Laboratory guidelines for the diagnosis of patients with cryoglobulinemic syndrome

Mariscal-Rodríguez, A.; Villar Guimerans, L.M.; López-Trascasa, M.; Hernández González, M.; Moga Naranjo, E.

doi:10.1016/j.rceng.2019.01.003

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Cryoglobulins were first observed in 1933 in a patient with Raynaud's phenomenon.<a class="elsevierStyleCrossRef" href="#bib0320">4</a> In 1947, these proteins were characterized as gamma globulins and were encompassed under the term cryoglobulins.<a class="elsevierStyleCrossRef" href="#bib0325">5</a>The mere presence of cryoglobulins in blood defines the term cryoglobulinemia, while the coexistence of symptoms related to cryoglobulins is what defines the syndrome and cryoglobulinemic vasculitis.<a class="elsevierStyleCrossRef" href="#bib0330">6</a>Cryoglobulinemia is a relatively uncommon disease, with a prevalence of 1:100,000 individuals, more often affecting the female sex than the male (ratio of 3:1) and mainly in the age range of 42–52 years.<a class="elsevierStyleCrossRefs" href="#bib0335">7,8</a> The disease affects populations from southern Europe more often than those from northern Europe and America.<a class="elsevierStyleCrossRef" href="#bib0345">9</a> The prevalence is closely associated with the underlying disease, with cryoglobulins found in 16% of patients with Sjögren's syndrome,<a class="elsevierStyleCrossRef" href="#bib0350">10</a> 17% of those with human immunodeficiency virus (HIV) infection,<a class="elsevierStyleCrossRef" href="#bib0355">11</a> 25% of those with systemic lupus erythematosus<a class="elsevierStyleCrossRef" href="#bib0360">12</a> and up to 60% of those with hepatitis C virus (HCV) infection.<a class="elsevierStyleCrossRefs" href="#bib0340">8,13</a> A small percentage of cases of cryoglobulinemia are not associated with disease and are referred to as essential cryoglobulinemia.<a class="elsevierStyleCrossRefs" href="#bib0345">9,14</a>Three types of cryoglobulins have been described based on the underlying disease and type of immunoglobulin (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0345">9</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Type i cryoglobulinsThese are monoclonal components mostly of type IgM, less frequently of type IgG and rarely of type IgA or free light-chains. This type of cryoglobulin is found less frequently (10–15%)<a class="elsevierStyleCrossRef" href="#bib0375">15</a> and is associated with hematologic disease, mainly monoclonal gammopathies of uncertain significance (40%) and other B-cell line abnormalities, such as multiple myeloma, Waldenstrom macroglobulinemia and chronic lymphocytic leukemia.<a class="elsevierStyleCrossRefs" href="#bib0380">16,17</a> Type I cryoglobulinemia is generally asymptomatic; in some cases, however, the precipitation of cryoglobulins in small vessels can create vascular occlusion and subsequently progress with cold-induced hyperviscosity syndrome.<a class="elsevierStyleCrossRefs" href="#bib0330">6,8,18</a> This small-vessel vasculitis mainly affects the kidneys and skin. Renal impairment, which presents mainly in the form of glomerulonephritis, involves proteinuria, microscopic hematuria, high creatinine levels and/or hypertension and is more common in class IgG cryoglobulinemia. Skin manifestations include purpura, livedo reticularis, Raynaud's phenomenon, acrocyanosis, necrosis and ulcers and are usually limited to distal extremities (fingers, ears, nose) and after exposure to cold. Peripheral neuropathy and arthralgia are less often observed.<a class="elsevierStyleCrossRefs" href="#bib0380">16,19</a>Type ii and iiicryoglobulins (mixed)Type ii cryoglobulins consist of polyclonal IgG and a monoclonal component, typically IgM, which present rheumatoid factor (RF) activity. These cryoglobulins are detected more frequently (50–60% of patients with cryoglobulinemia). Type iii cryoglobulins consist of polyclonal IgG and IgM, the latter with RF activity. These cryoglobulins are found at an intermediate rate compared with type i and ii (25–30%).<a class="elsevierStyleCrossRef" href="#bib0375">15</a> With the arrival of more sensitive technology, such as immunoblot and two-dimensional polyacrylamide gel electrophoresis, a certain percentage of type ii cryoglobulins have been detected composed of oligoclonal IgM or a mixture of oligoclonal and polyclonal. This subgroup could be a transition state for cryoglobulinemia from type iii to type ii and has been called type ii-iii cryoglobulins.<a class="elsevierStyleCrossRefs" href="#bib0370">14,20</a>Mixed cryoglobulins are associated with chronic infections (mainly type ii) and autoimmune diseases (mostly type iii), processes that involve immune system hyperstimulation in general and antibody synthesis in particular. The closest association is between type ii cryoglobulins and HCV infection (up to 95%).<a class="elsevierStyleCrossRef" href="#bib0340">8</a>Mixed cryoglobulinemia typically progresses with symptoms of vasculitis due to the deposit in small and medium vessels of immune complexes formed mainly by immunoglobulins, antigen and complement but also possibly consisting of local hematologic factors. Given its clinical and histological characteristics, mixed cryoglobulinemia is also classified within systemic small-vessel vasculitis.<a class="elsevierStyleCrossRefs" href="#bib0345">9,21</a> Compared with type i cryoglobulinemia, mixed cryoglobulinemia presents with constitutional symptoms such as fever, weakness, myalgia/arthralgia and anorexia, a reflection of the immune complex disorder.<a class="elsevierStyleCrossRef" href="#bib0385">17</a> The most common sign is isolated purpura, found in almost 90% of patients; however, a third of these patients also experience arthralgia and weakness (Meltzer's triad).<a class="elsevierStyleCrossRef" href="#bib0410">22</a> Kidney disease and neuropathy are similar to those that occur in type i cryoglobulinemia, although small-vessel occlusion by cryoglobulin aggregates is more likely to occur in type I cryoglobulinemia. The involvement of other organs in addition to the kidneys is generally rare; when other organs are involved, however, it is almost exclusively a sign of mixed cryoglobulinemia.<a class="elsevierStyleCrossRef" href="#bib0385">17</a>The symptoms are comparable among syndromes for type ii and iii cryoglobulins<a class="elsevierStyleCrossRef" href="#bib0345">9</a>; however, the symptoms vary enormously among patients, from the asymptomatic presence of cryoglobulins in serum to full cryoglobulinemic syndrome.CryoprecipitationThe process of cryoprecipitation is not completely understood, but it is known that it differs between type I and mixed cryoglobulins. In type I, the monoclonal component crystallizes and aggregates, a process that depends on temperature and concentration. In fact, when the concentration is very high, some precipitation can occur at room temperature and within a few hours.<a class="elsevierStyleCrossRef" href="#bib0385">17</a> In mixed cryoglobulinemia, however, cryoprecipitation occurs in the context of immune complex formation between IgG and IgM and complement fixation and is affected by the avidity of IgG for the antigen.<a class="elsevierStyleCrossRefs" href="#bib0415">23,24</a> In this type of cryoglobulinemia, the IgG or IgM components do not precipitate in isolation but rather jointly, and extended periods at low temperature are required for this precipitation to occur.<a class="elsevierStyleCrossRef" href="#bib0425">25</a>Diagnosis of cryoglobulinemiaCorrect patient classification is important in clinical practice and for epidemiological studies. For a diagnosis of disease or cryoglobulinemic vasculitis, the patient must present cryoglobulins in serum and meet a number of clinical and laboratory criteria.<a class="elsevierStyleCrossRefs" href="#bib0405">21,26,27</a> In 2011, a classification methodology for cryoglobulinemic syndromes was established, based mainly on the presence of cryoglobulins in serum as an inclusion criterion (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0390">18,28</a> It is therefore essential to standardize the detection of cryoglobulins in the laboratory among centers, in such a way that comparable results are obtained. There have been reports of patients with mixed cryoglobulinemic syndrome without cryoglobulins in serum. This phenomenon is usually temporary due to the wide variability in the percentage of cryoprecipitate in serum and possibly to the sensitivity of the laboratory technique employed. These patients need a repeated cryoglobulin reading for a correct diagnosis.<a class="elsevierStyleCrossRef" href="#bib0435">27</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Characterization of cryoglobulinsThe characterization of cryoglobulins in serum is limited by the need for strict preanalysis conditions, the subjective reading of results and the lack of standardized criteria.The mere detection of cryoglobulins (positive/negative) allows us to include or exclude a patient in the diagnosis of cryoglobulinemic syndrome. The main usefulness of classifying cryoglobulins (immunoglobulin type and monoclonality) is that it allows us to differentiate a cryoglobulinemia due to a malignant disorder from those due to immune system stimulation.