1210 LETTERS

7. Haimovitz A, Fuks Z, Galaili N , Treves AJ: Changes in peanut agglutinin binding in human monocytes during their maturation to macrophages. J Reticuloendothel SOC 31:187-192, 1982

8. Andrew CW, Rees ADM, Scoging A, Dobson N: Secretion of a macrophage activating factor distinct from yIFN by human T cell clones. Eur J Immunol 14:962-964, 1984

9. Groenewegen G, de Ley M, Jeunhomme GMAA, Buurman WA: Supernatants of human leukocytes contain mediators different from interferon y, which induces expression of MHC class I1 antigens. J Exp Med 164:131-143, 1986

10. Walker EB, Maino V, Sanchez-Lanier M, Warner N, Stewart C: Murine gamma interferon activates the release of a macro- phage-derived Ia-inducing factor that transfers la inductive capacity. J Exp Med 159:1532-1547, 1984

To the Editor: We appreciate the comments of Drs. Ridley and

Panayi. Their findings confirm our results demonstrating negligible y-interferon (y-IFN) production by unstimulated rheumatoid arthritis (RA) synovial tissue cells and low concentrations of y-IFN in RA synovial fluid (SF) ( I ) . These data suggest that the higher expression of HLA-DR on S F monocytes is due either to a unique sensitivity to y-IFN in RA or to other, non-yIFN cytokines. To investigate the first possibility, we used fluorescence-activated cell sorter analy- sis to compare the amount of y-IFN required in vitro to induce surface HLA-DR (also known as Ia) expression on peripheral blood rnonocytes, and found that RA mono- cytes were slightly less sensitive than normal monocytes to the effects of y I F N in vitro, as measured by Ia induction ( 2 ) . Therefore, it is unlikely that an increased sensitivity to y-IFN in RA accounts for the high level of Ia expression on SF monocytes and synovial tissue macrophages.

The role of non-IFN cytokines in the activation of SF monocytes was tested by examining the ability of a number of cytokines, including interleukins 1, 2 , 3, 4, and 6, granu- locyte-macrophage colony-stimulating factor (GM-CSF), CSF-I, and tumor necrosis factor (TNF), to induce Ia on normal monocytes. Of the mediators studied, only GM-CSF was found to consistently increase monocyte surface Ia expression (3); GM-CSF also decreased monocyte expres- sion of CD14, a monocyte differentiation antigen detected with the monoclonal antibody Mo2. The effect of GM-CSF was additive with low concentrations of y-IFN and syner- gistic with TNF.

Since GM-CSF is produced locally in rheumatoid synovium (4), we incubated RA synovial tissue culture supernatants with normal monocytes in the presence or absence of antibodies to y-IFN or GM-CSF. The superna- tants significantly increased surface DR expression, and only the anti-GM-CSF antibody neutralized this activity (3). These results strongly suggest that GM-CSF is largely re- sponsible for Ia expression in rheumatoid synovitis and for the “activated” phenotype (high HLA-DR, low Mo2) we observed on SF monocytes (5). Although y-IFN may con- tribute to these activities, it is more likely that interactions with other factors account for high monocyte/macrophage Ia expression in the joint.

In regard to the presence of Mo2 positive, HLA-DR positive monocytes in RA SF, it is important to note that although the activation of normal monocytes with y-IFN does decrease CD14 expression, many cells continue to express the antigen, albeit at a lower level (6). Two-color analysis of these monocytes demonstrates many cells that are strongly DR positive and still express some CD14 on their surface. A similar situation exists with “activated” monocytes in RA SF. Therefore, Drs. Ridley and Panayis’ data are not necessarily at variance with our own. Although the effect of culture conditions always needs to be consid- ered, the SF monocytes of several of our patients were examined both pre- and post-culture, and no difference was observed in the phenotype.

