J Med Genet: first published as 10.1136/jmg.26.10.631 on 1 October 1989. Downloaded from

Journal of Medical Genetics 1989, 26, 631-636

Transient nephrotic syndrome after anaesthesia resulting from a familial cryofibrinogen precipitating at 35°C

Y LOLIN*, P A RAZISt, P O'GORMANt, M HJELM§, AND A S WIERZBICKI* From *the Department of Chemical Pathology, The National Hospitals for Nervous Diseases, Queen Square, London WCJ; tDepartment of Anaesthesia, University College Hospital, Gower Street, London WCI; fDepartmentofChemical Pathology, Brook GeneralHospital, ShootersHillRoad, Blackheath, London SE18; and§DepartmentofClinicalBiochemistry, The HospitalforSick Children, Great OrmondStreet, London WCI.

SUMMARY Transient nephrotic syndrome, haematuria, and cryofibrinogenuria in a child after anaesthesia were found in association with a plasma cryofibrinogen that precipitated at 35°C. Investigation of the family showed this to be a familial trait probably with dominant inheritance.

In 1955, Korst and Kratochvill coined the term biopsy because of a history of postoperative cryofibrinogen to describe a plasma protein which and 'myoglobinuria'. She was born after a normal precipitated on cooling and redissolved on re- pregnancy and delivery with bifida occulta spina and copyright. warming to 37°C. Since then, cryofibrinogenaemia spinal dysraphism. She has two healthy sisters. The has been found to occur in 3% of hospital patients.2 3 father had congenital dislocation of the hips and one It has been described in association with a variety of of the paternal uncles is mentally subnormal. The conditions including malignancy,3 6 infection,' 7-9 father and the maternal grandmother were the only autoimmune disorders,57 10 thromboembolic members of the family who were known to have had disease, 3 5 711 glomerulonephritis,12 13 diabetes operations, both as adults, with uncomplicated mellitus,3 pregnancy,3 14 and in women taking oral recoveries. The proband had had seven operations contraceptives.15 In rare instances when no under- between the ages of two weeks and six years, all lying disease has been found, the cryofibrino- under general anaesthesia, for the correction of foot http://jmg.bmj.com/ genaemia has been termed primary or essential.3 5 16 deformities and a right eye squint. Four of the Cold related symptoms usually sugest the di- operations were followed by uneventful recoveries, agnosis, but they may be absent.3 5 6 but three were followed by nausea, vomiting, Heat loss is a common accompaniment of anaes- myalgia (with on one occasion a recorded creatine thesia18 because of the use of cold and dry gases, kinase activity (CK) of 24 000 U/l), and the passage exposure to a cool environment of often vasodilated of 'dark' urine, with spontaneous, full recovery patients, heat loss from the operation site, the three to five days postoperatively. Inheritance of a infusion of cold fluids, and abolition of the shivering gene for malignant hyperpyrexia was excluded in on October 6, 2021 by guest. Protected reflex by muscle relaxants. It is greatest in children both parents. The child's temperature had never because of their larger surface area to volume ratio, been recorded as higher than 37 5°C, but had been with most heat loss occurring in the first operative 35°C (axilla) on at least one occasion. She had also hour. We report an unusual presentation of the had measles, chickenpox, and 'gastroenteritis' that complications of a cryofibrinogen that precipitated had followed a 'normal' course. However, one at 35°C in a child after anaesthesia and a hitherto month before the present admission she had a 'cold' undescribed familial form of the condition. and because she was febrile the mother had un- covered her for about an hour and had opened the Case report windows. Several hours later the child developed the same symptoms and signs as above. The proband, a seven year old girl, was admitted to When admitted the child was well, cheerful, and the National Hospital in June 1987 for a muscle active. She walked with orthopaedic supports and Received for publication 21 March 1989. wore nappies because of frequent incontinence. Accepted for publication 20 April 1989. There was severe wasting of the muscles below the 631 J Med Genet: first published as 10.1136/jmg.26.10.631 on 1 October 1989. Downloaded from

