Hyperviscosity and cryoglobulinaemia

• Hyperviscosity syndrome (HVS) is thickened blood, usually from a very high monoclonal paraprotein, most often IgM in Waldenstrom macroglobulinaemia (WM). It is a medical emergency.
• The classic triad is mucosal bleeding, visual disturbance and neurological dysfunction; the diagnosis is confirmed by a high serum viscosity or paraprotein level, but treatment should start on clinical suspicion.
• Plasmapheresis (TPE) removes paraprotein and quickly relieves HVS; it must always be followed by systemic treatment of the underlying disease.
• HVS occurs in roughly 10 to 30% of WM and in 2 to 6% of multiple myeloma. ^[2]
• Cryoglobulinaemia is the reversible precipitation of immunoglobulins below 37 degrees C. Type I (monoclonal) is linked to plasma-cell and lymphoid neoplasms and may itself cause hyperviscosity; mixed cryoglobulinaemia (type II and III) is an immune-complex vasculitis, most often driven by hepatitis C virus (HCV). ^[3]
• Treatment of cryoglobulinaemia treats the underlying cause and the vasculitis: antiviral therapy for HCV or HBV, chemotherapy for lymphoma, rituximab for the B-cell disease, and plasmapheresis for severe or life-threatening organ involvement.

By the end of this page you should be able to:

1. Explain why blood viscosity rises and what "hyperviscosity syndrome" means.
2. List the causes of plasma and whole-blood hyperviscosity and recognise the clinical triad and retinal signs.
3. Plan the initial investigations and know which results matter most.
4. Outline acute and definitive management, including when and how to use plasmapheresis.
5. Classify cryoglobulinaemia as type I, II or III, and as essential or secondary.
6. Recognise the features of monoclonal cryoglobulinaemia syndrome (MoCs) and mixed cryoglobulinaemia syndrome (MCs/cryoglobulinemic vasculitis).
7. Choose antiviral, immunosuppressive and apheresis therapy for cryoglobulinaemia, including rituximab doses and cautions.
8. Cross-check these conditions with Waldenstrom macroglobulinaemia and with each other.

Viscosity is the resistance of a fluid to flow. Water has a viscosity of 0.894 centipoise (cP), serum in health is 1.5 cP or less in absolute terms, and the relative plasma viscosity in health (water set at 1.0) is roughly 1.4 to 1.8. ^[1][2] Serum behaves as a Newtonian fluid, so a single number describes it, but whole blood is non-Newtonian and its viscosity depends on shear rate and vessel size.

Plasma hyperviscosity usually means IgM in WM (which is 75 to 80% intravascular), but IgA and IgG3 paraproteins in multiple myeloma and IgG in polyclonal hypergammaglobulinaemia can also raise viscosity. ^[2] Whole-blood hyperviscosity occurs in polycythaemia (primary or secondary) and in extreme leucocytosis, for example leukaemic leukostasis. ^[1]

The term is used for both the laboratory phenomenon and the syndrome. Clearer usage separates serum cryoglobulin (the laboratory finding) from the clinical syndromes: monoclonal cryoglobulinaemia syndrome (MoCs) and mixed cryoglobulinaemia syndrome (MCs), also called cryoglobulinaemic vasculitis. ^[3] Each may be essential (no underlying cause found) or secondary to another disorder. ^[3]

Cryoglobulins are classified by immunoglobulin composition:

Type I cryoglobulins usually occur at high concentration and can precipitate inside vessels, producing non-inflammatory thrombotic occlusion and ischaemia. Mixed type II and III cryoglobulins form immune complexes that activate complement and produce leukocytoclastic vasculitis. ^[3]

The distinction matters clinically: hyperviscosity is a frightening complication of type I disease, and true hyperviscosity is very rare in mixed cryoglobulinaemia. ^[3]

