Chronic Ulcerative Colitis, Skin Necrosis, and Cryofibrinogenemia GENE V. BALL, M.D., F.A.C.P.; and LAWRENCE N. GOLDMAN, M.D.; Birmingham, Alabama
Necrotizing skin lesions developed in a man with chronic ulcerative colitis. No evidence of intrinsic disease of medium or small-sized vessels was found. A circulating cryofibrinogen was thought to be responsible for in situ thrombosis leading to skin infarctions. Sodium warfarin in a daily dose of 2.5 to 5 mg appears to have thwarted progression of developing lesions and the occurrence of new ones.
O F
T H E VARIOUS SKIN L E S I O N S o c c u r r i n g in p a t i e n t s with
chronic ulcerative colitis, e r y t h e m a n o d o s u m and p y o d e r m a g a n g r e n o s u m a r e most c o m m o n . Lethal c u t a n e o u s vasculitic gangrene, different in a p p e a r a n c e from p y o d e r m a g a n g r e n o s u m , h a s been reported by G o l d g r a b e r and Kirsner ( 1 ) in o n e patient with chronic ulcerative colitis and in a n o t h e r by W a c k e r s , Tytgat, a n d V r e e k e n ( 2 ) . Causes of vasculitis were reviewed but not adduced for either patient. This article describes a m a n with chronic ulcerative colitis, skin necrosis a n d a circulating cryofibrinogen probably responsible for t h e necrosis. Case Report The patient is a 56-year-old white man in whom signs of ulcerative colitis first appeared in 1973. From then until 1975 he had lower abdominal pain and unformed stools containing mucus and blood, varying in number from three to six daily. In December 1974, superficial thrombophlebitis was noted in the left leg. This improved with heparin and 5 mg sodium warfarin daily for 5 days. Admission to hospital in January 1975, was forced by severe lower abdominal pain and rectal bleeding. Sigmoidoscopy to 25 cm disclosed "reddened, friable mucosa with shallow ulcerations and exudates. N o normal mucosa was seen." Microscopic examination of tissue taken by punch biopsy from the lowest valve of Houston showed a severe inflammatory reaction and crypt abscesses. Loss of normal haustrations in the descending and sigmoid colon and rectal ampulla was described on barium enema examination. He was begun on sulfasalizine, 4 g daily, which he took for a few days. Pain and bleeding diminished, and he was discharged from hospital. One week later, sudden ecchymosis was noted; and during the next few days four separate lesions evolved: [1] ecchymosis of the left fourth finger progressing to gangrene of the terminal phalanx; [2] infarction and gangrene of the right second finger beyond the proximal interphalangeal joint; [3] ecchymosis of the left knee, which cleared slowly; and [4] ecchymosis of the right heel with slow, complete resolution. Prednisone was started by mouth, 15 mg daily. The patient was • From the Department of Medicine, School of Medicine, University of Alabama in Birmingham; Birmingham, Alabama.
464
Downloaded from https://annals.org by Tulane University user on 01/17/2019
transferred to the University of Alabama Hospitals and Clinics for further evaluation. On admission he was not acutely ill, although he was having four to six nonbloody stools daily. Pertinent physical findings included gangrene of the left fourth finger and right second finger. (Figure 1) Although its significance was not apparent immediately, a recently thrombosed vein in the right arm was also observed. Funduscopic and neurologic examinations were normal as was examination of the chest and abdomen. Proctoscopy showed a granular mucosa with easy friability and minimal purulent exudate. At admission complete blood count, urinalysis, and blood chemistries were normal; the latex fixation and antinuclear antibody tests were negative, and the serum protein electrophoretic pattern was normal. The entire left foot became painful, red, and purpuric on the second day of hospitalization. The posterior tibial and dorsalis pedis pulses were normal. Hydrocortisone sodium succinate and dextran-40 were given, and there was gradual clearing of purpura with only a 1-cm necrotic area remaining at the base of the left fifth toe. A few days later purpura developed within minutes on the medial aspect of the left knee; the purpura cleared slowly after administration of dextran-40. Subsequent episodes were treated with warm water soaks, which appeared to reverse the purpura, perhaps preventing gangrene. Thrombosis of three veins in upper and lower extremities were also noted, though they were overshadowed by the more dramatic skin changes. Upon completion of the various studies and demonstration of a cryofibrinogen, sodium warfarin was restarted in small doses of 2.5 to 5 mg daily, and the patient was advised to avoid exposure to cold. He denied recurrences of vasculitis when seen 10 weeks later. The ulcerative colitis has since been inactive, permitting continued use of sodium warfarin with only one interruption, which was followed by infarction of an area of abdominal skin. Sodium warfarin was reinstituted, and there has been no other skin lesion during 9 months of observation. SPECIAL STUDIES LESIONS)
