Factor XII deficiency with systemic lupus erythematosus. Biological implications.

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.     

Severe fletcher factor (plasma prekallikrein) deficiency with partial deficiency of hageman factor (factor xii): Report of a case with observation on in vivo and in vitro leukocyte chemotaxis

A case of cross-reacting material-negative Fletcher trait with additional partial deficiency of Hageman factor (HF, Factor XII) is described. Although the patient presented with a recent history of frequent epistaxis, he had no other personal or family history of a tendency toward bleeding or infection. Similar to other cases of Fletcher trait, his plasma showed a markedly prolonged partial thromboplastin time which could be corrected by prolonged incubation with the surface-activator kaolin. Surface-induced fibrinolysis, amidolysis of α-N-benzoyl-proline-L -phenylalanine-L -arginine-p-nitro- anilide, and cold-promoted enhancement of factor VII activity, reactions requiring the presence in the plasma of Fletcher factor (pre-kallikrein), in addition to Hageman factor and Fitzgerald factor (high-molecular weight kininogen), were also defective. In vivo chemotaxis of polymorphonuclear leukocytes and monocytes (Rebuck's skin window technique) in response to skin abrasions was defective, but was normal when diphtheria-tetanus toxoid was also applied. In vitro leukocyte chemotaxis (Boyden chamber technique) in response to normal or patient's own serum activated with zymosan was normal. Together with previous observations that kallikrein generated chemotactic activity, possibly via activation of C5, the present observations suggest that prekallikrein activation may be important for in vivo leukocyte chemotactic response to skin abrasion. The inheritance of Fletcher trait in this patient is unclear. Although the father was an apparent heterozygote, the mother was completely normal for Fletcher factor procoagulant activity and antigen. The mild Hageman factor deficiency in the patient did not contribute significantly to the plasma defects described and was likely inherited from the father who had a low HF procoagulant activity.     

A Case of Hageman Factor Deficiency with Myeloid Leukaemia

Summary: The co-existence of blastic transformation of chronic myeloid leukaemia and an isolated deficiency of coagulation factor XII (Hageman Factor), is reported, In the absence of any evidence of factor XII deficiency in the patient's siblings and children, it is uncertain if this represents an acquired factor XII deficiency due to myeloid leukaemia, or the coincidental occurrence of myeloid leukaemia with this autosomal recessive condition.     

Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction

The paper reports the occurrence of myocardial infarctions in a patient with severe deficiency of blood coagulation factor XII (Hageman factor). Factor XII plays a central role in the intrinsic activation of fibrinolysis and consequently the defective intrinsic fibrinolytic activity detected in the present case casts some doubt on its role in the increased vulnerability to thrombotic accident.     

Circulating inhibitors of blood coagulation associated with procainamide-induced lupus erythematosus

We studied a patient being treated with procainamide in whom we observed a high antinuclear antibody titer and prolonged activated partial thromboplastin (PTT), prothrombin (PT), and Stypven times (ST). Serum antibody concentrations against single-stranded DNA were elevated while those against native DNA were not elevated, suggesting the procainamide-induced lupus syndrome. Dilution of the patient's plasma with normal plasma failed to correct the PTT and PT, indicating the presence of an inhibitor(s) to blood coagulation. The anticoagulant activity was associated with the IgG fraction of the patient's serum. Addition of purified or partially purified human factors IX, X, VIII, VII, XIa, prekallikrein, high molecular weight kininogen, or phospholipids to the patient's plasma failed to correct the PTT, PT, or ST; however, purified human factor XII and prothrombin corrected the PTT and ST, respectively. These results indicate that production of antibodies directed against antigenic determinants on coagulation proteins can be a manifestation of procainamide-induced lupus erythematosus.     

