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Biomedical subjects

G F Savidge

Publications and source records attributed to G F Savidge.

At least 73 records · Page 4Linked to original sources
PubMed1989

Primary thrombocythaemia: diagnostic criteria and a simple scoring system for positive diagnosis.

Forty new patients with elevated platelet counts (greater than 600 x 10(9)/l) and without palpable splenomegaly were assigned to diagnostic groups defined by essentially conventional criteria after 3 months follow up: Proliferative (17), reactive (17) or unclassified (six). Mean platelet volume (MPV), platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), unstimulated BFU-E derived colony formation from peripheral blood, spleen scan and clinical ischaemia were assessed at the outset, with a view to defining diagnostic criteria for distinguishing primary thrombocythaemia from reactive thrombocytosis. All except the first variable were significantly associated with diagnostic group (P less than 0.05). A simple scoring system was devised: enlarged spleen on scan, or presence of BFU-E, each scored 2; elevated PDW (greater than 2 SD from mean), elevated ATP:ADP (greater than 4 SD from mean) or presence of clinical ischaemia, each scored 1. Score totals greater than or equal to 3 predicted primary thrombocythaemia, and totals less than 3 suggested reactive thrombocytosis (predictive value 89%). The system correctly predicted diagnosis in four out of four (probably six out of six) patients whose diagnosis was not apparent initially, and thus whose results were not used in constructing the scoring system. Exclusion of BFU-E from the system resulted in only one incorrect prediction in this group.

Blood Platelets↗
PubMed1989

Uptake of plasma fibrinogen into the alpha granules of human megakaryocytes and platelets.

The origin of platelet alpha-granule fibrinogen (Fg), whether from endogeneous synthesis or exogeneous derivation, remains unknown. Although Fg biosynthesis by megakaryocytes (MK) has been suggested, recent studies have demonstrated that certain alpha-granular proteins originate primarily from plasma. To study the origin of alpha-granule Fg, platelet-associated Fg was measured by ELISA and Western blotting, and localized by immunofluorescence and immunoelectron microscopy in a patient with symptomatic congenital afibrinogenemia before and after replacement therapy with cryoprecipitate. alpha-Granule Fg was detected in the majority of platelets as early as 24 h postinfusion, suggesting that direct platelet uptake was occurring. Platelet Fg reached a maximum value of 42.5% of normal values at 3 d postinfusion and was localized in the alpha-granules, while plasma levels followed a typical half-life profile. Significant alpha-granule Fg was still detectable at 13 d postinfusion, with plasma Fg virtually absent. Studies on cultured CFU-MKs from the patient also confirmed that MKs can incorporate exogeneous Fg into alpha-granules. These results indicate that platelet alpha-granule Fg can be derived from the circulating plasma pool and that Fg uptake can occur in both platelets and MKs.

Adult↗
PubMed1989

Uncoordinated expression of fibrinogen compared with thrombospondin and von Willebrand factor in maturing human megakaryocytes.

The localization of three known alpha-granule proteins, thrombospondin (TSP), von Willebrand factor (vWF), and fibrinogen (Fg) has been studied in human megakaryocytes (MK) by immunofluorescence and immunoelectron microscopy. For this study, highly purified populations of MK were prepared from human bone marrow either by counterflow centrifugal elutriation or by cell culture from normal subjects and from two patients with megakaryoblastic leukemia. In normal bone marrow immature MK, TSP, and vWF were observed in the Golgi-associated vesicles and in small immature alpha-granules; in mature MK, they were found in the matrix of the mature large alpha-granules. Surprisingly, Fg was detected neither in the Golgi area, nor in the small precursors of alpha-granules; it was only found in the mature alpha-granules but this labeling was generally weaker than in blood platelets. In order to confirm these differences between the expression of Fg and vWF or TSP additional studies were performed on cultured maturing MK: immunofluorescent and ultrastructural immunogold labeling confirmed that vWF appeared early in the maturation while the same immature MK were negative for Fg. In the late maturation stage, the three proteins were detected in the alpha-granules. In order to know whether Fg was lately synthesized or endocytosed from the outside medium, normal MK were grown in the presence of either normal or afibrinogenemic plasma, and normal serum. Fg was detected only in the alpha-granules of MK grown in normal plasma. Similar results were observed with malignant MK, whose maturation was independent of the culture conditions. In conclusion, this study brings immunocytochemical evidence that vWF and TSP are synthesized by immature MK, whereas Fg appears later in the MK alpha-granules and its expression is dependent of the presence of an exogenous Fg source.