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> Additionally, cryoglobulin quantification is useful when making decisions about the therapy and when monitoring the treatment of choice.<a class="elsevierStyleCrossRef" href="#bib0450">30</a> In type i cryoglobulinemia, which is associated with lymphoproliferative disorders, the type of cryoglobulin has greater relevance in the pathogenesis of the underlying disease than the cryoglobulin burden.<a class="elsevierStyleCrossRefs" href="#bib0385">17,19</a>The characterization of cryoglobulins is performed in serum samples, and the laboratory procedure can be divided into 3 phases:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Preanalysis phase</li><li class="elsevierStyleListItem" id="lsti0010">2.Detection phase</li><li class="elsevierStyleListItem" id="lsti0015">3.Analysis phase</li></ul>Preanalysis phaseIn this phase, it is essential that the temperature not fall below 37°C for extended periods, so as to prevent cryoprecipitation.<a class="elsevierStyleCrossRef" href="#bib0320">4</a>The recommendation is to extract at least 10mL of venous blood without anticoagulant (in tubes with or without gel) so as to avoid false positives due to cryofibrinogen or proteins that precipitate in the presence of heparin.<a class="elsevierStyleCrossRef" href="#bib0435">27</a> The sample volume should not be less than 10mL because the presence of trace cryoglobulins is clinically relevant,<a class="elsevierStyleCrossRefs" href="#bib0390">18,25</a> and these traces cannot be detected in a small volume. There are protocols for this extraction that recommend allowing all materials to reach room temperature (needles, syringes and tubes).<a class="elsevierStyleCrossRefs" href="#bib0330">6,25,27,31</a>Once the blood sample has been drawn, it should be transported to the laboratory in a thermos containing water or sand or another container<a class="elsevierStyleCrossRefs" href="#bib0460">32,33</a> that ensures the temperature will remain around 37°C.<a class="elsevierStyleCrossRef" href="#bib0470">34</a> Once in the laboratory and before separating the serum, the sample should be incubated for at least 1h at 37°C to dissolve the cryoglobulins that might have precipitated.<a class="elsevierStyleCrossRefs" href="#bib0455">31,35,36</a>After an hour of incubation, the serum is separated by centrifugation. Several protocols recommend centrifuging at 37°C,<a class="elsevierStyleCrossRefs" href="#bib0455">31,32,36,37</a> centrifuging at room temperature if the laboratory does not have temperature-controlled centrifuges<a class="elsevierStyleCrossRefs" href="#bib0475">35,38,39</a> or leaving the sample at 37°C and collecting the supernatant without centrifuging.<a class="elsevierStyleCrossRef" href="#bib0455">31</a> Once the serum has been separated, it is advisable to add sodium azide at 0.1g/L<a class="elsevierStyleCrossRef" href="#bib0500">40</a> to preserve it. The serum is then divided, according to the laboratory procedure to follow: if the quantification is performed based on the cryocrit, most of the serum will be collected in a sedimentation tube or hematocrit tube, and an additional tube will be aliquoted (tube 2). If the quantitative method of choice is concentration of total proteins or of immunoglobulins, 2 aliquots will be performed (tube 1 and tube 2). All tubes will be incubated at 4°C for 5–7 days.Detection phaseIn this phase, the most common practice is to perform a visual screening to rule out those samples in which a visible precipitate does not form after incubation at 4°C.<a class="elsevierStyleCrossRefs" href="#bib0425">25,27,31,32</a> This precipitate generally presents a whitish appearance but can exceptionally appear gelatinous or transparent, which impedes its visualization and can categorize the sample as negative. Therefore, technicians responsible for performing the characterization of cryoglobulins should be trained. After this incubation has been completed, tube 2 of the samples with visible precipitate should be used to check that the precipitate disappears when incubating at 37°C. It is a common practice to catalog samples as negative if the precipitate does not disappear at this temperature. However, there are cryoglobulins that have difficulty dissolving, especially those that drag large quantities of complement and other proteins. So as not to erroneously classify a cryoglobulin as negative, the sample should be incubated for at least 1h at 37°C. Samples that redissolve will be subjected to the typing phase (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Analytical phaseThe recommended laboratory protocol for subjecting the samples to the analytical phase is outlined in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>There are 3 acceptable quantification methods: percentage of total serum volume occupied by the cryoprecipitate (cryocrit), total protein concentration and immunoglobulin concentration. The “rapid laboratory test” has also been proposed, which consists of measuring turbidimetry at 10°C and continuously until cryoprecipitation occurs. This test is performed in a complementary manner to classical tests when the objective is cryoglobulin characterization (patients for an initial reading) or exclusively for the follow-up of the disease and checking the efficacy of the plasmapheresis.<a class="elsevierStyleCrossRef" href="#bib0505">41</a>Among the most widespread methods, cryocrit and total proteins contain the immunoglobulin fraction and other relevant factors that co-precipitate (such as the complement); however, they can also contain unwanted protein contaminants, such as albumin.<a class="elsevierStyleCrossRef" href="#bib0390">18</a> These contaminates can be reduced by washing the cryoprecipitate. Nevertheless, up to a third of the cryoprecipitate can be lost in each flushing, a relevant fact especially in cryoglobulins that are found at low concentrations. The cryocrit measurement is a fast and inexpensive method with good sensitivity but requires a considerable sample volume and has poorer reproducibility than the quantification of total proteins and is not useful for comparing disease indices among patients and is not standardized in terms of volume.<a class="elsevierStyleCrossRef" href="#bib0375">15</a> Total protein quantification has better reproducibility and greater accuracy than the cryocrit method, given the technique's automation and objective quantification of the result.<a class="elsevierStyleCrossRefs" href="#bib0445">29,35</a> and helps minimize the interference of proteins that co-precipitate with cryoglobulins if the difference is calculated between the tube concentration at 4°C (tube 1) and at 37°C (tube 2), i.e., using tube 2 as the target of the technique.Normal ranges have not been standardized for total protein concentration, although a number of authors have established them at 20–80mg/L.<a class="elsevierStyleCrossRefs" href="#bib0445">29,35</a> There is a single study that has established immunoglobulin values, resulting in 23% of 214 patients with cryoglobulinemia exceeding this normal limit.<a class="elsevierStyleCrossRef" href="#bib0510">42</a> Due to the current lack of studies, each laboratory should establish the normal limit by testing a reference population of patients without cryoglobulinemia.After the quantitative analysis, the samples that resulted positive (or negative but with a high clinical suspicion) should be characterized to complete the study. Cryoglobulins can be characterized by electrophoretic (either gel or capillary) or nonelectrophoretic methods (immunoblot,<a class="elsevierStyleCrossRef" href="#bib0475">35</a> laser nephelometry,<a class="elsevierStyleCrossRef" href="#bib0515">43</a> immunodiffusion<a class="elsevierStyleCrossRefs" href="#bib0485">37,44</a> or light scattering methods<a class="elsevierStyleCrossRef" href="#bib0525">45</a>). Since the objective of this review is to recommend a protocol for interlaboratory standardization, we believe that immunofixation is the most sensitive method,<a class="elsevierStyleCrossRefs" href="#bib0530">46,47</a> given that it provides both the cryoglobulin class and clonality (clinically relevant information) and is available in most laboratories. This method should be performed with cryoprecipitate washed at 4°C and resuspended at 37°C. The recommended laboratory procedure is indicated in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Additional testingThe diagnostic criteria for cryoglobulinemic syndromes include the measurement of RF and C4. Determining the acute-phase reactants and completing the complement study (C1q, C2, C3, and CH50) in the initial reading is also useful,<a class="elsevierStyleCrossRef" href="#bib0540">48</a> as is quantifying the immunoglobulins both in the initial reading and in subsequent measurements.<a class="elsevierStyleCrossRef" href="#bib0545">49</a> Another approach to completing the cryoglobulin study is quantifying immunoglobulins in the supernatant that remains after allowing the solution to precipitate for 5–7 days at 4°C.