Lupus erythematosus in a patient with amyloidosis,adrenal insufficiency,and subsequent immunoblastic sarcoma. Demonstration of the le phenomenon in the lung

A patient with systemic lupus erythematosus of long duration developed secondary amyloidosis and finally died after the additional complication of malignant lymphoproliferative disease. Multiple system involvement, typical serologic findings, and postmortem evidence substantiated the diagnosis of lupus erythematosus. Amyloid deposition was found in several organs, but was notably extensive in the adrenal cortex. This extensive deposition resulted in adrenal insufficiency, which was diagnosed clinically and treated until the patient's death from lymphoma. The particular nature of the malignant lymphoma is emphasized; a distinctive feature was the disappearance of positive lupus erythematosus cells from the buffy coat and the reduction in titers of relevant serologic tests toward the end of the illness. In spite of this reduction, many hematoxylin bodies and abundant complete lupus erythematosus cells were found in the lungs on postmortem examination.     

Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme

A cDNA for coagulation factor XII has been used to investigate the presence of gene lesions and restriction fragment length polymorphisms in two brothers with Hageman trait and their family. A TaqI polymorphic fragment has been found in the two propositi and in 11 members of the paternal lineage. This polymorphism, absent in the normal population, is correlated with the reduction of factor XII activity and enables the identification of heterozygous factor XII deficiency. Factor XII gene deletion as the cause of Hageman trait in this family has been excluded. A restriction map has been constructed, and the TaqI polymorphic site has been localized within the 5' portion of the gene. The mutation in the polymorphic site is probably the cause of the factor XII deficiency. Data suggest the presence of one factor XII gene per haploid genome.     

Studies on a circulating anticoagulant in procainamide-induced lupus erythematosus

Circulating anticoagulant activity that had at least two distinct mechanisms--one directed against factor XII and one directed against blood thromboplastin (prothrombin activator complex)--developed in a patient with clinical and laboratory evidence of procainamide hydrochloride-induced systemic lupus erythematosus. The anticoagulant activity behaved as a gamma-globulin in chromatographic and electrophoretic analyses, with the majority of activity behaving as an IgM immunoglobulin. Despite markedly abnormal coagulation study results, no clinical bleeding occurred. Anticoagulant activity paralleled clinical and laboratory evidence of the inflammatory disease and improved on discontinuance of procainamide therapy.     

Acquired hypoprothrombinemia: Effects of Danazol® treatment

The lupus anticoagulant may be accompanied by an acquired factor II deficiency and bleeding. We report on a patient with a lupus anticoagulant and factor II (FII) deficiency responsive to Danazol®. Acquired hypoprothrombinemia (FII) with the lupus anticoagulant (LA) may be accompanied by a hemorrhagic diathesis. A 64-year-old male with discoid lupus erythematosis bled after an intestinal polypectomy. His FII level was 18%, and his FII antigen level was 20%. Danazol® (D) (600 mg per day) administration was associated with a rise in FII activity and antigen to 50% within 10 days. The patient underwent abdominal surgery. We studied the effect(s) of D on the FII level and on other coagulation factors in this patient. The patient's plasma FII antigen had a single precipitin arc compared to the two peaks of normal plasma on counterimmunoelectrophoresis with Ca⁺⁺. The samples pre- and during D therapy had the same positively charged arc as normal samples, although they were quantitatively different. Neuraminidase treatment demonstrated a decrease in the positively charged migration of normal and the patient's FII antigen. Affinity chromatography of normal and patient plasma on a Sepharose protein A column revealed FII antigen present in the patient's bound fraction. The relative percentages of bound FII before and during D treatment were similar. During D therapy, levels of FIX and X rose 50-100%, and protein C rose 20-25%, while free protein S did not change. D is an effective therapy for acquired FII deficiency associated with LA. D does not affect the binding of Ig to FII, but D raises FII levels by increasing synthesis of the FII protein. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis

Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45′′) due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.     

Interactions among Hageman factor, plasma prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent.

To investigate the earliest steps of the intrinsic clotting pathway, Hageman factor (Factor XII) was exposed to Sephadex gels to which ellagic acid had been adsorbed; Hageman factor was then separated from the gels and studied in the fluid phase. Sephadex-ellagic acid-exposed Hageman factor, whether purified or in plasma, activated plasma thromboplastin antecedent, but only when high molecular weight kininogen was presnet. In the absence of plasma prekallikrein, maximal activation of plasma thromboplastin antecedent was slightly delayed in plasma, a delay not observed with similarly treated purified Hageman factor. Thus, high molecular weight kininogen was needed for expression of Hageman factor's clot-promoting properties and plasma prekallikrein played a minor role in the interaction of ellagic acid-treated Hageman factor and plasma thromboplastin antecedent.     

