Biomedical subjects
C Christopoulos
Publications and source records attributed to C Christopoulos.
Localised gastrocnemius myositis in Crohn's disease.
A19-year-old woman presented with pain and tenderness in both calves associated with pyrexia and neutrophil leukocytosis. Gastrocnemius muscle biopsy showed a non-specific lymphocytic myositis and she was found to have positive c-ANCA, in the absence of other evidence of systemic vasculitis. Subsequent investigation of her gastrointestinal tract revealed extensive Crohn's disease. The myositis responded promptly to treatment with prednisolone 0.5 mg/kg. A review of the literature showed that localised calf pain in the setting of Crohn's disease can be caused by non-specific myositis, granulomatous myositis or vasculitis. It is proposed that the "gastrocnemius myalgia syndrome" be included in the typical - albeit rare - extraintestinal manifestations that may herald the appearance of inflammatory bowel disease.
The effect of human platelet alloantigen polymorphisms on the in vitro responsiveness to adrenaline and collagen.
A number of clinical studies have suggested that carriage of the low frequency allele (b) of the human platelet antigen 1 (HPA-1) system is a risk factor for coronary thrombosis. We have examined the effect of a series of HPA biallelic polymorphisms (systems -1, -2, -3 and -5) on the in vitro platelet aggregation in response to adrenaline and collagen in 30 healthy volunteers. There was a significantly higher prevalence (10 out of 18) of carriers of the HPA-1b polymorphism among subjects showing a > 50% aggregation response to adrenaline ('responders') than the prevalence (1/12) in 'non-responders' (P < 0.05). Platelets heterozygous for the HPA-1b polymorphism showed a significantly higher rate (slope) and greater extent (%) of adrenaline-induced aggregation than platelets not carrying the HPA-1b allele (P < 0.05). A greater extent of collagen-induced aggregation was also demonstrated in HPA-1ab platelets (P < 0.05). Inhibition of adrenaline-induced aggregation following incubation with aspirin was greater (P < 0.01) in HPA-1ab than in HPA-1aa platelets. Collagen-induced aggregation was slower in carriers of the HPA-5b allele than in HPA-5aa subjects (P < 0.05). Polymorphisms of the HPA-2 and HPA-3 systems were not associated with different aggregation responses to either adrenaline or collagen. These results support the clinical observation that polymorphism HPA-1b may predispose to increased platelet thrombogenicity and suggest that the presence of polymorphism HPA-5b might render the platelet less reactive to collagen.
Concomitant angioimmunoblastic T-cell lymphoma and low grade B-cell lymphoproliferative disorder.
The presence of a rearranged immunoglobulin gene, in addition to the expected T-cell receptor gene rearrangement, is a frequent, albeit poorly understood, finding in the setting of angioimmunoblastic lymphadenopathy. A case of an angioimmunoblastic T-cell lymphoma is presented, where this apparently paradoxical dual gene rearrangement could be ascribed to the coexistence of an occult B-cell lymphoproliferative disorder.
Pyrexia, pancytopenia and macrophage inclusions in an elderly woman.
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The place of myeloid growth factors in the treatment of hairy-cell leukaemia.
A patient with hairy-cell leukaemia was treated with granulocyte colony stimulating factor lenograstim (Granocyte) 300 micrograms daily by subcutaneous injections. His pre-existing neutropenia remitted and the therapy was continued for a total of 4 months. When the therapy was discontinued the neutropenia returned. There was no evidence that the growth factor itself had any disease modifying activity.
Presence of the bcr/abl rearrangement in a patient with chronic neutrophilic leukaemia.
An 83 year old women presented with a myeloproliferative disorder involving the myeloid and megakaryocytic lines, and characterised by mature neutrophil leucocytosis. There was a high/normal neutrophil alkaline phosphatase activity and absence of the Philadelphia chromosome, features compatible with a diagnosis of chronic neutrophilic leukaemia (CNL). Southern blot analysis of the patient's DNA revealed the presence of the bcr/abl rearrangement. Combined with a previous report of detection of Ph1 chromosome in long term bone marrow cultures in a patient with CNL, this finding suggests that the bcr/abl hybrid gene might occasionally result in a myeloproliferative disorder with a phenotype closely resembling that of CNL.
Hodgkin's disease in a patient with common variable immunodeficiency.
A 61 year old man with long standing common variable immunodeficiency presented with pyrexia, anaemia and leucopenia. A diagnoses of Hodgkin's disease of the bone marrow was made. The typical histopathological and immunophenotypic appearances were clearly distinct from those of T cell lymphoma with Reed-Sternberg-like cells which, in contrast to Hodgkin's disease, is a known complication of common variable immunodeficiency. Complete clinical and histological remission was achieved with combination chemotherapy. The latter was complicated by severe myelosuppression, unusually severe erosive mucositis and viral retinitis.
Platelet surface IgG in patients receiving infusions of Fab fragments of a chimaeric monoclonal antibody to glycoprotein IIb-IIIa.
