Chapter 169. Cryoglobulinemia and Cryofibrinogenemia

Epidemiology

Cryoglobulinemia may be a symptomless phenomenon that is incidentally found, or it may produce a clinical syndrome involving the skin as a primary organ. In a historic large-scale examination, 11% of patient sera were shown to have cyoglobulinemia, but detection rates vary greatly with the patient population studied.1 Reliable figures on the incidence or prevalence of cryoglobulinemia or symptomatic cryoglobulinemic syndrome are lacking. The epidemiologic study is hampered by factors such as selection bias from the referral of patients to tertiary care hospitals, by the heterogeneity of clinical presentations inclusion criteria, and by the different geographic distribution of underlying etiologies such as HCV infection. There is a geographic predominance of cryoglobulinemia in Southern Europe as compared to Northern Europe or the United States that might be explained by this latter fact. The frequency distribution of different cryoglobulinemia subtypes among all types of cryoglobulinemia is approximately type I 25%, type II 25%, type III 50%, making the mixed cryoglobulinemias (types II and III) the most abundant form.2 The vast majority (>90%) of mixed cryoglobulinemias occurs in association with chronic HCV infection. Thus, HCV-associated mixed cryoglobulinemia is the form among all cryoglobulinemias that has been studied best. On average, 30% of chronically HCV-infected subjects develop cryoglobulinemia, and this proportion can go up to 90% when patients with very longstanding disease are examined.3–5 Development of cryoglobulins is more frequent with HCV genotype 1 as compared to genotypes 2 and 3.6 However, on average, the symptomatic cryoglobulinemic vasculitis syndrome is present in only 2% to 5% of chronically HCV-infected patients7 though figures as high as 15% have been proposed.8,9 With a conservatively estimated prevalence of chronic HCV infection of ∼1% in mind,10 the calculated prevalence of HCV-associated cryoglobulinemic vasculitis in the USA would be 20–50 per 100,000. The true prevalence is probably on the lower end of this estimation. Given the increasing proliferation of HCV infection worldwide, rising figures might be expected on a global perspective.11 The prevalence of “essential mixed cryoglobulinemia,” i.e., mixed cryoglobulinemia without an identifiable cause, has been estimated to be 1:100,000 in former studies, with a female-to-male ratio of 3:1. However, this number is difficult to interpret since many cases that are nowadays recognized to be associated with HCV or other viruses were formerly attributed to be “essential.”12

Etiology and Pathogenesis

In 1933, Wintrobe and Buell first noted the in vitro phenomenon of cryoprecipitation, i.e., the cold-induced precipitation of plasma or serum proteins that is reversible upon rewarming at 37°C (98.6°F).13 In 1947, Lerner and Watson described immunoglobulins and mixtures of immunoglobulins with other proteins that precipitate in the cold and called them cryoglobulins.1 In 1974, Brouet introduced the classification of cryoglobulins based on molecular properties that is currently used.2 Cryoglobulinemia describes the presence of cryoglobulins in a patient's serum (see Fig. 169-1). It can be asymptomatic, meaning that its presence usually goes undetected outside academic study screening protocols, or it can cause occlusive vasculopathy or the so-called cryoglobulinemic syndrome, which is characterized by immune-complex deposition causing vasculitis that involves the skin and mainly neural and renal tissues.

The classification scheme of Brouet, estimated frequency and composition of cryoglobulins is depicted in Table 169-1. Type-I cryoglobulins consist of a single monoclonal immunoglobulin (Ig), typically IgM, less commonly IgG or IgA or free Ig light chains (Bence Jones proteins). Complement components are not routinely found in type I cryoprecipitates. Type I cryoglobulins are often present in substantial amounts, ranging from 1 to 30 mg/mL. The large molecular size of monoclonal IgM and other molecular characteristics, such as absence of sialic acid moieties, deficient carbohydrate side chains, and weak noncovalent factors may predispose these Igs to precipitation.14 Type I cryoglobulinemia is associated with hematologic disorders, such as Waldenström macroglobulinemia, multiple myeloma, or lymphoproliferative diseases (e.g., B-cell lymphoma).

Type II and type III cryoglobulins are immune complexes composed of polyclonal IgGs and mono- or polyclonal IgMs. Type II and type III cryoglobulins are typically present in relatively small amounts and generally result from chronic inflammatory states. Type II and type III cryoglobulins may fix complement.

Type II cryoglobulins represent a mixture of two Ig components: polyclonal Igs are associated with a monoclonal Ig that exhibits rheumatoid factor (RF) activity. Typically, a monoclonal IgM RF is complexed with a polyclonal IgG. HCV infection is the classical underlying disease.

