779:
spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.
148:
with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes three subtypes of cryoglobulinemic diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorder. The following table lists these three types of cryoglobulinemic disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total cryoglobulinemic disease cases, and class of disorders associated for each type.
461:(i.e., episodic painful reductions in blood flow to the fingers and toes). While the glomerulonephritis occurring in mixed disease appears to be due to inflammatory vasculitis, the glomerulonephritis occurring in type I disease appears due to the interruption of blood flow. The hematological, infectious, and autoimmune diseases underlying type II cryoglobulinemic disease and the infectious and autoimmune diseases underlying type III cryoglobulinemic disease are also critical parts of the disease's clinical findings.
761:. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryofibrinogenemia, fibrinogen deposition. In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each cases clinical findings.
42:
380:
macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free Îș light chains, or free λ light chains are extremely high in patients with non-IgM MGUS, non-IgM smoldering multiple myeloma, or multiple myeloma. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and
844:); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis. Along with this urgent treatment, severely symptomatic patients are commonly started on therapy to treat any underlying disease; this treatment is often supplemented with anti-inflammatory drugs such as
147:
by
Meltzer et al. in 1967, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia, that is cryoglobulinemic disease that is unassociated with an underlying disorder, has fallen. Currently most cases of this disease are found to be associated
908:
Treatment of mixed cryoglobulinemic disease is, similar to type I disease, directed toward treating any underlying disorder. This includes malignant (particularly
Waldenström's macroglobulinemia in type II disease), infectious, or autoimmune diseases in type II and III disease. Recently, evidence of
713:
or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens. These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for
307:
The clinical features of cryoglobulinemic disease can reflect those due not only to the circulation of cryoglobulins but also to any underlying hematological premalignant or malignant disorder, infectious disease, or autoimmune syndrome. The following sections of clinical features focuses on those
926:
using rituximab in combination with antiviral therapy or used alone in patients refractory to antiviral therapy has also proven successful in treating the hepatitis C-associated disease. Data on the treatment of infectious causes other than hepatitis C for the mixed disease are limited. A current
564:. Among these purely monoclonal immunoglobulin causes of cryoglobulinemic disease, Waldenström macroglobulinemia and multiple myeloma together account for â40% of cases; their pre-malignant precursors account for â44% of cases; and the other cited hematological diseases account for â16% of cases.
379:
and deposition of cryoglobulins within the blood vessels which reduce or stop blood perfusion to tissues. These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering
Waldenström's macroglobulinemia, or Waldenström's
778:
Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a
294:
methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the
96:(clump together) at temperatures below normal body temperature – 37 degrees Celsius (99 degrees Fahrenheit) – and will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become
509:(C4). The particular components involved are a reflection of the disorders which are associated with, and considered to be the cause of, the cryoglobulinemic disease. The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows:
295:
cryoglobulins of â10% of type II and III disease cases. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease and that some of the type III cases associated with the expression of low levels of a one or more
287:. Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease. The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.
913:
infection has been reported in the majority of mixed disease cases with rates being 70-90% in areas with high incidences of hepatitis C. The most effective therapy for hepatitis C-associated cryoglobulinemic disease consists of a combination of anti-viral drugs,
424:
Types II and III (or mixed or variant) cryoglobulinemic disease may also present with symptoms and signs of blood hyperviscosity syndrome and deposition of cryoglobulins within blood vessels but also include those attributable to cryoglobulinemic vasculitis.
1652:
Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M (2014). "Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the
Origgio study".
756:
to detect and quantify the presence of monoclonal IgG, IgM, IgA, Îș light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and
366:
The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e., mixed) cryoglobulinemic disease.
791:
and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins. Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e.g.,
699:
of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM, IgG or IgG, and complement components, particularly complement component 4
769:
All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.
1722:
1707:
1196:
1009:
111:
In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various
1833:
1368:
Tissot JD, Schifferli JA, Hochstrasser DF, et al. (1994). "Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide".
