Antiphospholipid Antibody Syndrome.

Antiphospholipid antibody syndrome (APS) is a recently defined autoimmune disorder characterized by recurrent vascular thromboses or recurrent pregnancy morbidity; these features are linked to the presence in blood of autoantibodies against negatively charged phospholipids or phospholipid-binding proteins. Thrombosis can occur in any tissue, in veins, arteries, or the microvasculature. Pregnancy morbidity in APS includes miscarriages or premature birth. Criteria that define the major clinical and laboratory features of APS were published in 1999. In patients with antiphospholipid antibodies and prior thrombosis or pregnancy morbidity, there is a high risk of recurrence that persists as long as antiphospholipid antibodies occur in blood. This risk for recurrence of thrombosis or pregnancy morbidity is greatly reduced by preventive anticoagulant therapy. Patients presenting with thrombosis in APS are initially managed in much the same way as are patients with vascular thrombosis owing to other causes. However, in patients with APS, high-intensity anticoagulation is usually needed to prevent recurrences of thrombosis. Thrombosis in APS is often multifactorial, as with non-APS thrombosis. Therefore, in all patients with APS, other reversible risk factors for thrombosis should be sought. The pregnancy outcome of women with APS who have had prior miscarriages is greatly improved by treatment during pregnancy with a combination of heparin and low-dose aspirin.

Antibodies to cardiolipin and beta2-glycoprotein-1 in HTLV-1-associated myelopathy/tropical spastic paraparesis

Anticardiolipin and anti-beta2GP1 antibodies were measured in 50 patients with HTLV-1-associated Myelopathy-Tropical Spastic Paraparesis (HAM-TSP) and the results were compared with those obtained for 34 HTLV-1-positive and 35 HTLV-1-negative controls, as well as 128 SLE patients. aCL but not anti-beta2GP1 was associated with HTLV-I infection. aCL was more prevalent than anti-beta2GP1 (32 percent vs. 8 percent) and was not associated with anti-beta2GP1 in HAM-TSP. IgA was the dominant isotype of aCL and anti-beta2GP1. The data suggest that tin HAM-TSP, IgA aCL are frequent and are associated with HTLV-1 infection.(Au)

IGA antiphospholipid antibodies in HLTV-1-associated tropical spastic paraparesis

A retrovirus human T cell lymphotropic virus type I (HTLV-I), is an essential but not a sufficient aetiological factor for tropical spastic paraparesis (TSP). Because some TSP patients have biological false positive tests for trepomemal infections (BFP-STS), we used EISA to study BFP-STS and anticardiolipin antibodies in 42 Jamaican TSP patients. The data indicate that in TSP anticardiolipin antibodies accur in about 26 percent of patients, are associated with biological false positive treponemal serology, are relatively restricted to the IgA isotype and may be induced by HTLV-I or other non-treponemal infections. (Au)

Clinical and genetic aspects of primary antiphospholipid antibody syndrome - abstract

Antibodies against phopholipids are associated with recurrent arterial and venous thromboses, thrombocytopenia and pregnancy loss. This antiphospholipid antibody syndrome is most commonly seen in systemic lupuis erythematosus (SLE); in previous studies we demonstrated that deficiency alleles of the fourth component of the complement system are associated with the presence of antiphospholipid antibodies in SLE. A primary antiphospholipid antibody syndrome is also known to occur in the absence of evidence of a defined connective tissue disorder; the aetiological relationship of this primary antiphospholipid antibody syndrome to SLE is unclear, but previous studies have suggested a genetic basis for some components of this syndrome. We investigated a 26-year-old woman who presented in 1986 with all the features of primary anti-phospholipid antibody syndrome. During the previous 4 years she had developed one episode of deep venous thrombosis and two pregnancy losses during the second trimester. On presentation, she was thrombocytopenic, had a false positive test for syphilis, a circulating lupus anticoagulant and persistently very high levels of IgG anticardiolipin antibody. However, antinuclear antibodies were repeatedly absent from serum. She subsequently developed two episodes of stroke, with radiological evidence of cerebral infarction. The anticardiolipin antibody levels were incompletely suppressed by plasmaphaeresis and intravenous cyclophosphamide, but she improved clinically after anticoagulation with warfarin was instituted. Studies of plasma and of DNA from this patient revealed the presence of a large heterozygous gene deletion at one of loci of the fourth component of the complement system (C4A) and the adjacent 21 hydroxylase-A gene. This deletion was present in only 7 percent of a control normal population. We and others have shown this deletion to be a risk factor for systemic lpus erythematosus. We are continuing long-term follow-up of this patient and studies among her family members to further elucidate the relationship of this and other genetic factors to the antiphospholipid antibody syndrome. This is the first report of the presence of a C4A gene deletion in a patient with the primary antiphospholipid antibody syndrome and it supports the idea that there is a close genetic relationship between this syndrome and systemic lupus erythematosus (AU)

