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SUMMARY In a prospective longitudinal study 130 patients with systemic lupus erythematosus (SLE) were studied at least monthly for a relationship between the anti-dsDNA levels and disease activity. We observed 13 patients who developed 15 periods of exacerbations of their disease. All 15 exacerbations were preceded by a continuous increase of the anti-dsDNA levels. In 13 of the 15 exacerbations studied the exacerbation was preceded by an increase of anti-dsDNA with a doubling time (T2) of less than 6 weeks; in 4 of the 5 other exacerbations the T2 was less than 10 weeks. Four other patients with an increase of the anti-dsDNA levels showed no exacerbation. In these 4 patients the T2 was larger than 10 weeks. The other 1 13 patients did not show an increase of anti-dsDNA over the 2 years of monitoring and showed no signs of serious disease activity (no major symptoms). These observations suggest that an SLE patient who is followed up frequently and who shows a continuous increase of anti-dsDNA with a T2 shorter than 10 weeks is bound to develop an exacerbation.With the proper assay systems the diagnostic value of antibodies to double-stranded (ds)DNA seems to be beyond doubt.' Antibodies to dsDNA are found in high frequency in the serum of patients with active systemic lupus erythematosus2 (SLE) but not in the serum of normal persons and patients with a variety of other autoimmune diseases, such as discoid lupus erythematosus,3 chronic hepatitis,4 or rheumatoid arthritis.5 6 A more difficult problem is the relation between the anti-dsDNA level and disease activity. Systematic longitudinal studies are scarce and suffer from inadequate quantitation of anti-dsDNA and infrequent serum sampling. This might be the reason why no conclusion has yet emerged about the relation of anti-dsDNA level to disease activity. The only consistent finding is that patients with a persistently high anti-dsDNA level are bound to develop a major flare-up of the disease more frequently than patients with a low level.7Elevated levels of anti-dsDNA, however, may persist for several years before such a flare-up occurs. On treatment of the patient the anti-dsDNA level decreases, and it has been suggested that this might be used to monitor therapy.7`9

Increased plasma levels of prothrombin fragment 1 + 2 (F1 + 2) found in patients with sickle-cell disease reflect enhanced endogenous thrombin generation. We postulate that hypercoagulability contributes to vaso-occlusion. The intensity of acenocoumarol treatment required to reduce the F1 + 2 level to 50% of pretreatment level was investigated in seven patients with symptomatic sickle-cell anaemia during steady-state disease for a period of 2 months. All patients had increased levels of F1 + 2 compared with an age-matched control group. Normalization of the F1 + 2 was achieved at a median INR of 1.64 (range 1.18-2.2). It is concluded that low-intensity oral anticoagulation normalizes the hypercoagulability in sickle-cell disease.

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Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of lowadjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6À2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20À59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical bene®t (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing speci®c events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study. Am.

1. Glomerular filtration rate and effective renal blood-flow were normal in a series of patients with sickle cell anaemia. Fractional creatinine excretion and fractional urea excretion were increased.2. During indomethacin administration there were significant falls in glomerular filtration rate, effective renal blood-flow, creatinine clearance and urea clearance in the patients with sickle cell anaemia; fractional urea excretion also fell markedly. In control subjects none of these variables changed after indomethacin.3. Serum concentration of urea rose markedly during indomethacin administration in sickle cell anaemia, owing to both the decrease in glomerular filtration rate and the increase in fractional urea reabsorption. 4. We conclude that prostaglandins have an important role in maintaining a normal glomerular filtration rate and effective renal blood-flow in sickle cell anaemia. The abnormal urea handling in patients with this disease remains to be elucidated.

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