714:
them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease. Cryoglobulinemic disease must also be distinguished from
567:
Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly
927:
recommendation treats the underlying disease with appropriate antiviral, anti-bacterial, or anti-fungal agents, if available; in cases refractory to an appropriate drug, the addition of
718:
as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e.g.,
931:
to the therapeutic regimen may improve results. Mixed cryoglobulinemic disease associated with autoimmune disorders is treated with immunosuppressive drugs: combination of a
437:, and generalized weakness occurs in â33% of patients presenting with type II or type III disease. One or more skin lesions including palpable purpura, ulcers, digital
1826:
533:
343:
in type II and type III disease, deposit on the endothelium of blood vessels and activate the blood complement system to form pro-inflammatory elements such as
1819:
100:. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons:
1881:
1403:
Toyonaga, Ellen; Iwata, Hiroaki; Hotta, Moeko; Yoshimoto, Norihiro; Izumi, Kentaro; Shimizu, Hiroshi (2016). "Keep It Cool: Cryoglobulinemic
Purpura".
540:. Non-IgM monoclonal immunoglobulin-based cases of cryoglobulinemic disease are less commonly associated with other B-cell lymphocytic diseases viz.,
104:
cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and
1961:
275:, and thereby form tissue deposits that contain IgM, IgG (or, rarely, IgA), and components of the complement system, including in particular
1566:
Caimi G, Carlisi M, Urso C, Lo Presti R, Hopps E (2017). "Clinical disorders responsible for plasma hyperviscosity and skin complications".
522:
856:
drugs. Cases where no underlying disease is known are also often treated with the latter corticosteroid and immunosuppressive medications.
1113:
Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974). "Biologic and clinical significance of cryoglobulins. A report of 86 cases".
453:
in 19-44% of cases), kidney disease (primarily membranoproliferative glomerulonephritis (30%), joint pain (28%), and, less commonly,
279:. The vascular deposition of these types of cryoglobulin-containing immune complexes and complement can cause a clinical syndrome of
1078:
Ghetie D, Mehraban N, Sibley CH (2015). "Cold hard facts of cryoglobulinemia: updates on clinical features and treatment advances".
722:
and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens),
405:
612:
66:
869:
514:
196:
1201:
1014:
864:
Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (see
549:
537:
200:
841:
280:
1438:
592:
1896:
787:
People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent
616:
576:
291:
225:
676:
445:
occur in 69-89% of these mixed disease cases (see attached photograph); less common findings include painful
1606:
Grada A, Falanga V (2017). "Cryofibrinogenemia-Induced
Cutaneous Ulcers: A Review and Diagnostic Criteria".
1842:
873:
652:
561:
250:
184:
965:
348:
284:
188:
1966:
1915:
1903:
691:, and others. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses
688:
498:
494:
175:
518:
384:. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of
108:
healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.
833:
267:
The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have
93:
1737:
801:
557:
413:
308:
attributed to the cryoglobulins. Cryoglobulins cause tissue damage by three mechanisms; they can:
1046:
Retamozo S, Brito-ZerĂłn P, Bosch X, Stone JH, Ramos-Casals M (2013). "Cryoglobulinemic disease".
980:
376:
344:
316:
82:
696:
528:
Monoclonal IgG or, rarely, IgA, Îș light chain, or λ light chain cryoglobulins occur in cases of
1971:
1932:
1811:
990:
928:
853:
506:
450:
276:
135:
Since the first description of cryoglobulinemia in association with the clinical triad of skin
1777:
1854:
865:
805:
749:
479:
446:
381:
1875:
951:
have been used successfully to treated mixed disease associated with autoimmune disorders.
837:
660:
656:
541:
329:
deposit in small arteries and capillaries thereby plugging these blood vessels and causing
296:
254:
888:
in cells accumulating immunoglobulins) in patients with monoclonal immunoglobulin-induced
8:
1908:
1726:
975:
813:
748:
is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by
735:
644:
475:
648:
246:
1631:
1345:
1318:
1174:
1149:
960:
915:
900:
surface antigen-bearing lymphocytes) in patients with
Waldenstroms macroglobulinemia).
727:
710:
680:
668:
664:
620:
458:
426:
393:
242:
124:
120:
1731:
337:
of tissues including in particular skin (e.g., ears), distal extremities, and kidneys;
1892:
1748:
1670:
1623:
1583:
1545:
1503:
1420:
1385:
1381:
1350:
1286:
1244:
1179:
1130:
1126:
1095:
1055:
970:
745:
731:
723:
719:
692:
553:
502:
272:
268:
258:
49:
1635:
1887:
1871:
1662:
1615:
1575:
1537:
1493:
1412:
1377:
1340:
1330:
1278:
1236:
1169:
1161:
1122:
1087:
936:
545:
529:
486:
454:
192:
1788:
758:
299:
of circulating monoclonal immunoglobulin(s) are in transition to type II disease.
