Bortezomib, thalidomide (dose-limiting toxicity)
3. Infections: Opportunistic infections (PJP, VZV) with rituximab/immunosuppression
4. IgM flare: Rituximab can transiently increase IgM; monitor viscosity closely
5. Tumour lysis syndrome: Rare in WM/myeloma; more common in acute leukaemia

BTK Inhibitor Complications:

1. Bleeding: Impaired platelet function; avoid concurrent anticoagulants/antiplatelets
2. Atrial fibrillation: Ibrutinib 5-10%; zanubrutinib lower risk
3. Hypertension: Monitor BP; treat with antihypertensives
4. Infections: Bacterial, fungal (opportunistic)

---

Prognosis and Outcomes

Acute HVS Prognosis

With Prompt Plasmapheresis:

• Rapid symptom improvement within hours to days
• Neurological symptoms: Resolve in 70-80% if treated early
• Visual symptoms: Improve in 60-70%; complete recovery depends on retinal damage extent
• Bleeding: Resolves in 80-90%
• Mortality: less than 2%

Delayed Treatment (> 48-72 Hours):

• Increased risk of permanent neurological deficit (stroke, cognitive impairment): 20-30%
• Vision loss: 10-15% permanent blindness
• Mortality: 5-10%

Untreated:

• Progressive encephalopathy, coma
• Stroke, ICH
• Mortality: 10-15% within weeks

Long-Term Prognosis (Depends on Underlying Disease)

Waldenström Macroglobulinaemia:

• Indolent lymphoproliferative disorder
• Median survival: 5-8 years (improved with BTK inhibitors, rituximab-based therapy)
• HVS recurrence: 10-20% during relapse if inadequate disease control
• 5-year survival: 60-70%

Multiple Myeloma:

• More aggressive than WM
• Median survival (transplant-eligible): 8-10 years
• Median survival (transplant-ineligible): 5-6 years
• HVS in myeloma indicates high tumour burden; associated with worse prognosis
• 5-year survival (IgA myeloma with HVS): 40-50%

Polycythaemia Vera:

• Chronic myeloproliferative neoplasm
• With treatment (venesection, hydroxycarbamide): Near-normal life expectancy
• HVS rare if well-controlled (Hct less than 45%)
• Risk of transformation to myelofibrosis (10-15%) or acute leukaemia (2-5%)

Prognostic Factors

Favourable Prognostic Factors:

• Early diagnosis and treatment (less than 48 hours symptom onset)
• Waldenström's (vs myeloma)
• Low tumour burden
• Good response to definitive therapy (paraprotein reduction > 50%)
• Absence of complications (stroke, ICH, renal failure)

Unfavourable Prognostic Factors:

• Delayed treatment (> 72 hours)
• Myeloma (vs WM)
• High β2-microglobulin (> 5.5 mg/L)
• Renal impairment (creatinine > 200 μmol/L)
• Complications: Stroke, ICH, dialysis-dependent renal failure
• Relapsed/refractory disease
• Adverse cytogenetics (myeloma: del(17p), t(4;14); WM: TP53 mutation)

Recurrence Risk

• HVS can recur if underlying disease relapses or progresses
• Monitor paraprotein levels closely (monthly SPEP, FLC)
• Rising IgM > 30 g/L or IgA > 50 g/L: High recurrence risk
• Preemptive plasmapheresis may be considered if rapid paraprotein rise + prodromal symptoms
• Disease-directed therapy reduces recurrence risk

---

Evidence and Guidelines

Key Evidence

Hyperviscosity Syndrome Pathophysiology and Clinical Features:

1. Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018;132(13):1379-1385. PMID: 30104220 DOI: 10.1182/blood-2018-06-846816

   • Authoritative review of HVS mechanisms, clinical features, and management across different causes (WM, myeloma, polycythaemia)

2. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119(10):2205-2208. PMID: 22223821 DOI: 10.1182/blood-2011-10-387969