(DONE
WHILE
PATIENT
HAD ACTIVE
SKIN
Abdominal and left femoral arteriograms showed no evidence of large or medium vessel disease other than mild atheromatous changes of the abdominal aorta. A biopsy of involved but viable skin from the knee showed capillary thrombi with mild endothelial hyperplasia and perivascular infiltrates. N o immunoglobulins or complement were found within the walls of the thrombosed vessels using standard immunofluorescence techniques. The prothrombin time, partial thromboplastin time, clot lysis time, and clot retraction were normal. The platelet count was 380 000/mm 3 ; platelet aggregation studies using epinephrine and A D P as the aggregating agents were normal. Split products of fibrin were present in a 1:20 dilution (greater than 40 /ig/ml) using the Thrombo-Wellocotest kit*. The plasma fibrinogen was 248 mg/dl. To collect blood for the cryofibrinogen studies, four anticoagulated tubes were used. These tubes contained citrate, EDTA, heparin, and 100 extra units of heparin. Blood for * Burroughs Wellcome Co.; Research Triangle Park, North Carolina. Annals of Internal Medicine 85:464-466, 1976
serum was collected in a plain nonsiliconized glass tube. All tubes were maintained at 37 °C from time of collection until the serum tube had clotted and the clot had retracted. The tubes were then centrifuged at 37 °C, and the serum and plasma were refrigerated immediately at 4 °C in Wintrobe tubes and in 12-x-75-mm glass tubes. The tubes were observed at 24 h and at 48 h; no cryoprecipitate was present in the serum tubes. A cryoprecipitate, significant in comparison with controls, was found in the plasma samples. These precipitates were present at both 24 and 48 h in roughly the same amount. The cryoprecipitates were washed three times with cold normal saline and then dissolved in 37 °C normal saline. Counterimmunoelectrophoresis showed a reaction between the washed resuspended precipitate and Meloy goat antihuman fibrinogen. No reaction occurred between the patient's serum and the antihuman fibrinogen antiserum. Small quantities of Clq and C4 were also identified in the precipitate using highly purified antisera to these complement components. There was no evidence of C5. It seemed that complement components had become "enmeshed" in the cryoprecipitate without having undergone activation. Values for serum CH50 and B1C/B1A were normal before and during acute episodes. The amount of cryofibrinogen was estimated by measuring plasma fibrinogen before and after cryoprecipitation. On two specimens obtained 2 weeks apart, the differences between the fibrinogen before and after cryoprecipitation were 30 mg/dl and 83 mg/dl. As has been noted by other investigators, the amount of cyroprecipitate appeared to be increased in the heparin and "extra heparin" tubes. The precipitate from the plasma did not redissolve when the plasma containing the precipitate was warmed at 37 °C (3). Discussion
The differential diagnosis of this patient's lesions is circumscribed by the history, physical examination, laboratory studies, and the results of the biopsy. Of the forms of necrotizing cutaneous vasculitis that might be associated with a colitis syndrome, polyarteritis nodosa can be excluded primarily by history as well as the normal abdominal and femoral arteriograms and the biopsy ( 4 ) . Small-vessel disease displays a wide variety of syndromes. Essential for the diagnosis of leucocytoclastic vasculitis ("allergic" or "cutaneous-systemic" vasculitis),
Figure 1. Gangrene of the distal portions of the second phalanx of the right hand and the fourth phalanx of the left hand. Note the evolving area of purpura on the dorsum of the left foot.
Figure 2. Skin biopsy. There is occlusion of a small dermal vein by amorphous precipitate in which occasional leukocytes are entrapped. Note the lack of marked inflammatory response. (Hematoxylin and eosin; original magnification, x 200.)
