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Rivaroxaban, which targets factor Xa and does not reduce proteins C/S, was chosen to treat a 6-year-old girl with homozygous protein S (PS) deficiency who developed skin necrosis while on warfarin. Owing to the lack of experience with rivaroxaban in children, the girl was started with 5 mg once-daily, which was gradually increased to 40 mg daily. The increasing dosage was driven by the need to avoid recurrence of skin necrosis. During dose-escalation, four pharmacokinetics assays were carried out measuring drug plasma concentrations and their effect on hemostatic parameters. We report the laboratory work-up, with special reference to parameters of thrombin-generation. Rivaroxaban concentrations by HPLC were correlated with those by the anti-factor Xa assay (r(2) = 0.92, p < 0.01), but there was an overestimation by HPLC. Thrombin-generation parameters, such as the area under the curve (referred to as ETP), peak-thrombin, and velocity-index, when measured after addition of thrombomodulin, showed unexpected changes: ETP decreased, but peak-thrombin and velocity-index increased. Similar patterns were obtained in a PS-depleted plasma and in plasma from patients with heterozygous PS deficiency, but not in plasma from controls. In conclusion, these preliminary results suggest that PS may be a determinant of velocity and peak-thrombin, but not of the total amount of thrombin generated.

Protein S deficiency, the protein C cofactor main physiological inhibitor of coagulation, is a thrombophilic state with various events from thrombosis to miscarriage in pregnant women. The context of hypercoagulability and hyperfibrinolysis during pregnancy induced in deciency women, an increased risk of miscarriage and his recurrence. We report the case of a 33 year-old woman whose diagnosis of protein S deficiency was made at the waning of an assessment of repeated spontaneous abortions.

Background: Vitamin K deficiency is the major cause of coagulopathy-induced intracranial bleeding in term neonates and is considered first in any term neonate with severe hemorrhage. The most common manifestation of hereditary prothrombotic disorders during the neonatal period is thrombosis of the A. cerebri media or sinus thrombosis., Case Report: A 4-day-old newborn was admitted with seizures and hemorrhagic shock. Ultrasound revealed a left-sided intraparenchymatous bleeding. MRI findings supported a subarachnoidal and intracerebral mass bleeding. Vitamin K deficiency-related bleeding or hemophiliac diseases were excluded; however, homozygous protein S deficiency with a new mutation in the protein S (PROS1) gene (c.701A>G, p.Tyr234Cys) was found. The patient experienced an additional thrombosis of the A. abdominalis and expired., Conclusion: Congenital prothrombotic disorders have to be considered in the differential diagnosis of neonatal intracranial hemorrhage. This newly described mutation in the PROS1 gene (c.701A>G, p.Tyr234Cys) appears to be of clinical relevance., (Copyright © 2010 S. Karger AG, Basel.)

Variceal bleeding is frequently the initial presentation of a previously unknown cirrhosis. Portal hypertension and its complications without liver cirrhosis should raise the possibility of presinusoidal portal hypertension, and the diagnosis of hepatoportal sclerosis. These patients need to be investigated for coagulation disorders. A hypercoagulable state is often associated. Risks and benefits of anticoagulation should be further investigated in these patients.

These guidelines address developmental aspects of neonatal haemostasis and thrombosis, the laboratory investigation of the neonate, and the diagnosis and clinical management of haemostatic and thrombotic conditions occurring in this period (defined as the first 4 weeks of life following birth). Relevant scientific papers were identified by a systematic literature review from Medline 1975-2000 using index terms which incorporated the various component subjects of these guidelines. Further publications were obtained from the references cited and from reviews known to the members of the working party and to the Haemostasis and Thrombosis Task Force. Evidence and graded recommendations presented in these guidelines are in accordance with the US Agency for Health Care Policy and Research, as described in the Appendix. It will be noted that there is a lack of a strong evidence base for many of the recommendations suggested, as the appropriate clinical and laboratory trials have not been and perhaps never will be undertaken in neonates. Most of the recommendations are therefore of Grade C evidence levels IV: higher levels are mentioned specifically throughout the document when relevant.

The issue discusses the case of a young male patient (35 years old), with bilateral retinal vein thrombosis. The onset of the ocular disease was eight years ago, in the left eye, with decreased visual acuity and complicated with neovascular glaucoma; with an adequate treatment, anatomical and functional evolution was good. A new retinal vein thrombosis, this time in the right eye, make us to concentrate our efforts on the etiology of the disease. Thus, we found a blood hyperviscosity syndrome, caused by a congenital deficiency of protein "S" and resistance at the activated protein "C", which may produce recurrent venous thrombosis.