HVS is uncommon and is clinically apparent in 10 to 30% of patients with WM and in 2 to 6% of patients with multiple myeloma. ^[2] Polyclonal hypergammaglobulinaemic HVS has been reported in Sjogren disease, HIV infection, rheumatoid arthritis, IgG4-related disease and autoimmune lymphoproliferative syndromes. ^[2]

Cryoglobulinaemia is estimated at about 1 in 100,000. Roughly 50% of individuals with chronic HCV infection have cryoglobulins, but only a minority develop the syndrome. ^[2] Mixed cryoglobulinaemia is HCV-driven in about 80 to 90% of cases and is secondary to other viruses (HBV, HIV), autoimmune disease or chronic lymphoproliferative disease in 10 to 20%. ^[2] There is strong geographical variation, with HCV-related disease much more common in the Mediterranean basin and Southern Europe than in Northern Europe or North America. ^[3] The introduction of direct-acting antivirals (DAAs) has markedly reduced HCV-related mixed cryoglobulinaemia in developed countries. ^{[3] [1]}

Causes of plasma (protein) hyperviscosity, in approximate order of importance:

• Waldenstrom macroglobulinaemia (monoclonal IgM, above 4 g per dL; most common cause of symptomatic HVS).
• Multiple myeloma with IgA (6 to 7 g per dL) or IgG3 (4 g per dL) paraprotein. ^[1]
• IgM or IgA monoclonal gammopathy of undetermined significance, smouldering WM and related B-cell neoplasms.
• Type I cryoglobulinaemia, especially with WM.
• Polyclonal hypergammaglobulinaemia (IgG above 6 g per dL): Sjogren disease, rheumatoid arthritis, HIV infection, IgG4-related disease. ^[2]
• Cryoglobulin gel and crystal phenomena at low monoclonal concentrations (rare).

Causes of whole-blood hyperviscosity:

• Primary and secondary polycythaemia.
• Hyperleukocytosis in acute leukaemia (leukostasis), particularly acute myeloid leukaemia.
• Extreme thrombocytosis.

Risk factors for developing HVS in WM include serum IgM above 4600 mg per dL (hazard ratio 3.1) and a measured viscosity above 2.2 cP (hazard ratio 7.6); patients in this unpooled group had a 36% cumulative probability of developing HVS within 6 months. ^{[1] [2]}

Underlying domains, in order of frequency:

• B-cell lymphoproliferative disease (MGUS, smouldering WM, multiple myeloma, B-cell non-Hodgkin lymphoma, CLL): dominant in type I disease, where over 90% of patients have an underlying lymphoproliferative disorder. ^[3]
• Infection: HCV in over three-quarters of mixed cryoglobulinaemia, then HBV, HIV, EBV, parvovirus B19 and other viruses. ^[3]
• Autoimmune disease: primary Sjogren disease (commonly overlapping), systemic lupus erythematosus, rheumatoid arthritis.
• Toxic agents and essential (idiopathic) forms.

In a series of 102 patients with monoclonal cryoglobulinaemia, 87% were symptomatic and 92% had an underlying lymphoproliferative disorder, so that the essential form was uncommon. ^[3] Older age, baseline renal involvement and high rheumatoid factor titres predict a weaker response or relapse after therapy. ^[3]

The clinical threshold for symptoms is 4 g per dL of IgM (or 4 g per dL of IgG3, 6 to 7 g per dL of IgA, or 6 g per dL of polyclonal IgG) with a relative plasma viscosity above 4 cP. ^[2] Because IgM is 75 to 80% intravascular, even a modest fall in IgM concentration produces a large fall in viscosity; each plasmapheresis reduces viscosity by 20 to 30%, so 1 to 2 exchanges usually suffice for IgM disease, while 4 to 5 may be needed for IgG-associated disease. ^[2]

HVS becomes symptomatic from shear damage to small vessels, retinal venous engorgement and mucosal bleeding. Most patients become symptomatic at relative viscosities of 6 to 7 cP. ^[2] The viscosity level at which a given patient becomes symptomatic is usually reproducible for that patient. ^[2]