   • Systematic review of plasmapheresis efficacy and timing

Waldenström Macroglobulinaemia: 3. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124(9):1404-1411. PMID: 25000216 DOI: 10.1182/blood-2014-03-565135

• International consensus guidelines for WM treatment including HVS management

4. Castillo JJ, Treon SP. Management of Waldenström macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020;2020(1):372-379. PMID: 33275686 DOI: 10.1182/hematology.2020000121

   • Updated WM management including BTK inhibitors (ibrutinib, zanubrutinib)

5. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):1430-1440. PMID: 25853747 DOI: 10.1056/NEJMoa1501548

   • Landmark trial demonstrating ibrutinib efficacy in WM (90% response rate)

Multiple Myeloma and HVS: 6. Kwaan HC, Rosenstein R. Hyperviscosity in multiple myeloma and related disorders. Clin Hemorheol Microcirc. 2016;63(2):75-83. PMID: 27163285 DOI: 10.3233/CH-162043

• Detailed analysis of myeloma-associated HVS mechanisms

7. Moreau P, Kumar SK, San Miguel J, et al. Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group. Lancet Oncol. 2021;22(3):e105-e118. PMID: 33662263 DOI: 10.1016/S1470-2045(20)30756-7
   • IMWG consensus on myeloma therapy

Plasmapheresis/Therapeutic Plasma Exchange: 8. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice – evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue. J Clin Apher. 2019;34(3):171-354. PMID: 31180581 DOI: 10.1002/jca.21705

• ASFA guidelines: TPE for HVS is Category I (standard first-line therapy)

9. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the seventh special issue. J Clin Apher. 2016;31(3):149-162. PMID: 27322218 DOI: 10.1002/jca.21470
   • ASFA 7th edition: TPE for HVS

Retinal Manifestations: 10. Menke MN, Feke GT, McMeel JW, Treon SP. Effect of plasmapheresis on hyperviscosity-related retinopathy and retinal hemodynamics in patients with Waldenström's macroglobulinemia. Invest Ophthalmol Vis Sci. 2008;49(3):1157-1160. PMID: 18326745 DOI: 10.1167/iovs.07-1363

• Detailed study of retinal changes in HVS and response to plasmapheresis

Serum Viscosity Measurement: 11. Rosenson RS, McCormick A, Uretz EF. Distribution of blood viscosity values and biochemical correlates in healthy adults. Clin Chem. 1996;42(8 Pt 1):1189-1195. PMID: 8697575

• Normal serum viscosity values and measurement techniques

Bleeding Mechanisms: 12. Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol. 2016;91(9):908-916. PMID: 27229735 DOI: 10.1002/ajh.24471

• Mechanism of acquired vWS in paraprotein disorders

Polycythaemia Vera: 13. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. PMID: 23216616 DOI: 10.1056/NEJMoa1208500

• CYTO-PV trial: Target Hct less than 45% reduces thrombosis risk

Rituximab IgM Flare: 14. Treon SP, Branagan AR, Hunter Z, et al. Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenström's macroglobulinemia. Ann Oncol. 2004;15(10):1481-1483. PMID: 15367405 DOI: 10.1093/annonc/mdh397

• Describes rituximab-induced IgM flare phenomenon

BTK Inhibitors (Zanubrutinib): 15. Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv. 2020;4(23):6009-6018. PMID: 33252694 DOI: 10.1182/bloodadvances.2020003010

• ASPEN trial: Zanubrutinib efficacy in WM

Neurological Complications: 16. Soubeyrand M, Badoual C, Roux J, et al. Grade IV glioma in Waldenström's macroglobulinemia: association with hyperviscosity syndrome. J Neurooncol. 2008;86(3):363-366. PMID: 17879138 DOI: 10.1007/s11060-007-9477-6

• Case series of neurological complications in HVS

Prognosis: 17. Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood. 2009;113(18):4163-4170. PMID: 19196866 DOI: 10.1182/blood-2008-08-174961