1858:
1742:
1666:
1541:
1498:
1481:
1416:
1396:
985:
628:
588:
1799:
579:, and, less commonly or rarely, with cases of other infectious diseases such as
1920:
1579:
1282:
1240:
932:
889:
845:
788:
753:
632:
271:
activity. That is, they bind to polyclonal immunoglobulins, activate the blood
86:
1753:
1716:
1619:
1091:
358:
seen in cryoglobulinemia may also be referred to as cryoglobulinemic purpura.
1955:
1424:
944:
849:
817:
739:
636:
315:
increase blood viscosity thereby reducing blood flow to tissues to cause the
112:
228:; hematological diseases particularly B cell disorders; autoimmune diseases
127:
diseases that are the underlying cause for production of the cryoglobulins.
1866:
1674:
1627:
1587:
1549:
1507:
1354:
1319:"Managing refractory cryoglobulinemic vasculitis: challenges and solutions"
1290:
1248:
1183:
1099:
1059:
940:
877:
825:
821:
672:
596:
389:
70:
1389:
1134:
375:
Signs and symptoms due to the cryoglobulins of type I disease reflect the
1772:
910:
709:
Cryoglobulinemia and cryoglobulinemic disease must be distinguished from
684:
584:
580:
568:
501:
free light chain portions of these antibodies, and proteins of the blood
217:
1699:
1335:
319:(i.e., headache, confusion, blurry or loss of vision, hearing loss, and
1794:
1165:
881:
829:
809:
434:
401:
330:
171:
140:
97:
78:
54:
347:
thereby initiating the systemic vascular inflammatory reaction termed
1783:
948:
919:
893:
885:
715:
640:
409:
397:
320:
116:
1269:
Tedeschi A, BaratĂš C, Minola E, Morra E (2007). "Cryoglobulinemia".
1227:
Tedeschi A, BaratĂš C, Minola E, Morra E (2007). "Cryoglobulinemia".
65:
is a medical condition in which the blood contains large amounts of
41:
1845:
797:
600:
474:
Cryoglobulins consists of one or more of the following components:
442:
438:
334:
144:
74:
556:; they occur rarely in non-B cell hematological disorders such as
624:
608:
604:
430:
385:
355:
136:
1841:
782:
1711:
923:
824:, causing acute abdominal pain, general malaise, fever, and/or
793:
408:; and cardiovascular disturbances such as shortness of breath,
1651:
1045:
643:. These mixed-protein cryoglobulins are also associated with
283:
characterized by systemic vasculitis and inflammation termed
1367:
419:
1402:
903:
897:
534:
non-IgM monoclonal gammopathy of undetermined significance
1565:
1268:
1226:
572:
490:
482:
221:
81:
at reduced temperatures. This should be contrasted with
1112:
519:
IgM monoclonal gammopathy of undetermined significance
513:
Monoclonal IgM-based cryoglobulin occurs in cases of
390:
blue discoloration of the arms or legs (acrocyanosis)
361:
1689:
1077:
859:
410:
inadequate levels of oxygen in the blood (hypoxemia)
1528:Michaud M, Pourrat J (2013). "Cryofibrinogenemia".
210:Monoclonal IgM plus polyclonal IgG or, rarely, IgA
1147:
828:; vasculitis-driven pulmonary disturbances (e.g.,
370:
16:Presence of cold-sensitive antibodies in the blood
1479:
532:and the pre-malignant precursors to this cancer,
517:and the pre-malignant precursors to this cancer,
1953:
1439:"Overview of cryoglobulins and cryoglobulinemia"
773:
1647:
1645:
1601:
1599:
1597:
1561:
1559:
1523:
1521:
1519:
1517:
1475:
1473:
1471:
1469:
1467:
1465:
1463:
1461:
1459:
1527:
1316:
1312:
1310:
1308:
1306:
1304:
1302:
1300:
1222:
1220:
1218:
1216:
1214:
1212:
1210:
1073:
1071:
1069:
1041:
1039:
1037:
1035:
1033:
1031:
1029:
1027:
1025:
1023:
1827:
783:Severely symptomatic cryoglobulinemic disease
1642:
1605:
1594:
1556:
1514:
1456:
1297:
1207:
1066:
1020:
35:Cryoglobulinaemia, cryoglobulinemic disease
1834:
1820:
1106:
1080:Rheumatic Disease Clinics of North America
523:smoldering Waldenstrom's macroglobulinemia
236:Polyclonal IgM plus polyclonal IgG or IgA
40:
1497:
1344:
1334:
1173:
420:Types II and III cryoglobulinemic disease
1608:American Journal of Clinical Dermatology
1264:
1262:
1260:
1258:
1141:
947:or combination of a corticosteroid with
904:Type II and III cryoglobulinemic disease
406:membranoproliferative glomerulonephritis
1148:Ferri C, Zignego AL, Pileri SA (2002).