which can cause at least transient diarrhea and melena, is demonstration of histopathologic changes not seen in this biopsy: vascular fibrinoid necrosis and polymorphonuclear cell infiltration. Although not reported to cause digital infarctions, sodium warfarin has been incriminated as a cause of skin necrosis in anticoagulated patients. The pathogenesis appears to be related to extravasation of blood into tissues, corresponding to prolongation of the prothrombin time. The occurrence of our patient's lesions remote from sodium warfarin anticoagulation and the apparent effectiveness of this drug in preventing new lesions obviate the diagnosis of sodium warfarin necrosis ( 5 ) . Autoantibodies of various types and of questionable significance have been reported in the occasional patient with chronic ulcerative colitis. The major histopathologic change shown here of in-situ thrombosis, with only slight perivascular inflammation and with no evidence of immunoglobulins within the vessel walls, tends to negate a primary immunologic cause for the skin changes (6, 7 ) . Rachmilewitz, Sacks, and Zlotnick (8) have discussed three patients having essential cryofibrinogenemia, whose major clinical manifestations included extensive gangrene in the extremities and buttocks. Examination of biopsy material showed obstruction of small blood vessels by dense precipitates of amorphous material, changes similar to those reported here. (Figure 2) Other findings reported by Rachmilewitz and colleagues included estimated plasma cryofibrinogens of 600, 17, and 54 mg per dl. Although McKee, Kalbfleisch, and Bird (9) found that thromboses occurred with similar frequencies in patients with both trace and heavy (more than 100 mg cryofibrinogen per 1000 ml plasma) cryoprecipitates, none of their patients without heavy precipitation had unexplained bleeding, which term was used to encompass purpura and ecchymosis. Cryofibrinogenemia is found most often accompanying neoplasms and occasionally with inflammatory conditions. Although chronic ulcerative colitis is usually included among the conditions associated with cryofibrinogenemia, we have found no documentation for this association ( 3 ) . Ball and Goldman • Colitis and Cryofibrinogenemia
Downloaded from https://annals.org by Tulane University user on 01/17/2019
465
The clinical expression of cryofibrinogenemia is frequently cutaneous gangrene, Raynaud's phenomenon, and recurrent thrombophlebitis. Its pathogenesis is unknown, although cryofibrinogenemia in one patient having a severe bleeding disorder was related to the presence of an immunoglobulin G antibody against crosslinking sites in fibrinogen-fibrin (10). Thromboembolism is said to occur in as many as 30% of patients with chronic ulcerative colitis ( 1 1 ) ; consideration of cryofibrinogenemia would be appropriate whenever these complications are noted. Anticoagulation in bleeding patients may be contraindicated; if so, treatment with varidase may be suitable ( 8 ) . ACKNOWLEDGMENTS: The authors thank Dr. James A. Olive, in whose coagulation laboratory the coagulation profile was done, and Dr. John Volanakis, who looked for complement components in the precipitate. Received 3 March 1976; revision accepted 23 June 1976. • Requests for reprints should be addressed to Gene V. Ball, M.D.; Department of Medicine; 1919 Seventh Avenue South; Birmingham, AL 35294. References
ated with chronic ulcerative colitis. A case study. Gastroenterology 39:94-103, 1960 2. WACKERS FJ, TYTGAT GN, VREEKEN J: Necrotizing vasculitis and
ulcerative colitis. Br Med J 4:83-84, 1974 3. RITZMANN SE, LEVIN WC: Cryopathies: a Review. Classification; diagnostic and therapeutic considerations. Arch Intern Med 107:754-772, 1961 4. MORDECAI H, CITRON BP: Necrotizing angiitis associated with drug abuse. Am J Roentgenol Radium Ther Nucl Med 111:663671, 1971 5. KOCH-WESER J: Coumarin necrosis (editorial note). Ann Intern Med 68:1365-1367, 1968 6. BROBERGER O, PERLMANN P: Autoantibodies in human ulcerative colitis. J Exp Med 110:657-674, 1959 7. KRAFT SC, KIRSNER JB: Immunological apparatus of the gut
and inflammatory bowel disease. Gastroenterology 60:922-951, 1971 8. RACHMILEWITZ EA, SACKS MI, ZLOTNICK A:
9. MCKEE PA, KALBFLEISCH JM, BIRD RM:
10. ROSENBERG RD, COLMAN RW, LORAND L: A new haemorrhagic
disorder with defective fibrin stabilization and cryofibrinogenaemia. Br J Haematol 26:269-284, 1974 11. KEHOE EL, NEWCOMER KL: Thromboembolic phenomena in
October 1976 • Annals of Internal Medicine • Volume 85 • Number 4
Downloaded from https://annals.org by Tulane University user on 01/17/2019
Incidence and sig-
nificance of cryofibrinogenemia. J Lab Clin Med 61:203-210, 1963
1. GOLDGRABER MB, KIRSNER JB: Gangrenous skin lesions associ-
466
Essential cryo-
fibrinogenemia. Clinical, pathological and immunological studies. Isr J Med Sci 6:32-43, 1970
ulcerative colitis. Two case reports. Arch Intern Med 113:711715, 1964
Necrotizing skin lesions developed in a man with chronic ulcerative colitis. No evidence of intrinsic disease of medium or small-sized vessels was found. A circulating cryofibrinogen was thought to be responsible for in situ thrombosis leading to skin infarctions. Sodium warfarin in a daily dose of 2.5 to 5 mg appears to have thwarted progression of developing lesions and the occurrence of new ones.