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> RF and acute-phase reactant levels are typically high. Classical complement pathway factors (mainly C4)<a class="elsevierStyleCrossRef" href="#bib0425">25</a> are decreased in mixed cryoglobulinemia, although they can also be decreased in simple cryoglobulinemia.<a class="elsevierStyleCrossRef" href="#bib0395">19</a> However, C3 is within normal ranges or even slightly high due to a regulatory mechanism exerted by C4bp and factor i on classical pathway C3 convertase in these patients.<a class="elsevierStyleCrossRef" href="#bib0550">50</a> These serological abnormalities have independently led to the erroneous diagnosis of rheumatoid vasculitis by not considering the presence of cryoglobulins<a class="elsevierStyleCrossRef" href="#bib0445">29</a> and should therefore not be used in isolation without the detection of cryoglobulins but rather as a complementary criterion.For patients positive for type i cryoglobulins and lacking an underlying diagnosis, it is advisable to conduct a serum proteinogram to rule out hematologic disorders.<a class="elsevierStyleCrossRef" href="#bib0395">19</a> Patients with mixed cryoglobulinemia require an assessment of infection markers for HCV, given the high association, in the event that the patient is not already diagnosed with this viral hepatitis.<a class="elsevierStyleCrossRefs" href="#bib0555">51,52</a> It is advisable to conduct a study of infection markers for other viruses (HBV, HIV),<a class="elsevierStyleCrossRefs" href="#bib0315">3,11</a> as well as an autoimmune screening.<a class="elsevierStyleCrossRefs" href="#bib0350">10,12,21,53</a>DiscussionDetecting cryoglobulins is essential to diagnosing cryoglobulinemic syndromes. The nature of cryoglobulins and the cryoprecipitation mechanism result in a very long analytical procedure (approximately 7 days), which is difficult to automate and standardize. Nevertheless, it is important to standardize as much as possible the protocol for characterizing cryoglobulins among the various laboratories. A study conducted in 2008<a class="elsevierStyleCrossRef" href="#bib0570">54</a> observed considerable variability in cryoglobulin readings. Of the 140 laboratories that participated in the survey, only 36% used some method to ensure that the temperature did not fall below 37°C until the serum had been separated. In terms of the cryoprecipitation phase, the time varied significantly (from 12h to 9 days), with 30% of laboratories waiting less than 3 days for the precipitate at 4°C before the detection phase. After the cryoprecipitation, 21% of the laboratories did not redissolve the cryoprecipitate at 37°C. In terms of the analysis, only 42% employed a quantitative method, and 37% did not characterize the type of cryoglobulin, reporting only the cryoprecipitate concentration as cryocrit, total protein concentration and/or immunoglobulin concentration. Only 3 laboratories (2%) provided specific reference values for the total protein quantity of the cryoprecipitate, and none provided them for the immunoglobulin concentration.The most critical phase for detecting cryoglobulins is the preanalysis. Although not essential, preheating the extraction material is recommended when collecting samples,<a class="elsevierStyleCrossRefs" href="#bib0305">1,17,36,39,55,56</a> given that neither time nor the fall in temperature during the few seconds that are needed for the extraction are sufficient to allow the cryoglobulins to precipitate. As with most protocols published to date, we consider the transport of the sample to the laboratory at 37°C crucial, as well as the 1-h incubation at 37°C to prevent false negatives due to cryoglobulin precipitates prior to the separation of the serum. For this separation, centrifuge at 37°C. However, if the laboratory does not have this option, it is preferable to centrifuge at room temperature<a class="elsevierStyleCrossRef" href="#bib0585">57</a> than to leave it to sediment, because centrifuging results in a serum with fewer traces of red blood cells and fibrin, elements that interfere with the subsequent measurement of cryoglobulins, resulting in false positives. The risk of obtaining a false positive in this manner is greater that the risk of obtaining a false negative by cryoglobulin precipitation during centrifugation at room temperature, given that at this temperature only some type i cryoglobulins that are found at very high concentrations can partially precipitate but will remain mostly soluble and detectable in their subsequent analysis.<a class="elsevierStyleCrossRefs" href="#bib0475">35,39</a>Once the serum has been obtained, it should be kept at 4°C to enable cryoprecipitation. The appropriate time varies depending on the author, from a minimum of 2<a class="elsevierStyleCrossRefs" href="#bib0305">1,44</a> or 3 days<a class="elsevierStyleCrossRefs" href="#bib0390">18,32,36,39</a> up to 7.<a class="elsevierStyleCrossRefs" href="#bib0330">6,11,15–17,20,27,35,37,51,55,58</a> An incubation of less than 5 days can result in up to 30% false negatives because type iii cryoglobulins are slower to precipitate.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> Therefore, samples should be incubated at 4°C for 5–7 days. Once the incubation has finished, the most widespread technique is to catalog as negative those samples with no visible precipitates. The most appropriate method would be to perform the full procedure on all samples, given that lipids (especially chylomicrons) and fibrinogen can interfere with cryoglobulins that are at lowest concentration and will not be visible to the naked eye.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> For procedural reasons, some samples are incubated for less than 5 days, which might be insufficient for precipitation and can entail false negatives. In all of these situations, a complete reading should be performed, at least for patients with a high diagnostic suspicion, even though precipitates are not observed.<a class="elsevierStyleCrossRefs" href="#bib0330">6,42</a>When processing samples during the analytical phase, we propose that the cryoprecipitate be subjected to 3 flushings at 4°C, the optimum number of flushings to eliminate protein contaminants and lose the least amount of cryoprecipitate.<a class="elsevierStyleCrossRef" href="#bib0510">42</a> In terms of methods for characterizing the cryoprecipitate, the recommendation is the combination of a quantitative method followed by a qualitative method for positive samples. Numerous groups recommend the cryocrit as the quantitative method.<a class="elsevierStyleCrossRefs" href="#bib0330">6,14,16,17,36,44,55,58</a> Due to its poor reproducibility and lack of reliability when comparing among patients, cryocrit is not a good method for exclusive use and should be combined with other quantitative methods,<a class="elsevierStyleCrossRef" href="#bib0460">32</a> such as immunoglobulin quantification with reagents able to detect low concentrations.<a class="elsevierStyleCrossRefs" href="#bib0565">53,57</a> Total protein quantification is a good approximation of the cryoprecipitate, at least in mixed cryoglobulinemia,<a class="elsevierStyleCrossRefs" href="#bib0475">35,39,51</a> given that the quantity of antibodies has not been related to the level of cryoprecipitate, which also consists of proteins and complement factors, especially in cryoglobulinemia associated with viral infections, in which viral antigens are found.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> When cryoprecipitating, these proteins can be a direct cause of the damage, given that they are found in the damaged tissue of patients with cryoglobulinemia.<a class="elsevierStyleCrossRefs" href="#bib0595">59,60</a> Given that we can simultaneously quantify a sample at 37°C and thereby the interference due to proteins that nonspecifically co-precipitate, protein quantification does not need to be combined with another quantitative method. Lastly, as a qualitative method for characterizing the cryoprecipitate, we agree with most recommendations in the literature on serum immunofixation.<a class="elsevierStyleCrossRefs" href="#bib0330">6,11,14,16–18,32,36,55,58</a>The aim of this review is therefore to recommend a protocol that eliminates or at least decreases the considerable variability among laboratories both in the measurement methodology and in the type of reported results.Conflicts of interestThe authors declare that they have no conflicts of interest in the preparation of the present manuscript." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1271824" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1176791" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1271825" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1176792" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Type i cryoglobulins" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Type ii and iiicryoglobulins (mixed)" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Cryoprecipitation" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis of cryoglobulinemia" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Characterization of cryoglobulins" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Preanalysis phase" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Detection phase" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Analytical phase" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Additional testing" ] ] ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 12 => array:2 [ "identificador" => "xack436623" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-10-15" "fechaAceptado" => "2018-10-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1176791" "palabras" => array:3 [ 0 => "Cryoglobulinemic syndromes" 1 => "Vasculitis" 2 => "Cryoglobulins" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1176792" "palabras" => array:3 [ 0 => "Síndromes crioglobulinémicos" 1 => "Vasculitis" 2 => "Crioglobulinas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Cryoglobulinemic syndromes include a collection of manifestations that are found in various diseases and that share a pathophysiological mechanism: cryoglobulin deposit in vascular beds. For these syndromes, the presence of cryoglobulins is a diagnostic criterion, and their correct detection and characterization are therefore essential. The Immunochemistry Group of the Spanish Society of Immunology conducted a comprehensive clinical and methodological review, due to the interlaboratory heterogeneity in techniques, with the objective of providing a useful and effective tool for diagnosing cryoglobulinemic syndromes." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los síndromes crioglobulinémicos comprenden un conjunto de manifestaciones que se encuentran en diversas enfermedades y que comparten un mismo mecanismo fisiopatológico: el depósito de crioglobulinas en lechos vasculares. La presencia de crioglobulinas es criterio diagnóstico de estos síndromes por lo que es imprescindible su correcta detección y caracterización. El Grupo de Inmunoquímica de la Sociedad Española de Inmunología ha realizado una revisión exhaustiva clínica y metodológica, debido a la heterogeneidad técnica interlaboratorios, con el objetivo de proporcionar una herramienta útil y efectiva para el diagnóstico de síndromes crioglobulinémicos." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Mariscal-Rodríguez A, Villar Guimerans LM, López-Trascasa M, Hernández González M, Moga Naranjo E, on behalf of grupo de inmunoquímica de la Sociedad Española de Inmunología. Guía de laboratorio para el diagnóstico de pacientes con síndrome crioglobulinémico. Rev Clin Esp. 2019;219:505–513." ] 1 => array:3 [ "etiqueta" => "1" "nota" => "The members of the Immunochemistry Group of the Spanish Society of Immunology are listed in <a class="elsevierStyleCrossRef" href="#sec0070">Appendix</a>." "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0070" ] ] ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from De Vita et al.<a class="elsevierStyleCrossRef" href="#bib0440">28</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2178 "Ancho" => 2504 "Tamanyo" => 387447 ] ] "descripcion" => array:1 [ "en" => "Preliminary classification criteria for cryoglobulinemic syndromes. Abbreviations: CNS, central nervous system; RF, rheumatoid factor." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2275 "Ancho" => 1587 "Tamanyo" => 169166 ] ] "descripcion" => array:1 [ "en" => "Recommended algorithm for studying cryoglobulins." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2195 "Ancho" => 2504 "Tamanyo" => 208675 ] ] "descripcion" => array:1 [ "en" => "Laboratory protocol for studying cryoglobulins. Abbreviation: IF, immunofixation." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: AI, autoimmune; CMV, cytomegalovirus; MGUS, monoclonal gammopathy of undetermined significance; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin's lymphoma; MM, multiple myeloma; WM, Waldenstrom macroglobulinemia; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cryoglobulin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Composition \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Associated disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Volume \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Precipitation time \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IgM, IgG, IgA or monoclonal free light-chains \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10–15% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphoproliferative diseases (MGUS, MM, WM, CLL, NHL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30–80% of serum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">min to h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monoclonal IgM+polyclonal IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50–60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral infections (HCV, HBV, HIV, EBV, CMV), bacterial and parasitical, autoimmune and lymphoproliferative disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.5–30% of the serum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">h to days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polyclonal IgM and IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25–30% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5–1.5% of serum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3–5 days \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Classification and characteristics of the various cryoglobulins." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviation: RT, room temperature." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cryocrit tube: centrifuge at 1000g for 10min at 4°C and read the percentage that the cryoprecipitate occupies compared with the total serum volume. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tube 1 (5–7 days at 4°C): \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Centrifuge at 2000×g 10min at 4°C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Separate the supernatant. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Add 1.5mL of cold PBS to the precipitate. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stir with vortex for approximately 30seconds or until no precipitate is visible. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Centrifuge and repeat the flushing process twice more. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resuspend the cryoprecipitate in PBS. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Incubate the samples for 1h at 37°C before subjecting them to the quantitative method of choice. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tube 2 (1h at 37°C): Follow the same procedure as for tube 1, centrifuging at 37°C (or RT) and perform flushing with PBS at 37°C. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Recommended laboratory protocol for processing cryoglobulin samples." ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 15520 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A role for hepatitis C virus infection in type II cryoglobulinemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "V. 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less frequently of type IgG and rarely of type IgA or free light-chains&#46; This type of cryoglobulin is found less frequently &#40;10&#8211;15&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> and is associated with hematologic disease&#44; mainly monoclonal gammopathies of uncertain significance &#40;40&#37;&#41; and other B-cell line abnormalities&#44; such as multiple myeloma&#44; Waldenstrom macroglobulinemia and chronic lymphocytic leukemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;17</span></a> Type I cryoglobulinemia is generally asymptomatic&#59; in some cases&#44; however&#44; the precipitation of cryoglobulins in small vessels can create vascular occlusion and subsequently progress with cold-induced hyperviscosity syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;8&#44;18</span></a> This small-vessel vasculitis mainly affects the kidneys and skin&#46; Renal impairment&#44; which presents mainly in the form of glomerulonephritis&#44; involves proteinuria&#44; microscopic hematuria&#44; high creatinine levels and&#47;or hypertension and is more common in class IgG cryoglobulinemia&#46; Skin manifestations include purpura&#44; livedo reticularis&#44; Raynaud&#39;s phenomenon&#44; acrocyanosis&#44; necrosis and ulcers and are usually limited to distal extremities &#40;fingers&#44; ears&#44; nose&#41; and after exposure to cold&#46; Peripheral neuropathy and arthralgia are less often observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;19</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Type <span class="elsevierStyleSmallCaps">ii</span> and <span class="elsevierStyleSmallCaps">iii</span>cryoglobulins &#40;mixed&#41;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Type <span class="elsevierStyleSmallCaps">ii</span> cryoglobulins consist of polyclonal IgG and a monoclonal component&#44; typically IgM&#44; which present rheumatoid factor &#40;RF&#41; activity&#46; These cryoglobulins are detected more