A mixture of polyclonal Igs or polyclonal Ig-nonimmunoglobulin cryoprecipitates results in detection of type III cryoglobulins. Polyclonal IgM–IgG cryoglobulins with complement as an integral component are the most frequent scenario in type III cryoglobulinemia that is commonly associated with HCV infection or connective tissue diseases.

A new type of cryoglobulins, called type II–III cryoglobulin, containing polyclonal IgG associated with a mixture of polyclonal and monoclonal (oligoclonal) IgM has recently been described.15 This type of cryoprecipitate describes an intermediate, developing state between types III and II, suggesting a continuous transition from a purely polyclonal to a partially monoclonal composition by a process of successive clonal selection.

Types II and III cryoglobulinemias are classically referred to as “mixed cryoglobulinemias”. Circulating mixed cryoglobulins are commonly detected in a great number of infectious or systemic disorders (see Table 169-1). The term “essential” is originally reserved for instances of mixed cryoglobulinemia in the absence of a well-defined underlying disease and, given the striking association between mixed cryoglobulinemia and HCV, is actually referred to only a minority of cryoglobulinemic patients.

Prevalence of serum anti-HCV antibodies and/or HCV RNA in cryoglobulinemic patients ranges from 70% to 100%. Type II cryoglobulinemia is more strongly associated with HCV than type III (90% vs. 70%, respectively). Presence of cryoglobulins increases with duration of HCV infection: cryoglobulins are found in 55%–90% of patients with longstanding infection. However, overt cryoglobulinemic syndrome develops in only 2%–5% of these cases (see also Section “Epidemiology”). The precise role of viral or host factors contributing to this discrepancy remains largely unknown. Specific HCV genotypes or distinct HLA subtypes, like HLA-DR11 or HLA-DR6 may predispose to extrahepatic systemic manifestations of cryoglobulinemia.16,17 Pathogenesis of mixed cryoglobulinemia is probably a multifactorial and multistep process. Viral HCV antigens exert a chronic stimulus on the host immune system, resulting in specific immune dysregulatory mechanisms with B-cell proliferation and autoantibody production. HCV-related B-cell lymphoproliferative disorders comprise a spectrum of disease, ranging from asymptomatic clonal B-cell expansions to pathogenic cryoglobulinemia and lymphoma.18 From that perspective, HCV-associated mixed cryoglobulinemia is a benign lymphoproliferative B-cell disease with a potential for subsequent development of B-cell lymphoma.19,20 Development of HCV-associated cryoglobulinemic vasculitis syndrome is associated with longstanding infection, old age, type II cryoglobulins, higher cryoglobulin levels, and clonal B-cell expansion.21,22

The group of non-HCV-induced mixed cryoglobulinemias is small. The following associations have been described: An association of cryoglobulinemia with various other infectious viral agents, for example, hepatitis B virus, cited as a major causative agent,23 and HIV with or without HCV coinfection has also been demonstrated.24 Parvovirus B19 has been implicated in a mild form of cryoglobulinemic syndrome.25 Another important association is the one with Sjögren syndrome. According to one study, 16% of patients with primary Sjögren syndrome had cryoglobulins, and of those, 56% had cryoglobulinemic syndrome.26,27 A study by the same group found cryoglobulinemia in 25% of patients with systemic lupus erythematosus.28

Clinical Findings

Approach to the Patient

In almost all cases, the possibility of a diagnosis of cryoglobulinemia or cryoglobulinemic syndrome is primarily suggested by the presence of purpura of the distal extremities or by acral cyanosis and necrosis, depending on the potential presence of type I or types II and III cryoglobulinemia. Alternatively, the potential diagnosis may be suggested by the presence of a candidate underlying disease. A targeted review of systems and subsequent clinical examination will guide the physician towards the entire picture of organ involvement or differential diagnoses. The laboratory panel must include parameters relevant to both cryoglobulinemia and important differential diagnoses. Box 169-1 presents an algorithm for the diagnostic approach to the patient, including laboratory testing. eTable 169-1.1 summarizes the symptoms, signs, cutaneous, extracutaneous and laboratory findings of cryoglobulinemia. Of note, there are still only preliminary diagnostic criteria for the classification of mixed cryoglobulinemic patients (see eTable 169-1.2).

