Jan J. Veltkamp

Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families.

Protein C is the zymogen of a vitamin K-dependent serine protease involved in blood coagulation. In the absence of protein C the inactivation of activated factors V and VIIIC is impaired, and the fibrinolytic capacity of the circulating blood is reduced. These conditions promote excessive fibrin formation and thus constitute a risk factor for thrombosis. Using an immunologic assay for protein C, we identified 18 patients (11 male and 7 female) in three unrelated Dutch families as fulfilling the criteria for an isolated protein C deficiency. In 12 patients who were not receiving oral anticoagulant treatment the mean protein C antigen concentration was 0.48 +/- 0.09 U per milliliter (+/- S.D.), and in 6 patients who were receiving adjusted doses of oral anticoagulants and had stable anticoagulation, the mean value was 0.17 +/- 0.05 U per milliliter. (The value in healthy subjects is 0.98 +/- 0.19 U per milliliter.) Fourteen of the 18 patients had a history of venous thromboembolism, with superficial thrombophlebitis as the hallmark of this condition (in 13 patients). These data are consistent with an autosomal dominant trait with variable expressivity.

Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome.

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.

Detection of Heterozygotes for Recessive von Willebrand's Disease by the Assay of Antihemophilic-Factor-like Antigen

Abstract Asymptomatic relatives of a girl with an extremely severe form of von Willebrands disease who had consanguineous parents were investigated to determine whether they carried the von Willebrand gene. Bleeding time, procoagulant antihemophilic-factor activity (one-stage method), and antihemophilic-factor-like antigen level (quantitative immunoelectrophoresis) and antibody-neutralizing capacity were estimated in 22 relatives. All showed normal antihemophilic-factor procoagulant activity, but five had significantly low levels of antihemophilic-factor-like antigen. Comparison of the levels of antigen and antihemophilic-factor activity (on the basis of a regression analysis) made it possible to identify three additional carriers of this von Willebrand gene. These results suggest that the antigen is more directly related to the primary gene-product of the von Willebrand locus than antihemophilic-factor activity. (N Engl J Med 289:882–885, 1973)

A CRM-Positive Variant of Factor-VII Deficiency and the Detection of Heterozygotes with the Assay of Factor-like Antigen

Summary. 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.

Evaluation of the detection rate of hemophilia carriers

The detection rate of hemophilia A carriers was evaluated on the basis of AHF-activity and AHF-like antigen determination. Statistical tolerance regions were constructed containing 50 and 95% of the AHF-activity and AHF-like antigen determinations of individuals of the normal or carrier group. Using these regions 18 out of 22 obligatory carriers are outside the 95% tolerance region of the normals. On the basis of AHF-activity alone only 8 out of 22 obligatory carriers are outside the 95% tolerance interval for the normals. For individual counselling for possible or potential carriers, with a prior chance (i.e. genetically determined) on carriership, the probabilities of carriership are calculated with the theorem of Bayes.

Detection of carriers of haemophilia B.

Summary. 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 probabilites 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‐.

Coagulation Factors in the Human Fetus of about 20 Weeks of Gestational Age

Summary 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 VIII:CAg) (0·19 U/ml), factor IX coagulant activity (0·05 U/ml), factor IX antigen (≤0·03 U/ml), factor X (0·19 U/ml) and antithrombin III (AT‐III) (0·23 U/ml).

The Prophylactic Treatment of Hemophilia B Leyden with Anabolic Steroids

Excerpt Hemophilia B Leyden is an X-linked recessively inherited bleeding disorder that cannot be distinguished from severe cross-reactive material-negative hemophilia B in patients under 15 years ...

Immunoradiometric assay of procoagulant factor VIII antigen (VIIICAG)

An immunoradiometric assay of procoagulant factor VIII antigen was developed using a human antibody to the procoagulant activity of factor VIII (VIII:C). The assay measures specifically the antigen related to factor VIII procoagulant activity (VIIICAG) both in plasma and in serum. VIII:C and VIIICAG were measured in a group of healthy individuals and in a group of haemophilia A patients. In haemophilia A at least four groups can be recognised on the basis of the presence or absence of VIII:C and VIIICAG and the VIII:C/VIIICAG ratio.

Coagulation factors in the premature infant born after about 32 weeks of gestation

In plasma samples from 10 premature infants born after about 32 weeks of gestation, a number of coagulation factors have been determined. For 9 infants, who were healthy, mean values are given: fibrinogen-antigen, 311 mg/dl; factor II, +/- 0.46 U/ml; factor V, 0.80 U/ml; factor VII, 0.59 U/ml; factor VIII coagulant activity, 0.93 U/ml; factor VIII-related antigen, 1.66 U/ml; procoagulant factor VIII antigen, 1.15 U/ml; factor IX coagulant activity, 0.41 U/ml; factor IX antigen, 0.42 U/ml; factor X coagulant activity, 0.52 U/ml; factor X antigen, 0.61 U/ml, and antithrombin III-antigen (AT-III), 0.43 U/ml. In 5 infants a second sample was taken a week after the first one; for most values there was no significant rise, except for factor II and AT-III. The values we found in this group of premature infants are within the range of those reported in earlier literature. They are higher than the ones we found in early fetal samples and most of them are similar to those we found in early fetal samples and most of them are similar to those we found in the cord blood of full-term newborns.