frequently &#40;50&#8211;60&#37; of patients with cryoglobulinemia&#41;&#46; Type <span class="elsevierStyleSmallCaps">iii</span> cryoglobulins consist of polyclonal IgG and IgM&#44; the latter with RF activity&#46; These cryoglobulins are found at an intermediate rate compared with type <span class="elsevierStyleSmallCaps">i</span> and <span class="elsevierStyleSmallCaps">ii</span> &#40;25&#8211;30&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> With the arrival of more sensitive technology&#44; such as immunoblot and two-dimensional polyacrylamide gel electrophoresis&#44; a certain percentage of type <span class="elsevierStyleSmallCaps">ii</span> cryoglobulins have been detected composed of oligoclonal IgM or a mixture of oligoclonal and polyclonal&#46; This subgroup could be a transition state for cryoglobulinemia from type <span class="elsevierStyleSmallCaps">iii</span> to type <span class="elsevierStyleSmallCaps">ii</span> and has been called type <span class="elsevierStyleSmallCaps">ii</span>-<span class="elsevierStyleSmallCaps">iii</span> cryoglobulins&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">14&#44;20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Mixed cryoglobulins are associated with chronic infections &#40;mainly type <span class="elsevierStyleSmallCaps">ii</span>&#41; and autoimmune diseases &#40;mostly type <span class="elsevierStyleSmallCaps">iii</span>&#41;&#44; processes that involve immune system hyperstimulation in general and antibody synthesis in particular&#46; The closest association is between type <span class="elsevierStyleSmallCaps">ii</span> cryoglobulins and HCV infection &#40;up to 95&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Mixed cryoglobulinemia typically progresses with symptoms of vasculitis due to the deposit in small and medium vessels of immune complexes formed mainly by immunoglobulins&#44; antigen and complement but also possibly consisting of local hematologic factors&#46; Given its clinical and histological characteristics&#44; mixed cryoglobulinemia is also classified within systemic small-vessel vasculitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;21</span></a> Compared with type <span class="elsevierStyleSmallCaps">i</span> cryoglobulinemia&#44; mixed cryoglobulinemia presents with constitutional symptoms such as fever&#44; weakness&#44; myalgia&#47;arthralgia and anorexia&#44; a reflection of the immune complex disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a> The most common sign is isolated purpura&#44; found in almost 90&#37; of patients&#59; however&#44; a third of these patients also experience arthralgia and weakness &#40;Meltzer&#39;s triad&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> Kidney disease and neuropathy are similar to those that occur in type <span class="elsevierStyleSmallCaps">i</span> cryoglobulinemia&#44; although small-vessel occlusion by cryoglobulin aggregates is more likely to occur in type I cryoglobulinemia&#46; The involvement of other organs in addition to the kidneys is generally rare&#59; when other organs are involved&#44; however&#44; it is almost exclusively a sign of mixed cryoglobulinemia&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The symptoms are comparable among syndromes for type <span class="elsevierStyleSmallCaps">ii</span> and <span class="elsevierStyleSmallCaps">iii</span> cryoglobulins<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a>&#59; however&#44; the symptoms vary enormously among patients&#44; from the asymptomatic presence of cryoglobulins in serum to full cryoglobulinemic syndrome&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Cryoprecipitation</span><p id="par0050" class="elsevierStylePara elsevierViewall">The process of cryoprecipitation is not completely understood&#44; but it is known that it differs between type I and mixed cryoglobulins&#46; In type I&#44; the monoclonal component crystallizes and aggregates&#44; a process that depends on temperature and concentration&#46; In fact&#44; when the concentration is very high&#44; some precipitation can occur at room temperature and within a few hours&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a> In mixed cryoglobulinemia&#44; however&#44; cryoprecipitation occurs in the context of immune complex formation between IgG and IgM and complement fixation and is affected by the avidity of IgG for the antigen&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">23&#44;24</span></a> In this type of cryoglobulinemia&#44; the IgG or IgM components do not precipitate in isolation but rather jointly&#44; and extended periods at low temperature are required for this precipitation to occur&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis of cryoglobulinemia</span><p id="par0055" class="elsevierStylePara elsevierViewall">Correct patient classification is important in clinical practice and for epidemiological studies&#46; For a diagnosis of disease or cryoglobulinemic vasculitis&#44; the patient must present cryoglobulins in serum and meet a number of clinical and laboratory criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">21&#44;26&#44;27</span></a> In 2011&#44; a classification methodology for cryoglobulinemic syndromes was established&#44; based mainly on the presence of cryoglobulins in serum as an inclusion criterion &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#44;28</span></a> It is therefore essential to standardize the detection of cryoglobulins in the laboratory among centers&#44; in such a way that comparable results are obtained&#46; There have been reports of patients with mixed cryoglobulinemic syndrome without cryoglobulins in serum&#46; This phenomenon is usually temporary due to the wide variability in the percentage of cryoprecipitate in serum and possibly to the sensitivity of the laboratory technique employed&#46; These patients need a repeated cryoglobulin reading for a correct diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Characterization of cryoglobulins</span><p id="par0060" class="elsevierStylePara elsevierViewall">The characterization of cryoglobulins in serum is limited by the need for strict preanalysis conditions&#44; the subjective reading of results and the lack of standardized criteria&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The mere detection of cryoglobulins &#40;positive&#47;negative&#41; allows us to include or exclude a patient in the diagnosis of cryoglobulinemic syndrome&#46; The main usefulness of classifying cryoglobulins &#40;immunoglobulin type and monoclonality&#41; is that it allows us to differentiate a cryoglobulinemia due to a malignant disorder from those due to immune system stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> Additionally&#44; cryoglobulin quantification is useful when making decisions about the therapy and when monitoring the treatment of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> In type <span class="elsevierStyleSmallCaps">i</span> cryoglobulinemia&#44; which is associated with lymphoproliferative disorders&#44; the type of cryoglobulin has greater relevance in the pathogenesis of the underlying disease than the cryoglobulin burden&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17&#44;19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The characterization of cryoglobulins is performed in serum samples&#44; and the laboratory procedure can be divided into 3 phases&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Preanalysis phase</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Detection phase</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Analysis phase</p></li></ul></p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Preanalysis phase</span><p id="par0090" class="elsevierStylePara elsevierViewall">In this phase&#44; it is essential that the temperature not fall below 37<span class="elsevierStyleHsp" style=""></span>&#176;C for extended periods&#44; so as to prevent cryoprecipitation&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The recommendation is to extract at least 10<span class="elsevierStyleHsp" style=""></span>mL of venous blood without anticoagulant &#40;in tubes with or without gel&#41; so as to avoid false positives due to cryofibrinogen or proteins that precipitate in the presence of heparin&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> The sample volume should not be less than 10<span class="elsevierStyleHsp" style=""></span>mL because the presence of trace cryoglobulins is clinically relevant&#44;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#44;25</span></a> and these traces cannot be detected in a small volume&#46; There are protocols for this extraction that recommend allowing all materials to reach room temperature &#40;needles&#44; syringes and tubes&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;25&#44;27&#44;31</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Once the blood sample has been drawn&#44; it should be transported to the laboratory in a thermos containing water or sand or another container<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#44;33</span></a> that