1954:
1361:
67:pathological cold sensitive antibodies
1962:Hepatitis C virus-associated diseases
1815:
1568:European Journal of Internal Medicine
1480:Muchtar E, Magen H, Gertz MA (2017).
1255:
302:
183:Hematological diseases, particularly
695:activity and therefore binds to the
550:B-cell chronic lymphocytic leukemia
538:non-IgM smoldering multiple myeloma
257:; infectious diseases particularly
13:
362:Essential cryoglobulinemic disease
216:Infectious diseases, particularly
14:
1983:
1685:
281:cutaneous small-vessel vasculitis
130:
1530:Journal of Clinical Rheumatology
1405:The American Journal of Medicine
1323:Journal of Inflammation Research
469:
163:Association with other diseases
1431:
1048:Oncology (Williston Park, N.Y.)
870:Waldenström's macroglobulinemia
860:Type I cryoglobulinemic disease
800:) and/or cardiovascular (e.g.,
617:subacute bacterial endocarditis
577:Hepatitis C and HIV coinfection
515:Waldenström's macroglobulinemia
371:Type I cryoglobulinemic disease
226:Hepatitis C and HIV coinfection
197:Waldenström's macroglobulinemia
85:, which cause agglutination of
1482:"How I treat cryoglobulinemia"
1411:(11). Elsevier BV: 1163â1165.
1317:Ostojic P, Jeremic IR (2017).
1190:
1003:
1:
1897:Waldenström macroglobulinemia
996:
876:). This involves appropriate
774:Asymptomatic cryoglobulinemia
1667:10.1016/j.autrev.2013.11.005
1542:10.1097/RHU.0b013e318289e06e
1499:10.1182/blood-2016-09-719773
1417:10.1016/j.amjmed.2016.08.002
1382:10.1016/0022-1759(94)90284-4
1202:Dorland's Medical Dictionary
1127:10.1016/0002-9343(74)90852-3
1015:Dorland's Medical Dictionary
874:chronic lymphocytic leukemia
836:, X-ray evidence of diffuse
764:
704:
653:systemic lupus erythematosus
593:EpsteinâBarr virus infection
562:chronic myelogenous leukemia
464:
290:More recent high resolution
251:systemic lupus erythematosus
201:chronic lymphocytic leukemia
7:
966:Cryoglobulinemic vasculitis
954:
896:(antibody directed against
880:regimens which may include
842:diffuse alveolar hemorrhage
689:inflammatory bowel diseases
613:poststreptococcal nephritis
349:cryoglobulinemic vasculitis
285:cryoglobulinemic vasculitis
189:smoldering multiple myeloma
10:
1988:
1580:10.1016/j.ejim.2017.04.001
1283:10.1016/j.blre.2006.12.002
1241:10.1016/j.blre.2006.12.002
816:, intestinal perforation,
1930:
1853:
1763:
1693:
1620:10.1007/s40257-016-0228-y
1092:10.1016/j.rdc.2014.09.008
1054:(11): 1098â1105, 1110â6.
834:acute respiratory failure
796:, mental impairment, and
558:myelodysplastic syndromes
176:their Îș or λ light chains
48:
39:
31:
26:
884:(promotes cell death by
802:congestive heart failure
677:HenochâSchönlein purpura
493:antibodies, monoclonal
414:congestive heart failure
392:, necrosis, ulcers, and
92:Cryoglobulins typically
77:themselves) that become
981:Hyperviscosity syndrome
929:immunosuppressive drugs
317:hyperviscosity syndrome
292:protein electrophoresis
1933:hypergammaglobulinemia
1086:(1): 93â108, viiiâix.