O F
T H E VARIOUS SKIN L E S I O N S o c c u r r i n g in p a t i e n t s with
chronic ulcerative colitis, e r y t h e m a n o d o s u m and p y o d e r m a g a n g r e n o s u m a r e most c o m m o n . Lethal c u t a n e o u s vasculitic gangrene, different in a p p e a r a n c e from p y o d e r m a g a n g r e n o s u m , h a s been reported by G o l d g r a b e r and Kirsner ( 1 ) in o n e patient with chronic ulcerative colitis and in a n o t h e r by W a c k e r s , Tytgat, a n d V r e e k e n ( 2 ) . Causes of vasculitis were reviewed but not adduced for either patient. This article describes a m a n with chronic ulcerative colitis, skin necrosis a n d a circulating cryofibrinogen probably responsible for t h e necrosis. Case Report The patient is a 56-year-old white man in whom signs of ulcerative colitis first appeared in 1973. From then until 1975 he had lower abdominal pain and unformed stools containing mucus and blood, varying in number from three to six daily. In December 1974, superficial thrombophlebitis was noted in the left leg. This improved with heparin and 5 mg sodium warfarin daily for 5 days. Admission to hospital in January 1975, was forced by severe lower abdominal pain and rectal bleeding. Sigmoidoscopy to 25 cm disclosed "reddened, friable mucosa with shallow ulcerations and exudates. N o normal mucosa was seen." Microscopic examination of tissue taken by punch biopsy from the lowest valve of Houston showed a severe inflammatory reaction and crypt abscesses. Loss of normal haustrations in the descending and sigmoid colon and rectal ampulla was described on barium enema examination. He was begun on sulfasalizine, 4 g daily, which he took for a few days. Pain and bleeding diminished, and he was discharged from hospital. One week later, sudden ecchymosis was noted; and during the next few days four separate lesions evolved: [1] ecchymosis of the left fourth finger progressing to gangrene of the terminal phalanx; [2] infarction and gangrene of the right second finger beyond the proximal interphalangeal joint; [3] ecchymosis of the left knee, which cleared slowly; and [4] ecchymosis of the right heel with slow, complete resolution. Prednisone was started by mouth, 15 mg daily. The patient was • From the Department of Medicine, School of Medicine, University of Alabama in Birmingham; Birmingham, Alabama.
464
Downloaded from https://annals.org by Tulane University user on 01/17/2019
transferred to the University of Alabama Hospitals and Clinics for further evaluation. On admission he was not acutely ill, although he was having four to six nonbloody stools daily. Pertinent physical findings included gangrene of the left fourth finger and right second finger. (Figure 1) Although its significance was not apparent immediately, a recently thrombosed vein in the right arm was also observed. Funduscopic and neurologic examinations were normal as was examination of the chest and abdomen. Proctoscopy showed a granular mucosa with easy friability and minimal purulent exudate. At admission complete blood count, urinalysis, and blood chemistries were normal; the latex fixation and antinuclear antibody tests were negative, and the serum protein electrophoretic pattern was normal. The entire left foot became painful, red, and purpuric on the second day of hospitalization. The posterior tibial and dorsalis pedis pulses were normal. Hydrocortisone sodium succinate and dextran-40 were given, and there was gradual clearing of purpura with only a 1-cm necrotic area remaining at the base of the left fifth toe. A few days later purpura developed within minutes on the medial aspect of the left knee; the purpura cleared slowly after administration of dextran-40. Subsequent episodes were treated with warm water soaks, which appeared to reverse the purpura, perhaps preventing gangrene. Thrombosis of three veins in upper and lower extremities were also noted, though they were overshadowed by the more dramatic skin changes. Upon completion of the various studies and demonstration of a cryofibrinogen, sodium warfarin was restarted in small doses of 2.5 to 5 mg daily, and the patient was advised to avoid exposure to cold. He denied recurrences of vasculitis when seen 10 weeks later. The ulcerative colitis has since been inactive, permitting continued use of sodium warfarin with only one interruption, which was followed by infarction of an area of abdominal skin. Sodium warfarin was reinstituted, and there has been no other skin lesion during 9 months of observation. SPECIAL STUDIES LESIONS)