Immunophenotypic and HLA studies in childhood acute lymphoblastic leukemia in Trinidad, West Indies

Between October 1983 and May 1986, 17 cases of childhood acute lymphoblastic leukemia (ALL) were admitted to the General Hospital, Port of Spain, Trinidad. Fifteen of those cases were under 10 years of age, seven of whom presented with joint or bone pains. Boys outnumbered girls by almost 5:1 and the ethnic distribution showed a preponderance of patients of East Indian origin. At last follow-up (May 1989), the survival rate of the 15 under-ten-year-old patients was 71 percent. Immunophenotype studies on nine of the 17 patients revealed six carrying T cell markers and three carrying markers suggestive of a pre-B phenotype. HLA tissue typing on ten patients showed an enhanced frequency of the HLA-B40 antigen when compared with controls (p less than 0.05). This antigen was present in six of the patients typed and four carried the HLA-A2 and B40 antigens together, two of whom also carried the CW3 antigen and the other two carried untypable C antigens. Three of the four carrying HLA-A2 and B40 have died. Two of the three pre-B cases also carried the HLA-A2 and B40 antigens. HLA studies on three of the four families showed that HLA-A2 and B40 were on the same chromosome, i.e., a haplotype inherited from the mother in each case. None of the cases carried the HLA-B5 antigen although this antigen had a frequency of 37.8 percent in the control group (p less than 0.05 percent). None of the controls with the HLA-B40 antigen carried the CW3 antigen. Further evidence of a disease association must await typing of the D locus antigens but current evidence would suggest an association between HLA-B40 and childhood ALL in Trinidad. (AU)

Serum urate concentrations in homozygous sickle cell disease

Serum and urinary urate concentrations were studied in 44 patients with homozygous sickle cell (SS) disease, and in 27 controls with normal haemoglobin. Hyperuricaemia (>0.39 mmol/1(6.5 mg/100ml)) occurred in 41 percent of SS patients and inversely correlated with renal urate clearance but not with indices of bone marrow turnover. Higher serum urate concentrations occurred in patients with proteinuria, probably due to associated tubular damage. Higher serum urate concentrations and lower urate clearance occurred in males compared to females (AU)

Plasma haemoglobin and complement activation in sickle cell disease

The role of haemolysis in producing deficient complement function in homozygous sickle cell disease was studied by measuring indices of complement activation and of haemolysis in 30 asymptomatic patients. Plasma concentration of C3d (an index of increased C3 turnover) was elevated in 40 percent of patients and modest decreases in serum concentration of C3 and functionally (haemolytically) active factor B were found. There was a positive correlation between C3d and plasma haemoglobin concentration (r = 0.56, p less than 0.005). Reticulocyte count and foetal haemoglobin concentration also contributed to variation in C3d, though to a lesser extent than plasma haemoglobin. Intravascular haemolysis in sickle cell disease may produce activation of complement and thus cause partial depletion of functional factor B and C3. This may reduce the immune function of the alternative pathway. (AU)

Prevalence of drug-induced immunologic changes in hypertensive Jamaicans

Of 137 hypertensive black Jamaicans who took methyldopa for a mean period of 36 months, a positive ANA was found in 1.5 percent and a positive direct Coombs' test in 0.7 percent. In 36 patients in whom hydralazine was induced in the therapeutic regimen, a positive ANA was seen in only 6 percent. These results suggest that in black populations, immunologic abnormalities induced by antihypertensive drugs are less common than has been reported in white patients. (AU)

Activation of the alternative pathway of human complement by haemoglobin

Haemoglobin solutions (concentration >1.5mg/ml), prepared from lysates of erythrocytes from a normal subject and from a patient with sickle cell anaemia, caused factor B and C3 cleavage and loss of haemolytic activity of factor B when incubated with fresh autologous serum. Under the same experimental conditions, preparations of erythrocyte stroma or of buffy coat lysates did not produce factor B and C3 cleavage. This reaction required Mg++ but not Clq or C4, indicating that the alternative complement pathway was activated (Summary)

Dengue fever in Jamaica with shock and hypocomplementaemia, haemorrhagic, visceral and neurological complications

