High levels of circulating thrombomodulin in human foetuses and children.

Thrombomodulin (TM) is an endothelial cell surface proteoglycan with anticoagulant functions, also implicated in cell proliferation, cell-cell adhesion and differentiation. In this study we determined circulating plasma TM (pTM) levels in human foetuses at different stages of pregnancy, at birth and in childhood. TM levels increased with gestational age, the median level reaching a peak of approximately 165 ng/ml between the 23rd and 26th week, thereafter decreasing gradually, reaching a value of 108 ng/ml at birth. pTM continues to decrease progressively during childhood, reaching in the 5-15 years group a median of 56 ng/ml which approaches the adult value. The pTM peak was statistically significant and represents a specific foetal phenomenon as it was independent of the corresponding maternal values. As a whole, the pTM pattern during foetal maturation appears totally different from that of protein C, prothrombin and other coagulation activators and inhibitors and thus, TM may play in the foetus another role in addition to its well-known anticoagulant function.

Predictive value of plasma thrombomodulin in preeclampsia and gestational hypertension.

In a prospective longitudinal study, 130 primigravidae at risk for preeclampsia were examined and plasma sampling performed in 45 of them. Plasma thrombomodulin (pTM) was sequentially measured at weeks 12, 24 and 32 of gestation and after delivery in 20 primigravidae who developed either mild preeclampsia (n = 8) or gestational hypertension (n = 12) between weeks 32 and 39 of gestation and in 25 (age-matched) primigravidae who had uneventful pregnancies. pTM elevations were not observed until week 32 in uneventful pregnancies, but were present by week 24 (p = 0.002) in patients who later developed hypertensive complications. A net individual pTM increase > or = 4.2 ng/ml between weeks 12 and 24 (more than 8 times that of normotensive primigravidae) and/or pTM level > or = 47.5 ng/ml at week 32 predicted the development of hypertensive complications with 80% accuracy. Serial pTM determinations can be useful to select pregnancies who may benefit from early pharmacological intervention.

An unknown source of vitamin K1 in patients on total parenteral nutrition.

We found a level of 20.8 +/- 3.4 mug/dl of vitamin K1 (VK1) in Intralipid 20% and initiated a study based on the follow-up of children receiving total parenteral nutrition without any other exogenous VK1 intake than from Intralipid 20% (1 g/kg/day). This lipid administration was sufficient to cover the needs during a study period of 4 to 29 weeks.

Coagulation assays as diagnostic markers of hepatocellular carcinoma.

With the aim of improving the biological diagnosis of hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP) and factor V levels were assayed in 119 patients with HCC and 60 cirrhotic patients without HCC. Among the patients with HCC, increased levels of AFP (greater than 300 ng/ml) and of DCP (greater than 15 mU/ml) were observed in 36% and 69% of the cases, respectively. None of the 60 patients without HCC had increased AFP, and one had abnormal DCP; in this patient, DCP level returned to normal value after vitamin K1 injection. No significant correlation was found between increased AFP and DCP, thus indicating that the two tests complement each other for the diagnosis. A factor V level higher than expected from the reduced prothrombin time test of the patient was detected in 50% of patients with HCC and only 7% of those without HCC. No correlation was found between increased factor V and abnormal AFP or DCP. The thrombin time, fibrinogen activity to antigen ratio, and polymerization index failed to differentiate between cirrhosis and HCC. We conclude that AFP, DCP and factor V may give complementary informations in the diagnosis of HCC, one of these markers at least being positive in 88% of the patients.

Placental transfer of vitamin K1 and its implications in fetal hemostasis.

Vitamin K status was evaluated using coagulation studies and/or vitamin K1 assays in a total of 53 normal fetuses and 47 neonates. Second trimester fetal blood samples were obtained for prenatal diagnosis under ultrasound guidance. Endogenous vitamin K1 concentrations (determined by high performance liquid chromatography) were substantially lower than maternal levels. The mean maternal-fetal gradient was 14-fold at mid trimester and 18-fold at birth. Despite low vitamin K levels, descarboxy prothrombin, detected by a staphylocoagulase assay, was elevated in only a single fetus and a single neonate. After maternal oral supplementation with vitamin K1, cord vitamin K1 levels were boosted 30-fold at mid trimester and 60-fold at term, demonstrating placental transfer. However, these levels were substantially lower than corresponding supplemented maternal levels. Despite elevated vitamin K1 concentrations, supplemented fetuses and neonates showed no increase in total or coagulant prothrombin activity. These results suggest that the low prothrombin levels found during intrauterine life are not due to vitamin K deficiency.