Red-cell hypoplasia and increased bone marrow reticulin in systemic lupus erythematosis: Reversal with corticosteroid therapy

A 29-year-old Chinese male developed severe aregenerative anemia. The bone marrow was diffusely hypercellular with increased marrow reticulin and a persistent failure of eryihroid differentiation beyond the pronormoblast stage. Although he did not manifest classic features of systemic lupus erythematosus, multiple serologic studies were in accord with this diagnosis. The patient's defect in erythropoiesis was studied by an in vitro technique for the growth of erythroid colonies. Despite the severe erythroid hypoplasia, the patient's marrow yielded abundant large erythroid colonies. Serum erythropoietin activity was high as judged by use of this in vitro assay. Although the patient's native serum did not affect colony formation, a separated IgG fraction was markedly inhibitory to colony growth. This suggests that the erythroid hypoplasia may have resulted from a unique autoantibody. The patient's hematologic abnormalities completely reversed following treatment with corticosteroids.     

Percutaneous vertebroplasty treatment of steroid-induced osteoporotic compression fractures

This report describes the case of a woman in whom multiple compression fractures of the lower thoracic and lumbar spine occurred in association with long-term corticosteroid therapy for systemic lupus erythematosus. Pain markedly limited the patient's mobility and daily activities, and conservative therapy with bracing and narcotic analgesics gave little improvement. Affected vertebrae were treated with polymethylmethacrylate, introduced percutaneously under fluoroscopic guidance. The resulting reinforcement of the fractured vertebral bodies climinated the pain and the need for narcotic analgesics. The utilization of percutaneous verterbroplasty as a therapeutic alternative for the treatment of pain resulting from osteoporotic compression fractures is described.     

Hereditary angioedema and "familial" lupus erythematosus in identical twin boys

Complement system proteins, C4 metabolism and serologic markers of systemic lupus erythematosus were studied in identical male twins with chronic discoid lupus erythematosus and hereditary angioedema. Systemic lupus erythematosus was confirmed in their mother at age 22 during the twins' gestation. She also manifested symptoms suggesting hereditary angioedema. Low C1&;#x0304; inhibitor (C1&;#x0304; INH) and C4 have been documented since age 13 in both twins. At this time, metabolic studies disclosed a combined C4 fractional hypercatabolism (0.96 to 1.02/day) and decreased synthesis (3.0 to 3.15 mg /kg/day). Normal C1&;#x0304; inhibitor and C4 concentrations are present in their healthy father and maternal grandparents, indicating that the C1&;#x0304; inhibitor deficiency in the twins was inherited as an autosomal codominant from their mother in whom a spontaneous mutation had occurred. Positive antinuclear antibody, increased antibody to denatured deoxyribonucleic acid and immunoglobulin deposits in normal skin in both twins are evidence of systemic lupus erythematosus. In addition, a chronic biologic false-positive serology is present in one twin. We postulate that the association of hereditary angioedema and “familial” systemic lupus erythematosus is a biologically relevant phenomenon. It is proposed that the secondary C4 deficiency predisposed the patient to the development of systemic lupus erythematosus in some presently unknown manner.     

Medical and psychosocial predictors of sexual outcome among women with systemic lupus Erythematosus

The influence of medical and psychosocial variables on sexual outcome in 100 women with systemic lupus erythematosus was examined. Subjects were administered a sexual adjustment interview and scales assessing depression, body image, and relationship qualilty. Medical data were obtained from patients and physicians. Key predictors of sexual outcome were disease severity (P < 0.001), premorbid sexual adjustment (P < 0.05), and relationship quality (P < 0.05). Results suggest that the impact of systemic lupus erythematosus on sexual response may best be understood by considering a combination of interpersonal, psychological, and medical conditions in a patient's life.     