ensures the temperature will remain around 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a> Once in the laboratory and before separating the serum&#44; the sample should be incubated for at least 1<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C to dissolve the cryoglobulins that might have precipitated&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">31&#44;35&#44;36</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">After an hour of incubation&#44; the serum is separated by centrifugation&#46; Several protocols recommend centrifuging at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#44;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">31&#44;32&#44;36&#44;37</span></a> centrifuging at room temperature if the laboratory does not have temperature-controlled centrifuges<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#44;38&#44;39</span></a> or leaving the sample at 37<span class="elsevierStyleHsp" style=""></span>&#176;C and collecting the supernatant without centrifuging&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> Once the serum has been separated&#44; it is advisable to add sodium azide at 0&#46;1<span class="elsevierStyleHsp" style=""></span>g&#47;L<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> to preserve it&#46; The serum is then divided&#44; according to the laboratory procedure to follow&#58; if the quantification is performed based on the cryocrit&#44; most of the serum will be collected in a sedimentation tube or hematocrit tube&#44; and an additional tube will be aliquoted &#40;tube 2&#41;&#46; If the quantitative method of choice is concentration of total proteins or of immunoglobulins&#44; 2 aliquots will be performed &#40;tube 1 and tube 2&#41;&#46; All tubes will be incubated at 4<span class="elsevierStyleHsp" style=""></span>&#176;C for 5&#8211;7 days&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Detection phase</span><p id="par0110" class="elsevierStylePara elsevierViewall">In this phase&#44; the most common practice is to perform a visual screening to rule out those samples in which a visible precipitate does not form after incubation at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">25&#44;27&#44;31&#44;32</span></a> This precipitate generally presents a whitish appearance but can exceptionally appear gelatinous or transparent&#44; which impedes its visualization and can categorize the sample as negative&#46; Therefore&#44; technicians responsible for performing the characterization of cryoglobulins should be trained&#46; After this incubation has been completed&#44; tube 2 of the samples with visible precipitate should be used to check that the precipitate disappears when incubating at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; It is a common practice to catalog samples as negative if the precipitate does not disappear at this temperature&#46; However&#44; there are cryoglobulins that have difficulty dissolving&#44; especially those that drag large quantities of complement and other proteins&#46; So as not to erroneously classify a cryoglobulin as negative&#44; the sample should be incubated for at least 1<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Samples that redissolve will be subjected to the typing phase &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Analytical phase</span><p id="par0115" class="elsevierStylePara elsevierViewall">The recommended laboratory protocol for subjecting the samples to the analytical phase is outlined in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">There are 3 acceptable quantification methods&#58; percentage of total serum volume occupied by the cryoprecipitate &#40;cryocrit&#41;&#44; total protein concentration and immunoglobulin concentration&#46; The &#8220;rapid laboratory test&#8221; has also been proposed&#44; which consists of measuring turbidimetry at 10<span class="elsevierStyleHsp" style=""></span>&#176;C and continuously until cryoprecipitation occurs&#46; This test is performed in a complementary manner to classical tests when the objective is cryoglobulin characterization &#40;patients for an initial reading&#41; or exclusively for the follow-up of the disease and checking the efficacy of the plasmapheresis&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Among the most widespread methods&#44; cryocrit and total proteins contain the immunoglobulin fraction and other relevant factors that co-precipitate &#40;such as the complement&#41;&#59; however&#44; they can also contain unwanted protein contaminants&#44; such as albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a> These contaminates can be reduced by washing the cryoprecipitate&#46; Nevertheless&#44; up to a third of the cryoprecipitate can be lost in each flushing&#44; a relevant fact especially in cryoglobulins that are found at low concentrations&#46; The cryocrit measurement is a fast and inexpensive method with good sensitivity but requires a considerable sample volume and has poorer reproducibility than the quantification of total proteins and is not useful for comparing disease indices among patients and is not standardized in terms of volume&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> Total protein quantification has better reproducibility and greater accuracy than the cryocrit method&#44; given the technique&#39;s automation and objective quantification of the result&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">29&#44;35</span></a> and helps minimize the interference of proteins that co-precipitate with cryoglobulins if the difference is calculated between the tube concentration at 4<span class="elsevierStyleHsp" style=""></span>&#176;C &#40;tube 1&#41; and at 37<span class="elsevierStyleHsp" style=""></span>&#176;C &#40;tube 2&#41;&#44; i&#46;e&#46;&#44; using tube 2 as the target of the technique&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Normal ranges have not been standardized for total protein concentration&#44; although a number of authors have established them at 20&#8211;80<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">29&#44;35</span></a> There is a single study that has established immunoglobulin values&#44; resulting in 23&#37; of 214 patients with cryoglobulinemia exceeding this normal limit&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> Due to the current lack of studies&#44; each laboratory should establish the normal limit by testing a reference population of patients without cryoglobulinemia&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">After the quantitative analysis&#44; the samples that resulted positive &#40;or negative but with a high clinical suspicion&#41; should be characterized to complete the study&#46; Cryoglobulins can be characterized by electrophoretic &#40;either gel or capillary&#41; or nonelectrophoretic methods &#40;immunoblot&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> laser nephelometry&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> immunodiffusion<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">37&#44;44</span></a> or light scattering methods<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a>&#41;&#46; Since the objective of this review is to recommend a protocol for interlaboratory standardization&#44; we believe that immunofixation is the most sensitive method&#44;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">46&#44;47</span></a> given that it provides both the cryoglobulin class and clonality &#40;clinically relevant information&#41; and is available in most laboratories&#46; This method should be performed with cryoprecipitate washed at 4<span class="elsevierStyleHsp" style=""></span>&#176;C and resuspended at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The recommended laboratory procedure is indicated in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Additional testing</span><p id="par0140" class="elsevierStylePara elsevierViewall">The diagnostic criteria for cryoglobulinemic syndromes include the measurement of RF and C4&#46; Determining the acute-phase reactants and completing the complement study &#40;C1q&#44; C2&#44; C3&#44; and CH50&#41; in the initial reading is also useful&#44;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> as is quantifying the immunoglobulins both in the initial reading and in subsequent measurements&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> Another approach to completing the cryoglobulin study is quantifying immunoglobulins in the supernatant that remains after allowing the solution to precipitate for 5&#8211;7 days at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> RF and acute-phase reactant levels are typically high&#46; Classical complement pathway factors &#40;mainly C4&#41;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> are decreased in mixed cryoglobulinemia&#44; although they can also be decreased in simple cryoglobulinemia&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> However&#44; C3 is within normal ranges or even slightly high due to a regulatory mechanism exerted by C4<span class="elsevierStyleHsp" style=""></span>bp and factor <span