• IPSSWM prognostic score for WM

RBC Transfusion Caution: 18. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29(5):467-471. PMID: 14631547 DOI: 10.1055/s-2003-44554

• Discusses RBC transfusion risks in HVS

Emergency Management: 19. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101(7):2496-2506. PMID: 12456500 DOI: 10.1182/blood-2002-07-2299

• Includes discussion of plasma cell disorder emergencies

Bendamustine-Rituximab: 20. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. PMID: 23433739 DOI: 10.1016/S0140-6736(12)61763-2

• Landmark trial establishing BR efficacy in lymphoproliferative disorders

Guideline Summary

Evidence Levels

• Level I (High): Systematic reviews, RCTs, large prospective cohort studies

  • Plasmapheresis efficacy (ASFA Category I)
  • BTK inhibitor trials (ibrutinib, zanubrutinib)
  • Polycythaemia vera Hct targets (CYTO-PV trial)

• Level II (Moderate): Smaller RCTs, prospective cohort studies, consensus guidelines

  • Rituximab-based chemotherapy regimens (DRC, BR)
  • Myeloma treatment protocols (VRd, bortezomib)
  • IWWM consensus recommendations

• Level III (Low): Case series, expert opinion, retrospective studies

  • Retinal manifestations description
  • IgM flare phenomenon
  • Optimal plasmapheresis protocols (volume, frequency)

Key Gaps in Evidence

• Optimal plasmapheresis protocol (exchange volume, frequency, stopping criteria): Largely expert consensus
• Preemptive plasmapheresis thresholds (IgM/IgA level, viscosity) in asymptomatic patients: No RCT data
• Comparison of albumin vs FFP replacement fluid: No head-to-head trial
• Long-term neurological and ophthalmological outcomes: Limited follow-up data
• Optimal timing of definitive therapy initiation relative to plasmapheresis: Expert opinion

---

Patient and Family Information

What is Hyperviscosity Syndrome?

Hyperviscosity syndrome (HVS) is a condition where your blood becomes too thick (viscous) due to abnormal proteins. This thick blood flows more slowly through small blood vessels, reducing oxygen delivery to organs like the brain, eyes, and kidneys.

What Causes It?

HVS is caused by high levels of abnormal proteins (called paraproteins) produced by blood cancers:

• Waldenström macroglobulinaemia: A rare blood cancer that produces IgM protein (most common cause)
• Multiple myeloma: A cancer of plasma cells that produces IgA or IgG protein
• Polycythaemia vera: A condition with too many red blood cells (less common cause)

What Are the Symptoms?

HVS causes three main types of symptoms:

1. Brain symptoms: Headache, confusion, dizziness, blurred thinking
2. Eye symptoms: Blurred vision, double vision, or sudden vision loss
3. Bleeding: Nosebleeds, gum bleeding, easy bruising

Other symptoms include shortness of breath, fatigue, and chest pain.

How is It Diagnosed?

Your doctor will:

• Examine your eyes (look at the back of your eye with an ophthalmoscope)
• Order blood tests to measure blood thickness (viscosity) and protein levels
• Perform scans (CT or MRI) if you have neurological symptoms

Key finding: "Sausage-link" veins in the eye (seen on eye examination) are a classic sign of HVS.

How is It Treated?

Emergency Treatment:

• Plasmapheresis (plasma exchange): A procedure to filter your blood and remove the abnormal proteins. This is done urgently and provides rapid symptom relief (within hours to days).
• The procedure involves connecting you to a machine that removes your plasma (the liquid part of blood containing the protein) and replaces it with albumin (a safe protein solution).
• You may need daily sessions for 3-5 days.

Long-Term Treatment:

• Treatment for the underlying blood cancer (Waldenström's or myeloma):
  • Chemotherapy (drugs to kill cancer cells)
  • Immunotherapy (antibodies like rituximab)
  • Targeted therapy (pills like ibrutinib)
• These treatments reduce the abnormal protein production and prevent HVS from recurring.

