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An IgG inhibitor against coagulation factor XIII: Resolution of bleeding after plasma immunoadsorption with staphylococcal protein A
BRIEF CLINICAL
OBSERVATIONS
During the subsequent 2 years, she developed nine additional episodes of stridor, five of which required urgent intubation. All of the episodes were preceded by either fever, arthralgia/arthritis, or hematuria. On each occasion, she responded to high doses of hydrocortisone and epinephrine inhalation. Patient 2. A 22-year-old pregnant woman was admitted because of anemia, large joint arthritis, oral ulcers, malar rash, and a sore throat. Pertinent laboratory test results at that time were positive ANA and antiDNA antibodies (6 pg/mL), as well as proteinuria and reduced creatinine clearance (43 mL/minute). Delivery was induced and a healthy infant was born. Laryngoscopy was performed because of persistent sore throat and revealed laryngeal and arytenoid edema. She was treated with oral prednisone (200 mg/day) and epinephrine inhalation. Improvement was slow and the sore throat and laryngoscopic findings persisted for 3 weeks, subsequently resolving with intensified inhalation therapy. She was discharged receiving prednisone (50 mg/day) but was readmitted several days later because of hoarseness, stridor, and severe laryngeal edema, which necessitated emergency tracheostomy. During hospitalization, renal function deteriorated and proteinuria, seizures, transient pleural effusion, and cutaneous vasculitis developed. Since highdose corticosteroids failed to suppress her active disease as well as her laryngeal symptoms, she was treated with repeated courses of intravenous cyclophosphamide. Gradual improvement in all disease parameters was observed and the tracheostomy was closed 2 months later. Comments. Laryngeal involvement is a rare manifestation of SLE [l]. Symptoms range from 110
January
1992
The American
Journal
mild hoarseness to life-threatening respiratory failure. The first case, reported by Scarpelli et al [3], described a 21-year-old man with severe active SLE who died due to serious laryngeal edema. Fibrinoid degeneration of collagen and hematoxylin bodies were noted on histologic evaluation of laryngeal tissue. Previous reports have emphasized the correlation between laryngeal symptoms and SLE activity and claimed adequate response of laryngeal involvement to steroid therapy [461.
Each of our patients presented with multiple episodes of stridor due to severe laryngitis, which responded only partially to highdose corticosteroid treatment. Considering the potential grave outcome of laryngeal involvement in SLE, a high index of suspicion and aggressive drug management are required. EYALRAZ,M.D. Universitv 1, of California , La Jolla,
at San Diego California
MICHAELBURSZTYN,M.D. Hadassah
University Hospital Mount Scopus Jerusalem, IsFael
TALMAROSENTHAL.M.D. Chaim
Sheba Medical Center Tel Hashomer, Israel
ALANRUBINOW,M.D. Hadassah
University
Hospital Ein Karem Jerusalem, Israel
1. Wallace DJ, Dubois EL. Lupus erythematosus. Philadelphia: Lea & Febiger, 1987: 407. 2. Smith GA, Ward PH, Berci G. Laryngeal lupus erythematosus. J Laryngol Otol 1978; 92: 67-73. 3. Scarpelli DG, McCoy FW, Scott JK. Acute lupus erythematosus with laryngeal involvement. N Engl J Med 1959; 261: 691-4. 4. Petri M. Katzenstein P, Hellman D. Laryngeal infection in lupus. Report of nocardiases and review of laryngeal involvement in lupus, J Rheumatol 1988; 15: 1014-5. 5. Balow JE. Austin HA Ill, Muenz LR, et al. Effect of treatment in the evolution of renal abnormalities in lupus nephritis. N Engl J Med 1984; 311: 491-5. 6. Toomey JM, Snyder GG, Maenza RM, eta/. Acute epiglottitis due to systemic lupus erythematosus. Laryngoscope 1974; 84: 522-7. Submitted
of Medicine
December
Volume
4, 1990, and accepted in revised form May 18. 1991
92