991:Plasma cell dyscrasias
826:bloody bowel movements
740:hypercoagulable states
507:complement component 4
451:mononeuritis multiplex
449:(often manifesting as
277:complement component 4
866:plasma cell dyscrasia
838:pulmonary infiltrates
806:myocardial infarction
750:immunoelectrophoresis
447:peripheral neuropathy
382:peripheral neuropathy
1876:Plasma cell leukemia
1655:Autoimmunity Reviews
661:polyarteritis nodosa
657:rheumatoid arthritis
542:Non-Hodgkin lymphoma
255:rheumatoid arthritis
1921:Primary amyloidosis
1909:Heavy chain disease
1843:Immunoproliferative
1370:J. Immunol. Methods
1336:10.2147/JIR.S114067
976:Hematopoietic ulcer
814:intestinal ischemia
759:hepatitic C antigen
736:ecthyma gangrenosum
645:autoimmune diseases
243:Autoimmune diseases
73:â proteins (mostly
1764:External resources
1166:10.1136/jcp.55.1.4
1010:"Cryoglobulinemia"
961:Cryofibrinogenemia
728:cholesterol emboli
711:cryofibrinogenemia
681:pemphigus vulgaris
669:temporal arteritis
665:systemic sclerosis
621:coccidioidomycosis
459:Raynaud phenomenon
394:livedo reticularis
303:Signs and symptoms
249:and less commonly
174:IgG, IgM, IgA, or
1967:Medical diagnosis
1949:
1948:
1893:Macroglobulinemia
1809:
1808:
971:Dysfibrinogenemia
854:immunosuppressive
830:coughing up blood
746:Rheumatoid factor
732:warfarin necrosis
724:purpura fulminans
720:dysfibrinogenemia
693:rheumatoid factor
554:Castleman disease
503:complement system
273:complement system
269:rheumatoid factor
265:
264:
160:Percent of cases
60:
59:
21:Medical condition
1979:
1941:Cryoglobulinemia
1872:Multiple myeloma
1836:
1829:
1822:
1813:
1812:
1800:Cryoglobulinemia
1691:
1690:
1679:
1678:
1649:
1640:
1639:
1603:
1592:
1591:
1563:
1554:
1553:
1525:
1512:
1511:
1501:
1477:
1454:
1453:
1451:
1449:
1443:www.uptodate.com
1435:
1429:
1428:
1400:
1394:
1393:
1365:
1359:
1358:
1348:
1338:
1314:
1295:
1294:
1266:
1253:
1252:
1224:
1205:
1194:
1188:
1187:
1177:
1145:
1139:
1138:
1110:
1104:
1103:
1075:
1064:
1063:
1043:
1018:
1007:
937:cyclophosphamide
808:) disturbances;
651:, less commonly
649:Sjögren syndrome
546:Hodgkin lymphoma
530:multiple myeloma
455:dry eye syndrome
247:Sjögren syndrome
193:multiple myeloma
151:
150:
83:cold agglutinins
63:Cryoglobulinemia
44:
27:Cryoglobulinemia
24:
23:
1987:
1986:
1982:
1981:
1980:
1978:
1977:
1976:
1952:
1951:
1950:
1945:
1926:
1849:
1840:
1810:
1805:
1804:
1759:
1758:
1702:
1688:
1683:
1682:
1650:
1643:
1604:
1595:
1564:
1557:
1526:
1515:
1478:
1457:
1447:
1445:
1437:
1436:
1432:
1401:
1397:
1366:
1362:
1315:
1298:
1267:
1256:
1225:
1208:
1195:
1191:
1154:J. Clin. Pathol
1150:"Cryoglobulins"
1146:
1142:
1111:
1107:
1076:
1067:
1044:
1021:
1008:
1004:
999:
986:Paraproteinemia
957:
922:; depletion of
906:
862:
846:corticosteroids
785:
776:
767:
707:
647:, particularly
629:schistosomiasis
589:cytomegalovirus
575:infection, and
505:, particularly
472:
467:
441:, and areas of
427:Meltzer's triad
422:
373:
364:
305:
245:, particularly
224:infection, and
133:
87:red blood cells
75:immunoglobulins
22:
17:
12:
11:
5:
1985:
1975:
1974:
1969:
1964:
1947:
1946:
1944:
1943:
1937:
1935:
1928:
1927:
1925:
1924:
1912:
1900:
1884:
1879:
1869:
1863:
1861:
1851:
1850:
1846:immunoglobulin
1839:
1838:
1831:
1824:
1816:
1807:
1806:
1803:
1802:
1791:
1780:
1768:
1767:
1765:
1761:
1760:
1757:
1756:
1745:
1734:
1719:
1703:
1698:
1697:
1695:
1694:Classification
1687:
1686:External links
1684:
1681:
1680:
1641:
1593:
1555:
1513:
1492:(3): 289â298.