What Can I Expect?

Short-Term:

• Symptoms improve rapidly with plasmapheresis (within hours to 1-2 days)
• Confusion, headache, and blurred vision typically resolve first
• Bleeding improves within 1-2 days

Long-Term:

• Prognosis depends on the underlying blood cancer
• Most people respond well to treatment
• Regular monitoring (blood tests every 3 months) is needed to detect early relapse

What Should I Watch For?

Contact your doctor immediately if you develop:

• Sudden confusion or difficulty speaking
• Sudden vision loss or severe blurred vision
• Severe headache
• Uncontrolled nosebleeds or bleeding
• Shortness of breath or chest pain

These may indicate HVS recurrence and require urgent treatment.

Can It Be Prevented?

• Regular monitoring of protein levels (blood tests every 3 months)
• Good hydration (drink 2-3 litres of water daily)
• Prompt treatment of the underlying blood cancer
• Avoid dehydration (can worsen blood thickness)

Important Points

• HVS is a medical emergency but responds very well to treatment
• Plasmapheresis is highly effective and safe
• Early treatment prevents permanent complications (stroke, blindness)
• Long-term outcome depends on controlling the underlying blood cancer

Support Resources

• Blood Cancer UK: bloodcancer.org.uk – Information and support for blood cancer patients
• Macmillan Cancer Support: macmillan.org.uk – Practical and emotional support
• Myeloma UK: myeloma.org.uk – Myeloma-specific information
• Waldenström's Macroglobulinaemia UK: wmuk.org.uk – WM-specific support
• Leukaemia Care: leukaemiacare.org.uk – Patient support and information

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Examination Focus (MRCP, FRACP)

PACES Station 5: History-Taking (Acute Medical Presentation)

Scenario: "A 68-year-old man presents to the emergency department with a 2-week history of headache, blurred vision, and confusion. His wife reports nosebleeds over the past week. He was diagnosed with Waldenström macroglobulinaemia 6 months ago but has not yet started treatment. Please take a focused history."

Key Points to Elicit:

1. Neurological Symptoms:

   • Headache: Onset, severity, character, exacerbating factors
   • Confusion: Gradual or sudden? Memory problems, disorientation?
   • Any focal weakness, speech difficulty, or seizures?

2. Visual Symptoms:

   • Blurred vision: Gradual or sudden? Unilateral or bilateral?
   • Diplopia, visual field defects, or scotomas?
   • Any sudden vision loss?

3. Bleeding Symptoms:

   • Epistaxis: Frequency, severity, which nostril, self-limiting or required intervention?
   • Gum bleeding, bruising, haematuria, or GI bleeding?

4. Cardiovascular/Respiratory:

   • Dyspnoea, orthopnoea, ankle swelling (heart failure)?
   • Chest pain?

5. Underlying Disease:

   • When diagnosed with WM? Any treatment started?
   • Baseline paraprotein level (IgM)?
   • Other complications (anaemia, renal impairment)?

6. Precipitants:

   • Recent dehydration, infection, or illness?
   • Any recent blood transfusions?

7. Red Flags:

   • Sudden neurological deterioration, seizures, coma?
   • Sudden vision loss?
   • Severe uncontrolled bleeding?

Differential Diagnosis to Discuss:

• Hyperviscosity syndrome (most likely)
• Stroke (ischaemic or haemorrhagic)
• Uraemic encephalopathy (if renal impairment)
• Intracerebral bleed
• Metabolic encephalopathy (hypercalcaemia if myeloma)

Investigations to Propose:

• Urgent serum viscosity
• SPEP, IFE (quantify IgM)
• FBC, coagulation, U&E, Ca²⁺
• Fundoscopy (sausage-link veins)
• CT head (exclude ICH, stroke)

Management Plan:

• Urgent haematology referral
• Arrange plasmapheresis
• Avoid RBC transfusion before plasmapheresis
• IV hydration
• Initiate definitive WM therapy (DRC, BR, or ibrutinib)

PACES Station 1: Respiratory/Abdominal Examination (Hepatosplenomegaly)

Scenario: "This 65-year-old woman has been referred with fatigue and weight loss. Please examine her abdomen."