[Assay of decarboxy-prothrombin: its value in the diagnosis of hepatocellular carcinoma]. / Le dosage de la décarboxy-prothrombine: son intérêt dans le diagnostic des carcinomes hépatocellulaires.

Serum decarboxy-prothrombin (DCP) was raised in 70.7% of histologically confirmed cases of hepatocellular carcinoma and, with alpha foetoprotein, constitutes a complementary biochemical marker for this disease. It is usually normal in other hepatic diseases but pathological values of DCP have been observed in a few cases of cirrhosis and in some pancreatic carcinomas with hepatic metastases. The differential diagnosis may be established by administering 20 mg of Vitamin K1 by slow intravenous injection: if the DCP remains pathological 15 days after Vitamin K1 the diagnosis of hepatocellular carcinoma is very probable. On the other hand, if the DCP is normal a Vitamin K deficiency may be diagnosed.

Specificity of increased des-gamma-carboxyprothrombin in hepatocellular carcinoma after vitamin K1 injection.

The des-gamma-carboxyprothrombin (DCP) level was found to be increased in the majority of hepatocellular carcinomas (HCC). This increase has to be distinguished from an increased DCP level linked to a vitamin K deficiency. We studied the evolution of increased DCP level in 6 patients with histologically proven HCC and in 10 without HCC after slow injection of 20 mg of vitamin K1. The DCP assays performed subsequent to the vitamin K1 injection showed: first, a durable normalisation of the DCP level in the patients without HCC, suggesting that the increased DCP was linked, in them, to an underlying vitamin K deficiency; second, a transitory decrease followed by a return to the abnormal level in the patients with HCC. We can conclude that an increased DCP level which persists following vitamin K1 injection is specific for HCC. The minimal delay for the DCP assay after vitamin K1 injection seems to be 15 days.

A new method to assay des-gamma-carboxyprothrombin. Results obtained in 75 cases of hepatocellular carcinoma.

A new method for assaying the activity of des-gamma-carboxyprothrombin (DCP), using staphylocoagulase on undiluted adsorbed plasma, is described. The thrombin-coagulase formed is measured on a chromogenic substrate, and the results are expressed in milliunits per milliliter of increment of the optical density following the release of p-nitroaniline. Levels of DCP in 96 normal subjects were under 10 mU/ml (mean, 3.58 mU/ml). Of 70 nonhepatectomized patients with hepatocellular carcinomas, 74% had increased DCP levels of between 20 and 420 mU/ml (most of the values were between 20 and 100 mU/ml). Des-carboxyprothrombin and alpha-fetoprotein measurements gave complementary information, one marker or the other being positive in 87% of hepatocellular carcinoma. Fourteen of 15 patients with metastatic carcinoma of the liver had normal DCP levels, as did 95 patients with liver cirrhosis and 13 patients with chronic hepatitis. When the level of "total factor II" is below 40%, it is recommended that a second determination of DCP be performed 5 days after the injection of vitamin K, to exclude any vitamin K deficiency (in the case of hepatocellular carcinoma the DCP level will remain elevated). The DCP assay appears more sensitive and more specific than the alpha-fetoprotein assay for the diagnosis of hepatocellular carcinoma; furthermore, both tests are complementary.

A new case of high-molecular-weight kininogen inherited deficiency.

A preoperative hemostasis study discovered a prolonged activated partial thromboplastin time in a 23-year-old Portuguese Caucasian woman without personal or past family history of hemorrhage or thrombosis. This was corrected by pooled plasma that excluded circulating anticoagulant. Activated partial thromboplastin time was prolonged whatever the activator, particularly ellagic acid, and was not corrected by prolonged kaolin incubation. Levels of factors VIII and XII were normal; factor XI and prekallikrein levels were either moderately low or normal according to activators and defective reagents used. High-molecular-weight kininogen (HMWK) level assessed by coagulation and immunological method was virtually nil. Fibrinolysis activity was normal before and after venous occlusion. The programmed operation was performed without any particular preparation and no complication arose. Family investigation found heterozygous HMWK deficiency in the proposita's father and three of her siblings.