Gary S. Firestein, MD Nathan J. Zvaifler, MD University of Cal$omia San Diego, CA

I . Firestein GS, Zvaifler NJ: Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. 11. Low levels of synovial fluid and synovial tissue interferon suggest that ’y- interferon is not the primary macrophage activating factor. Arthritis Rheum 30:864-871, 1987

2. Bergroth V, Zvaifler NJ, Firestein GS: Variable class I1 MHC induction by gamma interferon (IFN-gamma) on normal and rheumatoid arthritis (RA) monocytes. Submitted for publication

3. Avaro-Gracia JM, Zvaifler NJ, Firestein GS: GM-CSF is a major macrophage activating factor (MAF) in rheumatoid synovitis. Submitted for publication

4. Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler NJ: Cytokines in chronic inflammatory arthritis: GM-CSF in rheuma- toid synovial effusions. J Clin Invest (in press)

5 . Firestein GS, Zvaifler NJ: Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. I. A cytofluoro- graphic study of monocyte differentiation antigens and class I1 antigens and their regulation by yinterferon. Arthritis Rheum 30:

6. Firestein GS, Zvaifler NJ: Down regulation of human monocyte differentiation antigens by interferon. Cell Immunol 104:343-354, 1987

857-863, 1987

Severe hemorrhage in a patient with circulating anticoagulant, acquired hypoprothrombinemia, and systemic lupus erythematosus

To the Editor: The presence of both arterial and venous thrombo-

ses, fetal loss, thrombocytopenia, and positive findings on the Coombs’ test have all been reported to correlate with the presence of serum antiphospholipid antibodies (1,2). Al- though these antibodies often inhibit coagulation in vitro and prolong the partial thromboplastin time (PTT) (lupus anti- coagulant [LAC]), there are very few case reports of bleed- ing associated with the presence of this antibody alone, without other hemostatic abnormalities (3,4). I recently saw a patient with systemic lupus erythematosus (SLE) who presented with life-threatening hemorrhage associated with the presence of both circulating LAC and severe hypopro- thrombinemia, probably related to antibody-mediated dis-

LETTERS 121 1

ease. Prompt treatment with corticosteroids led to dimin- ished bleeding and normalization of the PTT and the prothrombin time (PT).

The patient, a 22-year old man, developed severe alopecia 6 months prior to admission. Laboratory evaluation at that time revealed high-titer antinuclear antibody and severely depressed hemolytic complement levels (CH50 0, normal 120-180 units; C3 35 mg/dl, normal 70-176; C4 3 mg/dl, normal 16-45). The hemoglobin level at that time was 14 gm%, the white blood cell (WBC) count was 3,900/mm3, and the platelet count was 1 14,000/mm3. The erythrocyte sedimentation rate (ESR) was 15 mm/hour; the VDRL result was negative, and urinalysis revealed several red blood cells (RBC), but no other significant abnormalities. Skin biopsy revealed positive immunofluorescent staining on the base- ment membrane and light microscopy findings compatible with SLE. The level of antiphospholipid antibody (anticar- diolipin), measured (by solid-phase enzyme-linked immuno- sorbent assay) as absorbance at 410 nm, was 0.51 (normal c0.40).

Within 2 months, the patient developed joint pain, significant adenopathy, weight loss, severe nose bleeds, and hemorrhaging from his gums. The ESR was 58 mm/hour, and urinalysis showed microscopic hematuria, RBC casts, and proteinuria. The PTT was 118 seconds (normal 25-39), and the PT was 23 seconds (normal 10-12). The hemoglobin level was 7 gm%, the platelet count was 150,000/mm3, and the WBC count was 3,000/mm3. Results of an LE cell prepara- tion test were positive, and the blood urea nitrogen and creatinine values were within normal limits.