1455:
1430:
1395:
1360:
1296:
1277:(4): 183â200.
1254:
1235:(4): 183â200.
1206:
1197:"Cryoglobulin"
1189:
1140:
1105:
1065:
1019:
1001:
1000:
998:
995:
994:
993:
988:
983:
978:
973:
968:
963:
956:
953:
933:corticosteroid
916:pegylated INFα
905:
902:
890:kidney failure
861:
858:
789:plasmapharesis
784:
781:
775:
772:
766:
763:
754:immunofixation
738:, and various
706:
703:
702:
701:
633:echinococcosis
603:, lepromatous
565:
526:
471:
468:
466:
463:
429:" of palpable
421:
418:
396:; spontaneous
377:hyperviscosity
372:
369:
363:
360:
353:
352:
338:
324:
304:
301:
263:
262:
240:
237:
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229:
214:
211:
208:
204:
203:
181:
178:
169:
165:
164:
161:
158:
155:
132:
131:Classification
129:
58:
57:
52:
46:
45:
37:
36:
33:
29:
28:
20:
15:
9:
6:
4:
3:
2:
1984:
1973:
1972:Medical signs
1970:
1968:
1965:
1963:
1960:
1959:
1957:
1942:
1939:
1938:
1936:
1934:
1929:
1922:
1918:
1917:
1913:
1910:
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1901:
1898:
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1890:
1889:
1885:
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1880:
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1814:
1801:
1797:
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1779:
1775:
1774:
1770:
1769:
1766:
1762:
1755:
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1746:
1744:
1740:
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1735:
1733:
1729:
1728:
1724:
1720:
1718:
1714:
1713:
1709:
1705:
1704:
1701:
1696:
1692:
1676:
1672:
1668:
1664:
1661:(6): 609â14.
1660:
1656:
1648:
1646:
1637:
1633:
1629:
1625:
1621:
1617:
1614:(1): 97â104.
1613:
1609:
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1600:
1598:
1589:
1585:
1581:
1577:
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1562:
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1272:
1265:
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1234:
1230:
1229:Blood Reviews
1223:
1221:
1219:
1217:
1215:
1213:
1211:
1204:
1203:
1198:
1193:
1185:
1181:
1176:
1171:
1167:
1163:
1159:
1155:
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1144:
1136:
1132:
1128:
1124:
1121:(5): 775â88.
1120:
1116:
1109:
1101:
1097:
1093:
1089:
1085:
1081:
1074:
1072:
1070:
1061:
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946:
945:mycophenolate
942:
938:
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925:
921:
917:
912:
901:
899:
895:
891:
887:
883:
879:
875:
871:
867:
857:
855:
851:
850:dexamethasone
847:
843:
839:
835:
831:
827:
823:
819:
818:cholecystitis
815:
811:
807:
803:
799:
795:
790:
780:
771:
762:
760:
755:
751:
747:
743:
741:
737:
733:
729:
725:
721:
717:
712:
698:
694:
690:
686:
682:
678:
674:
670:
666:
662:
659:, and rarely
658:
654:
650:
646:
642:
638:
637:toxoplasmosis
634:
630:
626:
622:
618:
614:
610:
606:
602:
598:
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582:
578:
574:
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566:
563:
559:
555:
551:
547:
543:
539:
535:
531:
527:
524:
520:
516:
512:
511:
510:
508:
504:
500:
496:
492:
488:
484:
481:
477:
470:Cryoglobulins
462:
460:
456:
452:
448:
444:
440:
436:
432:
428:
417:
415:
411:
407:
403:
399:
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391:
387:
383:
378:
368:
359:
357:
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336:
332:
328:
325:
322:
318:
314:
311:
310:
309:
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293:
288:
286:
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278:
274:
270:
260:
256:
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177:
173:
170:
167:
166:
162:
159:
156:
153:
152:
149:
146:
142:
138:
128:
126:
122:
118:
114:
113:pre-malignant
109:
107:
103:
99:
95:
90:
88:
84:
80:
76:
72:
71:cryoglobulins
68:
64:
56:
53:
51:
47:
43:
38:
34:
30:
25:
19:
1940:
1914:
1902:
1886:
1867:Plasmacytoma
1793:
1782:
1771:
1747:
1736:
1721:
1706:
1658:
1654:
1611:
1607:
1571:
1567:
1536:(3): 142â8.
