A 68-year-old male patient from North East of India, presented to the hospital with a history of easy fatigability for the past 6-8 months. The patient had been receiving repeated blood transfusions 6 to 8 times over the past 6 months with decreasing interval between each transfusion. He also presented with skin plaques, over his lower limbs and lower back measuring about 1x 0.8 cms. (Figure 7)

He walked into the phlebotomy area to give his blood sample for haematological and biochemical tests. The phlebotomist noticed that the moment he drew blood into the vacutainer system, it would form an immediate precipitate, get clotted and the sample of blood could not be inverted for mixing with the anticoagulant (Figure 1). The sample when processed for CBC gave spurious and bizzare results (Figure 2)

The patient’s blood sample was again collected but this time the vacutainer was immediately kept in an incubator at 37⁰ C for half an hour. The precipitate present in the blood sample dissolved and was immediately fed into the automated haematology analyser. The counts showed a significant improvement (Figure 3) Consecutively smears were made on pre warmed slides and stained with Leishman stain. The EDTA sample was brought to room temperature to again re visualise the formation of the precipitate and Leishman stained peripheral smear again made. Microscopic examination of the smears showed the presence of blue deposits in the smear with maximum of it seen in the smear made at room temperature (Figure 4 & 5).  and almost absent in the smear made at 37⁰ C. Rouleaux formation was noted in all smears.

A differential diagnosis of cryoglobulinemia was made on smear. Biochemical tests revealed reversal in albumin globulin ratio. Serology tests like ANA, ANCA, dsDNA for connective tissue disorder were found to be negative.  

In view of presence of cryoglobulins, intense rouleaux formation, reversal of albumin globulin ratio, bone marrow aspiration was done. Bone marrow examination showed an aparticulate bone marrow aspirate smears with blood dilute trails with predominance of plasma cells (Figure 6) The possibility of Lymphoplasmacytic lymphoma (Waldenstrom’s Macroglobulinemia) was suggested in correlation with serum protein electrophoresis and protein Immunofixation studies. Immunofixation electrophoresis showed IgM lambda monoclonal gammopathy.

With the above mentioned findings and clinical history a diagnosis of lymphoplasmacytic lymphoma was made.

Cryoglobulinemia is defined as the presence of circulating monoclonal immunoglobulins that will precipitate in colder temperatures and dissolve with warming. There are three types of cryoglobulins, Type I, II, and III. Type 1 usually occurs secondary to multiple B-cell lymphoproliferative disorders like monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia, or multiple myeloma and occurs because of aberrant and abnormal production of a monoclonal cryoglobulin by these neoplastic cells ^1,2,3

Cryoprecipitates indicate underlying disease therefor careful examination of patient with further evaluation by BMA, trephine biopsy, HCV status, serology and immunofixation when necessary. 

At phlebotomy level, with respect to collection of samples, they have to be collected in pre-warmed vacutainers and the optimal temperature has to be maintained during transportation and processing to prevent the cryoprecipitation.

One must be also mindful of the fact that cryoprecipitate may cause spurious CBC results. According to their size, they may only affect PLT counts but if they cluster together or if their size is larger, reaching that of leukocytes, WBC count is spuriously increased.

For pathologists, a careful screening of smears for blue precipitates fetches an early diagnosis and therefore careful microscopy is very valuable.

1.    Terrier B., Karras A., Kahn J.E. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore) 2013;92(2):61–68. [PMC free article] [PubMed] [Google Scholar]

2.    2. Harel S., Mohr M., Jahn I. Clinico-biological characteristics and treatment of type I monoclonal cryoglobulinaemia: a study of 64 cases. Br J Haematol. 2015;168(5):671–678. [PubMed] [Google Scholar]

3.    3. Kolopp-Sarda M.N., Miossec P. Cryoglobulinemic vasculitis: pathophysiological mechanisms and diagnosis. Curr Opin Rheumatol. 2021;33(1):1–7. [PubMed] [Google Scholar]