(DONE
WHILE
PATIENT
HAD ACTIVE
SKIN
Abdominal and left femoral arteriograms showed no evidence of large or medium vessel disease other than mild atheromatous changes of the abdominal aorta. A biopsy of involved but viable skin from the knee showed capillary thrombi with mild endothelial hyperplasia and perivascular infiltrates. N o immunoglobulins or complement were found within the walls of the thrombosed vessels using standard immunofluorescence techniques. The prothrombin time, partial thromboplastin time, clot lysis time, and clot retraction were normal. The platelet count was 380 000/mm 3 ; platelet aggregation studies using epinephrine and A D P as the aggregating agents were normal. Split products of fibrin were present in a 1:20 dilution (greater than 40 /ig/ml) using the Thrombo-Wellocotest kit*. The plasma fibrinogen was 248 mg/dl. To collect blood for the cryofibrinogen studies, four anticoagulated tubes were used. These tubes contained citrate, EDTA, heparin, and 100 extra units of heparin. Blood for * Burroughs Wellcome Co.; Research Triangle Park, North Carolina. Annals of Internal Medicine 85:464-466, 1976
serum was collected in a plain nonsiliconized glass tube. All tubes were maintained at 37 °C from time of collection until the serum tube had clotted and the clot had retracted. The tubes were then centrifuged at 37 °C, and the serum and plasma were refrigerated immediately at 4 °C in Wintrobe tubes and in 12-x-75-mm glass tubes. The tubes were observed at 24 h and at 48 h; no cryoprecipitate was present in the serum tubes. A cryoprecipitate, significant in comparison with controls, was found in the plasma samples. These precipitates were present at both 24 and 48 h in roughly the same amount. The cryoprecipitates were washed three times with cold normal saline and then dissolved in 37 °C normal saline. Counterimmunoelectrophoresis showed a reaction between the washed resuspended precipitate and Meloy goat antihuman fibrinogen. No reaction occurred between the patient's serum and the antihuman fibrinogen antiserum. Small quantities of Clq and C4 were also identified in the precipitate using highly purified antisera to these complement components. There was no evidence of C5. It seemed that complement components had become "enmeshed" in the cryoprecipitate without having undergone activation. Values for serum CH50 and B1C/B1A were normal before and during acute episodes. The amount of cryofibrinogen was estimated by measuring plasma fibrinogen before and after cryoprecipitation. On two specimens obtained 2 weeks apart, the differences between the fibrinogen before and after cryoprecipitation were 30 mg/dl and 83 mg/dl. As has been noted by other investigators, the amount of cyroprecipitate appeared to be increased in the heparin and "extra heparin" tubes. The precipitate from the plasma did not redissolve when the plasma containing the precipitate was warmed at 37 °C (3). Discussion
The differential diagnosis of this patient's lesions is circumscribed by the history, physical examination, laboratory studies, and the results of the biopsy. Of the forms of necrotizing cutaneous vasculitis that might be associated with a colitis syndrome, polyarteritis nodosa can be excluded primarily by history as well as the normal abdominal and femoral arteriograms and the biopsy ( 4 ) . Small-vessel disease displays a wide variety of syndromes. Essential for the diagnosis of leucocytoclastic vasculitis ("allergic" or "cutaneous-systemic" vasculitis),
Figure 1. Gangrene of the distal portions of the second phalanx of the right hand and the fourth phalanx of the left hand. Note the evolving area of purpura on the dorsum of the left foot.
Figure 2. Skin biopsy. There is occlusion of a small dermal vein by amorphous precipitate in which occasional leukocytes are entrapped. Note the lack of marked inflammatory response. (Hematoxylin and eosin; original magnification, x 200.)