632 Y Lolin, P A Razis, P O'Gorman, M Hjelm, and A S Wierzbicki knees consistent with her spinal cord disorder and acrocyanosis over uncovered noses and cheeks when she had a right third nerve palsy. The muscle biopsy exposed to the cold, the symploms being relieved was performed on the left vastus lateralis under only after several hours in the warmth. The proband general anaesthesia using etomidate for induction, was most affected. The mother had, however, alfentanil, nitrous oxide in oxygen, and trichloro- stayed indoors most of the time and remained ethylene from a 'halothane free' machine for symptom free. maintenance, under standard hospital theatre conditions. During the 20 minute procedure the Initial investigation and results on proband child's extremities were left uncovered. Axilla temperatures varied betwen 35°C and 36*5°C. The BLOOD operation and recovery from the anaesthetic were Routine preoperative investigations showed normal uneventful, but the child remained nauseated and haematological and biochemical indices except for a irritable for the rest of the day. The next day she slightly raised serum CK activity (83 U/l, reference developed a temperature of 37-5°C, complained of range 10 to 70). However, on the first postoperative pain in the thighs, was noted to have bilateral day the CK activity rose to 11 460 U/l (the serum lumbar tenderness, and started passing 'dark' urine. CK activity was 400 U/l one day after performing a She was treated with intravenous fluids only and by muscle biopsy under similar conditions in another the fifth postoperative day she was well again and young patient) and the white blood cell count was the urine was clear. 17-5x 109/l (84% neutrophils). The plasma and Detailed histories indicated that the maternal serum samples received on that day were haemo- grandmother had had symptoms suggestive of lysed. The blood urea remained normal throughout Raynaud's phenomenon in the fingers for most of her hospital stay and postoperative serum creatinine her life, and that one maternal uncle developed joint level was normal. Further investigations showed and muscle pains and a rash in cold weather. normal clotting studies, degradation

However, in January 1988, nine members of the products of less than 10 mg/l, insignificant antibodycopyright. family, including the proband, went for the first time titres to an extensive panel of viruses (including the on a skiing holiday (in Austria), and encountered Epstein Barr virus and mycoplasma pneumoniae), a low temperatures (fig 1). Seven of them developed negative autoantibody screen and 1gM cold agglu- tinins, which, however, reacted at less than 20°C.

URINE A routine mid stream urine (MSU) sample examined before surgery was clear and contained no protein, casts, or cells. A sample received during the http://jmg.bmj.com/ first postoperative day contained brown and white granular material, comprising a third of the total volume after centrifugation, and with a clear super- 32'C 32C 35C 32tC* * natant. There was no excess of porphyrins. Dipstick (Labsticks, Ames, Slough, UK) analysis showed the presence of heavy and haematuria. 33"C 35°C 33'C 35'C 35°C 28'C showed red and white blood

Microscopy cells, on October 6, 2021 by guest. Protected granular casts, and large amounts of amorphous * * Cryofibriniogen detected deposit. The protein content of the supematant absent (biuret method) was 10 gIl. Agarose electrophoresis Cryofibrinogen (Coming Medical, Halstead, Essex) of the whole * Cold related symptoms before stu(ly urine, the x 100 concentrated supematant, and of A Presence of acrocyanosis on skiing holiday the sediment showed and a,, a2, and I8 A Absence of acrocyanosis on skiing holiday bands with, in addition, a prominent band in the 0b * Uncle with mental subnormality region (fig 2). Immunoelectrophoresis of the whole ** Father with congenital dislocation of hipts urine, supematant, and sediment, using antisera *** Proband with spina bifida against heavy (Guildhay, Surrey) and light immuno- ? Symptomatology unknown globulin chains (both bound and free) (Daco, FIG 1 Pedigree offamily showing the subjects Denmark) and fibrinogen (Daco, Denmark), with or without cryofibrinogenaemia, with or without showed an excess of free light chains around the cold related symptoms, or with other disease. The origin and fibrinogen in the j6 region. Myoglobi- cryofibrinogen precipitating temperatures are indicated. nuria was excluded by spectroscopy, by electro- J Med Genet: first published as 10.1136/jmg.26.10.631 on 1 October 1989. Downloaded from