The patient’s abnormal PTT and PT could not be corrected by administration of normal plasma at a 1:l dilution, and the presence of LAC was diagnosed. The Factor I1 (prothrombin) level was 4% (normal 80-120), while all other coagulation factors were within normal limits. Since we were able to demonstrate the presence of the LAC, in addition to the possibility that there was antibody directed against prothrombin, the patient was given hydrocortisone, 100 mg intravenously every 8 hours, in addition to blood transfusions. His nose was packed to decrease bleeding. Within 3 days, all bleeding ceased. After 7 days, the PT, PTT, and prothrombin level returned to normal. Gradually, the corticosteroid dosage was decreased, and the patient has been maintained on a regimen of prednisone, 15 mg daily. The PT and PTT have remained normal, but the CH5O level has continued to be 0. There has been no further bleeding, and no other manifestations of significant SLE activity.

The majority of patients with the lupus anticoagulant have demonstrated a predisposition to clotting (thromboses) rather than bleeding. Those patients who have developed bleeding have an associated defect, often hypoprothrombi- nemia, which is thought to be antibody-mediated (3,4). Studies by Bajaj et al have demonstrated that this acquired hypoprothrombinemia stems from the rapid clearance of prothrombin antigen-antibody complexes from the circula- tion (3). Such patients not only have prolongation of the PTT, but significant prolongation of the PT, due to the severe prothrombin deficiency.

Our patient presented with the LAC and hypopro- thrombinemia, along with significant life-threatening hemor- rhage. Based on his case and a review of the literature, it

appears that patients with circulating anticoagulants who have bleeding generally have an associated defect, and the presence of antibody to prothrombin is a major consider- ation in such patients. The presence of a significantly in- creased PT, associated with the prolongation of the PTT, should alert the clinician to the possibility of these 2 defects. The LAC itself significantly prolongs the PTT, but not the PT. The fact that this disease is probably antibody-mediated suggests that immunosuppressive therapy, in conjunction with conservative measures such as blood transfusions and surgical packing, should be effective in controlling the con- dition. Our patient responded quite promptly to cortico- steroid therapy, with resolution of both the bleeding and the laboratory abnormalities.

There appears to be a low incidence of bleeding in patients who have the lupus anticoagulant without associ- ated coagulation defects. However, should the patient have evidence of other coagulation abnormalities, such as throm- bocytopenia, an increased PT, or hypoprothrombinemia, the possibility of a clinical bleeding diathesis should be consid- ered and appropriate measures taken to prevent any signif- icant complications. The presence of circulating anticoagu- lant not only suggests an increased risk for thrombosis, but may be associated with clinical hemorrhage.

Peter Small, MD Jewish General Hospital and McGill University Montreal, Quebec, Canada

1 . Espinoza LR, Hartmann RC: Significance of the lupus anticoa- gulant. Am J Hematol 22:331-337, 1986

2. Harris EN, Hughes GRV, Gharavi AE: Antiphospholipid anti- bodies: an elderly statesman dons new garments. J Rheumatol

3. Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB: A mechanism for the hypoprothrombinemia of the acquired hypo- prothrombinemia-lupus anticoagulant syndrome. Blood 61 : 6 8 4 692, 1983

4. Lechner K: Acquired inhibitors in nonhemophilic patients. Hae- mostasis 3:65-93, 1974

14~208-212, 1987

Anticardiolipin antibody and complement

To the Editor: In their prospective study of 44 women with idio-

pathic habitual abortion, Petri et a1 (1) found elevated levels of anticardiolipin antibody (ACLA) in 5 (1 1%) of the women. This is in contrast to the results of a similar study by Unander et al (2), who found increased ACLA levels in 42 (42%) of 99 women with habitual abortion. In addition, Unander’s group noted significantly decreased levels of complement factor C4 in conjunction with high ACLA activity, whereas Petri and coworkers reported higher C4 levels in the habitual aborters than in controls.

In a study of 39 patients who had confirmed systemic lupus erythematosus (SLE) which met the American Rheu- matism Association revised criteria (3), our findings were more consistent with those of Unander et al. A diagnosis of SLE was the sole determining factor for inclusion in our study; habitual abortion was not a requirement for inclusion.