Retinal changes are sensitive: the mean IgM level at which the earliest retinal changes appear is 5442 mg per dL. ^[1] In WM cohorts, an IgM above 6000 mg per dL carried a median time to clinically identified HVS of 3 months. ^[1] By contrast, among 24 asymptomatic patients with IgM above 6000 mg per dL at diagnosis, the median viscosity was only 1.6 cP, none exceeded 4 cP, and none developed HVS over follow up. ^[1] Numbers alone never make the diagnosis; symptoms and examination do. ^[1]

Type I monoclonal cryoglobulins precipitate inside vessels as hyaline thrombi, producing non-inflammatory occlusion and ischaemia (skin ulcers, digital gangrene, peripheral neuropathy and, in large amounts, hyperviscosity). ^[3] Mixed cryoglobulins (type II/III) form immune complexes that deposit in small vessels, consume complement (C4 falls, often with low C3) and rheumatoid factor is positive in most cases, producing leukocytoclastic vasculitis of small vessels and membranoproliferative glomerulonephritis. ^[3]

A very high cryocrit can itself raise viscosity, but cryocrit does not correlate with disease severity or prognosis. ^[3] Hyperviscosity complicates MoCs and is very rare in MCs. ^[3]

Symptoms depend on position, volume and rate of viscosity rise. The presentation is classically a triad:

• Bleeding tendency (epistaxis, gingival bleeding).
• Visual disturbance (blurred vision, retinal haemorrhage, even bilateral central retinal vein occlusion).
• Neurological dysfunction (headache, light-headedness, somnolence, ataxia, coma, stroke-like events, sudden deafness from cochlear venous stasis, tinnitus, vertigo).

Other manifestations include congestive heart failure (plasma volume expansion), dyspnoea and pulmonary hypertension, and general symptoms such as fatigue and anorexia. ^[2]

A fundoscopic examination is the single most useful bedside test: venous tortuosity, venous "sausaging" and retinal haemorrhages are typical, and retinal changes in an otherwise asymptomatic patient with WM can reverse dramatically after a single TPE. ^[1][2]

Cryoglobulins are often detected incidentally and may cause no symptoms. When symptomatic, the patterns differ:

Monoclonal cryoglobulinaemia syndrome (type I / MoCs). In a series of 102 patients, 87% were symptomatic: cutaneous findings in 63% (purpura in 42%, ulcers or gangrene in 34%), peripheral neuropathy in 32% (sensory type in 24%), Raynaud phenomenon in 25%, arthralgias in 24% and renal (glomerulonephritis) involvement in 14%. ^[3] Hyperviscosity and cold-induced intravascular occlusion produce digital ischaemia, necrotic acral lesions and sudden deafness. ^[3]

Mixed cryoglobulinaemia syndrome (MCs / cryoglobulinemic vasculitis). The hallmark is a triad of purpura, weakness and arthralgias (Meltzer triad), often with: ^[3]

• cutaneous leukocytoclastic vasculitis and ulcers (ulcers in 25 to 30% of patients); ^[4]
• membranoproliferative glomerulonephritis (renal involvement in 20 to 30%);
• peripheral neuropathy (paresthesiae and pain in up to 90%, abnormal EMG in nearly 80%); ^[4]
• arthralgia, sicca symptoms in about half of patients; ^[3]
• less often pulmonary, gastrointestinal, cardiac or central nervous system vasculitis. ^[4][3]

Tissue deposits of IgG-IgM immune complexes with complement are seen on immunofluorescence, and C4 is typically low. ^[3]

Laboratory clues to mixed disease. Low C4 with positive rheumatoid factor in a patient with purpura, arthralgias and neuropathy is strongly suggestive; C3 may be normal. ^[3] Very high cryocrit can be seen in paucisymptomatic patients, and very low cryocrit can be found in severe MCs, so cryocrit does not track severity. ^[3]