Cutaneous Lesions

Cutaneous lesions are the most frequent manifestations (Fig. 169-2). Type I cryoglobulinemia per se is often asymptomatic and cutaneous signs are related to hyperviscosity and/or thrombosis that induce ischemic vasculopathy presenting as Raynaud phenomenon, digital ischemia, livedo reticularis, or purpura. Type II and III cryoglobulinemic vasculitis is mediated by deposition of antigen–antibody complexes in small- and medium-sized arteries, leading to inflammation of vessel walls. Intermittent orthostatic palpable purpura, frequently observed late in the afternoon when highest cryoglobulin concentrations are present, is the most common presentation and particularly affects the lower extremities.29 Dimension and diffusion of purpuric lesions can vary from sporadic isolated petechias or erythematous macules to severe vasculitic lesions with ulcerations. Leukocytoclastic vasculitis is the histopathological hallmark of mixed cryoglobulinemia and is easily detectable by skin biopsy (see Chapter 163 see also eFig. 169-2.1). Nail-fold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.

Related Physical Findings

Renal involvement is a serious complication, typically manifests early in the course of the disease and can present as a broad range of clinical findings, including hematuria with or without renal insufficiency (41%), isolated proteinuria, nephrotic syndrome (21%) or acute nephritic syndrome.30 Chronic renal insufficiency without significant renal abnormalities and acute renal failure are less common. The incidence of renal disease in cryoglobulinemia varies from 5% to 60% and is typically immune complex mediated (type II and III), but may also occur secondary to thrombosis (type I) (for details see eTable 169-1.3).

Neurological manifestations, typically affecting the sensory peripheral nervous system secondary to epineural vasculitis frequently complicate the clinical course. Patients typically describe paresthesias with burning symptoms in the lower limbs, often with nocturnal exacerbation, leading to severely compromised quality of life. Electromyographic and nerve conduction studies demonstrated peripheral neuropathy in up to 80% of patients with mixed cryoglobulinemia, but many symptom-based demographic studies report prevalence of only 5% to 45%. Peripheral neurologic disease manifests as a progressive, chronic distal mild sensory neuritis and only rarely as acute mononeuritis. Clinically apparent central nervous system dysfunction is rare.

Musculoskeletal complaints, typically arthralgias and myalgias, are described in more than 70% of persons with cryoglobulinemia, predominantly in type II and III disease. The association of cryoglobulinemia with palpable purpura, arthralgia and myalgia was referred to as Meltzer triad in the late 1960s. Arthralgias classically affect the proximal interphalangeal and metacarpophalangeal joints of the hands, the knees, and ankles. Clear clinical signs of myositis or arthritis are rare.

Abnormal liver function tests, hepatomegaly including signs of cirrhosis or abnormal histological results in liver biopsy were reported in up to 90%. Also, thyroid disorders and diabetes mellitus seem to be associated with cryoglobulinemia.39

Unspecific abdominal pain can affect 2% to 22%. Intestinal vasculitis of the small mesenteric vessels leading to acute abdomen has been reported.

Approximately 40% of patients are symptomatic with dyspnea, cough, or pleuritic pain. Pulmonary function tests often reveal evidence of small airways disease and chest radiographs sometimes show interstitial infiltrates or signs of subclinical alveolitis. Severe pulmonary disease, for example, bronchiolitis obliterans organizing pneumonia (BOOP) or pulmonary vasculitis are very uncommon.

Hyperviscosity due to high levels of monoclonal cryoglobulins, typically seen in Waldenström macroglobulinemia and less frequently in multiple myeloma, can induce microcirculation impairment and reduced platelet function, leading to skin and mucosal bleeding. A variety of neurologic symptoms have been reported in hyperviscosity syndrome: blurring or loss of vision, headache, vertigo, nystagmus, dizziness, sudden deafness, diplopia, ataxia, confusion, dementia, disturbances of consciousness, stroke, seizures, somnolence or coma. A characteristic retinal venous engorgement (“sausaging”) on funduscopic inspection can serve as a diagnostic clue.

Laboratory Tests

In clinical practice, cryoglobulin testing is underutilized, most probably due to the expenditure of time and stringent temperature requirements.

Serum must be obtained in warm tubes (37°C) in the absence of anticoagulants. After clotting and centrifugation at 37°C, the separated serum is stored at 4°C and inspected daily for a precipitate. Type I cryoglobulins tend to precipitate within the first 24 hours (at concentrations >5 mg/mL), whereas type III cryoglobulins may require 7 days (see Fig. 169-1). For calculation of cryocrit (volume of packed cryoglobulins as percentage of original serum volume), the cryoprecipitate has to be spun in a graded (e.g., Wintrobe) tube. A cryocrit ≥2% is considered to be positive. Cryocrit levels usually do not correlate with severity and prognosis of disease.

