Biomedical subjects
Publications and source records attributed to J J Veltkamp.
A new method is introduced for the rapid detection of vitamin K deficiency. The method is based on the direct measurement of the precursor factor II molecules that enter the blood in cases of vitamin K deficiency. The practical use of the new method has been evaluated on the basis of the results obtained in 28 plasma samples of patients suspected of liver disease and/or vitamin K deficiency.
Changes in the coagulation mechanism were studied during and after 15(S)-15-methylprostaglandin F2 alpha (15-me-PGF2 alpha) administration for termination of pregnancy because of intrauterine fetal death after 20 wk pregnancy. 12 patients, of whom 2 were under and 6 over 28 wk, were studied. 2-Hourly intramuscular administration of 250 microgram 15-me-PGF2 alpha resulted in expulsion in a median time of 9 h (range: 2-24.3 h). Although the drug may have some inhibitory effect on platelet aggregation, its influence on coagulation and the hemostatic mechanism was negligible.
A family is described in which the haemolytic uraemic syndrome (HUS) occurred in two generations. Both juvenile and adult onset of this syndrome were observed in this family. Those affected were all women, three developed HUS in the postpartum period, one towards the end of pregnancy and one as a five-year old child. Because five cases were observed over a period of 16 years, exposure to the same infectious agent is highly unlikely. Although the transmission of a "dormant" virus cannot be excluded, the occurrence of HUS in two generations of one and the same family seems compatible with the hypothesis that susceptibility to the disease is transmitted as an autosomal dominant characteristic. This observation suggests a genetic influence on the development of HUS, possibly in conjunction with other factors, such as infectious agents, pregnancy and/or delivery.
In plasma samples of 11 fetuses of about 20 weeks of gestational age the following coagulation factors have been determined (mean values found are given in parentheses): fibrinogen (0.30 U/ml), prothrombin (+/-0.17 U/ml), factor V (0.28 U/ml), factor VII (0.21 U/ml), factor VIII coagulant activity (factor VIII:C) (0.12 U/ml), factor VIII-related antigen (factor VIIIR:Ag) (1.04 U/ml), coagulant factor VIII-related antigen (factor VII:CAg) (0.19 U/ml), factor IX coagulant activity (0.05 U/ml), factor IX antigen (less than or equal to 0.03 U/ml), factor X (0,19 U/ml) and antithrombin III (AT-III) (0.23 U/ml). Our data support the evidence that prenatal diagnosis of haemophilia A is at present possible; less optimism is warranted where haemophilia B is concerned. the number of samples is sufficient to establish normal values for the age group. Means of quality control of the sample-which is often difficult to obtain-are disscussed.
A study was performed to assess the reliability and sensitivity of ultrasound for the screening of asymptomatic children of patients with known adult polycystic kidney disease (APKD) and to compare this technique with the IVP and conventional laboratory techniques. Ultrasound appears to be at least as sensitive as IVP for identifying carriers of the gene for polycystic kidney disease. The identification of about 50% of a group of 21 asymptomatic individuals-at-risk in the 21-30-year age group as gene carriers, both with ultrasound and IVP, is promising for the early detection of this disease and therefore for genetic counselling in the future. This is the first step toward the construction of an age-specific detection curve for gene carriers, which is necessary in order to be able to calculate the probability that symptomatic subjects-at-risk carry the APKD gene.
Factor VIII-related antigen was assayed in adults in venous citrated samples and in samples taken with heparinized and plain capillaries blown out in citrate. The three sampling methods gave nearly identical results in a wide range of values. Two of the sampling methods were used in newborns and again the results showed excellent correlation.
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The metabolic rate of prothrombin, factors VII, IX and X, was studied in nine hypothyroid patients. Disappearance rates of the four vitamin-K-dependent factors, called the prothrombin complex, were measured after assumedly complete blocking of their synthesis with adequate doses of a coumarin congener (acenocoumarol). Reappearance rates were assessed by induction of synthesis with high doses of vitamin K1 (phytomenadion) when stable hypocoagulability had been achieved. Normal values for these rates were derived from earlier studies in our laboratory. In hypothyroid patients the rates of both disappearance and reappearance were significantly slower for all factors tested. Practical consequences of these observations are discussed. The initial level of factor-IX activity in all nine patients was substantially lower than in normal individuals. Therapy by thyroxine-substitution led to normal levels of factor-IX. This implies a divergency in the retardation of the breakdown and production rates in hypothyroidism. The reappearance rate was indeed found to be more retarded than the disappearance rate.
Plasma levels of factor IX activity and factor IX antigen were determined in 18 definite carriers of haemophilia B-, 10 definite carriers of haemophilia B+ and 40 control subjects. Factor IX antigen was determined by the electroimmunoassay technique of Laurell using a rabbit antiserum against factor IX. In haemophilia B-, statistical tolerance regions were constructed containing 90% of the factor IX activity and factor IX antigen values for the carriers and the control subjects. Of the 18 carriers, 10 were outside the tolerance region for the control subjects, and of the 40 control subjects, 17 were outside the tolerance region for the carriers. A better separation of the probabilities of being a carrier was obtained for the B- carriers and the control subjects when factor IX antigen was determined in addition to factor IX activity. In haemophilia B+, factor IX antigen was present in excess of factor IX activity in nine of the 10 carriers. The values for factor IX activity and factor IX antigen for these nine carriers fell outside the 90% tolerance region for the control subjects. It is concluded that the quantitative determination of factor IX antigen may be of value in the detection of carriers of both haemophilia B+ and haemophilia B-.