AN IgG INHIBITORAGAINST COAGULATIONFACTORXIII: RESOLUTIONOF BLEEDING AFTERPLASMA IMMUNOADSORPTIONWITH STAPHYLOCOCCALPROTEINA Coagulation factor XIII (FXIII) is a plasma protease that strengthens clots by catalyzing the formation of covalent bonds within fibrin strands. Deficiency of FXIII is characterized by delayed bleeding from superficial wounds and soft tissue bleeding, because clots lacking covalent cross-links are unstable [I]. This report describes a patient with bleeding due to an acquired IgG inhibitor that interfered with FXIII function, and the termination of acute bleeding after plasma immunoadsorption with staphylococcal protein A. A 70-year-old man was transferred to Washington University because of severe rectal bleeding of 10 days’ duration after a transrectal prostate needle biopsy. Attempts to surgically repair the biopsy site failed to control the bleeding. There was a 3-month history of intermittent hematuria before the biopsy, but no bleeding or bruising prior to this and no family history of bleeding problems. A myocardial infarction occurred 3 years earlier, at which time treatment with procainamide was started. Results of physical examination were notable only for bleeding from the rectum. The following values were observed: platelet count, 350 X log/L; prothrombin time, 11.2 seconds (control = 11.3 seconds); partial thromboplastin time, 27.2 seconds; thrombin time, 13.2 seconds (control = 12.0 seconds); bleeding time, 540 seconds (normal, 180 to 570 seconds); fibrinogen, 10.0 pmol/L; and fibrin degradation products, negative. A clotted sample of plasma was unstable in 5 M urea and was not corrected by a 1:l
BRIEF CLINICAL
mix with normal plasma. Passing the patient’s plasma across a staphylococcal protein A column resulted in a normal urea clot lysis test result, indicating the presence of an IgG inhibitor against FXIII. The effect of the inhibitor on fibrinogen crosslinking was demonstrated by polyacrylamide gel electrophoresis of 1251-fibrinogen-labeled plasma clots (Figure 1) [2]. a, P, and y represent the three chains of the fibrinogen molecule. Lane A represents unclotted normal plasma; lane B, normal clotted plasma; and lane C, clotted patient plasma. Note the lack of fibrinogen a-polymers and y-y dimers in lane C due to abnormal cross-linking. Bleeding did not respond to fresh frozen plasma or cryoprecipitate. Treatment with plasma immunoadsorption using a staphylococcal protein A-sepharose plasmapheresis system (DuPont) was performed on 4 consecutive days. After the first day of treatment, the rectal bleeding resolved and the urea clot lysis assay became normal. The clot lysis assay was abnormal again 4 days after the last immunoadsorption procedure; however, there was no recurrence of bleeding. Procainamide was discontinued, and after 3 months the inhibitor was no longer detectable. This report describes an IgG inhibitor to FXIII that appears to have been induced by procainamide, a drug associated with the formation of autoantibodies. FXIII inhibitors have been described with isoniazid therapy, but no previous association with procainamide has been reported. The antibody may have interfered with FXIII activation or activity by directly binding to FXIII. Alternatively, the inhibitor could have been directed against part of .the fibrinogen molecule involved in the crosslinking reaction. Previous reports
Figure clots.
1.
Polyacrylamide
gel
electrophoresis
of FXIII inhibitors described a number of therapeutic approaches including plasmapheresis, immunosuppressive therapy, and transfusional support [3]. In general, these measures appeared to have had little impact on acute bleeding episodes. Our patient had rapid resolution of bleeding after a single immunoadsorptive procedure. The temporary removal of the inhibitor apparently January
1992
The American
&SERVAT~~NS
of 1251-fibrinogen-labeled
plasma
allowed for proper cross-linking of fibrin at the wound site. In 1981, Nilsson and colleagues [4] reported the use of plasma immunoadsorption using staphylococcal protein A to remove an anti-factor IX IgG in a patient with hemophilia B. This technique has subsequently been used for factor VIII inhibitors [5]. Immunoadsorption is a reasonable therapeutic approach to reJournal
oi Medicine
Volume
92
111
BRIEF CLINICAL
OBSERVATIONS
fractory bleeding associated with an IgG coagulation factor inhibitor. It may also be useful in preparing patients with a known inhibitor for situations in which a hemostatic challenge is anticipated. DAVID GAILANI, M.D. Washington University School of Medicine St. Louis, Missouri