Some authors recommend proof of reversibility of the cryoprecipitate by rewarming an aliquot at 37°C for 24 hours.12 For phenotyping and identification of cryoglobulin components specific immunologic assays are performed at 37°C.

Clinical diagnosis of hyperviscosity can be established by measuring serum viscosity with an Oswald-type viscometer. Reference serum viscosity, measured as flow time through the viscometer of the patient's serum divided by that of water or saline, is between 1.4 and 1.8, while most symptomatic patients have values between 5 and 8. Again, clinical manifestations are often not proportional to serum viscosity.

As hypocomplementemia (with the typical pattern of low or undetectable C4 and normal or relatively normal C3 levels) occurs in up to 90% of patients with mixed cryoglobulinemia, C3 and C4 levels, usually measured in nephelometric immunoassays, should be routinely determined. A sudden increase in complement C4, raised to abnormally high levels can be observed in some patients developing a B-cell lymphoma.40

RF is often positive in type II and III cryoglobulinemia. Testing for antinuclear antibodies (ANAs, SS-A, SS-B) and other autoantibodies (e.g., anti-smooth-muscle Abs) is indicated upon clinical suspicion of underlying systemic connective tissue disease (e.g., SLE, Sjögren syndrome). Although the immunofluorescence ANA assay is the current diagnostic gold standard, titer and specificity of ANAs may vary considerably.

Particularly in patients with HCV-associated mixed cryoglobulinemia serum levels of IL-1β, IL-6, and TNF-α are significantly elevated.41 Increased levels of the chemokines CXCL10 and CXCL13, also known as BCA-1 (B-cell-attracting chemokine-1), seem to be associated with active vasculitis.42,43

Special Tests

Vasculitic purpura is histologically characterized by dermal leukocytoclastic vasculitis that extends variably to the subcutaneous interstitial space (Cross-reference leukocytoclastic vasculitis). For detailed histological findings in leukocytoclastic vasculitis (e.g., composite of inflammatory infiltrates) see Figure X, Section Leukocytoclastic Vasculitis. Deposition of immunoglobulin, complement and HCV-associated proteins in mixed cryoglobulinemia is common. Abnormalities of uninvolved skin include basement membrane alterations and deposits in vessel walls.

Membranoproliferative glomerulonephritis type I (MPGN I) is responsible for 80% of all renal lesions in essential mixed cryoglobulinemia (see eFig. 169-2.2). Histology shows both thickening of the glomerular basement membrane and cellular proliferation. Specific renal findings for cryoglobulin-induced renal disease include (i) intraluminal thrombi composed of precipitated cryoglobulins on light microscopy, (ii) diffuse IgM deposits in the capillary loops on immunofluorescence microscopy, and (iii) subendothelial deposits on electron microscopy. Autopsy studies have showed unsuspected vasculitis of multiple organs, with a typical eosinophilic material in the lumen of small vessels with frequent extension into the vessel intima and inflammation of the vessel wall.

Differential Diagnosis

Starting from the symptom of purpura all small vessel cutaneous vasculitides, especially those involving the histopathological picture of leukocytoclastic vasculitis must be considered in the differential diagnosis of mixed cryoglobulinemia. Major differential diagnosis of vasculopathy, typical for type I cryoglobulinemia, includes diseases causing Raynaud syndrome, acrocyanosis, and acral ischemia.

See Box 169-2 for a complete overview on differential diagnosis of cryoglobulinemia (and cryofibrinogenemia).

Complications

Acute severe complications directly caused by cryoglobulins are rare with any type of cryoglobulinemia. The organs most vulnerable to complications are the nervous system and the kidneys. In Type I cryoglobulinemia, they are mostly related to an acute vaso-occlusive crisis caused by increased serum viscosity leading to acute acral ischemia and to cerebral and renal ischemia causing stroke or acute renal failure. In addition, the underlying hematologic disease of type I cryoglobulinemia can directly cause renal failure (e.g., myeloma kidney); see also eTable 169-1.3. At advanced stages, complications are defined by the underlying hematologic disease itself: immunosuppression leading to infection and sepsis, coagulation disorders with severe bleeding, and side effects of hematologic disease-specific treatments. Mixed cryoglobulinemic vasculitis may involve the peripheral nerves leading to life-threatening situations or cause acute-on-chronic renal failure. Again, advanced stages of the underlying disease (mostly hepatitis C or other types of liver disease) can result in acute liver failure or problems associated with hepatic insufficiency, i.e., coagulation disorders, malnutrition, ascites, and the hepatorenal syndrome. Skin necrosis and vasculitic lesions can be entry sites for infection. Catastrophic individual patient courses have been described.44

