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M Makris

Publications and source records attributed to M Makris.

At least 55 records · Page 3Linked to original sources
PubMed2000

Major structural defects in the antithrombin gene in four families with type I antithrombin deficiency--partial/complete deletions and rearrangement of the antithrombin gene.

The molecular basis of quantitative antithrombin deficiency was investigated in four families predicted to have major antithrombin gene rearrangements. A 1,442 bp deletion and insertion of the sequence 5'T(n = 38-40)GAGACG was characterised in one case. Sequence surrounding the breakpoints contained two perfect, and one imperfect, inverted repeats which may have mediated formation of a stem loop structure on one strand during DNA replication potentiating the deletion. A 9,219 bp deletion spanning introns 2 to 5 was identified in a second family. The identical 6 bp sequence was upstream of each breakpoint and the 5' breakpoint was located in a sequence of the Alu 3 repeat predicted to be susceptible to strand breakage during transcription. This may have promoted misalignment, and deletion, of one of the repeats and the intervening DNA. A novel 1.8 kb antithrombin gene fragment was present in DNA digests from affected members of the third family suggesting a partial antithrombin gene duplication event while in the remaining family, evidence supporting a complete gene deletion was obtained.

Adolescent↗
PubMed2000

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors.

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.

Abdomen↗
PubMed1999

A rapid method for haemophilia B mutation detection using conformation sensitive gel electrophoresis.

Conformation sensitive gel electrophoresis (CSGE) was confirmed as an effective procedure for screening the factor IX (FIX) gene by detecting 10/10 previously known FIX gene mutations. The FIX genes of a further 11 haemophilia B patients with unknown mutations were then screened and an abnormal CSGE profile was identified in all cases. Subsequent DNA sequencing demonstrated one of these to be a novel mutation (31133insT, Arg338Fs), the remaining 10 having been previously reported on the haemophilia B database. Mutation screening of the FIX gene using CSGE was demonstrated to be a rapid and efficient means of carrier analysis in families with haemophilia B.

Electrophoresis, Agar Gel↗
PubMed1999

Spinal epidural haematoma in haemophilia A with inhibitors--efficacy of recombinant factor VIIa concentrate.

We report the case of a 21-year-old man with severe haemophilia A and factor VIII inhibitors who presented with an extensive spinal epidural haematoma (C2-T12), probably induced by sit-up exercises. The bleed was defined by magnetic resonance imaging of the cervical and thoracic spine and prompt treatment with recombinant factor VIIa concentrate led to complete resolution at 4 weeks. Neurological sequelae were averted and surgical decompression was not necessary. We discuss the difficulties in diagnosis and management of such a case.

Adult↗
PubMed1999

Acute renal failure in acquired haemophilia following the use of high dose intravenous immunoglobulin.

High dose intravenous immunoglobulin (IVIG) is a useful form of treatment in patients with acquired haemophilia, a rare bleeding disorder due to auto-antibodies to factor VIII. We describe a patient with acquired haemophilia who developed acute renal failure rapidly after treatment with a high sucrose content IVIG preparation. We speculate that the sucrose content of the preparation was responsible for the renal failure and make recommendations on the use of IVIG in patients with acquired haemophilia.

Acute Kidney Injury↗
PubMed1999

Alternative models of delivery of anticoagulant services.

The dramatic increase in patients on oral anticoagulants in the last decade has led to the development of alternative models of anticoagulant care delivery. Some degree of decentralization is desirable to maintain the efficiency and quality of the anticoagulant control service. One effective model, which has relatively few resource implications, is the decentralized system whereby patients have blood drawn in the general practice premises but analysis and dosing is still performed by the hematology department, a model that provides increased efficiency while maintaining the standards of clinical care. The use of computerized decision support systems has been central to the decentralization process and has led to improvements in quality of service in hospitals and the primary-care setting. Regardless of the model adopted, it is important to follow clinical guidelines, take part in external quality-control, and perform regular audits to assess the delivery of the service.

Anticoagulants↗
PubMed1999

Mesenteric infarction due to combined protein C deficiency and prothrombin 20210 defects.

The prothrombin gene mutation, 20210A, a guanine to adenine substitution at nucleotide position 20210, has recently been described as an additional risk factor for venous thromboembolic disease. We describe the case of a patient with combined heterozygous prothrombin 20210A mutation and type 1 protein C deficiency who presented with massive mesenteric venous infarction of his small bowel and survived following the use of protein C concentrate and extensive small bowel resection.

