Clinical features and molecular analysis of a family with multiple colon tumours and reduced plasminogen activator activity.

A family is reported in which a pair of brothers has developed recurrent venous thromboses, which have been shown in one brother (the proband) to result from a reduced level of tissue plasminogen activator (t-PA) activity. Both brothers have also developed multiple synchronous and metachronous colorectal adenomas. Other pedigree members have developed colon cancers, but not multiple colonic tumours. We have shown that HNPCC and FAP/AAPC are unlikely causes of the family's phenotypes. Previous studies have found low levels of t-PA in sporadic colon tumours. In this family, mutations in the t-PA gene, at a linked locus, or at a locus controlling t-PA activity/release may modify the colon tumour phenotype to cause multiple lesions.

POEMS syndrome and Waldenström's macroglobulinaemia.

A 58 year old man presented with a three year history of impotence, night sweats and ankle swelling. On examination, the patient fulfilled the diagnostic criteria for POEMS syndrome, but was unusual in that he also had underlying Waldenström's macroglobulinaemia with IgM kappa paraproteinaemia. The patient was treated with intermittent chlorambucil and made a good recovery. POEMS syndrome has been described in association with osteosclerotic myeloma and Castleman's disease. The paraprotein involved is usually IgG or IgA with lambda light chains. This case indicates that the presence of lambda light chains is not essential for the pathogenesis of POEMS syndrome. It also emphasises the diversity of plasma cell dyscrasias that can manifest as POEMS syndrome.

Acute lymphoblastic transformation of essential thrombocythaemia.

Essential thrombocythaemia is a myeloproliferative disorder which may transform to acute myeloid leukaemia, especially following therapy with alkylating agents or radioactive phosphorus. We describe the rare occurrence of acute lymphoblastic leukaemia transformation in a patient with known essential thrombocythaemia.

Plasma D-dimer as a marker for postoperative deep venous thrombosis. A study after total hip or knee arthroplasty.

Plasma levels of D-dimer have been found useful as a marker of deep venous thrombosis in those patients in whom thrombosis is suspected, but their usefulness in postoperative screening is less clear. We have investigated the relationship of D-dimer to deep venous thrombosis in 90 patients after total hip and knee arthroplasty. From the first postoperative day the D-dimer levels were found to be highly significantly raised in patients with deep venous thrombosis. A combined result over the first six postoperative days in excess of 1200 ng/ml correlated with thrombosis with a specificity of 100%, sensitivity of 45%, positive predictive value of 60%, and negative predictive value of 100%. However, individual estimations were not discriminatory.

Haemophilia B caused by a missense mutation in the prepeptide sequence of factor IX.

In the course of analysing mutation in the factor IX gene from 200 haemophilia B patients in Sweden and the UK, we have identified one patient with a prepeptide missense mutation. He has severe, antigen negative haemophilia, and complete analysis of his coding sequence reveals a single base transversion (A-->T) causing substitution of isoleucine by asparagine at position -30. This change disrupts the hydrophobic core of the prepeptide, a feature which is required for secretion. Thus, haemophilia in this patient is caused by a failure to secrete factor IX from the hepatocytes.

The use of D-Dimer assay by enzyme immunoassay and latex agglutination techniques in the diagnosis of deep vein thrombosis.

The blood of 107 patients undergoing venography for suspected deep vein thrombosis (DVT) was tested for D-Dimers using enzyme immunoassay (EIA) and two latex agglutination techniques. D-Dimer levels by EIA were raised in 88% of patients with proven DVT. However, levels detected with the two agglutination tests were much less sensitive, being raised in only 43% patients with DVT. A more sensitive rapid screening test is needed to provide a useful non-invasive test for the exclusion of DVT.

Familial exudative vitreoretinopathy associated with familial thrombocytopathy.

Two families with familial exudative vitreoretinopathy were studied in which platelet aggregation defects were found in all the affected members. The major defect observed was absent platelet aggregation with arachidonic acid. In addition platelet aggregation with collagen and adrenaline was reduced in one severely affected member. The implication of the platelet aggregation defect in the pathogenesis of this retinal vascular disorder is discussed.

Evidence against vitamin K deficiency in normal neonates.

Umbilical cord plasmas from 24 normal full-term neonates were studied. We confirmed the prolonged prothrombin time and low levels of Vitamin K dependent clotting factors previously described (1), but using a number of recently developed immunological and coagulation techniques we could find no evidence of vitamin K deficiency. We conclude that the decreased levels of vitamin K dependent clotting factors of normal neonates are the result of decreased synthesis by the immature liver and that it is questionable whether vitamin K prophylaxis is necessary for these infants.

Percutaneous liver biopsy and chronic liver disease in haemophiliacs.

Systematic screening of forty-seven haemophiliacs in Sheffield revealed abnormal liver-function tests in thirty-six (77%), with a tendency for these abnormalities to persist. To assess the importance of these abnormalities, percutaneous liver biopsy was carried out on eight symptom-free patients under factor-VIII cover. A wide spectrum of chronic liver disease was demonstrated, including chronic aggressive hepatitis and cirrhosis. The liver pathology bore no relation to clinical history or to biochemical findings. Hepatitis-B-virus markers were common, but evidence suggests that this is not the only factor contributing to the development of liver disease. The high incidence of chronic liver disease seems to be a recent development and is probably related to factor-concentrate replacement therapy.