Ingrid Pabinger-Fasching

C677T MTHFR Mutation and Factor V Leiden Mutation in Patients with TIA/Minor Stroke: A Case-Control Study

A common C677T mutation in the gene for the enzyme 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) has been linked to elevated levels of homocysteine and was therefore suspected to be a candidate genetic risk factor for arterial occlusive disease. Another mutation, factor V Leiden, has been established as a common hereditary risk factor for venous thrombosis, but its role in arterial disease remains controversial. We investigated the prevalence of both the C677T MTHFR mutation and the factor V Leiden mutation in 81 patients with transient ischemic attack (TIA) or minor stroke (MS) and in 81 age- and sex-matched control subjects free from clinically manifest vascular disease. We further compared clinical and laboratory data as well as clinical course of patients carrying the factor V Leiden mutation alone or in combination with the C677T MTHFR mutation and mutation-free patients. The prevalence of the MTHFR mutation did not differ between patients and control subjects with 11.1% homozygous carriers in both groups (OR for homozygous carriers 1.0; 95% CI 0.38-2.66). However, there was a trend towards a higher prevalence of carriers of factor V Leiden in patients (12.3%) than in control subjects (4.9%) (OR 2.75; 95% CI 0.83-9.17;p=0.09). Furthermore, we found some evidence that the combined occurrence of the C677T MTHFR mutation and factor V Leiden might unfavorably affect the clinical course of the disease, but the number of respective patients was small. Larger studies with a greater number of carriers of both the C677T MTHFR mutation and factor V Leiden seem therefore warranted.

Hemostatic and fibrinolytic parameters in patients with acute myeloid leukemia: Activation of blood coagulation, fibrinolysis and unspecific proteolysis

SummaryBlood coagulation, fibrinolytic and unspecific proteolytic parameters were investigated in 34 patients with acute myeloid leukemia. An increased activity of the coagulation system, documented by elevated thrombin-antithrombin III-complex (TAT) plasma levels, was found in 91% of the patients; 50% had increased elastase plasma levels. Hyperfibrinolysis, as shown by elevated fibrin split-product D-Dimer plasma levels, was detected in 91% of AML patients. Activation of these enzyme systems was not associated with relevant defects in blood coagulation or fibrinolysis in the majority of the patients investigated. In selected cases of promyelocytic M3 and monoblastic M5 leukemia, however, hypofibrinogenemia and α2-plasmininhibitor defiency was found, most likely due to depletion of these proteins in the course of disseminated intravascular coagulation and secondary hyperfibrinolysis. Significant correlations were calculated between TAT and fibrinogen (r = −0.57,P < 0.005), TAT and D-Dimer (r = 0.89,P < 0.0005), and D-Dimer and α2-plasmininhibitor (r = −0.77,P < 0.0005) levels. Indications of a pathogenetic importance of primary hyperfibrinolysis or unspecific proteolysis for hypofibrinogenemia and α2-PI deficiency were not found.

EVALUATION OF A NEW SCREENING ASSAY PROC® GLOBAL FOR IDENTIFICATION OF DEFECTS IN THE PROTEIN C/PROTEIN S ANTICOAGULANT PATHWAY

In the present study a new assay, ProC Global, globally estimating the activity of the main plasma components of anticoagulant protein C/protein S pathway, was evaluated with respect to test characteristics and its sensitivity in the detection of deficiency states of protein C and protein S and of increased aPCR. In the ProC Global assay procedure protein C is activated in patients plasma by an activator reagent (venom from agkistrodon contortrix). The extent of the prolongation of a samples aPTT, caused by the activation of protein C, is taken as a measure for its anticoagulant capacity. Ninety-eight patients with one of the above mentioned defects were investigated. Decreased plasma protein C activity and increased aPCR were detected with a sensitivity of 1.0, while only 11 of 14 patients with decreased levels of free protein S antigen showed abnormal results in the ProC Global assay (sensitivity = 0.79). The test can be used in heparinized samples up to 1.0 anti Xa U/ml heparin (UFH and LMWH). When samples from patients on oral anticoagulant treatment are prediluted with factor V deficient plasma the test is sensitive for increased aPCR.

Anticardiolipin Antibodies in Patients with Venous Thrombosis

The levels of anticardiolipin antibodies (ACA) and lupus anticoagulant (LAC) were measured in 266 consecutive unselected patients with a history of venous thrombosis. 19 (7.1%) had elevated levels of IgG- or IgM-ACA. The prevalence of LAC was 1 of 266 (0.4%) in the whole patient group and 1 of 19 (5.3%) in the ACA-positive group. Patients with elevated ACA levels did not differ from those with normal ACA with regard to age at the first thrombosis, risk of recurrence, presence of arterial thrombosis, and other clinical features. 8 out of 19 (42.1%) patients with elevated ACA levels also had elevated levels of antinuclear antibodies, but only 1 fulfilled the criteria of systemic lupus erythematosus. These data indicate that in some patients with elevated ACA, autoimmune processes may be present. The clinical significance of elevated ACA levels is uncertain.

Reduced corticosteroid use in adult patients with primary immune thrombocytopenia receiving romiplostim

Abstract **Adult patients with primary immune thrombocytopenia requiring first-line treatment typically receive corticosteroids, which are associated with low response rates and many potential side effects. In a retrospective analysis of two 6-month, placebo-controlled, phase III trials, corticosteroid use decreased from 30 to 26% among patients treated with the novel thrombopoietin-mimetic romiplostim (n = 83) and remained above 30% for placebo-treated patients (n = 42). Moreover, compared to placebo, patients were spared 7 weeks of corticosteroid treatment for every 100 weeks of romiplostim treatment. Thereafter, corticosteroid use continued to decrease significantly, from 35 to 20%, in patients treated with romiplostim for up to 3 years in an open-label extension study (n = 101), and patients were spared a further 8 weeks of corticosteroid treatment for each additional 100 weeks of romiplostim treatment. Such reductions in corticosteroids may improve health-related quality of life in patients with primary immune thrombocytopenia.

Disseminated intravascular coagulation and decrease in fibrinogen levels induced by vincristine/prednisolone therapy of lymphoid blast crisis of chronic myeloid leukemia

SummaryTherapy with vincristine (2 mg i.v. weekly) and prednisolone (100 mg p.o. daily) caused a decrease in fibrinogen levels in nine patients treated for lymphoid blast crisis (LBC) of chronic myeloid leukemia (CML). During the first days of treatment disseminated intravascular coagulation (DIC), evidenced by a positive ethanol gelation test, markedly increased thrombin-antithrombin III complex and fibrin-split product D-dimer levels, and a rapid fall in fibrinogen levels was observed in two patients. The induction of DIC in these two patients caused profuse bleeding in one and necessitated substitution therapy with fibrinogen and platelet concentrates. The remaining seven patients revealed no signs of DIC; nevertheless, four of them showed a moderate increase in D-dimer levels after initiation of therapy. In these patients a well-known side effect of long-term steroid therapy, namely a decrease of fibrinogen levels, was observed within the first week of treatment. Fibrinogen levels did not fall below 150 mg/dl and increased after dose reduction from 100 mg/day to 50 mg/day. We conclude from our results that two types of disturbances in fibrinogen metabolism can be observed during vincristine/prednisolone therapy of LBC of CML: (a) a decrease of fibrinogen levels due to a steroid-mediated impairement of liver synthesis, and (b) a rapid fall in fibrinogen levels in the course of DIC, most likely induced by the release of procoagulants from detoriorating blast cells, leading to severe bleeding in selected cases.