Expected Findings:

• Splenomegaly (WM, myeloma with extramedullary disease)
• Hepatomegaly (WM, amyloidosis)
• No lymphadenopathy (typically; cervical/axillary LN in WM less common than splenomegaly)

Viva Discussion:

• Differential diagnosis of splenomegaly
• Paraprotein disorders (WM, myeloma, CLL)
• Complications (hyperviscosity, anaemia, bleeding)

PACES Station 2: Neurological Examination (Encephalopathy)

Scenario: "This 70-year-old man presented with confusion and headache. Please assess his neurological status."

Expected Findings:

• Reduced GCS (13-14/15): Confused, disoriented
• No focal neurological signs (unless stroke has occurred)
• Fundoscopy: Sausage-link veins, retinal haemorrhages, papilloedema

Viva Discussion:

• Causes of encephalopathy
• Hyperviscosity as cause
• Urgent management (plasmapheresis)
• Prognosis (excellent if treated early)

PACES Station 5: Brief Clinical Consultation (Communication Skills)

Scenario: "A 67-year-old man with Waldenström macroglobulinaemia has been diagnosed with hyperviscosity syndrome. He is due to undergo plasmapheresis. Please explain the diagnosis and treatment to him."

Key Points to Cover:

1. Explain Diagnosis:

   • "Your blood has become too thick due to high levels of protein produced by your condition (Waldenström's)."
   • "This thick blood flows slowly through small vessels in your brain and eyes, causing your symptoms (headache, blurred vision)."

2. Explain Plasmapheresis:

   • "We need to perform a procedure called plasmapheresis to 'clean' your blood."
   • "This involves connecting you to a machine that removes the protein from your blood and replaces it with albumin (a safe protein)."
   • "The procedure takes 2-3 hours and is similar to dialysis."

3. Expected Benefits:

   • "Your symptoms should improve within hours to 1-2 days."
   • "Most people feel much better after 1-2 sessions."

4. Risks:

   • "The procedure is generally safe, but you may experience tingling (due to calcium changes), low blood pressure, or infection risk from the catheter."

5. Long-Term Plan:

   • "After plasmapheresis, we'll start treatment for your Waldenström's to prevent this from happening again."
   • "This may involve chemotherapy or tablets."

6. Answer Questions:

   • Address patient concerns about procedure, prognosis, and long-term outlook

Viva Voce Questions

Question 1: "A 65-year-old woman with Waldenström macroglobulinaemia presents with confusion and blurred vision. Her IgM is 45 g/L. How would you manage her?"

Model Answer:

• Suspect hyperviscosity syndrome (classic triad: neurological + visual symptoms in WM patient)
• Confirm diagnosis: Serum viscosity (if available), fundoscopy (sausage-link veins), SPEP (IgM 45 g/L high)
• Emergency management: Urgent plasmapheresis (daily sessions until symptoms resolve)
• Avoid RBC transfusion before plasmapheresis (worsens viscosity)
• IV hydration (avoid dehydration)
• Supportive care: Analgesia, treat heart failure if present
• Definitive therapy: Initiate WM treatment (DRC, BR, or ibrutinib/zanubrutinib)
• Monitor: Daily viscosity, FBC, repeat fundoscopy

Question 2: "What is the mechanism of bleeding in hyperviscosity syndrome despite high protein levels?"

Model Answer:

• Paradoxical bleeding (not thrombosis) due to multiple mechanisms:
  1. Platelet dysfunction: Paraprotein (especially IgM) coats platelets, impairing adhesion and aggregation
  2. Acquired von Willebrand syndrome: IgM binds and adsorbs vWF, reducing functional levels
  3. Vascular fragility: Hyperviscosity causes vascular engorgement and increased transmural pressure, leading to venule/capillary rupture
  4. Coagulation factor interference: Rarely, paraprotein interferes with fibrin polymerisation or has intrinsic anticoagulant activity
• Result: Mucosal bleeding (epistaxis, gum bleeding), retinal haemorrhages, GI bleeding

Question 3: "Why is IgM more likely to cause hyperviscosity than IgG or IgA?"