A genetic variant of factor IX is described that behaves identically to PIVKA/IX (the precursor factor IX molecule induced by the absence of vitamin K or presence of vitamin K antagonists, acarboxy factor IX). It shows an increased electrophoretic mobility in the presence of Ca2+, a low affinity for adsorption to A1(OH)3 and a very low specific coagulant activity. This variant of factor IX has been demonstrated in the plasma of a patient with severe haemophilia B and in the plasmas of a number of possible carriers from the probands' pedigree.
A rather large proportion of the hemophilia B patients can be characterized as hemophilia B+ because of the presence in their plasma of a protein which is immunologically identical with human factor IX. In a group of 33 hemophilia B patients we found 14 cases of hemophilia B+ belonging to 11 independent pedigrees. The variant factor IX molecules of these families have been compared with respect to the following properties: 1) factor IX activity and its dependence on phospholipid concentration; 2) factor IX antigen; 3) prolongation of prothrombin time with an ox brain thromboplastin; 4) electrophoretic mobility; 5) Ca(+) binding capacity; 6) affinity for binding to heparin and 7) susceptibility of the factor IX antigen to contact-induced activation. In the study of these parameters the use of a precipitating antibody against highly purified human factor IX showed to be of great value. According to our criteria at least 7 different factor IX variants were present in the 11 families with hemophilia B+ studied. Because of this rather high heterogeneity a suitable nomenclature for subclassification of hemophilia B+ variants is proposed.
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Antithrombin III levels were studied in relation to the occurrence of thromboembolism in 48 patients with various degrees of proteinuria. Nine of these patients had clinical signs of thrombosis, including four with renal vein thrombosis. In eight of these nine patients, antithrombin III concentrations were below 70 per cent. There was a significant negative correlation between the antithrombin III concentration and the urinary protein excreation (P less than 0.001). Antithrombin III was found in the urine of 32 of 42 patients. There was a significant correlation between the renal clearance and the degree of antithrombin III serum deficiency (P less that 0.001). The clearance and serum level of albumin closely paralleled these changes. We conclude that thrombosis in patients with severe proteinuria is associated with a deficiency of antithrombin III due to urinary excretion of this protein.
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Coagulation studies (plasma fibrinogen, ethanol gelation test, and fibrin/fibrinogen degradation product concentration) were done in 150 patients who were admitted after blunt head injury. Results were abnormal in 60 patients and were found to be correlated with the level of consciousness and with the presence of neurological signs. Many of these patients had fractures, but findings in a control group of 26 patients with major fractures without head injury indicate that fractures were not of paramount importance in causing clotting changes. Conclusive evidence of disseminated intravascular coagulation was found in 12 patients. Cases with a fatal clinical course were mostly associated with very high fibrin/fibrinogen degradation product concentrations. Some case histories are reported, confirming the hypothesized correlation between coagulation results and brain tissue destruction rather than brain compression. It was concluded that some degree of disseminated intravascular coagulation in patients with blunt head injury occurs more often than expected and that coagulation studies might have both diagnostic and prognostic value.
The relatives of two patients with medullary cystic disease associated with retinitis pigmentosa were studied. A new case was found in one of these families, and consanguinity of the parents was established in another. Conventional fundoscopic examination of relatives without renal disease did not show retinal abnormalities, but electro-ophthalmologic investigation demonstrated retinal dysfunction in three relatives, including two of the four parents who may be considered obligatory heterozygotes under the assumption of autosomal recessive inheritance of this syndrome. Less severe electro-ophthalmological abnormalities were observed in the other two parents. It is considered highly probable that all three patients are homozygous for a mutant gene causing both the renal and the retinal abnormalities. The results of this study support the view that medullary cystic disease associated with retinitis pigmentosa is transmitted as an autosomal recessive trait, in contrast to the dominant form, which is reported not to be associated with eye abnormalities. With respect to genetic couseling and donation of kidneys by relatives, it is important to establish the mode of inheritance of cystic medullary disease in a given family. Electro-ophthalmologic examination should therefore be included in the examination of families in which medullary cystic disease occurs.
Nine patients with severe factor-VII deficiency, belonging to seven pedigrees were studied for the presence of factor-VII-CRM with an inhibitor neutralization assay. The antibody, raised in rabbits, did not precipitate the antigen and could only be used in a fluid phase assay to measure the capacity of plasma to neutralize inhibitory activity directed against factor-VII activity. In one of these nine patients normal amounts of factor-VII-CRM could be demonstrated. The CRM + patient did not show a clinical picture at variance with that of the CRM-patients. The investigation into this CRM+ pedigree revealed heterozygosity in nine out of 12 persons when using the ratio between biological factor-VII activity and factor-VII-CRM as the criterion.