Prognosis and Clinical Course

Prognosis is defined by the severity of the cryoglobulinemic syndrome and by the treatability of the underlying disease causing cryoglobulinemia. In type I cryoglobulinemia this will depend on the nature and stage of the hematological disease. A favorable prognosis in a patient with type I cryoglobulinemia can only be expected when control of the underlying disease can be achieved. In type II cryoglobulinemic vasculitis, data suggest that prognosis is generally benign in 50% of cases, but 30% have a moderate to severe course, especially because of renal and/or hepatic insufficiency. Consequently, 10-year-survival rates are significantly lower than in the normal population.29,45,46 These data integrate a heterogeneous population that includes hepatitis C-associated cases that were treated by differing approaches ranging from symptomatic steroid therapy to antiviral treatment. It can be expected, however, that prognostic outlook will improve in the future since currently used antiviral treatment aimed at elimination of hepatitis C infection may cure or completely control HCV-associated mixed cryoglobulinemic vasculitis. In these patients, complications and side effects of antiviral treatment and the course of underlying hepatic disease will have a major impact on prognosis.47

Renal involvement is a poor prognostic sign in patients with cyroglobulinemic vasculitis with 15% progressing to end stage renal disease (ESRD).29 MPGN I from any cause including noncyroglobulinemic ones has a poor prognosis: 50% of patients progress to ESRD within 10 years. Small studies report successful treatment of MPGN I by antiviral strategies.48,49 The prognosis of cryoglobulinemia with no identified underlying disease (essential mixed cryoglobulinemia) is not well predictable, and, again, renal involvement is associated with poor prognosis (renal failure in 10% of patients).50 The spectrum of renal disease in non-HCV mixed cryoglobulinemia has been recently studied.51

Treatment

Generally three levels of treatment can be considered when treating cryoglobulinemia: (1) etiologic treatment, which is aimed at the cure or safe containment of the underlying disease; (2) pathogenetic treatment, which is aimed at reducing the production of cryoglobulins while the underlying etiology remains untreated; and (3) symptomatic treatment that is aimed at reducing the cryoglobulin burden by removal from plasma or at mitigating the tissue's vasculitic reaction. Sometimes a combination of these approaches is used. The decision for initiation of a therapy should be informed by the severity of the symptoms with benefits outweighing risks. Cryoglobulinemia without symptoms does not justify treatment, unless there is an underlying condition that merits therapy. eTable 169-1.4 summarizes all available approaches, while integrated therapeutic concepts for typical clinical situations are presented here.

Type I Cryoglobulinemia

Etiologic treatment is the treatment of choice. The underlying hematologic disease, typically multiple myeloma, Waldenström macroglobulinemia or lymphoma must be treated with chemotherapy directed by a hematologist according to current standards of care. In addition to this, severely symptomatic hyperviscosity syndrome of type I cryoglobulinemia can be reduced by repeated plasma exchange or by cryofiltration (see eFig. 169-2.3). This may be necessary as a bridging therapy until therapy of the underlying disease shows an effect. In plasma exchange, the patient's plasma is removed by an apheresis membrane and substituted using approximately 3.5 L of donor plasma per session. Cryofiltration operates by passing the cooled patient's plasma through a specialized membrane unit designated at the removal of cryoprecipitates without necessitating plasma substitution. However, this latter approach may be hampered by rapid clogging of the membrane in the setting of high cryglobulin concentrations. In severe cases of type I cryoglobulinemia, it may be necessary that these removal procedures be performed daily over a period of two weeks or more. Intriguingly, the occurrence of plasmapheresis rebounds in disease activity has also been described.