class="elsevierStyleSmallCaps">i</span> on classical pathway C3 convertase in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> These serological abnormalities have independently led to the erroneous diagnosis of rheumatoid vasculitis by not considering the presence of cryoglobulins<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> and should therefore not be used in isolation without the detection of cryoglobulins but rather as a complementary criterion&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">For patients positive for type <span class="elsevierStyleSmallCaps">i</span> cryoglobulins and lacking an underlying diagnosis&#44; it is advisable to conduct a serum proteinogram to rule out hematologic disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Patients with mixed cryoglobulinemia require an assessment of infection markers for HCV&#44; given the high association&#44; in the event that the patient is not already diagnosed with this viral hepatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">51&#44;52</span></a> It is advisable to conduct a study of infection markers for other viruses &#40;HBV&#44; HIV&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">3&#44;11</span></a> as well as an autoimmune screening&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">10&#44;12&#44;21&#44;53</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">Detecting cryoglobulins is essential to diagnosing cryoglobulinemic syndromes&#46; The nature of cryoglobulins and the cryoprecipitation mechanism result in a very long analytical procedure &#40;approximately 7 days&#41;&#44; which is difficult to automate and standardize&#46; Nevertheless&#44; it is important to standardize as much as possible the protocol for characterizing cryoglobulins among the various laboratories&#46; A study conducted in 2008<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> observed considerable variability in cryoglobulin readings&#46; Of the 140 laboratories that participated in the survey&#44; only 36&#37; used some method to ensure that the temperature did not fall below 37<span class="elsevierStyleHsp" style=""></span>&#176;C until the serum had been separated&#46; In terms of the cryoprecipitation phase&#44; the time varied significantly &#40;from 12<span class="elsevierStyleHsp" style=""></span>h to 9 days&#41;&#44; with 30&#37; of laboratories waiting less than 3 days for the precipitate at 4<span class="elsevierStyleHsp" style=""></span>&#176;C before the detection phase&#46; After the cryoprecipitation&#44; 21&#37; of the laboratories did not redissolve the cryoprecipitate at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; In terms of the analysis&#44; only 42&#37; employed a quantitative method&#44; and 37&#37; did not characterize the type of cryoglobulin&#44; reporting only the cryoprecipitate concentration as cryocrit&#44; total protein concentration and&#47;or immunoglobulin concentration&#46; Only 3 laboratories &#40;2&#37;&#41; provided specific reference values for the total protein quantity of the cryoprecipitate&#44; and none provided them for the immunoglobulin concentration&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The most critical phase for detecting cryoglobulins is the preanalysis&#46; Although not essential&#44; preheating the extraction material is recommended when collecting samples&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;17&#44;36&#44;39&#44;55&#44;56</span></a> given that neither time nor the fall in temperature during the few seconds that are needed for the extraction are sufficient to allow the cryoglobulins to precipitate&#46; As with most protocols published to date&#44; we consider the transport of the sample to the laboratory at 37<span class="elsevierStyleHsp" style=""></span>&#176;C crucial&#44; as well as the 1-h incubation at 37<span class="elsevierStyleHsp" style=""></span>&#176;C to prevent false negatives due to cryoglobulin precipitates prior to the separation of the serum&#46; For this separation&#44; centrifuge at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; However&#44; if the laboratory does not have this option&#44; it is preferable to centrifuge at room temperature<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> than to leave it to sediment&#44; because centrifuging results in a serum with fewer traces of red blood cells and fibrin&#44; elements that interfere with the subsequent measurement of cryoglobulins&#44; resulting in false positives&#46; The risk of obtaining a false positive in this manner is greater that the risk of obtaining a false negative by cryoglobulin precipitation during centrifugation at room temperature&#44; given that at this temperature only some type <span class="elsevierStyleSmallCaps">i</span> cryoglobulins that are found at very high concentrations can partially precipitate but will remain mostly soluble and detectable in their subsequent analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#44;39</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Once the serum has been obtained&#44; it should be kept at 4<span class="elsevierStyleHsp" style=""></span>&#176;C to enable cryoprecipitation&#46; The appropriate time varies depending on the author&#44; from a minimum of 2<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;44</span></a> or 3 days<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#44;32&#44;36&#44;39</span></a> up to 7&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;11&#44;15&#8211;17&#44;20&#44;27&#44;35&#44;37&#44;51&#44;55&#44;58</span></a> An incubation of less than 5 days can result in up to 30&#37; false negatives because type <span class="elsevierStyleSmallCaps">iii</span> cryoglobulins are slower to precipitate&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> Therefore&#44; samples should be incubated at 4<span class="elsevierStyleHsp" style=""></span>&#176;C for 5&#8211;7 days&#46; Once the incubation has finished&#44; the most widespread technique is to catalog as negative those samples with no visible precipitates&#46; The most appropriate method would be to perform the full procedure on all samples&#44; given that lipids &#40;especially chylomicrons&#41; and fibrinogen can interfere with cryoglobulins that are at lowest concentration and will not be visible to the naked eye&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> For procedural reasons&#44; some samples are incubated for less than 5 days&#44; which might be insufficient for precipitation and can entail false negatives&#46; In all of these situations&#44; a complete reading should be performed&#44; at least for patients with a high diagnostic suspicion&#44; even though precipitates are not observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;42</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">When processing samples during the analytical phase&#44; we propose that the cryoprecipitate be subjected to 3 flushings at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; the optimum number of flushings to eliminate protein contaminants and lose the least amount of cryoprecipitate&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> In terms of methods for characterizing the cryoprecipitate&#44; the recommendation is the combination of a quantitative method followed by a qualitative method for positive samples&#46; Numerous groups recommend the cryocrit as the quantitative method&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;14&#44;16&#44;17&#44;36&#44;44&#44;55&#44;58</span></a> Due to its poor reproducibility and lack of reliability when comparing among patients&#44; cryocrit is not a good method for exclusive use and should be combined with other quantitative methods&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> such as immunoglobulin quantification with reagents able to detect low concentrations&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">53&#44;57</span></a> Total protein quantification is a good approximation of the cryoprecipitate&#44; at least in mixed cryoglobulinemia&#44;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#44;39&#44;51</span></a> given that the quantity of antibodies has not been related to the level of cryoprecipitate&#44; which also consists of proteins and complement factors&#44; especially in cryoglobulinemia associated with viral infections&#44; in which viral antigens are found&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> When cryoprecipitating&#44; these proteins can be a direct cause of the damage&#44; given that they are found in the damaged tissue of patients with cryoglobulinemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">59&#44;60</span></a> Given that we can simultaneously quantify a sample at 37<span class="elsevierStyleHsp" style=""></span>&#176;C and thereby the interference due to proteins that nonspecifically co-precipitate&#44; protein quantification does not need to be combined with another quantitative method&#46; Lastly&#44; as a qualitative method for characterizing the cryoprecipitate&#44; we agree with most recommendations in the literature on serum immunofixation&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;11&#44;14&#44;16&#8211;18&#44;32&#44;36&#44;55&#44;58</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The aim of this review is therefore to recommend a protocol that eliminates or at least decreases the considerable variability among laboratories both in the measurement methodology and in the type of reported results&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest in the preparation of the present manuscript&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Background"