Platelet surface immunoglobulin G (PSIgG) was measured ex vivo in nine patients with stable angina pectoris receiving continuous (48-96 h) infusions of Fab fragments of a chimaeric MoAb (human IgG with murine variable regions) to platelet glycoprotein IIb-IIIa. PSIgG was measured using flow cytometry (FC) and an Fc-specific anti-IgG polyclonal antibody, which did not cross-react with the chimaeric Fab fragment (c7E3-Fab). A variable but statistically significant (P < 0.05) elevation of PSIgG was present within 24 h after the onset of the infusion, and was more marked (P < 0.01) several days after the end of the infusion despite an exponential fall in platelet surface c7E3-Fab post-infusion. PSIgG returned to normal within 2 weeks after the end of the infusion. The timing of IgG recruitment to the platelet surface suggested the pre-existence in the patients' plasma of IgG binding to c7E3-Fab-bearing platelets. None of the patients developed thrombocytopenia. In order to assess the incidence of IgG bindable to c7E3-Fab-bearing platelets in controls clinically comparable to the c7E3-Fab infusion patients, normal platelets coated with either chimaeric (c) or murine (m) 7E3-Fab were incubated with plasmas from 21 patients with ischaemic heart disease, and recruitment of IgG to the platelet surface was measured by FC. Fourteen of the 21 plasmas contained IgG bindable to c7E3-Fab-coated platelets, whereas only one of the 21 plasmas contained IgG bindable to m7E3-Fab-coated platelets (a highly significant difference, P < 0.001). These findings indicate that infusions of Fab fragments of the chimaeric anti-platelet antibody 7E3 are often associated with elevations in PSIgG, which are probably due to pre-existing 'naturally occurring' antibodies to the Fab fragments of chimaeric (but not murine) 7E3, and most probably other chimaeric MoAbs. The possible clinical significance of such ex vivo measured activities is at present a matter for speculation, and requires further study.
Acquired pseudo-pseudo Bernard-Soulier syndrome complicating Gaucher's disease.
AIMS: To investigate the abnormality in platelet function in two patients with type I Gaucher's disease causing a chronic bleeding tendency despite normalisation of the platelet count after spleen removal. METHODS: Routine laboratory methods were used to assess baseline coagulation. Platelet aggregometry was used to assess platelet responses to a range of agonists, and abnormalities were further assessed in mixing experiments using washed platelets and patients' plasma. RESULTS: Platelets from both patients with Gaucher's disease failed to agglutinate to ristocetin, despite normal platelet surface glycoprotein (GP) Ib and plasma von Willebrand factor activity. The agglutination of normal washed platelets was abolished by incubation in patient plasma. The inhibitory activity did not lie in the IgG fraction of patient plasma, and was found to be loosely associated with the patient platelet surface. CONCLUSIONS: The inhibition of ristocetin induced platelet agglutination in patients with Gaucher's disease causes a prolonged skin bleeding time. This could be due to the accumulated glucocerebroside in the plasma coating the platelet membrane. It is suggested that the term pseudo-pseudo Bernard-Soulier syndrome would be appropriate, as on initial screening, the abnormality has the features of Bernard-Soulier syndrome, but further investigation shows normal plasma von Willebrand activity and platelet surface GP Ib concentrations. The inhibitory activity is not due to a platelet specific antibody as is the case in pseudo-Bernard Soulier syndrome.
Flow cytometric observations on the in vivo use of Fab fragments of a chimaeric monoclonal antibody to platelet glycoprotein IIb-IIIa.
Fluorescence flow cytometry (FC) was employed to monitor the platelet surface in humans receiving intravenous infusions of Fab fragments of a chimaeric (murine/human) construct of monoclonal antibody 7E3, which binds to the fibrinogen receptor (glycoprotein IIb-IIIa) and inhibits platelet aggregation. Platelet surface-bound chimaeric 7E3-Fab (c7E3-Fab) was measured using a fluorescein-conjugated polyclonal anti-7E3 antibody and residual c7E3-Fab binding capacity was measured using fluorescein-conjugated c7E3-Fab. Turbidometrically measured platelet aggregation response to ADP was shown to be a linear function (r = 0.9) of the logarithm of residual free binding sites for c7E3-Fab. The distribution of c7E3-Fab in the platelet population was unimodal at all time points following the infusion, demonstrating in vivo transfer of antibody to newly released circulating platelets. Clearance of platelet surface-bound antibody followed an exponential model but all circulating platelets were bearing c7E3-Fab at time points well beyond the lifespan of the platelets exposed to c7E3-Fab during the infusion. Ex vivo and in vitro mixing experiments showed that c7E3-Fab transfer between platelets was possible and suggested that differences in the in vivo kinetics between monovalent and bivalent forms of monoclonal antibodies might be relevant in their therapeutic application.
Lack of specific binding of anticardiolipin antibodies to intact platelets.
The aims of this study were to investigate whether anticardiolipin antibodies (aCL) bind to intact (resting or activated) platelets in vitro. Suspensions of resting, activated (with a mixture of thrombin and collagen) and freeze-thawed platelets from healthy subjects were incubated with either affinity-purified aCL or pooled normal human immunoglobulin G (IgG). Platelet-bound IgG was measured by flow cytometric analysis of platelets incubated with a fluorescein-conjugated polyclonal goat anti-human IgG. There was no significant binding of IgG aCL to intact resting or activated platelets, while significant specific binding to freeze-thawed platelets was demonstrated. These results question the theory that aCL bind/activate intact platelets in vivo.
Platelet satellitism and alpha granule proteins.
Blood smears from a patient with severe generalised arteriopathy and an occluded synthetic femoropopliteal graft showed the phenomenon of EDTA dependent adherence of platelets to neutrophils (platelet satellitism). Immunoenzymatic staining with a monoclonal antibody to thrombospondin showed that adherence to neutrophils exclusively involved platelets that stained strongly positive for thrombospondin, while negative or weakly positive platelets showed no tendency to adhere. There was no increase in platelet surface immunoglobulins. This suggests a possible role for thrombospondin or some other cytoadhesive platelet alpha granule protein in mediating the adherence of platelets to neutrophils in cases of satellitism.
Does a siesta protect from coronary heart disease?
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Primary hypothyroidism presenting as amenorrhoea and galactorrhoea with hyperprolactinaemia and pituitary enlargement.
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