HCV‐Associated Type II and Type III Cryoglobulinemia in Patients with Mild‐to-Moderate Disease

The primary therapeutic approach depends on disease severity. Patients with mild-to-moderate cryoglobulinemic vasculitis without major organ failure are best treated using antiviral agents. While the effects of the treatment exhibit some delay, the approach has the advantage of offering a potentially complete and sustained remission of the vasculitic syndrome. This has been shown by a series of pioneering studies employing regimens of interferon alone or in combination with ribavirin in patients with HCV and cryoglobulinemia.55–63 Among those therapeutic regimens, the highest response rates were found using the current gold standard of therapy, PEGylated interferon α-2b and ribavirin55,62: recovery of purpura 87.5%, recovery of arthralgia 82%, recovery of peripheral neuropathy 74%, and recovery of nephropathy 50%. The rate of sustained viral response was similar to large patient study populations without cryoglobulinemia: 62.5%. The regimen is detailed in the current statements on the management of hepatitis C of the American Gastroenterological Association,64,65 and it is briefly described in eTable 169-1.4. There are several limitations of antiviral combination therapy. Applicability in renal insufficiency is reduced due to drug accumulation. Recommendations for dosage adjustment have been published in the current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines of 200866 and are summarized in eTable 169-1.5. While ribavirin is contraindicated at an estimated GFR <50 mL/min, it is a desirable drug rendering interferon therapy markedly more powerful.62,64 Therefore a dosage regimen guided by plasma levels has been proposed that could allow for off-label administration in settings of a GFR <50 mL/min.67 The contraindications and side effects of antiviral combination therapy are summarized in eTable 169-1.6. Of note, ribavirin can cause hemolytic anemia requiring pausing or dosage adjustments. If in doubt, collaboration with a hepatologist and a nephrologist is recommended in order to apply this most promising of all approaches in HCV-related mixed cryoglobulinemic syndrome to as many eligible patients as possible.

HCV-Associated Type II and Type III Cryoglobulinemia in Patients with Severe Disease

In the case of organ failure such as overt renal failure, possibly accompanied by the nephrotic syndrome or neuropathy, initial pathophysiologic and symptomatic therapy are required in order to achieve a reasonably rapid response. Traditionally, an immunosuppressive combination therapy using steroids possibly followed by cyclophosphamide, azathioprine, or chlorambucil have been used.68 Off-label use of the chimeric anti-CD20 (see also eTable 169-1.4.) antibody, rituximab has recently emerged as a powerful alternative to classic immunosuppression.69 The antibody targets B-lymphocytes leading to a depletion of 95% of the B-lymphocytic population. Thereby, the cryoglobulin-producing B lymphocytic clone is markedly reduced leading to marked cryoglobulin level reduction and consecutive remission. Taken together, this represents a pathophysiological approach to treatment (see eTable 169-1.4). Since the B-cell depletion is only transient after one course, a relapse will usually occur.70 As with classic immunosuppression, the therapy may lead to increased viral loads of HCV.70 For long-term effects, repeated dosages of rituximab or maintenance therapy using classic immunosuppression would be required. The best option is to use these strategies to reduce acute cryoglobulinemic disease burden in order to bridge patients to a state where antiviral treatment, as outlined above, can be safely initiated.68 Cases of successful remission of severe disease allowing for subsequent safe antiviral combination therapy have been reported.71,72 As a bridging therapy, plasma exchange and cryofiltration can also be applied (see Section “Type I Cryoglobulinemia” for details). Though reported to be generally well tolerated in patients with cryoglobulinemic syndrome, rituximab has several limitations. It cannot be used in patients with overt skin ulceration due to interference with wound healing. Progressive multifocal leukencephalopathy under rituximab has been reported.69 A recent report has pointed to a severe complication with worsening of cryoglobulinemic vasculitis syndrome on rituximab.73 Yet, given the enormous potential of rituximab, the NIH has initiated a clinical research study on rituximab for the treatment of HCV-associated cryoglobulinemic vasculitis (Protocol number: 02-I-0096).

Relapse of HCV-Associated Cryoglobulinemic Vasculitis

After initial successful antiviral treatment, relapses of HCV viremia with relapse of the vasculitic syndrome have been described. The recent study by Cacoub and coworkers has concluded a protocol recommendation using another course of IFN + ribavirin in combination with rituximab to address this problem.72 Another scenario of relapse after successful antiviral treatment has been described in one study where only the cryoglobulinemic vasculitis syndrome, but not the viremia reoccurred.74 Such a scenario would call into question the concept of HCV as a cause for cryoglobulinemic vasculitis. However, in two-thirds of the study's patients, B-cell lymphoma was found on follow-up. This stresses the pivotal role of HCV in inducing B-cell lymphoma, as its occurrence is elevated 35-fold in patients with chronic HCV infection,19,20 and stresses the importance of close medical follow-up in patients with a relapse of vasculitis despite successful clearance of the virus.