112
January
1992
The
American
Journal
1. Lorand L, Losowsky MS, Miloszewski man factor XIII-fibrin stabilizing factor.
KJM. HuProg Hae-
most Thromb 1980; 5: 245-90. 2. Greenberg CS. Enghild JJ. Mary A, Dobson JV, Achyuthan KE. Isolation of a fibrin-binding fragment from blood coagulation factor XIII capable of crosslinking fibrin(ogen). Biochem J 1988; 256: 10139. 3. Nakamura
S, Kato A, Sakata Y, Aoki N. Bleeding
tendency caused by IgG inhibitor to factor XIII, treated successfully by cyclophosphamide. Br J
of Medicine
Volume
92
Haematol 1988: 68: 313-9. 4. Nilsson IM. Jonsson S, Sundqvist SB, Ahlberg A, Bergentz SE. A procedure for removing high titer antibodies by extracorporeal protein A-sepharose adsorption in hemophilia. Blood 1981; 58: 38-44. 5. Uehlinger J, Watt R. Aledort LM. Extracorporeal immunoadsorption: an alternative treatment for hemophiliacs with high-responding inhibitors. Blood 1987; 70 Suppl 1: 334. Submitted
October
4, 1990, and accepted in revised form May 18, 1991
OBSERVATIONS
During the subsequent 2 years, she developed nine additional episodes of stridor, five of which required urgent intubation. All of the episodes were preceded by either fever, arthralgia/arthritis, or hematuria. On each occasion, she responded to high doses of hydrocortisone and epinephrine inhalation. Patient 2. A 22-year-old pregnant woman was admitted because of anemia, large joint arthritis, oral ulcers, malar rash, and a sore throat. Pertinent laboratory test results at that time were positive ANA and antiDNA antibodies (6 pg/mL), as well as proteinuria and reduced creatinine clearance (43 mL/minute). Delivery was induced and a healthy infant was born. Laryngoscopy was performed because of persistent sore throat and revealed laryngeal and arytenoid edema. She was treated with oral prednisone (200 mg/day) and epinephrine inhalation. Improvement was slow and the sore throat and laryngoscopic findings persisted for 3 weeks, subsequently resolving with intensified inhalation therapy. She was discharged receiving prednisone (50 mg/day) but was readmitted several days later because of hoarseness, stridor, and severe laryngeal edema, which necessitated emergency tracheostomy. During hospitalization, renal function deteriorated and proteinuria, seizures, transient pleural effusion, and cutaneous vasculitis developed. Since highdose corticosteroids failed to suppress her active disease as well as her laryngeal symptoms, she was treated with repeated courses of intravenous cyclophosphamide. Gradual improvement in all disease parameters was observed and the tracheostomy was closed 2 months later. Comments. Laryngeal involvement is a rare manifestation of SLE [l]. Symptoms range from 110
January
1992
The American
Journal
mild hoarseness to life-threatening respiratory failure. The first case, reported by Scarpelli et al [3], described a 21-year-old man with severe active SLE who died due to serious laryngeal edema. Fibrinoid degeneration of collagen and hematoxylin bodies were noted on histologic evaluation of laryngeal tissue. Previous reports have emphasized the correlation between laryngeal symptoms and SLE activity and claimed adequate response of laryngeal involvement to steroid therapy [461.
Each of our patients presented with multiple episodes of stridor due to severe laryngitis, which responded only partially to highdose corticosteroid treatment. Considering the potential grave outcome of laryngeal involvement in SLE, a high index of suspicion and aggressive drug management are required. EYALRAZ,M.D. Universitv 1, of California , La Jolla,
at San Diego California
MICHAELBURSZTYN,M.D. Hadassah
University Hospital Mount Scopus Jerusalem, IsFael
TALMAROSENTHAL.M.D. Chaim
Sheba Medical Center Tel Hashomer, Israel
ALANRUBINOW,M.D. Hadassah
University
Hospital Ein Karem Jerusalem, Israel
1. Wallace DJ, Dubois EL. Lupus erythematosus. Philadelphia: Lea & Febiger, 1987: 407. 2. Smith GA, Ward PH, Berci G. Laryngeal lupus erythematosus. J Laryngol Otol 1978; 92: 67-73. 3. Scarpelli DG, McCoy FW, Scott JK. Acute lupus erythematosus with laryngeal involvement. N Engl J Med 1959; 261: 691-4. 4. Petri M. Katzenstein P, Hellman D. Laryngeal infection in lupus. Report of nocardiases and review of laryngeal involvement in lupus, J Rheumatol 1988; 15: 1014-5. 5. Balow JE. Austin HA Ill, Muenz LR, et al. Effect of treatment in the evolution of renal abnormalities in lupus nephritis. N Engl J Med 1984; 311: 491-5. 6. Toomey JM, Snyder GG, Maenza RM, eta/. Acute epiglottitis due to systemic lupus erythematosus. Laryngoscope 1974; 84: 522-7. Submitted
of Medicine
December
Volume
4, 1990, and accepted in revised form May 18. 1991
92
