An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.

Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal-dominant transmission has been described with manifestations similar to those of sporadic ET. As the thrombopoietin gene (THPO) encodes a lineage-restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production, we tested the hypothesis that HT results from a mutation in the human THPO gene. In a Dutch family with eleven affected individuals, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at theta=0. A G-->C transversion was found in the splice donor site of intron 3 of the THPO gene in all affected family members. This mutation leads to THPO mRNAs with shortened 5'-untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.

H reflexes as a measure for uremic polyneuropathy. A longitudinal study in patients treated with dialysis or renal transplantation.

Assessment of peripheral nerve function in end stage uremia by clinical and conventional nerve conduction velocity studies was compared to that using H reflex measurements. The latter proved to be the most sensitive technique. The results of the test correlated well with clinical and with other neuro-physiological measures. Nerve function as evaluated by H reflexes remained stable during the first 2 years of dialysis, but deteriorated later on. H reflex latencies shortened after renal transplantation. The results of H reflex measurements did not correlate with biochemical parameters, which makes the test a less attractive overall measure for the efficiency of therapy in uremia. In the follow-up of patients under treatment for uremic polyneuropathy, however, recording of H reflexes provides an important measure.

Familial essential thrombocythemia: clinical characteristics of 11 cases in one family.

Reports on familial occurrence of essential thrombocythemia (ET) are scanty. Many clinical and hematological aspects of familial ET have not been clarified yet. We studied 16 family members in four successive generations. By laboratory tests and bone marrow examination they were divided into a non-thrombocythemia group (n = 5) and into ET patients (n = 11). Five ET patients were asymptomatic, three patients had both vaso-occlusive and hemorrhagic symptoms, and three patients only vaso-occlusive symptoms. The platelet count ranged from 500 to 1700 x 10(9)/l. Symptoms correlated with age but not with platelet count. ADP-induced platelet aggregation distinguished best between patients and non-ET subjects. Four patients and four non-ET subjects had factor VIII:C or von Willebrand factor antigen abnormalities; all but one had blood group O. These abnormalities were not due to inherited von Willebrand's disease according to haplotype analysis. Two patients and three non-ET subjects had a bleeding diathesis. One of these two patients and all three non-ET subjects had a decreased factor VIII:C or vWF:Ag. No chromosome abnormalities were found. In conclusion, familial ET has a relatively benign course with clinical manifestations similar to nonfamilial cases, and it is probably transmitted by an autosomal dominant mode of inheritance.

Encephalopathy in patients on continuous ambulatory peritoneal dialysis and patients on chronic haemodialysis.

A group of 121 patients, 22 with a preterminal chronic renal insufficiency (PCRI), 74 on chronic haemodialysis (CHD), and 25 on continuous ambulatory peritoneal dialysis (CAPD), was evaluated by means of neurophysiological and neuropsychological studies to detect signs of central nervous system dysfunction. CHD patients were studied the day before dialysis treatment. In each patient the neurophysiological and neuropsychological studies were performed on the same day. The same overall result emerged from the neurophysiological and neuropsychological studies: all three patient groups showed significant deviations from the values obtained from a healthy reference group, whereas no differences were found between the three patient groups. Biochemical variables (a.o. PTH, Al, PO4) showed inconsistent or only minor correlations with the encephalopathic parameters. Apparently traditional biochemical variables are not a reliable measure to safeguard renal patients from neurotoxic damage. With respect to central nervous system dysfunction CAPD appears to be as 'safe' as CHD.

The amount of plasminogen, tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in human thrombi and the relation to ex-vivo lysibility.

Thrombolytic therapy successfully reopens obstructed blood vessels in the majority of cases. However, it is not known why a substantial amount of thrombi are resistant to lysis by a fibrinolytic agent. In vitro studies have demonstrated that tissue-type plasminogen activator (t-PA) and plasminogen incorporated in the clot (during formation) increase lysibility. To test whether lysibility of in vivo formed human thrombi is related to their composition, we studied 25 venous thrombi obtained at autopsy and 21 arterial thrombi obtained during embolectomy. Plasminogen activator inhibitor-1 (PAI-1) antigen was measured in a phosphate-buffered saline (PBS) extract of each thrombus; t-PA antigen and plasminogen antigen were determined in a 6 M urea extract of the thrombus, representing bound proteins. Lysibility was measured as weight reduction during 8 h of incubation in PBS containing streptokinase (SK) 100 U/ml, corrected for spontaneous lysis, reflected by weight loss in PBS without SK. In addition, lysibility in SK was compared with lysibility in urokinase (UK) 100 U/ml and in t-PA 200 U/ml. Spontaneous lysis amounted to 29 +/- 5% (mean +/- SEM) and 33 +/- 5% in venous and arterial thrombi, respectively, and inversely correlated with the PAI-1 content of thrombi (r = -0.43, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[Polyarteritis nodosa with hepatitis and pancreatitis]. / Polyarteriitis nodosa met hepatitis en pancreatitis.

A 39-year-old man, known as a heavy drinker, presented with general malaise, abdominal pain, a history of icterus and progressive weight loss. He was found to have an acute hepatitis B infection and pancreatitis with pancreatic pseudocysts. A diagnosis of polyarteritis nodosa was made on clinical grounds, and confirmed pathologically. The patient was treated with high-dose corticosteroids, cyclophosphamide, antibiotics and drainage. However, the disease was progressive and the patient died. Pancreatitis in relation to polyarteritis nodosa, the association with hepatitis B infection, and new therapeutic possibilities are discussed.