Case report of an acquired factor XIII inhibitor: diagnosis and management.A 57-year-old man presented with a spontaneous upper-extremity hematoma and compartment syndrome. The patient experienced excessive bleeding following evacuation of the hematoma, and the results of routine coagulation studies were normal. Factor XIII activity was undetectable using a photometric assay, and the presence of an inhibitor was detected with mixing studies. Bleeding was controlled with infusions of fresh frozen plasma fresh frozen plasma
n. Abbr. FFP
Blood plasma frozen within 6 hours of collection.
fresh frozen plasma and cryoprecipitate cryoprecipitate /cryo·pre·cip·i·tate/ (-pre-sip´i-tat) any precipitate that results from cooling, sometimes specifically the one rich in coagulation factor VIII obtained from cooling of blood plasma. . Cyclophosphamide was started on the 16th hospital day, and four weekly doses of the monoclonal anti-CD20 antibody, rituximab, were begun 3 weeks later. One week after the initial dose of rituximab, the inhibitor was no longer detectable and the factor XIII level increased to 28%. After completion of the rituximab therapy, the factor XIII activity was 58% with no inhibitor present. This case illustrates the need to check for unusual defects such as factor XIII deficiency if a bleeding tendency is evident--even if routine studies are unrevealing.
Factor XIII is the final enzyme in the coagulation cascade and is responsible for catalyzing the intermolecular cross-linking of fibrin polymers, therefore increasing the mechanical rigidity of the fibrin clot (1). Hereditary deficiency of this enzyme is a rare cause of a lifelong bleeding disorder, and homozygotes for this autosomal recessive disorder have <1% factor XIII activity (2). Clinical features include recurrent soft tissue bleeding and delayed wound healing. Women with factor XIII deficiency have an increased incidence of fetal loss during pregnancy, although menorrhagia menorrhagia /men·or·rha·gia/ (men?ah-ra´jah) hypermenorrhea.
See hypermenorrhea. is not frequently seen. Unlike patients with hemophilia A and B, individuals with factor XIII deficiency are unlikely to develop hemarthrosis, although intracranial hemorrhage is a frequent cause of death. Since only 2% to 3% factor XIII activity is necessary to provide hemostasis and the enzyme has a half-life of 8 to 14 days, heterozygotes are asymptomatic. Transfusions of factor XIII in the form of fresh frozen plasma (FFP), cryoprecipitate, or factor XIII concentrates (fibrogammin, Hoechst) every 4 to 6 weeks is adequate therapy for congenitally deficient homozygotes.
Acquired deficiencies of factor XIII have been described in association with drugs, chronic renal failure chronic renal failure Chronic kidney failure Nephrology A slow decline in renal function, which may be 2º to chronic HTN, DM, CHF, SLE, or sickle cell anemia and, if extreme, leads to ESRD, mandating kidney dialysis; an abrupt decline in renal function may be , hepatic cirrhosis, and lymphoproliferative disorders. In most cases these acquired deficiencies are partial and do not lead to significant bleeding. The development of inhibitors to factor XIII represents a rare cause of depressed factor XIII activity. Such inhibitors have been described in patients congenitally deficient in factor XIII treated with multiple transfusions (3), but most inhibitors are IgG antibodies and develop in patients without preexisting factor XIII deficiency (4-6).
We describe a patient presenting with an acquired factor XIII deficiency secondary to a spontaneous inhibitor. Awareness of this rare coagulopathy is important since all screening coagulation studies routinely ordered in bleeding patients will be normal, including platelet count, prothrombin time (PT), partial thromboplastin thromboplastin: see blood clotting. time (PTT), platelet function assays, fibrinogen, thrombin clot time, and assays for von Willebrand's disease von Wil·le·brand's disease
A hereditary predisposition to hemorrhaging characterized by bleeding from mucous membranes and various abnormalities in the blood components responsible for clotting. . Specific assays for factor XIII by measuring clot solubility in dispersing agents such as 5M urea or 1% monochloracetic acid are necessary to identify this disorder. Once the etiology was identified, infusions of cryoprecipitate controlled bleeding acutely, with the inhibitor abating 1 month later, following treatment with cyclophosphamide and the chimeric anti-CD20 monoclonal antibody, rituximab.
A 57-year-old man presented to the emergency department complaining of progressive pain and swelling in the right forearm for 10 days. There was no history of any injury. He was diagnosed with compartment syndrome and promptly taken to the operating room for a right forearm fasciotomy and evacuation of the hematoma. After the procedure, the patient continued to bleed at the surgical site in spite of an infusion of aminocaproic acid. He required blood transfusions and additional irrigation and debridement procedures in the operating room. The patient described easy bruising for the prior 6 weeks and had urologic evaluation for gross hematuria hematuria
Blood in the urine. It usually indicates injury or disease of the kidney or another structure of the urinary system or possibly, in males, the reproductive system. It may result from infection, inflammation, tumours, kidney stones, or other disorders. , including abdominal ultrasound, computed tomography imaging, and cystoscopy Cystoscopy Definition
Cystoscopy (cystourethroscopy) is a diagnostic procedure that is used to look at the bladder (lower urinary tract), collect urine samples, and examine the prostate gland. . No anatomic cause for the hematuria was identified. There was no prior history of excessive bleeding with trauma, dental procedures, or surgery, including tonsillectomy tonsillectomy /ton·sil·lec·to·my/ (ton?si-lek´tah-me) excision of a tonsil.