1533:
1529:
1489:
1485:
1446:. Retrieved
1442:
1433:
1408:
1404:
1398:
1376:(1): 63â75.
1373:
1369:
1363:
1326:
1322:
1274:
1270:
1232:
1228:
1200:
1192:
1157:
1153:
1143:
1118:
1114:
1108:
1083:
1079:
1051:
1047:
1013:
1005:
941:azathioprine
935:with either
907:
878:chemotherapy
863:
822:pancreatitis
786:
777:
768:
744:
708:
673:polymyositis
597:Lyme disease
473:
423:
374:
365:
354:
340:
326:
312:
306:
289:
266:
157:Composition
134:
110:
105:
101:
91:
62:
61:
18:
1916:light chain
1904:heavy chain
1773:MedlinePlus
1160:(1): 4â13.
911:hepatitis C
685:sarcoidosis
591:infection,
587:infection,
585:hepatitis A
583:infection,
581:hepatitis B
571:infection,
569:hepatitis C
398:nose bleeds
220:infection,
218:hepatitis C
94:precipitate
32:Other names
1956:Categories
1795:Patient UK
1749:DiseasesDB
1448:August 31,
1115:Am. J. Med
997:References
882:bortezomib
840:caused by
810:vasculitis
480:polyclonal
476:monoclonal
435:joint pain
402:joint pain
331:infarction
261:infection
172:Monoclonal
141:joint pain
125:autoimmune
121:infectious
98:gangrenous
55:Hematology
1848:disorders
1784:eMedicine
1574:: 24â28.
1425:0002-9343
1329:: 49â54.
1271:Blood Rev
949:rituximab
920:ribavirin
894:rituximab
886:apoptosis
852:) and/or
765:Treatment
716:frostbite
705:Diagnosis
697:Fc region
641:Kala-azar
465:Mechanism
321:epistaxis
233:Type III
117:malignant
79:insoluble
50:Specialty
1675:24418294
1636:39645385
1628:27734332
1588:28390781
1550:23519183
1508:27799164
1355:28507447
1291:17289231
1249:17289231
1184:11825916
1100:25399942
1060:24575538
955:See also
812:-driven
798:myelitis
601:syphilis
443:necrosis
439:gangrene
335:necrosis
297:isotypes
207:Type II
145:weakness
69:called
1789:med/480
1743:D003449
1390:8034987
1346:5428757
1175:1769573
1135:4216269
924:B cells
848:(e.g.,
625:malaria
609:Q fever
605:leprosy
431:purpura
386:purpura
356:Purpura
239:25â30%
213:50â60%
180:10â15%
168:Type I
137:purpura
1931:Other
1778:000540
1673:
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794:stroke
639:, and
552:, and
412:, and
199:, and
143:, and
1732:273.2
1717:D89.1
1632:S2CID
1486:Blood
943:, or
820:, or
700:(C4).
497:, or
154:Type
123:, or
1882:MGUS
1855:PCDs
1754:3207
1738:MeSH
1727:9-CM
1671:PMID
1624:PMID
1584:PMID
1546:PMID
1504:PMID
1450:2017
1421:ISSN
1386:PMID
1351:PMID
1287:PMID
1245:PMID
1180:PMID
1131:PMID
1096:PMID
1056:PMID
918:and
898:CD20
892:and
752:and
655:and
560:and
536:and
521:and
333:and
253:and
185:MGUS
1888:IgM
1723:ICD
1708:ICD
1663:doi
1616:doi
1576:doi
1538:doi
1494:doi
1490:129
1413:doi
1409:129
1378:doi
1374:173
1341:PMC
1331:doi
1279:doi
1237:doi
1199:at
1170:PMC
1162:doi
1123:doi
1088:doi
1012:at
667:,
573:HIV
491:IgA
487:IgG
483:IgM
478:or
345:C5a
259:HCV
222:HIV
1958::
1859:PP
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1787::
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