Anticoagulants↗
PubMed1998

Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation.

The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main beta-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6 degreesC) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0 degreesC), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband's plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation.

Amino Acid Substitution↗
PubMed1998

Norethisterone therapy for bleeding due to gastrointestinal telangiectases in Glanzmann's thrombasthenia.

We report a case of a patient with Glanzmann's thrombasthenia and anti-GPIIb/IIIa alloantibodies who developed life-threatening and intractable bleeding from gastrointestinal telangiectatic lesions. After a period of transfusion-dependent gastrointestinal bleeding despite tranexamic acid, oral iron, omeprazole and platelet transfusions, the use of oral norethisterone produced a significant improvement with a marked reduction in her transfusion requirements.

Adult↗
PubMed1998

Acute liver failure induced by alcohol and paracetamol in an HCV-infected haemophiliac.

Paracetamol (acetaminophen) is frequently used by haemophiliacs in the management of acute or chronic pain, primarily due to its lack of adverse effects when taken at therapeutic doses. We describe acute hepatic and renal toxicity of paracetamol in a 36-year-old patient with haemophilia B, chronic hepatitis C and chronic alcohol abuse. Moderate doses of paracetamol (6 g/d for 4 d), taken with therapeutic intent, resulted in life-threatening organ dysfunction which gradually recovered with full supportive care.

Acetaminophen↗
PubMed1998

A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort.

In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene. In all but one case, the mutation caused type I deficiency. One individual had type III deficiency. While ectopic transcript analysis using the BstXI dimorphism in exon 15 failed to detect a transcript from the mutated allele, analysis of transcripts spanning exons 11 and 12 revealed a minor mRNA species. Sequencing confirmed the mutation created a new RNA acceptor site introducing 8 nucleotides of intronic sequence into the mature mRNA. Haplotype analysis of the defective PROS1 alleles in six families revealed the same haplotype in all affected individuals suggesting the presence of a common ancestor. Six of the fourteen relatives with the mutation experienced at least one venous thrombotic event strongly supporting the association of the mutation with venous thrombosis.

Alleles↗
PubMed1997

The successful use of protein C concentrate during pregnancy in a patient with type 1 protein C deficiency, previous thrombosis and recurrent fetal loss.

The risks of venous thrombosis and fetal loss are increased in patients with protein C deficiency. We describe a patient with a history of thrombosis and recurrent fetal loss who was found to have type 1 protein C deficiency. In view of her history and intolerance of heparin preparations, she was treated with protein C concentrate during the first and third trimesters of her seventh pregnancy. The patient suffered no thromboembolic event during this pregnancy and gave birth to a healthy infant. The implications of the success of this therapeutic strategy are discussed.

Abortion, Habitual↗
PubMed1997

Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy.

Haemorrhage, including intracranial bleeding, is a common, potentially lethal complication of warfarin therapy and rapid and complete reversal of anticoagulation may be life-saving. Fresh frozen plasma (FFP) and vitamin K are most frequently administered. Because of the variable content of vitamin K-dependent clotting factors in FFP, and the effects of dilution, the efficacy of this approach is open to doubt. We have therefore compared the effects of FFP and clotting factor concentrates on the INRs and clotting factor levels of orally anticoagulated subjects requiring rapid correction of their haemostatic defect. In many, the pre-treatment INR was considered to be dangerously above the target therapeutic range. In the 12 patients given FFP, the INR did not completely correct (range 1.6-3.8, mean 2.3) indicating an ongoing anticoagulated state in all. In contrast, the INR in 29 subjects given clotting factor concentrates was completely corrected in 28 (range 0.9-3.8, mean 1.3). Following treatment, marked differences were observed in clotting factor IX levels between the two groups. The median factor IX level was 19 u/dl (range 10-63) following FFP infusion and 68.5 u/dl (range 31-111) following concentrate. In FFP treated patients, poorer responses were also observed for each of the other vitamin K-dependent clotting factors but these were less marked than for factor IX, which was present in low concentrations in some batches of FFP. Thus, haemostatically effective levels of factor IX cannot be achieved, in most instances, by the conventional use of FFP in patients requiring reversal of their anticoagulant therapy. Clotting factor concentrates are the only effective option where complete and immediate correction of the coagulation defect is indicated in orally anticoagulated patients with life or limb-threatening haemorrhage.

Administration, Oral↗