Model Answer:

• Molecular size: IgM is pentameric (970 kDa) vs IgG monomeric (150 kDa) – IgM is ~6 times larger
• Hydrodynamic volume: Larger molecules occupy more space, increasing viscosity disproportionately
• Intravascular location: IgM cannot cross endothelial barrier (too large), so 100% remains intravascular
• Concentration-viscosity relationship: Viscosity ∝ concentration², so small IgM increases cause large viscosity increases
• Polymerisation: IgM can form polymers/aggregates, further increasing viscosity
• Result: Waldenström's (IgM) causes HVS in 10-30% vs myeloma (IgG/IgA) 2-5%

Question 4: "What is the role of rituximab in Waldenström macroglobulinaemia, and what complication should you monitor for?"

Model Answer:

• Role: Anti-CD20 monoclonal antibody; WM cells express CD20; rituximab induces B-cell apoptosis
• Use: Combined with chemotherapy (DRC: Dexamethasone-Rituximab-Cyclophosphamide; BR: Bendamustine-Rituximab)
• Complication: IgM flare (paradoxical transient IgM increase)
  • Occurs in 30-50% of WM patients within first 4-12 weeks of rituximab
  • "Mechanism: Release of IgM from dying WM cells or transient increase in IgM production"
  • "Risk: Can precipitate or worsen HVS"
• Monitoring: Check IgM and viscosity 2-4 weeks after rituximab initiation; may need additional plasmapheresis if symptomatic
• Alternative: Consider BTK inhibitors (ibrutinib, zanubrutinib) if high HVS risk – no IgM flare

Question 5: "Describe the fundoscopic findings in hyperviscosity syndrome."

Model Answer:

• Pathognomonic finding: "Sausage-link" or "box-car" retinal veins (dilated, segmented appearance due to rouleaux formation)
• Retinal vein engorgement: Dilated, tortuous retinal veins (venous stasis)
• Retinal haemorrhages: Flame-shaped (superficial nerve fibre layer) or dot-blot (deeper retinal layers)
• Papilloedema: Optic disc swelling with blurred margins (raised intracranial pressure or ischaemia)
• Optic disc hyperaemia: Red, swollen optic disc
• Cotton-wool spots: White patches (nerve fibre layer infarcts due to ischaemia)
• Exudates: Hard exudates (lipid deposits) less common
• Significance: Fundoscopy can be diagnostic even without viscosity measurement; sausage-link veins mandate urgent plasmapheresis

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Summary for Rapid Revision

Hyperviscosity Syndrome (HVS):

• Definition: Increased blood viscosity (> 4 cP, normal 1.4-1.8 cP) causing microcirculatory stasis
• Causes: Waldenström's IgM (85%), myeloma IgA/IgG3 (10-15%), polycythaemia vera (less than 5%)
• Classic triad: Neurological (confusion, headache, stroke) + Visual (blurred vision, sausage-link veins) + Bleeding (epistaxis, gum bleeding)
• Pathognomonic finding: Fundoscopy showing sausage-link/box-car retinal veins
• Emergency treatment: Urgent plasmapheresis (30-60% viscosity reduction per session)
• Avoid: RBC transfusion before plasmapheresis (worsens viscosity)
• Definitive therapy: Treat underlying disease – WM (DRC, BR, ibrutinib), myeloma (VRd, bortezomib)
• Prognosis: Excellent if treated promptly (less than 2% mortality); 10-15% mortality if untreated
• Key exam point: IgM pentameric (970 kDa) >> IgG monomeric (150 kDa) explains higher HVS frequency in WM

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