Adult↗
PubMed1989

Thrombophilia.

Disorders of coagulation and fibrinolysis which increase the tendency to clot are far more common than the well-known conditions which predispose to bleeding. An increased understanding of these processes will improve the management of patients with thrombosis.

Anticoagulants↗
PubMed1988

Chromatography of the VIII/vWF complex on dextran sulphate sepharose.

The applicability of Dextran Sulphate (DS) agarose in the purification of the VIII/vWf complex from cryoprecipitate was investigated. The elution profiles indicate high affinity of the VIII/vWf complex for the matrix. With application of combined salt/pH gradients good resolution of VIII/vWf from most of the applied proteins can be achieved. VIII/vWf normally elutes as a single component (70-90% vWf:Ag and vWf:RCo) with modest yields of factor VIII (30-40%) VIII:C and 50-70% VIII:Ag) providing calcium ions are present. Addition of L-lysine, Histidine and Arginine (all 1.0M) inhibit binding of proteins to the matrix. Alternatively, higher yields of VIII:C can be obtained (80% VIII:C and 100% VIII:Ag) by the application of L-lysine gradients (0-0.6M) but with loss of resolution from Fn and slight dissociation of VIII:C from vWf:Ag.

Chromatography, Affinity↗
PubMed1988

High-dose intravenous immunoglobulin and splenectomy for the treatment of HIV-related immune thrombocytopenia in patients with severe haemophilia.

Four patients with severe haemophilia A and one patient with severe Christmas disease developed severe immune thrombocytopenia (platelet count less than 20 x 10(9)/l). All five patients were HIV-antibody positive and one was HIV-antigen positive. Four patients were treated initially with prednisolone, but with only a transient platelet response in three and no response in the fourth. All patients were treated with high dose intravenous immunoglobulin (0.4 g/kg daily for 5 d) resulting in a rise in platelet count in all cases (range 138-300 x 10(9)/l) and then proceeded to splenectomy. Three remain in complete remission after 6-14 months, and one showed a good response with platelet counts ranging from 103 to 187 x 10(9)/l. The fifth patients achieved a normal platelet count for 3 months post-splenectomy, but suffered a relapse with platelet counts ranging from 25 to 108 x 10(9)/l over the next 3 years. However, following a severe Varicella infection 10 months ago, during which he developed a marked transient thrombocytosis, he has also maintained a normal platelet count.

Adolescent↗
PubMed1987

Chromatography of vWf on dextran sulphate sepharose.

A relatively simple and reproducible chromatographic separation using Dextran Sulphate (DS) Agarose is described for the purification of vWf:Ag from cryoprecipitate or plasma source material. The elution profiles suggest high affinity of vWf for the matrix permitting resolution from Fibrinogen, IgG and the unbound Albumin. The major contaminant fibronectin can be removed prior to the chromatography step by Gelatin-Sepharose adsorption. Chromatography of 125I-vWf, added to cryoprecipitate as a marker, gives two distinct peaks one of which elutes with the column wash through fractions and expresses negligible biological activity. The re-eluted bound material expresses normal vWf:RCo activity with full multimer integrity as assessed by SDS Agarose electrophoresis. DS sepharose chromatography offers an excellent method for the purification of 125I-vWf since all the viable label is resolved from excess free radiolabel and denatured protein. Low recoveries of VIII:C were demonstrated at both R.T. or 4 degrees C possibly due to the presence of Tri-Sodium citrate and the absence of sufficient free CaCl 2 in the buffers.

Chromatography, Affinity↗
PubMed1987

Hypothyroidism as a cause of acquired von Willebrand's disease.