HVS can be mistaken for acute stroke, retinal vein occlusion, severe thrombocytopenia or anaemia; a retinal examination looking for venous sausaging points to viscosity rather than those diagnoses. ^[1]

Mixed cryoglobulinaemia must be separated from several conditions:

Type I cryoglobulinaemia is hard to distinguish from uncomplicated monoclonal gammopathy; positivity for a monoclonal cryoprecipitate with skin ulcers, acral necrosis, neuropathy or hyperviscosity is the clue. ^[3]

• Serum viscosity (absolute and relative): normal values are up to 1.5 cP and 1.4 to 1.8 respectively, but levels do not need to be available before urgent TPE. ^[1][2]
• Serum protein electrophoresis and immunofixation, with quantitative immunoglobulins and free light chains.
• Full blood count and coagulation (paraproteins can interfere with assays).
• Dilated fundoscopy for venous sausaging and haemorrhages.
• Bone marrow biopsy and imaging as directed to stage WM, myeloma or lymphoma.

Sampling conditions matter: blood must be taken, clotted and centrifuged at 37 degrees C, then stored at 4 degrees C for 7 days for cryoprecipitation and characterisation; cryocrit is measured on a sample without anticoagulant. ^[3] Cryoprecipitate proteins are characterised by immunofixation at 37 degrees C. ^[3] Because cryoprecipitation can be intermittent, repeat testing is appropriate when the picture is typical but the first sample is negative. ^[3]

• Complement (C4 low, often C3 normal in mixed disease), rheumatoid factor.
• Autoantibodies (ANA, anti-Ro/SSA, anti-dsDNA) to separate Sjogren disease and SLE.
• HCV, HBV, HIV and other infection markers; liver function and viral load.
• Renal: urinalysis, creatinine, proteinuria, often renal biopsy showing membranoproliferative glomerulonephritis type I.
• EMG and nerve conduction if neuropathy is present.
• Bone marrow/lymph node assessment for occult lymphoma.

There are no internationally agreed criteria for HVS; the diagnosis is clinical (triad) plus paraprotein (above 4 g per dL IgM with relative viscosity above 4 cP, or the IgA/IgG thresholds above) and a reproducible symptomatic threshold in the same patient. ^[2]

For cryoglobulinaemia, GISC classification criteria from 1989 have been revised and validated in multicentre studies; clinical classification as MoCs versus MCs rests on type of cryoprecipitate, skin pathology (non-inflammatory thrombotic occlusion versus leukocytoclastic vasculitis) and clinical pattern. ^[3] Early assessment for possible underlying causes (B-cell neoplasm, infection, autoimmune disease) must be repeated regularly in all patients. ^[3]

Severity of mixed cryoglobulinaemic vasculitis (from the GISC rituximab consensus 2023, Quartuccio and colleagues): ^[4]

• Mild/minor: purpura, arthralgia, fatigue.
• Moderate to severe, not immediately life threatening: glomerulonephritis, necrotising skin ulcers or digital ischaemia, polyarthritis, gastrointestinal vasculitis, active neuropathy. (Glomerulonephritis occurs in 20 to 30% of patients and triples the mortality risk when present.) ^[4]
• Life threatening: rapidly progressive glomerulonephritis, acute motor or sensory-motor neuropathy, widespread vasculitis, pulmonary haemorrhage, intestinal or central nervous system vasculitis, and hyperviscosity syndrome. ^[4]

Key plasmapheresis points:

• Start TPE on suspicion; do not wait for the viscosity result, but send the sample. The procedure can be stopped if the diagnosis is not validated. ^[1]
• Symptomatic HVS is an ASFA category I, grade 1B indication for TPE. ^[2]
• Each TPE removes about 20 to 30% of viscosity; for IgM disease 1 to 2 exchanges usually control symptoms; IgG disease may need 4 to 5. ^[2]
• Daily or every other day until symptoms abate (generally 1 to 3 procedures); maintenance every 1 to 4 weeks is sometimes used. ^[2]
• Volume treated is 1 to 1.5 total plasma volumes; replacement fluid is albumin or plasma; room temperature handling avoids cryoprecipitation if that is also present. ^[2]
• IgM levels rebound to baseline about 3 to 5 weeks after TPE, so systemic therapy must follow quickly. ^[2]
• Acquired von Willebrand disease is described with high IgM; bleeding may be multifactorial. ^[2]
• Rituximab can produce an IgM flare in 30 to 70% of patients within 4 weeks, so if serum viscosity is above 3.5 cP or IgM is above 4 g per dL, prophylactic TPE is recommended before rituximab, or rituximab can be held for 1 to 3 chemotherapy cycles until IgM falls below 4 g per dL. This prophylactic TPE is an ASFA grade 1C indication. ^{[2] [1][4]}
• Anticoagulation does not remove the paraprotein; anticoagulation alone does not treat HVS. ^[1]

Rapid systemic options after TPE ( WM, Gertz): bortezomib-based regimens work in 85% of patients (flare in 11% only), carfilzomib reaches 50% IgM reduction in a median 2.1 months, and ibrutinib reaches 50% reduction in a median 4 weeks in previously treated patients; an IgM reduction of as little as 25% usually relieves symptoms. Rituximab, alkylator and purine-nucleoside regimens take months and so are not the first choice when the goal is rapid viscosity reduction. ^[1]

Asymptomatic cryoglobulinaemia (type I or mixed) needs no treatment; observe and monitor for progression and for emergence of an underlying disease. ^[2][3]

Mild MCs (purpura, arthralgia, fatigue): cold avoidance, simple analgesia, low-dose corticosteroids (6-methylprednisolone 2 to 8 mg per day) and treatment of any cause. ^[3][2]

Moderate to severe MCs (GISC 2023): treat the underlying cause first:

• HCV: direct-acting antiviral combinations achieve sustained virological response in more than 90% of cryoglobulinaemic vasculitis; purpura and arthralgia improve during or shortly after therapy, but neuropathy and renal disease may recover slowly or remain incomplete. 10 to 20% of patients have persistent or recurrent activity despite viral clearance and need immunomodulation. ^[3]
  • ASFA cites sofosbuvir 400 mg per day plus daclatasvir 60 mg per day as one open-label regimen giving 90% complete response at 12 weeks. ^[2]
• HBV: nucleos(t)ide analogues (entecavir, tenofovir) suppress replication; up to 80% of patients achieve partial or complete remission of vasculitic symptoms within 6 to 12 months. Interferon is no longer used. ^[3]
• B-cell neoplasms: treat as lymphoma or myeloma.
• Superimposed autoimmune disease: treat that disease.

Rituximab is the standard immunomodulator for severe or moderate MCs that is not immediately life threatening, preferred over cyclophosphamide for many patients. ^[4] Doses and evidence: ^[4]

• 375 mg per m2 intravenously once weekly for 4 weeks (lymphoma-derived regimen), or 1 g on day 1 and day 14.
• Low dose: 250 mg per m2 weekly for 2 weeks, which GISC considers equally effective in selected (non-life-threatening) cryoglobulinaemic vasculitis (one phase II study of 250 mg/mq weekly for 2 weeks produced an 85% response; other observational cohorts reported 80% and 70.96%). ^[4]
• High doses are preferred for rapidly progressive glomerulonephritis, acute motor neuropathy and life-threatening presentations. ^[4]
• Pre-medicate according to infusion protocol; infusion reactions are uncommon and severe reactions rare. ^[4]
• HBV: screen before rituximab and give prophylaxis or close HBV-DNA monitoring; reactivation can be life threatening. ^[4]
• Retreatment at relapse achieves complete remission in about one third and partial response in about another third (overall response about 66%); mean time to retreatment 22.3 months. ^[4]
• Rituximab is steroid-sparing: 7 of 8 steroid-treated patients were able to reduce or stop steroids shortly after starting 375 mg/m2 weekly for 4 weeks. ^[4]
• HCV: rituximab alone does not usually reactivate hepatitis clinically, although transient rises in HCV RNA can occur; combine with antivirals when possible. ^[4]
• Serious adverse event rates were similar to controls in meta-analysis; use caution with repeated courses and with cardiovascular comorbidity. One uncentred cohort had more serious events with 375 mg/m2 weekly for 4 weeks than with 1 g 2 weeks apart. ^[4]