Type II and Type III Cryoglobulinemic Vasculitis Not Associated with HCV

In type II and III cryoglobulinemic vasculitis not associated with HCV classic immunosuppression using steroids and possibly steroid-sparing agents as outlined in eTable 169-1.4 continues to represent a major therapeutic approach. However, successful treatment has also been reported using rituximab.69

In any case, careful monitoring for development of B-cell lymphoma should be conducted which then would lead to specific treatment. Likewise specific treatment of the underlying disease remains key. Symptomatic therapy may also include nonsteroidal anti-inflammatory drugs.

Epidemiology

Cryofibrinogenemia is often clinically asymptomatic. Of note, 2% to 9% of healthy persons may have demonstrable amounts of cryofibrinogen, usually in concentrations less than 50 mg/L. In the past, cryofibrinogenemia was considered rare, but recent single-center studies indicate that this disorder is possibly underrecognized due to (1) the infrequency with which it causes symptoms and (2) inconsistencies in laboratory investigations producing falsely negative results. Initial studies noted the prevalence of cryofibrinogenemia among hospitalized patients between 3.4% and 13%, with a female (female–male ratio 4:1) but without age or racial prediction. In a study by Saadoun and coworkers, 2,312 hospitalized patients were tested for cryofibrinogenemia between 1996 and 2006.75 A total of 515 (22.2%) patients had positive test results, of whom 88% had secondary and 12% had essential cryofibrinogenemia. Another retrospective single hospital 10-year report identified 61 patients having cryofibrinogenemia, which was essential in 18 (29.5%) and secondary in 43 (70.5%) patients.76

Etiology and Pathogenesis

Precipitation of patients’ native fibrinogen or fibrin by-products in plasma, but not serum, was first described by Korst and Kratochvil in 1955.77 The so-called cryofibrinogenemia can be classified as primary (also named essential or idiopathic) or secondary. Diagnosis of primary cryofibrinogenemia requires the presence of cryofibrinogens in plasma, absence of cryoglobulins, and one or more compatible clinical features (e.g., cold-induced thromboses, increases in blood viscosity and/or vascular reactivity) in an otherwise healthy individual. Some authors hypothesize that essential cryofibrinogenemia might be a prerequisite for a secondary disease.

Secondary cryofibrinogenemia is diagnosed when an associated disease or drug is present. The most frequently associated disorders include malignancy, infections, connective tissue and autoimmune diseases (see Table 169-2).

Cryofibrinogen is characteristically composed of fibrinogen, fibrin, fibronectin and/or fibrin degradation products. Other components include albumin, cold insoluble globulin, factor VIII, and plasma proteins as well as the plasmin activity inhibitors α1-antitrypsin, and α2-macroglobulin. Pathology in cryofibrinogenemia is attributed to “in situ” thrombosis, leading to thrombotic occlusion of small- and medium-sized dermal vessels and resultant ischemia. Defects in the fibrinolysis process might lead to further clotting in small and medium arteries. Additional immunologic mechanisms may play a significant role in the pathophysiology of cryofibrinogenemia.

Some people with cryofibrinogenemia are asymptomatic, while others have clinical features resulting from thrombosis that can be life threatening when untreated.

Secondary forms of cryofibrinogenemia are significantly more frequent in patients with combined cryofibrinogenemia and cryoglobulinemia than in those with isolated cryofibrinogenemia (79 vs. 47%).78 Among HCV-infected patients, cryofibrinogenemia is common, and closely correlated with cryoglobulinemia: in a study of 143 patients with HCV infection, 53 (37%) had cryofibrinogen levels >50 mg/L. Forty-seven of these cryofibrinogen-positive patients (89%) had positive tests for cryoglobulins.79

Clinical Findings

Approach to the Patient and History Taking

Patients with cryofibrinogenemia typically report a temporal association between cold exposure and onset of symptoms. Nonspecific general complaints of fever and malaise are common. For all patients with cryofibrinogenemia, age-appropriate malignancy screening and evaluation for possible underlying infection or systemic inflammatory disease are indicated. However, diagnostic workup should always be directed by the patient's clinical presentation.

Cutaneous Lesions

Clinical signs in cryofibrinogenemia are mostly cutaneous and are typically located on cold-exposed areas (hands, feet, buttocks, ear, nose). These cold-sensitive lesions often reflect cold-induced thromboses, increased viscosity, and/or vascular reactivity. Palpable purpura with underlying leucocytoclastic vasculitis is the most frequent clinical presentation. Other cutaneous features can include painful ulcerations, livedo racemosa, Raynaud phenomenon, segmental swelling, lower extremity nodules, painful or pruritic erythema (perniosis) of the extremities and cold urticaria. Cryofibrinogenemia may clinically simulate calciphylaxis, presenting normally in patients with end-stage renal disease (ESRD).