Three patients with bleeding tendency who met the criteria for type 1 von Willebrand's disease are described. In two patients, hypothyroidism was suspected and confirmed at presentation, and in the third hypothyroidism became apparent 4 years later. In all three, the history and clinical course after treatment with thyroxine indicated acquired von Willebrand's disease secondary to hypothyroidism. The possibility of hypothyroidism should be considered in patients presenting with von Willebrand's disease.

Adolescent↗
PubMed1987

Reduced risk of non-A, non-B hepatitis after a first exposure to 'wet heated' factor VIII concentrate.

The risk of post-infusion non-A, non-B hepatitis (NANBH) in patients receiving a first exposure to unheated or conventionally 'dry heated' factor VIII concentrates approaches 100%, implying invariable contamination of these products. Amongst 18 patients who received a first treatment with a 'wet heated' commercial concentrate, five (28%) developed asymptomatic NANBH, suggesting a more efficient inactivation of NANB agent(s) by this process. 2/9 (22%) of the batches of concentrate used in the study were implicated in NANBH transmission. One of those two batches, responsible for NANBH in four patients, had been prepared from a plasma pool containing an unusually large proportion of donations with high alanine aminotransferase (ALT) levels. A resulting high level of viral contamination in this batch may have been sufficient to override the effects of the sterilization process. All patients remained anti-HIV seronegative at 17-28 months of follow-up.

Adolescent↗
PubMed1987

Amaurosis fugax under the age of 40 years.

Sixteen patients who presented under the age of 40 years with amaurosis fugax have been studied. Follow up from the time of presentation was one to 13 years with a median of 3 years. One patient whose attacks of uniocular visual loss were associated with headache developed a permanent uniocular field defect. None of the other patients has suffered permanent visual loss, or had symptoms of cerebral or myocardial ischaemia. All angiograms were normal and it is suggested that carotid angiography is unnecessary in this age group. Four out of ten patients studied demonstrated evidence of platelet hyperaggregability to low concentrations of arachidonic acid and adenosine diphosphate with spontaneous aggregation. However, in six patients treated with aspirin, including three with previous platelet hyperaggregability, there was no change in the frequency of their attacks implying that the observed platelet abnormalities were not the cause of the amaurosis fugax.

Adenosine Diphosphate↗
PubMed1986

Combination therapy of steroids and immunoglobulin in chronic refractory idiopathic thrombocytopenic purpura (ITP) enabling renal stone fragmentation by lithotripsy.

A 27-year-old woman with idiopathic thrombocytopenic purpura (ITP), which had relapsed following splenectomy, was found to be refractory to a wide range of individual immunosuppressive agents. However, a normal platelet count was achieved with high-dose dexamethasone followed by intravenous immunoglobulins (i.v. Ig). Either agent used alone had previously produced clinically inadequate platelet increments. With this regime, successful renal stone fragmentation by lithotripsy was undertaken, which required no blood product support over the peri-operative period. It is suggested that patients with refractory ITP requiring major procedures, who have not responded to i.v. Ig treatment, merit a repeat trial following high-dose steroid.

Adult↗
PubMed1985

Transmission of non-A, non-B hepatitis by heat-treated factor VIII concentrate.

In-vitro and animal studies have shown that viral agents can be removed from or inactivated in clotting factor concentrates by physical or chemical treatment. However, clinical data have as yet not substantiated the results of these studies. 13 haemophilia A patients who had not been treated previously with blood or blood products were given a dry-heated factor VIII concentrate and were tested serologically over the next 12 months. Hepatitis developed in 11 patients (84%) and was invariably of type non-A, non-B. Morbidity was not related to the lot of the therapeutic material or to the number of infusions. The incubation period was either 5 or 8-11 weeks, and only 1 patient had symptoms. Aminotransferase elevation showed both monophasic and biphasic patterns. During the follow-up period signs of the disease disappeared in 10 patients (90%). These findings contrast with the absence of non-A, non-B hepatitis in chimpanzees given the same heated concentrate. Thus, clinical studies in first-exposure haemophiliacs are essential for the true evaluation of the safety of new "treated" concentrates.

Adolescent↗