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          "identificador" => "sec0010"
          "titulo" => "Type i cryoglobulins"
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        6 => array:2 [
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          "titulo" => "Type ii and iiicryoglobulins &#40;mixed&#41;"
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          "identificador" => "sec0020"
          "titulo" => "Cryoprecipitation"
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        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Diagnosis of cryoglobulinemia"
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        9 => array:3 [
          "identificador" => "sec0030"
          "titulo" => "Characterization of cryoglobulins"
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              "identificador" => "sec0035"
              "titulo" => "Preanalysis phase"
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            1 => array:2 [
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          "titulo" => "Discussion"
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          "titulo" => "Acknowledgements"
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        13 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2018-10-15"
    "fechaAceptado" => "2018-10-25"
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          "clase" => "keyword"
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          "palabras" => array:3 [
            0 => "Cryoglobulinemic syndromes"
            1 => "Vasculitis"
            2 => "Cryoglobulins"
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          "clase" => "keyword"
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          "palabras" => array:3 [
            0 => "S&#237;ndromes crioglobulin&#233;micos"
            1 => "Vasculitis"
            2 => "Crioglobulinas"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cryoglobulinemic syndromes include a collection of manifestations that are found in various diseases and that share a pathophysiological mechanism&#58; cryoglobulin deposit in vascular beds&#46; For these syndromes&#44; the presence of cryoglobulins is a diagnostic criterion&#44; and their correct detection and characterization are therefore essential&#46; The Immunochemistry Group of the Spanish Society of Immunology conducted a comprehensive clinical and methodological review&#44; due to the interlaboratory heterogeneity in techniques&#44; with the objective of providing a useful and effective tool for diagnosing cryoglobulinemic syndromes&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los s&#237;ndromes crioglobulin&#233;micos comprenden un conjunto de manifestaciones que se encuentran en diversas enfermedades y que comparten un mismo mecanismo fisiopatol&#243;gico&#58; el dep&#243;sito de crioglobulinas en lechos vasculares&#46; La presencia de crioglobulinas es criterio diagn&#243;stico de estos s&#237;ndromes por lo que es imprescindible su correcta detecci&#243;n y caracterizaci&#243;n&#46; El Grupo de Inmunoqu&#237;mica de la Sociedad Espa&#241;ola de Inmunolog&#237;a ha realizado una revisi&#243;n exhaustiva cl&#237;nica y metodol&#243;gica&#44; debido a la heterogeneidad t&#233;cnica interlaboratorios&#44; con el objetivo de proporcionar una herramienta &#250;til y efectiva para el diagn&#243;stico de s&#237;ndromes crioglobulin&#233;micos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mariscal-Rodr&#237;guez A&#44; Villar Guimerans LM&#44; L&#243;pez-Trascasa M&#44; Hern&#225;ndez Gonz&#225;lez M&#44; Moga Naranjo E&#44; on behalf of grupo de inmunoqu&#237;mica de la Sociedad Espa&#241;ola de Inmunolog&#237;a&#46; Gu&#237;a de laboratorio para el diagn&#243;stico de pacientes con s&#237;ndrome crioglobulin&#233;mico&#46; Rev Clin Esp&#46; 2019&#59;219&#58;505&#8211;513&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The members of the Immunochemistry Group of the Spanish Society of Immunology are listed in <a class="elsevierStyleCrossRef" href="#sec0070">Appendix</a>&#46;</p>"
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            "apendice" => "<p id="par0190" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0070"
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        "etiqueta" => "Figure 1"
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        "fuente" => "Adapted from De Vita et al&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Preliminary classification criteria for cryoglobulinemic syndromes&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; CNS&#44; central nervous system&#59; RF&#44; rheumatoid factor&#46;</p>"
        ]
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        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Recommended algorithm for studying cryoglobulins&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Laboratory protocol for studying cryoglobulins&#46; <span class="elsevierStyleItalic">Abbreviation</span>&#58; IF&#44; immunofixation&#46;</p>"
        ]
      ]
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; AI&#44; autoimmune&#59; CMV&#44; cytomegalovirus&#59; MGUS&#44; monoclonal gammopathy of undetermined significance&#59; CLL&#44; chronic lymphocytic leukemia&#59; NHL&#44; non-Hodgkin&#39;s lymphoma&#59; MM&#44; multiple myeloma&#59; WM&#44; Waldenstrom macroglobulinemia&#59; EBV&#44; Epstein-Barr virus&#59; HBV&#44; hepatitis B virus&#59; HCV&#44; hepatitis C virus&#59; HIV&#44; human immunodeficiency virus&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cryoglobulin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Composition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Associated disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Volume&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Precipitation time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type <span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IgM&#44; IgG&#44; IgA or monoclonal free light-chains&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#8211;15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymphoproliferative diseases &#40;MGUS&#44; MM&#44; WM&#44; CLL&#44; NHL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#8211;80&#37; of serum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">min to h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type <span class="elsevierStyleSmallCaps">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monoclonal IgM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>polyclonal IgG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#8211;60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral infections &#40;HCV&#44; HBV&#44; HIV&#44; EBV&#44; CMV&#41;&#44; bacterial and parasitical&#44; autoimmune and lymphoproliferative disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&#8211;30&#37; of the serum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">h to days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type <span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Polyclonal IgM and IgG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#8211;30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&#8211;1&#46;5&#37; of serum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8211;5 days&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Centrifuge at 2000&#215;<span class="elsevierStyleItalic">g</span> 10<span class="elsevierStyleHsp" style=""></span>min at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Stir with vortex for approximately 30<span class="elsevierStyleHsp" style=""></span>seconds or until no precipitate is visible&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Centrifuge and repeat the flushing process twice more&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Resuspend the cryoprecipitate in PBS&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Incubate the samples for 1<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C before subjecting them to the quantitative method of choice&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Tube 2 &#40;1</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">h at 37</span><span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleItalic">C&#41;&#58; Follow the same procedure as for tube 1&#44; centrifuging at 37</span><span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleItalic">C &#40;or RT&#41; and perform flushing with PBS at 37</span><span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleItalic">C&#46;</span>&nbsp;\t\t\t\t\t\t\n
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