Ten patients with severe dengue syndrome have been seen in the recent epidemic in Kingston, Jamaica. Two patients had dengue shock syndrome. One had abnormal coagulation indices and another had severe haemorrhagic diarrhoea. Five patients had neurological syndromes of whom 3 had encephalitis, one had a meningoencephalomyelitis and one had a post-infective type demyelination syndrome. Hepatitis occurred in 2 patients, one of whom had dengue haemorrhagic fever. Pancreatitis occurred in 2 patients, one of whom had haemorrhagic fever. Concentrations of several components of serum complement were reduced only in patients with dengue shock syndrome and not in those with other complications. Although altered dengue syndromes have occurred aginst a background of multiple dengue virus types, the incidence is much lower than occurs in South-East Asia, no definite fatalities have been confirmed and adults seem to have been primarily affected rather than children (AU)

Acute rupture of the knee joint in rheumatoid arthritis

Two cases of acute rupture of the knee joint are described. The use of arthrography in diagnosis is demonstrated, and the aetiology and management briefly discussed (AU)

Total body water, extracellular, and plasma volume compartments in sickle cell anaemia

The total body water (TBW), plasma (PV) and extracellular fluid volumes (ECFV) of twenty-nine subjects with sickle cell anaemia, ten of whom were in painful crisis, were studied. During asymtomatic periods (the steady state), the ECFV of subjects with the anaemia is increased when compared with normal controls, because of plasma volume expansion; the interstitial fluid volume (ISFV) is normal, and intra cellular water (ICFV) is diminished by 5 percent of weight. During painful crisis, there was a marked tendency to loss of plasma volume into the interstitial fluid compartment, and the data also suggested that there was acute cellular distruction. Most of the patients in this study managed, however, presumably by compensatory changes in renal function and fluid intake, to maintain a normal plasma volume during painful crisis (AU)

Systemic lupus erythematosus and sickle-cell anaemia

In view of the relationship between immunity deficiency states and immune complex diseases such as systemic lupus erythematosus (SLE) a possible association between SLE and sickle-cell disease, in which there is evidence of immunity deficiency, is of interest.(AU)

Deficiency of factor B of the complement system in sickle cell anaemia

Factors B and D as well as the total activity of the alternative pathway of complement activation were measured using a functional assay in sera from 29 patients with sickle cell anaemia and 18 normal controls. Total alternative pathway activity was reduced in the patients compared with controls. In patients with abnormally low total alternative pathway activity factor D levels were normal, whereas factor B levels were significantly depresed to a mean level of about half of normal. Regression analysis in patients also showed a singnificant relation between total alternative pathway activity and factor B levels. A deficiency of factor B is the likely cause of the defect in the complement system in patients with sickle cell anaemia. Such a defect may contribute to the excessive proneness of such patients to severe infection.(AU)

Renal function during painful sickle cell crisis

Glomerular filtration rate (GFR) was increased, and urine flow rate and sodium excretion diminished early in painful sickle cell crisis; the last two changes may be responses to a tendency to shrinkage of plasma volume. Increased GFR during painful crisis could in the presence of decreased fluid intake contribute to fluid loss, loss of plasma volume and circulatory stasis (AU)

Complement activation in asymptomatic patients with sickle cell anaemia

Previous reports have suggested that a defect in serum complement may contribute to the increased susceptibility to infection shown by patients with sickle cell anaemia (SCA). In order to define the nature of any complement abnormality in SCA, we investigated the complement system in eighty-seven patients during asymptomatic periods, and analysed factor B turnover in a small sample. In these patients geometric mean serum concentrations of functionally active factor B and factor D, and of C3 and C4 protein (expressed as a percentage of normal reference serum) were lower than in controls (78 percent vs. 107 percent, P<0.001, 86 percent vs. 103 percent, P<0.001, 91 percent vs. 100 percent, P<0.01, 89 percent vs. 105 percent, P<0.05 respectively). The ratio of the serum concentration of functionally active factor B to factor B protein was lower in patients than in controls (mean 75 percent s.d 16 percent vs. mean 93 percent, s.d 22 percent P<0.001), indicating a functional deficiency of factor B protein. In addition, the fractional catabolic rate of radiolabelled factor B was markedly increased in four out of seven asymptomatic patients studied, and was inversely related to the functional factor B concentration in serum (r=-0.59, P<0.05); factor B synthesis was uniformly increased. Complement activation was not related to the presence of circulating Clq binding material. We conclude that complement activation, rather than defective synthesis as previously suggested, contributes to the abnormalities in complement component concentration and function in asymptomatic subjects with sickle cell anaemia (Summary)