Transient nephrotic syndrome after anaesthesia 633

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FIG 2 The electrophoretic patterns ofthe plasma, serum, and urine obtained on thefirstpostoperative day, and ofthe urine samples from the fifth postoperative day. I=plasma. 2=serum. 3a=supernatant concentratedx 100. 3b=sediment. 3c= whole urine concentratedx 100 (allfirst postoperative day). 4= whole urine concentratedx300 (fifth postoperative day). S=myoglobin marker. -_--=the band in the Pb region. copyright. phoresis using a myoglobin marker, and by Methods ammonium sulphate precipitation. 19 A further urine sample obtained on the fifth postoperative day was The blood samples were collected with disposable clear and after concentrating it x300, only a trace of plastic syringes and 20 gauge needles into 5 and albumin was found on the electrophoretic pattern 10 ml plastic and glass screw top bottles containing with no free light chains or fibrinogen being lithium , EDTA, or no , and detected after immunoelectrophoresis (fig 2). transported to the laboratory in a 37°C water bath.

Muscle biopsy histology showed a predominance They were allowed to clot for three hours at 37°C http://jmg.bmj.com/ of type I fibres, with the few type II fibres present and were centrifuged at room temperature at 3000 being very atrophic. The appearance was consistent rpm for 10 minutes. Aliquots of each serum, EDTA, with long standing denervation owing to spinal and heparin plasmas were stored at 4, 15, 28, 30, 33, dysraphism. 34, 35, 36, and 37°C and examined for the presence The detection of free light chains and fibrinogen of a deposit every half hour. A portion of all the sera in the urine on the first postoperative day suggested and the EDTA and heparin plasmas was also first the possibility of a cryofibrinogenuria and thus incubated at 37°C and for half hourly intervals cryofibrinogenaemia, and led to a retrospective thereafter at temperatures decreasing by 1°C until a on October 6, 2021 by guest. Protected inspection of both heparin and EDTA plasmas and deposit was noted or the temperature of 25° was serum, obtained on the first postoperative day, for reached. The time for the precipitate to redissolve cryoproteins. Although the samples had been completely at 37°C was noted. The precipitation and frozen, a precipitate which could be partially dis- dissolution of the clots in the same samples were solved on warming at 37°C for 30 minutes was noted carried out several times. Control blood samples in both plasmas on thawing but not in serum. from two healthy volunteers from the laboratory were examined in parallel under identical conditions. Cryofibrinogen studies on the proband and her Aliquots of the EDTA plasmas and sera from the family patient, her two sisters, and her mother were also electrophoresed at the above temperatures. Scan- The proband and, where possible, each member of ning densitometry of the plasmas was used to the family was investigated for the presence of calculate the fibrinogen levels from total protein cryofibrinogenaemia on at least three separate concentrations. Deposits from their cold EDTA occasions in October and November 1987. The plasmas were also isolated, washed three times in proband had been well since her previous admission. 0*9% saline, dissolved, precipitated again, washed, J Med Genet: first published as 10.1136/jmg.26.10.631 on 1 October 1989. Downloaded from