Congenital protein S (PS) deficiency is associated with increased risk of venous thrombosis. To investigate the possibility of automating PS testing with decreased turnaround time, a clotting-based functional protein S assay was evaluated and compared to an antigenic method. Samples were collected from 126 patients within 5 days of their first acute cerebral infarction, from 62 controls and from 47 consecutive samples for thrombophilia investigation. The normal range for the clotting-based kit, calculated from the results of 20 healthy controls, was 62-136% (mean +/- 2 SD). Intra- and inter-assay co-efficients of variation were < 3.0 and 10.0% respectively. There was no significant correlation between the two methods (r = 0.30, P > 0.05). Two patients had low PS antigen results with normal functional levels. Both techniques were used to compare a further group of 53 patients with defined abnormalities which included nine antigenic protein S deficiencies, five protein C deficient patients, 10 patients with a lupus anticoagulant (LA), 17 Factor V Leiden (FVL) heterozygotes, two FVL homozygotes and 10 patients on therapeutic levels of heparin. In this group we found that four of nine antigenic PS deficient patients had normal functional PS levels. The test was susceptible to the FVL mutation with four of 17 FVL heterozygotes and both of two FVL homozygotes giving low levels. One of five protein C-deficient patients also had a low functional PS result with a normal antigenic level. Normal results were obtained by both methods for all of the LA and patients on therapeutic heparin. We concluded that the automated protein S clotting assay was rapid and simple to perform but appeared to be influenced by factors other than PS deficiency. Results need to be interpreted with caution but may be useful as part of a full thrombophilia investigation.

We report 10 patients with congenital deficiencies of the natural anticoagulant proteins S, C and antithrombin III. Thirteen of a total of 30 pregnancies were managed at the perinatal branch of our department. We discuss the mechanism of action of these proteins and their role in thrombotic events. We analyze the most frequent thrombotic complications and we discuss the general guidelines for the investigation of a patient with a suspected congenital thrombophilia with special regard to its management during pregnancy, delivery and perinatal outcome.

Activated protein C resistance (APCR) is a common cause of familial thrombophilia and venous thrombosis. The aim of the study was to investigate the prevalence of APCR associated with factor V Leiden mutation and its relevance in comparison to other risk factors for thromboembolic disorders in women with a history of previous complicated pregnancies (history of fetal loss in the second and third trimester n = 34, preeclampsia n = 46). The frequency of APCR was significantly higher in women with a history of fetal loss and preeclampsia (23.5 and 26.1%, respectively) compared with a control group (3.8%). The prevalence of antithrombin, protein C and protein S deficiencies and the presence of antiphospholipid antibodies were also investigated: the prevalence of at least one disorder was 41.2% in the group with previous fetal loss, 37.0% in the group with previous preeclampsia and 7.5% in the control group., (Copyright 2000 S. Karger AG, Basel)

Blood coagulation protein and platelet defects are now known to account for up to ninety percent of unexplained venous thrombosis and up to seventy percent of unexplained arterial thrombotic or ischemic events. This article summarizes the common and uncommon blood protein and platelet defects which should be suspected, and searched for, in patients with such events. Defining such defects will have major impact on secondary prevention and duration of antithrombotic therapy in the afflicted patient and impact on primary prevention for identified family members in those harboring hereditary defects.

Danazol, a synthetic attenuated anabolic steroid, has been administered for 36 months to a 32 year old male with hereditary Protein S (PS) deficiency who had become non-compliant for warfarin therapy. The patient has an eleven year history of venous thrombosis. Since danazol therapy was initiated, the patient has not experienced a thrombotic event or adverse side-effects. Levels of PS, other inhibitors, fibrinolytic components, and markers for thrombin and platelet activation were measured prior and subsequent to therapy. Following danazol administration, marked and sustained increases were noted in Free Protein S, Antithrombin, and Protein C. Platelet CD62 (P-selectin) positivity which was elevated before therapy, decreased to assay threshold limits within five weeks. Both Prothrombin Fragment 1.2 and thrombin-antithrombin complexes were elevated post danazol therapy indicating continued clearance of generated thrombin. These data suggest that the protective effect provided by danazol in this patient with hereditary PS deficiency, may in large part be due to suppression of platelet activation by thrombin inhibition than simply through elevation of PS.