Surgical removal of tonsils or a tonsil. and appendectomy. The patient did not have a family history of excessive bleeding or a known coagulation disorder.
Past medical history was significant for colitis, currently inactive, and Guillain-Barre syndrome several years earlier without neurologic sequelae sequelae Clinical medicine The consequences of a particular condition or therapeutic intervention . Medications included hyoscyamine hyoscyamine /hyo·scy·amine/ (hi?o-si´ah-men) an anticholinergic alkaloid that is the levorotatory component of racemic atropine and has similar actions but twice the potency; used as an antispasmodic in gastrointestinal and urinary tract , budesonide, mesalamine, pantoprazole, and fexofenadine.
Physical examination was significant for persistent serosanguineous drainage from the right forearm wound and a 10-cm bruise evident over the left inner thigh. Petechiae, lymphadenopathy, and splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. were absent.
Laboratory results included a hematocrit of 40%, a white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. of 9200/[micro]L with normal differential, and a platelet count of 322,000/[micro]L. Postoperatively, his PT was 11 seconds; PTT, 27 seconds; fibrinogen, 472 mg/dL; thrombin clot time, 15 seconds; and platelet function assay, normal. Results of assays for von Willebrand's disease were normal, including ristocetin cofactor cofactor
An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may (174%), factor VIII assay (208 U/dL), and von Willebrand's antigen (185 U/dL). Alpha 2-antiplasmin activity was 98%, and platelet factor 3 was present. Factor XIII activity was undetectable using a photometric assay (7). Results of an inhibitor assay were positive at a titer of >1:10.
The patient's clinical course over the ensuing 2 months is illustrated in the Figure. Prior medications were discontinued without improvement in factor XIII levels. On the ninth hospital day, with the diagnosis of factor XIII deficiency confirmed, the patient was transfused with FFP or cryoprecipitate intermittently. Therapy increased measurable levels of factor XIII for about 2 days. Immunosuppression with oral cyclophosphamide was started on the 16th hospital day, and the patient was discharged on every-other-day intravenous cryoprecipitate. The inhibitor was still present 2 weeks after cyclophosphamide was initiated, albeit at a lower titer of 1:2. Rituximab 375 mg/ml was started 3 weeks after cyclophosphamide with four weekly doses. One week after the initial dose of rituximab, the factor XIII activity was 28%, the inhibitor titer was negative, and no further cryoprecipitate was required. One week after the last dose of rituximab, the factor XIII level was 58%. Cyclophosphamide was continued for 5 months on a tapering schedule. Six months after treatment was initiated, the factor XIII level remained normal (67%) without evidence of recurrent bleeding.
Failure to recognize an uncommon acquired coagulation disorder can have serious consequences. The differential diagnosis of a hemorrhagic disorder with normal baseline coagulation studies (PT, PTT, thrombin clot time, fibrinogen, platelet count, platelet function assay and/or bleeding time) is limited. Von Willebrand's disease, even with a normal PTT and bleeding time, is the most common abnormality detected. Other etiologies include alpha 2-antiplasmin deficiency, platelet factor 3 deficiency, dysfibrinogenemia, and factor XIII deficiency. Appropriate studies in our case confirmed factor XIII deficiency due to an inhibitor, presumably pre·sum·a·ble
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster. acquired.
According to the classification of Lorand, inhibitors can interfere with factor XIII activity by preventing activation of factor XIII, interfering with the function of factor XIIIa, or altering the reactivity of the fibrin substrate (8, 9). Most cases of acquired factor XIII inhibitors are idiopathic or associated with prolonged drug ingestion, most commonly isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. (10, 11). Other drugs associated with acquired factor XIII inhibitors include penicillin (12), phenytoin phenytoin /phen·y·to·in/ (fen´i-toin?) an anticonvulsant used in the control of various kinds of epilepsy and of seizures associated with neurosurgery.
n. (13), and practolol (14). Patients with acquired factor XIII inhibitors usually present with severe subcutaneous and retroperitoneal retroperitoneal /ret·ro·peri·to·ne·al/ (-per?i-to-ne´al) posterior to the peritoneum.
Situated behind the peritoneum. bleeding that is often difficult to control, resulting in a high mortality rate. If an offending drug is suspected, the medication should be discontinued. Prompt clinical improvement may occur, but excessive bleeding will often persist for a period of weeks or months.