634 Y Lolin, P A Razis, P O'Gorman, M Hjelm, and A S Wierzbicki TABLE The fibrinogen content in the same ED TA fibrinogen remaining in solution at decreasing plasmas from the patient, her two sisters, and her mother, temperatures. At 37°C the total fibrinogen level in calculated from the peaks obtained after the samples all four subjects was significantly higher than the were electrophoresed (with previous incubation at the corresponding temperature for half an hour) upper limit of the laboratory reference range. In on agarose gel at decreasing temperatures. The differences three of them visible clotting was noted at 35°C and in the fibrinogen amount were thought to reflect the in one at 28°C. In all there was a significant fall in amount of cryoprecipitation occurring during the the fibrinogen remaining in solution at the relevant incubation stage. The albumin levels are shown temperatures. After immunoelectrophoresis, the in parentheses to show the consistency of other protein washed clots from the samples of the four subjects separations as temperatures fall. were confirmed as being fibrinogen, although a faint additional reaction was also noted with IgG anti- Temperature Fibrinogen content in EDTA plasmas (gil) serum. After two dimensional immunoelectro- CC) phoresis no difference in electrophoretic mobility Proband Mother Sister I Sister 2 between the proband's cryofibrinogen and the 37 6-72 (42-8) 7-11 4-64 5-55 fibrinogen from a control EDTA sample was noted. 35 5-74 (41-0) 5-25 4-75 4-88 34 5-74 (43-1) 4-95 4-65 4-88 33 4-40 (44-0) 4-35 4-61 4-14 32 390 (43-1) 481 4-80 2-60 Discussion 30 3-90 (44-0) 4-10 4-71 2-51 28 4-00 (43.2) 4-22 3-10 2-63 25 4-11 (42-0) 3-30 3-0 2-10 Although secondary cryofibrinogenaemia is rela- 4 3-43 (42-4) 3-11 2-90 2-10 tively common in adults, the primary form is rare.5 16 )=the concentration of albumin calculated from the albumin peak on the In children both are rare. There have been occasional same electrophoretic pattern. The actual albumin concentration measured on reports of transient or chronic secondary cryo- Technicon AA II was 43 g/l. The reference range for plasma fibrinogen in the laboratory is 1-46 to 3-8 g/l. fibrinogenaemia,8 9 20 21 but to our knowledge there

have been only two reports of persistent primarycopyright. cryofibrinogenaemia. 16 2 Trace amounts of cryoprecipitate in heparin and after dissolving in saline immunoelectro- plasma left overnight at 4°C are frequently observed. phoresed against antisera to IgG, IgA, IgM, and Although many reasons for that have been sug- fibrinogen. In addition a washed precipitate from gested, heparin (as anticoagulant in the blood the patient's EDTA plasma was dissolved in saline, bottle) is thought to be the most important factor.2 24 some added to a control EDTA plasma, and two The demonstration of a cryoprecipitate in plasma dimensional immunoelectrophoresis carried out on using other such as EDTA,25 the both. possibility of repeated precipitation and dissolu- http://jmg.bmj.com/ tion,17 as well as identification of the clot by Results immunochemistry,17 indicate the definite presence of a cryofibrinogen, which, if in a quantity of more A cryoprotein, precipitating at between 32 and 35°C than 1 g/1,7 17 is of pathological significance. The within one hour of incubation, was noted in the above could all be found in our study. In addition, EDTA as well as heparin plasmas, but not sera, parallel examination of control plasmas under

from the proband and nine members of her family identical conditions yielded no cryoprecipitate. on October 6, 2021 by guest. Protected on each of the three occasions when tested (fig 1). A The clinical pre;sentation of the child was unusual. cryoprotein was also detected in the EDTA and Although we had not excluded other causes for heparin samples from one other mem-ber of the myalgia and nephrotic syndrome, both were tran- family, precipitating within one hour of incubation, sient, occurred after a fall in body temperature, and but at 280C (fig 1, table). The precipitates com- were thus most likely to have been caused by prised at least a quarter of the sample volume, redis- the cryofibrinogen precipitating in the muscle and solved totally on warming at 37°C, usually within renal microvasculature. Cryofibrinogenaemia is 30 seconds although larger clots needed up to three frequently associated with proteinuria and glom- minutes, and could be precipitated and redissolved erulonephritis.12 13 Persistent cryofibrinogenaemia totally several times. No cryoprecipitate was noted may even cause nephropathy.12 However, transient in control EDTA and heparin plasmas and sera. heavy proteinuria has been described only once in The concentrations of the total fibrinogen in the association with cryoproteinaemia and was thought EDTA plasmas from the proband, her mother, and to be the result of 'reversible embolism' of the renal her two sisters, electrophoresed at 37°C, are shown vasculature.26 Cryofibrinogenuria is also rare, in the table together with the concentrations of the occurring in only 5% of patients with cryofibrino- J Med Genet: first published as 10.1136/jmg.26.10.631 on 1 October 1989. Downloaded from