Life-threatening cryoglobulinaemia or hyperviscosity: plasmapheresis, high-dose corticosteroids, cyclophosphamide (or rituximab) and chemotherapy as indicated, introduced promptly. ^[3]

Plasmapheresis in cryoglobulinaemia (ASFA 10th special issue, 2026): TPE is an ASFA category II indication for symptomatic severe disease (grade 2A); immunoadsorption is category II, grade 2B. ^[2]

• Removes cryoglobulins efficiently; use as a bridge because TPE does not stop production. ^[2]
• Best for acute moderate to severe disease with kidney impairment (often membranoproliferative glomerulonephritis), peripheral neuropathy, arthralgia or ulcerating purpura. ^[2]
• Technical: warm the room, draw/return lines and replacement fluid to avoid precipitation in the circuit; volume 1 to 1.5 total plasma volumes (IA 2 to 2.5); every 1 to 3 days; replacement fluid albumin (IA/DFPP not applicable). ^[2]
• Duration: 3 to 8 procedures for acute symptoms, then re-evaluate; weekly to monthly maintenance can follow an initial response. ^[2]
• Cryocrit is not a marker of disease activity and must not be used to start or stop apheresis. ^[2]
• In HBV/HCV, cyclophosphamide may increase viral replication, which is why antivirals are combined. ^[2]

Supportive measures for all patients: protect from cold (gloves, warm environment), wound care for ulcers, neuropathic pain treatment, blood pressure and renal protection, and malignancy surveillance.

• Untreated HVS: death from haemorrhage, coma or heart failure.
• HVS-related retinal damage, including bilateral central retinal vein occlusion; most recover with TPE if treated.
• Acquired von Willebrand deficiency with very high IgM causing bleeding.
• Cryoglobulinaemia complications: membranoproliferative glomerulonephritis and renal failure; digital gangrene; irreversible peripheral neuropathy; lymphoma transformation in both MoCs and MCs (especially cryoglobulinaemic vasculitis with Sjogren overlap).
• Treatment complications: IgM flare after rituximab (30 to 70% at 4 weeks, TPE before if viscosity above 3.5 cP or IgM above 4 g per dL); HBV reactivation; transient HCV viraemia; infusion reactions (very rarely severe); infusion-associated hypotension or fluid shifts after IgG-related exchange.

Gertz notes that hyperviscosity itself does not affect overall survival, and patients with very high IgM but no symptoms can remain untreated for years (median 9 years to frontline therapy in one asymptomatic cohort). ^[1] Prognosis in cryoglobulinaemia depends on the underlying cause and on renal or neurological involvement: glomerulonephritis increases mortality about 3-fold. ^[4] Relapses are frequent, particularly in MCs, and repeated rituximab courses are effective. ^{[4] [3]}

• Do not treat asymptomatic viscosity numbers alone; the patient, not the laboratory value, is the indication. ^[1]
• In WM with IgM above 6000 mg per dL, assess for HVS even without a viscosity measurement.
• Before rituximab in a paraprotein disorder: check IgM and viscosity; use prophylactic TPE if viscosity is above 3.5 cP or IgM is above 4 g per dL.
• Screen every new cryoglobulinaemia patient for HCV and HBV; vaccinate as appropriate to local practice.
• Repeat cryoglobulin testing when the presentation is typical even if the first sample is negative.
• Cold avoidance and infection prevention in established MCs.