Replacement therapy with cryoprecipitate or FFP has not always proven successful. Factor XIII concentrate has been used in patients with congenital factor XIII deficiency, but its use in patients with acquired factor XIII inhibitors is limited and the product is not yet commercially available. Nakamura et al reported that infusions of factor XIII concentrate controlled acute bleeding in a patient with an acquired inhibitor (5). Plasmapheresis plasmapheresis, see apheresis. may reduce inhibitor titers and result in clinical improvement, and immunosuppression with cyclophosphamide may reduce inhibitor titers and restore factor XIII activity. Cyclophosphamide has well-established immunosuppressive properties and is effective therapy for a variety of autoimmune hematologic disorders including chronic immune thrombocytopenia (ITP), autoimmune hemolytic anemia autoimmune hemolytic anemia
Either of two forms of hemolytic anemia involving autoantibodies against red cell antigens; a cold-antibody type, caused by hemagglutinating cold antibody; and a warm-antibody type, due to serum autoantibodies that react , and acquired factor VIII inhibitors.
Rituximab is a chimeric, human IgG1 kappa monoclonal antibody specific for the CD20 antigen expressed on the surface of B lymphocytes. The antibody is known to induce rapid in vivo depletion of both normal B lymphocytes and lymphoma B cells. Mechanisms of action include complement-mediated cytotoxicity, antibody-dependent cytotoxicity, inhibition of B-cell proliferation, and induction of apoptosis (15). Rituximab has demonstrated clinical efficacy in the treatment of B-cell lympho-proliferative disorders expressing the CD20 antigen. The drug's limited toxicity has led to the recent use of rituximab for the treatment of autoimmune disorders, anticipating a decrease in antibody production by [CD20.sup.+] B cells. Examples include ITP, autoimmune hemolytic anemia, and acquired hemophilia A.
Rituximab has been shown to diminish hemolysis hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs. in children with autoimmune hemolytic anemia. Zecca et al reported that 13 of 15 pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children.
Of or relating to pediatrics. patients previously treated with two or more immunosuppressive agents responded to treatment with rituximab with a median increase in hemoglobin levels of 4 g/dL. Ten patients demonstrated a sustained response, not requiring additional treatment (16).
Rituximab has efficacy in treating refractory chronic ITP. Twenty-five percent to 30% of patients with ITP will develop a chronic course, being refractory to corticosteroids, intravenous immunoglobulin, and splenectomy Splenectomy Definition
Splenectomy is the surgical removal of the spleen, which is an organ that is part of the lymphatic system. The spleen is a dark-purple, bean-shaped organ located in the upper left side of the abdomen, just behind the bottom of the . In a series reported by Stasi et al, 25 patients with ITP resistant to conventional therapy were treated with rituximab, including eight patients who had relapsed following splenectomy. Ten patients (40%) obtained at least partial response (platelet count >50,000/[micro]L). Seven of these patients had a response duration longer than 7 months (17).
Acquired hemophilia is a rare disorder characterized by the development of autoantibodies against factor VIII. Immunosuppressive treatment with corticosteroids and cytotoxic drugs alone or in combination is regarded as the mainstay of treatment. Wiestner et al reported that four patients with acquired factor VIII inhibitors responded to immunosuppressive regimens including rituximab (18). Recently, Stasi et al noted that eight of ten patients with acquired hemophilia and clinically significant bleeding experienced rapid clinical improvement following administration of rituximab, including normalization of factor VIII levels and disappearance of the inhibitor. Three patients relapsed within 20 weeks but responded to retreatment (19).
Our patient presented with severe, spontaneous bleeding due to the presence of an acquired factor XIII inhibitor. Bleeding was initially controlled with infusion of FFP and cryoprecipitate, but this therapy produced only a transient increase in factor XIII activity. Cyclophosphamide was started 6 days after the diagnosis was established, and rituximab was added 3 weeks later. The normalization of factor XIII activity and disappearance of the inhibitor was likely related to the combination of cyclophosphamide and rituximab. The inhibitor titer had started to decrease after 3 weeks of cyclophosphamide therapy before rituximab was initiated. One week after rituximab therapy was started, the factor XIII level was 28% with a negative inhibitor titer.
In conclusion, our case illustrates that patients presenting with acquired bleeding disorders can have normal routine coagulation test results. Studies for unusual, predominantly hereditary defects, such as factor XIII deficiency, should be included in the hemostatic evaluation if routine studies are unrevealing and a bleeding diathesis seems evident.
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Thomas F. Gregory, MD, and Barry Cooper, MD
From the Department of Oncology, Baylor Charles A. Sammons Cancer Center and Baylor University Medical Center Baylor University Medical Center (BUMC) is located at 3500 Gaston Avenue in east Dallas, Texas (USA). Its medical services are often listed in the annual U.S. News & World Report compilation of Best Hospitals. , Dallas, Texas.
Corresponding author: Barry Cooper, MD, 3535 Worth Street, Suite 200, Dallas, Texas 75246 (e-mail: firstname.lastname@example.org).