Autoantibodies to DEK oncoprotein in a patient with systemic lupus erythematosus and sarcoidosis

A patient was identified with an unusual autoimmune syndrome consisting of systemic lupus erythematosus and sarcoidosis. Her serum contained extremely high levels of autoantibodies to the DEK protooncogene product. The patient's serum was used to clone a dek complementary DNA, which was expressed as a histidine-tagged fusion protein in Escherichia coli. Using affinity-purified recombinant DEK protein, anti-DEK autoantibodies were found in the patient's serum at a titer of 1:10⁶ by enzyme-linked immunosorbent assay (ELISA). Longitudinal studies revealed marked variations in anti-DEK autoantibody levels over time. Although it has been suggested that anti-DEK auto-antibodies are a marker for pauciarticular juvenile rheumatoid arthritis with iridocyclitis, the present data suggest that they may be associated with other disease subsets as well. The quantitative ELISA technique will be useful for defining these subsets further and for examining the relationship between anti-DEK titers and disease activity.     

Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome

Forty female patients with either primary anti-phospholipid syndrome (n = 26) or systemic lupus erythematosus (anti-phospholipid syndrome positive) (n = 14) were investigated for levels of factor XII, the presence of lupus anticoagulant and antibodies to cardiolipin, beta 2-glycoprotein I and factor XII. Twenty-one patients had a history of recurrent fetal loss (> 2, mean = 2.6). Lupus anticoagulant positivity showed a weak association with recurrent fetal loss (odds ratio = 1.1). While there was no association between the presence of antibodies to cardiolipin or beta 2-glycoprotein I with recurrent fetal loss, antibodies to factor XII showed a strong and statistically significant association (odds ratio = 5.4, P = 0.025).     

Amidolytic properties of single-chain activated Hageman factor.

Activation of Hageman factor (Factor XII) upon exposure to negatively charged agents has been attributed to proteolytic cleavage of this molecule. To examine this question, purified Hageman factor was exposed to Sephadex gels to which ellagic acid had been adsorbed. Such Hageman factor, separated from the gels and studied in the fluid phase, was amidolytic. Nonetheless, no cleavage of Hageman factor treated in this way could be demonstrated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Thus, activation of Hageman factor by negatively charged agents was not necessarily accompanied by molecular scission.     

Development of the anti-Ro autoantibody response in a patient with systemic lupus erythematosus

Objective. To characterize the initial events in anti-Ro production by a patient with systemic lupus erythematosus, in whom this autoantibody is developing. Methods. The immune response to the Ro ribonucleoprotein and other autoantigens were studied by enzyme-linked immunosorbent assay for IgG and IgM, by isoelectric focusing, and by inhibition studies to determine apparent avidity. Results. The patient's sera showed an oligoclonal response to Ro that increased in complexity and affinity with time. IgM anti-Ro appeared shortly before IgG anti-Ro, and disappeared as IgG anti-Ro increased in titer and affinity. IgG antiribosomal P autoantibodies also appeared during the patient's course, but in contrast to anti-Ro, were not preceded by IgM antiribosomal P. Conclusion. These data are consistent with the Ro autoantigen being presented and processed in a manner similar to heterologous antigen, and with differences in the mechanisms that lead to the production of IgG anti-Ro autoantibodies as opposed to antiribosomal P autoantibodies.     

Regression of systemic lupus erythematosus after development of an acquired Toll‐like receptor signaling defect and antibody deficiency

Toll‐like receptor 9 (TLR‐9) and TLR‐7 may have a role in the production of anti‐DNA and anti‐RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to the development of systemic lupus erythematosus (SLE). Herein we describe a patient with SLE who had long‐lasting remission of her autoimmune disease after development of an antibody deficiency resembling common variable immunodeficiency (CVID). After CVID had developed, anti–double‐stranded DNA antibodies disappeared, although antinuclear antibodies remained positive for >10 years. In vitro studies revealed that the patient's B cells proliferated poorly and failed to differentiate into plasmablasts after stimulation of either TLR‐9 or TLR‐7, providing evidence for an acquired defect of the signaling pathway downstream of these TLRs. These observations suggest, although indirectly, that signaling through TLR‐9 and TLR‐7 is important in the pathogenesis of human SLE, and indicate that investigation of potential treatment strategies with TLR antagonists is warranted.