• Pregnancy. WM may present or worsen during pregnancy; maternal/fetal management requires obstetric, haematology and apheresis input. Pregnant patients who cannot receive systemic therapy may be managed with maintenance TPE. ^[2]Evidence in cryoglobulinaemia during pregnancy is limited; multidisciplinary care is needed.
• Older adults. Cardiovascular comorbidity makes rituximab and high-dose steroids riskier; start low and reassess. ^[4]
• HIV-related cryoglobulinaemia is recognised; treat the HIV and manage vasculitis as above.
• Children are rarely affected by type I disease; immunosuppressive decisions should be specialist-led.

• Diagnosis can be made without a viscometer: clinical triad plus paraprotein and a fundoscopic examination with venous sausaging. ^[1][2]
• If plasmapheresis is unavailable, prioritize rapid access to a centre, high-dose systemic therapy (bortezomib-based regimens work quickly), hydration and high-dose corticosteroids; manual plasma exchange is a poor substitute and only to be attempted by experienced teams. ^[1]
• In cryoglobulinaemic vasculitis without TPE available, use rituximab or cyclophosphamide with steroids for severe disease, and antiviral therapy for HCV/HBV where accessible.
• Cryocrit handling requires a 37 degree C water bath for collection and storage; if it is not possible, clinical diagnosis plus complement and serology will usually guide treatment.
• Ensure all biopsies reach histopathology.

Waldenstrom macroglobulinaemia and amyloidosis (T-0247); multiple myeloma; monoclonal gammopathy of undetermined significance; membranoproliferative glomerulonephritis; hepatitis C virus infection; B-cell non-Hodgkin lymphoma.

• HVS is thickened blood from a raised paraprotein, most often IgM in WM, and is an emergency.
• The clinical triad is bleeding, visual change and neurological dysfunction; fundoscopy is the key bedside test.
• Viscosity or paraprotein thresholds suggest HVS, but the patient and the examination make the diagnosis, not a single laboratory value.
• Plasmapheresis rapidly lowers viscosity; each exchange removes 20 to 30% and 1 to 2 exchanges usually suffice for IgM disease.
• TPE is only a bridge: start systemic therapy within weeks because IgM rebounds by 3 to 5 weeks.
• Rituximab can flare IgM in 30 to 70% of patients in the first 4 weeks; use prophylactic TPE if viscosity is above 3.5 cP or IgM is above 4 g per dL.
• Whole-blood hyperviscosity is a different problem (polycythaemia, leukostasis) and is treated with phlebotomy and cytoreduction.
• Cryoglobulinaemia is immunoglobulin precipitation below 37 degrees C; separate the laboratory finding from the syndrome.
• Type I (monoclonal) causes non-inflammatory vascular occlusion and is tightly linked to lymphoid neoplasms; mixed (type II/III) is immune-complex leukocytoclastic vasculitis and is most often HCV-driven.
• In type I disease, 87% of patients in one series were symptomatic, with ulcers or gangrene in 34% and GN in 14%.
• In mixed disease, the triad is purpura, weakness and arthralgia; glomerulonephritis in 20 to 30% (triples mortality) and ulcers in 25 to 30%.
• Treatment of cryoglobulinaemia treats cause (DAAs with over 90% SVR; nucleos(t)ide analogues in HBV with up to 80% remission by 6 to 12 months) plus vasculitis (rituximab 375 mg per m2 weekly x 4, or 1 g day 1 and 14, or 250 mg per m2 weekly x 2 in selected cases). ^[2]
• Plasmapheresis in cryoglobulinaemia (ASFA category II) is a bridge for severe disease (RP-GN, severe neuropathy, widespread vasculitis, hyperviscosity, extensive skin necrosis); 3 to 8 acute exchanges every 1 to 3 days.
• True hyperviscosity is very rare in mixed cryoglobulinaemia; a very high cryocrit can be asymptomatic.