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Cryoglobulins are serum paraproteins which may produced in association with several blood dyscrasias. Some are associated with monoclonal neoplastic disorders such as Waldenstrom's macroglobulinemia and multiple myeloma. Patients may present with inflammatory macules and papules, usually on the lower extremities. Ulceration may supervene with hemorrhagic bullae and crusts.


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Type I Waldenstrom's macroglobulinemia
Multiple myeloma
Monoclonal gammopathy of undetermined significance
Chronic lymphocytic leukemia or lymphoma
Type II  

Type-I cryoglobulinemia-like histopathologic changes in tick bites: a useful clue for tissue diagnosis in the absence of tick parts

Catherine M. Stefanato
Robert G. Phelps
Lynne J. Goldberg
Ann E. Perry
and Jag Bhawan
J Cutan Pathol 2002;29:101-106 Abstract quote

Background:The histopathologic findings of localized reactions to tick bites may present as diagnostic dilemmas, especially if there is no history of a tick bite, or if the tick's mouthparts are not present in the biopsied skin.

Objective:Skin biopsies of patients with a clinical history of a tick bite were selected and reviewed with the aim of detecting a common histopathologic denominator which could serve as a useful clue to the diagnosis, especially when the tick's mouthparts are absent.

Methods:Hematoxylin and eosin-stained slides of 15 skin biopsies of tick bites were retrieved from three dermatopathology and pathology laboratories. Where additional paraffin-embedded tissue was available, additional sections were also stained with periodic acid-Schiff (PAS) and phosphotungstic acid-hematoxylin (PTAH).

Results:In every case in which adequate tissue was available (13/15 biopsies), the capillaries and postcapillary venules of the superficial and deep vascular plexi adjacent to the attachment's site were filled with thrombi. Fibrin thrombi were seen in association with other more numerous thrombi characterized by homogeneous eosinophilic hyaline material similar to the cryoprecipitate present in type I (monoclonal) cryoglobulinemia. All thrombi were positive for PAS and PTAH; however, the latter staining was minimally present in the hyaline thrombi. In most cases, the site of the tick bite showed ulceration, with an underlying wedge-shaped superficial and deep perivascular and occasionally interstitial mixed lymphohistiocytic infiltrate. In addition, there were eosinophils, numerous neutrophils and extravasated erythrocytes. Other findings included suppurative necrosis (7/15) cases, giant-cell reaction (one case), fat necrosis (one case) and eccrine gland necrosis (one case).

Conclusions:Vascular eosinophilic hyaline thrombi were found to be a frequent histologic manifestation of a tick bite. This finding may be related to the secretory products of the tick's saliva during inoculation. We believe that a tick bite should be suspected when focal intravascular hyaline occlusion is observed, and that it should be included in the differential diagnosis of type I (monoclonal) cryoglobulinemia, even if there is no history of a tick bite or if tick parts are not present in the skin biopsy specimen.


Type I

Associated with monoclonal immunoglobulin of a single class, usually IgM or IgG

Type II  


Laboratory Markers High levels of circulating cryoglobulins associated with cutaneous deposits

Laboratory identification of cryoglobulinemia from automated blood cell counts, fresh blood samples, and blood films.

Fohlen-Walter A, Jacob C, Lecompte T, Lesesve JF.

Hematology Laboratory, Centre Hospitalier Universitaire Nancy, Vandoeuvre, France.

Am J Clin Pathol 2002 Apr;117(4):606-14 Abstract quote

Four cases showing different means to detect cryoglobulins are reported: effects on blood cell counts performed on 2 technologically different automated hematology instruments and microscopic features in fresh blood samples and on May-Grunwald-Giemsa-stained bloodfilms.

These cases were chosen for their instructive value in depicting all artifacts associated with cryoglobulins. Laboratory recognition of the cryoglobulins is important to correct factitious results with automated blood cell counters, mainly pseudoleukocytosis and pseudothrombocytosis.

Moreover cryoglobulin-induced laboratory artifacts may be the first factor prompting the assessment for cryoglobulinemia and the diagnosis of the underlying cause.


General-Type I

Inflammatory macules and papules
Raynaud phenomenon
Cold urticaria
Hemorrhagic crusts
Cutaneous ulcerations
Livedo reticularis

VARIANTS Lesions of the oral or nasal mucosa of the head and neck more common


General Intravascular deposits of eosinophilic, PAS positive hyaline material with little inflammatory reaction
VARIANTS Necrotizing vasculitis in rare cases

The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney.

Nash JW, Ross P Jr, Neil Crowson A, Taylor J, Morales JE, Yunger TM, Magro C.

Department of Pathology, Ohio State University Medical Center, Columbus, USA.


Am J Clin Pathol 2003 Jan;119(1):114-22 Abstract quote

Although the histologic characteristics of cryofibrinogenemia have been described in skin lesions, the literature is largely devoid of descriptions of this disorder in other organs.

This series is the first to document the histopathologic manifestations of intrapulmonary, intramuscular, and renal cryofibrinogenemia. We describe the histopathologic manifestations of cryofibrinogenemia in 10 cases with manifestations in 4 organ systems: skin in 7 cases, skeletal muscle in 2, lung in 2, and kidney in 1. Irrespective of anatomic site, all lesions showed an occlusive thrombotic diathesis comprising eosinophilic refractile deposits within vessel lumina with extension into the intima, with or without an accompanying characteristic granulomatous vasculitic component.

Ultrastructural examination of the renal deposits showed fibrillary material within glomerular capillary lumina with unique morphologic features not previously described. Analysis of plasma from several cases revealed a cold-precipitable protein, which in most cases included a monoclonal paraprotein. The laboratory and histologic distinctions between cryofibrinogenemia and cryoglobulinemia are addressed.

We provide guidelines for the proper handling of patient specimens in the workup of cryofibrinogenemia.


Special stains PAS positive intravascular deposits



Tick mouth parts occlusive vasculopathy: a localized cryoglobulinemic vasculitic response.

Galaria NA, Chaudhary O, Magro CM.

Department of Dermatology, Strong Memorial Hospital, Rochester, NY, USA, Medical School, University of Western Ontario, London, Ontario, Canada, and Department of Pathology, Ohio State University, OH, USA.

J Cutan Pathol. 2003 May;30(5):303-6. Abstract quote

BACKGROUND: The histologic hallmark of most arthropod bite reactions is a deep, wedge-shaped perivascular and interstitial infiltrate comprising lymphocytes, neutrophils, and eosinophils.

METHODS: We present a case series of six patients in whom tick bite reactions, when examined microscopically, were found to mimic mixed cryoglobulinemic vasculitis.

RESULTS: Though different in histology, clinically these lesions were indistinguishable from typical tick bite reactions.

CONCLUSION: As five of our six biopsy specimens were found to still harbor retained tick parts, it is possible that the actual retention of tick parts was involved in evoking this localized cryoprecipitate reaction.


Treatment Treatment of the underlying disease

J Am Acad Dermatol 1991;25:21-27
Arch Dermatol 1992;128:377-380
J Am Acad Dermatol 1999;40:507-535

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Last Updated 6/6/2003

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