Transient nephrotic syndrome after anaesthesia 635 genaemia, particularly if, as in our patient, they are is no correlation between the amount of cryofibrino- also secreting an excess of free light chain immuno- gen and fibrinogen in the plasma of the same globulins.27 subject examined serially. 2 However, the The precipitation of the protein at 35°C was proband, her mother, and her two sisters all had unusual. The highest recorded precipitating raised total fibrinogen levels. They may thus have temperature to date for cryofibrinogen has been abnormal both fibrinogen synthesis and clearance 27°C16 and for cryoglobulin 320C.28 The latter was from the circulation. detected in the serum of an adult who died post- After the diagnosis in the proband, necessary operatively in acute renal failure because of result- orthopaedic operations which had been postponed ing globulin precipitation in the kidneys. Her lowest will now be carried out since appropriate precautions body temperature was 34-8°C. and therapy can be applied,2 1 17 31 and the aware- While congenital fibrinogen abnormalities, ness of the condition in the proband and family may including afibrinogenaemia, hypofibrinogenaemia, minimise future possibly life threatening complica- and dysfibrinogenaemia, although rare, are well tions. documented,29 familial cryofibrinogenaemia has not been described before to our knowledge. The authors wish to thank Dr J A Morgan-Hughes Although this is the first such report, the condition (National Hospitals for Nervous Diseases, London) may not be uncommon. Most of the affected and Dr C M Weaver (University Hospital of Wales, members of the family gave no history of symptom- Cardiff) for allowing them to investigate the patient atic cryofibrinogenaemia before the study and some and her family, and Mrs Linda Dudderidge for her did so only after detailed questioning, but all invaluable assistance in the preparation of this developed acrocyanosis when exposed for the first manuscript. time to very low temperatures. Though asymptom- atic cryofibrinogenaemia is frequently found,S the paucity of symptoms in our family was surprising, References copyright. since the fibrinogen precipitating temperatures were l Korst DR, Kratochvil CM. 'Cryofibrinogen' formation in case of high. One of the reasons may have been the rapid lung neoplasms associated with thrombophlebitis migrans. dissolution of the clots which was total for larger Blood 1955;10:945-53. clots within three minutes and for smaller clots 2 Hobbs JR. Cryoproteins. Ann Med Interne (Paris) 1986;137: within seconds 254-9. of warming in vitro. Thus, any 3 Smith SB, Arkin C. Cryofibrinogenemia: incidence, clinical precipitate formed in the extremities in vivo may correlation, and a review of the literature. Am J Clin Pathol have dissolved rapidly on entering the central 1972;58:524-30. circulation. The patient developed serious symp- 4 Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other tomatic manifestations of chronic disseminated coagulopathy in patients http://jmg.bmj.com/ cryofibrinogenaemia, that is, myalgia and with neoplasms: clinical, pathophysiological, and therapeutic lumbar tenderness, only with cooling of large areas features. Medicine (Baltimore) 1977;56:1-37. of the body when precipitation of fibrinogen may 5 Zlotnick A, Shahin W, Rachmilewitz EA. Studies in cryo- have been more extensive. fibrinogenaemia. Acta Haematol (Basel) 1969;42:8-17. The cause of 6 Bell W, Bahr R, Waldmann TA, Carbone PP. 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636 Y Lolin, P A Razis, P O'Gorman, M Hjelm, and A S Wierzbicki

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