AN IgG INHIBITORAGAINST COAGULATIONFACTORXIII: RESOLUTIONOF BLEEDING AFTERPLASMA IMMUNOADSORPTIONWITH STAPHYLOCOCCALPROTEINA Coagulation factor XIII (FXIII) is a plasma protease that strengthens clots by catalyzing the formation of covalent bonds within fibrin strands. Deficiency of FXIII is characterized by delayed bleeding from superficial wounds and soft tissue bleeding, because clots lacking covalent cross-links are unstable [I]. This report describes a patient with bleeding due to an acquired IgG inhibitor that interfered with FXIII function, and the termination of acute bleeding after plasma immunoadsorption with staphylococcal protein A. A 70-year-old man was transferred to Washington University because of severe rectal bleeding of 10 days’ duration after a transrectal prostate needle biopsy. Attempts to surgically repair the biopsy site failed to control the bleeding. There was a 3-month history of intermittent hematuria before the biopsy, but no bleeding or bruising prior to this and no family history of bleeding problems. A myocardial infarction occurred 3 years earlier, at which time treatment with procainamide was started. Results of physical examination were notable only for bleeding from the rectum. The following values were observed: platelet count, 350 X log/L; prothrombin time, 11.2 seconds (control = 11.3 seconds); partial thromboplastin time, 27.2 seconds; thrombin time, 13.2 seconds (control = 12.0 seconds); bleeding time, 540 seconds (normal, 180 to 570 seconds); fibrinogen, 10.0 pmol/L; and fibrin degradation products, negative. A clotted sample of plasma was unstable in 5 M urea and was not corrected by a 1:l
BRIEF CLINICAL
mix with normal plasma. Passing the patient’s plasma across a staphylococcal protein A column resulted in a normal urea clot lysis test result, indicating the presence of an IgG inhibitor against FXIII. The effect of the inhibitor on fibrinogen crosslinking was demonstrated by polyacrylamide gel electrophoresis of 1251-fibrinogen-labeled plasma clots (Figure 1) [2]. a, P, and y represent the three chains of the fibrinogen molecule. Lane A represents unclotted normal plasma; lane B, normal clotted plasma; and lane C, clotted patient plasma. Note the lack of fibrinogen a-polymers and y-y dimers in lane C due to abnormal cross-linking. Bleeding did not respond to fresh frozen plasma or cryoprecipitate. Treatment with plasma immunoadsorption using a staphylococcal protein A-sepharose plasmapheresis system (DuPont) was performed on 4 consecutive days. After the first day of treatment, the rectal bleeding resolved and the urea clot lysis assay became normal. The clot lysis assay was abnormal again 4 days after the last immunoadsorption procedure; however, there was no recurrence of bleeding. Procainamide was discontinued, and after 3 months the inhibitor was no longer detectable. This report describes an IgG inhibitor to FXIII that appears to have been induced by procainamide, a drug associated with the formation of autoantibodies. FXIII inhibitors have been described with isoniazid therapy, but no previous association with procainamide has been reported. The antibody may have interfered with FXIII activation or activity by directly binding to FXIII. Alternatively, the inhibitor could have been directed against part of .the fibrinogen molecule involved in the crosslinking reaction. Previous reports
Figure clots.
1.
Polyacrylamide
gel
electrophoresis
of FXIII inhibitors described a number of therapeutic approaches including plasmapheresis, immunosuppressive therapy, and transfusional support [3]. In general, these measures appeared to have had little impact on acute bleeding episodes. Our patient had rapid resolution of bleeding after a single immunoadsorptive procedure. The temporary removal of the inhibitor apparently January
1992
The American
&SERVAT~~NS
of 1251-fibrinogen-labeled
plasma
allowed for proper cross-linking of fibrin at the wound site. In 1981, Nilsson and colleagues [4] reported the use of plasma immunoadsorption using staphylococcal protein A to remove an anti-factor IX IgG in a patient with hemophilia B. This technique has subsequently been used for factor VIII inhibitors [5]. Immunoadsorption is a reasonable therapeutic approach to reJournal
oi Medicine
Volume
92
111
BRIEF CLINICAL
OBSERVATIONS
fractory bleeding associated with an IgG coagulation factor inhibitor. It may also be useful in preparing patients with a known inhibitor for situations in which a hemostatic challenge is anticipated. DAVID GAILANI, M.D. Washington University School of Medicine St. Louis, Missouri
112
January
1992
The
American
Journal
1. Lorand L, Losowsky MS, Miloszewski man factor XIII-fibrin stabilizing factor.
KJM. HuProg Hae-
most Thromb 1980; 5: 245-90. 2. Greenberg CS. Enghild JJ. Mary A, Dobson JV, Achyuthan KE. Isolation of a fibrin-binding fragment from blood coagulation factor XIII capable of crosslinking fibrin(ogen). Biochem J 1988; 256: 10139. 3. Nakamura
S, Kato A, Sakata Y, Aoki N. Bleeding
tendency caused by IgG inhibitor to factor XIII, treated successfully by cyclophosphamide. Br J
of Medicine
Volume
92
Haematol 1988: 68: 313-9. 4. Nilsson IM. Jonsson S, Sundqvist SB, Ahlberg A, Bergentz SE. A procedure for removing high titer antibodies by extracorporeal protein A-sepharose adsorption in hemophilia. Blood 1981; 58: 38-44. 5. Uehlinger J, Watt R. Aledort LM. Extracorporeal immunoadsorption: an alternative treatment for hemophiliacs with high-responding inhibitors. Blood 1987; 70 Suppl 1: 334. Submitted
October
4, 1990, and accepted in revised form May 18, 1991