which can cause at least transient diarrhea and melena, is demonstration of histopathologic changes not seen in this biopsy: vascular fibrinoid necrosis and polymorphonuclear cell infiltration. Although not reported to cause digital infarctions, sodium warfarin has been incriminated as a cause of skin necrosis in anticoagulated patients. The pathogenesis appears to be related to extravasation of blood into tissues, corresponding to prolongation of the prothrombin time. The occurrence of our patient's lesions remote from sodium warfarin anticoagulation and the apparent effectiveness of this drug in preventing new lesions obviate the diagnosis of sodium warfarin necrosis ( 5 ) . Autoantibodies of various types and of questionable significance have been reported in the occasional patient with chronic ulcerative colitis. The major histopathologic change shown here of in-situ thrombosis, with only slight perivascular inflammation and with no evidence of immunoglobulins within the vessel walls, tends to negate a primary immunologic cause for the skin changes (6, 7 ) . Rachmilewitz, Sacks, and Zlotnick (8) have discussed three patients having essential cryofibrinogenemia, whose major clinical manifestations included extensive gangrene in the extremities and buttocks. Examination of biopsy material showed obstruction of small blood vessels by dense precipitates of amorphous material, changes similar to those reported here. (Figure 2) Other findings reported by Rachmilewitz and colleagues included estimated plasma cryofibrinogens of 600, 17, and 54 mg per dl. Although McKee, Kalbfleisch, and Bird (9) found that thromboses occurred with similar frequencies in patients with both trace and heavy (more than 100 mg cryofibrinogen per 1000 ml plasma) cryoprecipitates, none of their patients without heavy precipitation had unexplained bleeding, which term was used to encompass purpura and ecchymosis. Cryofibrinogenemia is found most often accompanying neoplasms and occasionally with inflammatory conditions. Although chronic ulcerative colitis is usually included among the conditions associated with cryofibrinogenemia, we have found no documentation for this association ( 3 ) . Ball and Goldman • Colitis and Cryofibrinogenemia
Downloaded from https://annals.org by Tulane University user on 01/17/2019
465
The clinical expression of cryofibrinogenemia is frequently cutaneous gangrene, Raynaud's phenomenon, and recurrent thrombophlebitis. Its pathogenesis is unknown, although cryofibrinogenemia in one patient having a severe bleeding disorder was related to the presence of an immunoglobulin G antibody against crosslinking sites in fibrinogen-fibrin (10). Thromboembolism is said to occur in as many as 30% of patients with chronic ulcerative colitis ( 1 1 ) ; consideration of cryofibrinogenemia would be appropriate whenever these complications are noted. Anticoagulation in bleeding patients may be contraindicated; if so, treatment with varidase may be suitable ( 8 ) . ACKNOWLEDGMENTS: The authors thank Dr. James A. Olive, in whose coagulation laboratory the coagulation profile was done, and Dr. John Volanakis, who looked for complement components in the precipitate. Received 3 March 1976; revision accepted 23 June 1976. • Requests for reprints should be addressed to Gene V. Ball, M.D.; Department of Medicine; 1919 Seventh Avenue South; Birmingham, AL 35294. References
ated with chronic ulcerative colitis. A case study. Gastroenterology 39:94-103, 1960 2. WACKERS FJ, TYTGAT GN, VREEKEN J: Necrotizing vasculitis and
ulcerative colitis. Br Med J 4:83-84, 1974 3. RITZMANN SE, LEVIN WC: Cryopathies: a Review. Classification; diagnostic and therapeutic considerations. Arch Intern Med 107:754-772, 1961 4. MORDECAI H, CITRON BP: Necrotizing angiitis associated with drug abuse. Am J Roentgenol Radium Ther Nucl Med 111:663671, 1971 5. KOCH-WESER J: Coumarin necrosis (editorial note). Ann Intern Med 68:1365-1367, 1968 6. BROBERGER O, PERLMANN P: Autoantibodies in human ulcerative colitis. J Exp Med 110:657-674, 1959 7. KRAFT SC, KIRSNER JB: Immunological apparatus of the gut
and inflammatory bowel disease. Gastroenterology 60:922-951, 1971 8. RACHMILEWITZ EA, SACKS MI, ZLOTNICK A:
9. MCKEE PA, KALBFLEISCH JM, BIRD RM:
10. ROSENBERG RD, COLMAN RW, LORAND L: A new haemorrhagic
disorder with defective fibrin stabilization and cryofibrinogenaemia. Br J Haematol 26:269-284, 1974 11. KEHOE EL, NEWCOMER KL: Thromboembolic phenomena in
October 1976 • Annals of Internal Medicine • Volume 85 • Number 4
Downloaded from https://annals.org by Tulane University user on 01/17/2019
Incidence and sig-
nificance of cryofibrinogenemia. J Lab Clin Med 61:203-210, 1963
1. GOLDGRABER MB, KIRSNER JB: Gangrenous skin lesions associ-
466
Essential cryo-
fibrinogenemia. Clinical, pathological and immunological studies. Isr J Med Sci 6:32-43, 1970
ulcerative colitis. Two case reports. Arch Intern Med 113:711715, 1964