Related Physical Findings

Cryofibrinogenemia has a broad spectrum of clinical manifestations including vessel, kidney, musculoskeletal and/or neuronal involvement. Various thrombotic events, nephritic or nephrotic syndrome, arthralgia, myalgia, multineuritis, and fever have been reported.80 In a recent study, main clinical manifestations included purpura (46.6%), skin necrosis (36.6%), and arthralgia (31.6%) with cold sensitivity in 40% and overall thrombotic events occurring in up to 40% of cases. A high cryofibrinogen plasma concentration was a significant predisposing factor for thrombotic events.75 Thrombotic events include cerebrovascular accidents (stroke, ocular thrombi including retinal arterial and/or venous occlusions), myocardial infarction, limb and bowel ischemia or infarction, and pulmonary emboli, although a causal relationship has not been proven for all described cases.81

Laboratory Tests

Laboratory workup is critical for the accuracy of cryofibrinogen detection, and ideally includes separation in a temperature controlled centrifuge (see also Section “Laboratory Tests” under “Cryoglobulinemia”).

The warm blood specimen should be anticoagulated with citrate, EDTA or oxalate, but not heparin, that nonspecifically precipitates fibrinogen. After centrifugation at 37°C, the plasma is placed in a Wintrobe tube, refrigerated at 4°C and observed for the formation of a precipitate for 72 hours. The cryocrit is quantitated by centrifuging the specimen while it remains cooled to 4°C. Each millimeter of visible precipitate in the Wintrobe tube represents 1% of cryocrit.

In parallel, a cryoglobulin test is simultaneously performed in a sample without anticoagulants, to ensure that the plasma precipitate is cryofibrinogen and not cryoglobulin.

Affinity-chromatography, immunodiffusion and/or electrophoresis are used for quantitation and/or identification of the individual cryofibrinogen components.

Special Tests

Histological Features

Irrespective of the anatomic site, cryofibrinogenemia shows an occlusive thrombotic diathesis comprising eosinophilic refractile deposits within vessel lumina with extension into the vessel intima, with or without an accompanying characteristic granulomatous vasculitic component.76,82 Cryofibrinogen precipitates have a cylindrical configuration in ultrastructural analysis, which is often displayed within the vessel lumina. Examination of renal deposits showed fibrillary material within glomerular capillary lumina and tubules with unique morphologic features not previously described.80

Complications

Typical complications due to thrombotic events include gangrene (5%), septicemia (5%), and leg amputation (3.3%).75 In some cases essential cryofibrinogenemia might be a prerequisite for a secondary disease, particularly lymphomas83: in a 2008 report, 27% of patients with primary cryofibrinogenemia developed lymphoma after a 5-year follow-up period.76

Prognosis/Clinical Course

Clinical data regarding prognosis in cryofibrinogenemia are limited. In one study, 3 out of 60 patients with essential cryofibrinogenemia died after a mean follow-up of 85 months.

Treatment

Smoking cessation, avoidance of cold exposure and eliminating the use of vasoconstricting drugs are nonpharmacologic interventions that are recommended, but are only partially effective. In secondary cryofibrinogenemia, specific treatment of the underlying disease can lead to improvement in related symptoms.

For essential cryofibrinogenemia, various pharmacological agents including fibrinolytic approaches and immunosuppressive agents have been proposed. Oral stanozolol (2–4 mg twice daily), a synthetic derivative of testosterone with substantial fibrinolytic properties, has been effective after several days of treatment.84 Streptokinase (sometimes in combination with streptodornase), given intravenously (e.g., 25,000–200,000 U/day) has a more rapid onset of action than stanozolol. Recently, the use of colchicine (0.6 mg twice daily) in combination with high-dose pentoxifylline (800 mg three times daily) has been described.85

Combinations of glucocorticoids (e.g., prednisone 10–60 mg/day) with other immunosuppressive agents (e.g., azathioprine 150 mg/day or chlorambucil 10 mg/day) have also been used in small studies with some benefit, including successful treatment of acute attacks.

Plasmapheresis might be considered when high levels of cryofibrinogens are present, and are associated with monoclonal proteins (e.g., myeloma, Waldenström macroglobulinemia), hyperviscosity, or clinically significant thrombosis. Long-term repeated plasmaphereses and anti-immunoglobulin adsorption improved the symptoms in one patient with secondary cryofibrinogenemia.86