Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis.

A patient who suffered a recurring thrombosis over the last 15 yr has been investigated. The only abnormality found in this patient was a significantly depressed level of plasminogen activity in plasma. In spite of the depressed plasminogen activity, the patient was found to have a normal level of plasminogen antigen concentration. It was calculated that the activity per milligram of plasminogen of the patient was approximately one-half the values of normal subjects. The same discrepancy between biological activity and antigen concentration was found in the other members of the kindred. A niece was found to have practically no plasminogen activity but possessed a normal concentration of plasminogen antigen. Both her parents were found to have approximately half the normal plasminogen activity and normal antigen levels. These studies suggested that the molecular abnormality was inherited as an autosomal characteristic, and the family members who had half the normal levels of activity with normal plasminogen antigen were heterozygotes whereas the one with practically no plasminogen activity was homozygote. Subsequent studies showed that the pattern of gel electrofocusing of purified plasminogen of the heterozygotes consisted of 10 normal bands and 10 additional abnormal bands, each of which had a slightly higher isoelectric point than each corresponding normal component. This indicates that plasminogen of the heterozygote is a mixture of normal and abnormal molecules in an approximately equal amount, which was substantiated by active site titration of purified plasminogen preparations obtained from the propositus and a normal individual. The gel electrofocusing pattern of the homozygote consisted of abnormal bands only. The defect is a hereditary abnormality of plasminogen.

Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese.

BACKGROUND AND PURPOSE: Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms (HindIII and PvuII) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). METHODS: We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for HindIII/PvuII restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. RESULTS: The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P=0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) (P=0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. HindIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P=0.031), but the frequency of PvuII polymorphism was not significantly different between groups. CONCLUSIONS: Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.

Polymorphism of the angiotensin-converting enzyme (ACE) gene in patients with thrombotic brain infarction.

The relationship between cerebrovascular disease and an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene is still being debated. We examined its role as a risk factor in patients with thrombotic brain infarction. The association between ACE polymorphism and ischemic stroke was examined in 181 patients with thrombotic brain infarction and 271 controls without strokes. The I/D polymorphism was examined using the polymerase chain reaction. Distributions of the ACE genotypes and alleles did not differ between the infarcted patients and the controls. Both distributions in patients with onset at age 60 years or younger were significantly higher than those in younger controls (genotype: chi 2 = 7.6, P = 0.02; allele: chi 2 = 5.6, P = 0.02). There were no significant differences in the distributions of ACE genotypes and alleles between the patients with lacunar infarcts and with cortical infarcts in all ages. There were also significant differences in the distribution of ACE genotypes and alleles between the younger and the elderly subgroup of patients with brain infarction (genotype: chi 2 = 12.9, P = 0.002; allele: chi 2 = 11.1, P = 0.0009). Furthermore, there was a significant decline in the frequency of the ACE D allele with increasing age in all patients with thrombotic brain infarction. These observations demonstrated a significant association between the ACE gene polymorphism and thrombotic brain infarction in patients age 60 years or younger in a Japanese population. Furthermore, there may be an association between the ACE D allele and mortality after cerebral infarction.

Thrombotic thrombocytopenic purpura in four siblings.

A family is described in which four members of a sibship of seven suffered from a hematologic and systemic disorder whcih has been fatal in three and has been proved at autopsy to have been fatal in three and has been proved at autopsy to have been thrombotic purpura. The fourth member has probably suffered the same disorder. The clinical laboratory and genetic features of the family are discussed at length. No cause of the disorder has been determined.

Vascular cell adhesion molecule-1 mRNA is expressed in immune-mediated and ischemic injury of the rat nervous system.

In this study we used nonradioactive in situ hybridization for the cellular localization of vascular cell adhesion molecule-1 (VCAM-1) mRNA in immune-mediated, ischemic and degenerative diseases of the rat nervous system. In the acute phase of experimental autoimmune encephalomyelitis and neuritis VCAM-1 mRNA was expressed not only on the luminal surface of inflamed vessels but also in perivascular cells suggesting a functional role of VCAM-1 in both endothelial adhesion and local restimulation of autoantigen-specific T cells. Accordingly, perivascular T cell accumulation was most pronounced at sites of local VCAM-1 mRNA expression. In addition, VCAM-1 mRNA was detected in the border zone around photochemically induced cerebral infarcts which is the predeliction site of T cell infiltration and expression of immune activation markers during the first week after ischemia. VCAM-1 mRNA was absent from the center of the infarcts as well as axotomized central and peripheral nerves undergoing Wallerian degeneration. These data indicate that VCAM-1-mediated adhesion processes are involved in immune-mediated and ischemic diseases of the nervous system but not in T cell-independent macrophage recruitment during Wallerian degeneration.

Inherited antithrombin III deficiency and cerebral thrombosis in a child.

Identification of a family affected by antithrombin III-heparin cofactor (AT-III) deficiency was made after diagnosis of the index case, a 15-year-old boy who suffered cerebral thrombosis. The proband had a two-year history of recurrent thrombosis involving the lower extremities. His mother and sister were also affected. Studies showed a decreased biological activity (AT-IIIc) and antigen (AT-IIIag) by the Laurell technique in the proband (AT-IIIc = 0.32, AT-IIIag = 46%), his sister (AT-IIIc = 0.29, AT-IIIag = 47%), and his mother (AT-IIIc = 0.41, AT-IIIag = 56%). Crossed immunoelectrophoresis (CIE) of the affected individuals' plasma in agarose-containing heparin demonstrated a normal pattern of migration. Treatment with warfarin sodium (Coumadin) resulted in an increase in activity in two of three affected family members, and in antigen in all three. Anticoagulant therapy did not affect the pattern of AT-III on CIE. This family represents a quantitative deficiency in antithrombin III. A review of the reported cases of antithrombin III deficiency indicates that individuals with this disorder may have thromboembolic disease in childhood.

Severe arterial cerebral thrombosis in a patient with protein S deficiency (moderately reduced total and markedly reduced free protein S): a family study.

Deficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis. In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits. In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

Factor V gene mutation is a risk factor for cerebral venous thrombosis.

To evaluate the association between coagulation defects and cerebral venous thrombosis, a case-control study was conducted in 25 patients who had no autoimmune, neoplastic or infections disease and 75 healthy individuals. There were no patients with deficiency of protein C or protein S. Four had resistance to activated protein C (APC) and one had APC resistance associated with antithrombin deficiency. APC resistance was investigated by DNA analysis, and diagnosed by the presence of a point mutation in the factor V gene, which predicts replacement of Arg506 with Gln at one of the two APC cleavage sites in activated factor V. The prevalence of APC resistance was 20% in patients and 2.7% in controls. This difference was statistically significant (p = 0.01) and the odds ratio was 9.1. A circumstantial factor predisposing to cerebral venous thrombosis (such as oral contraceptive intake, pregnancy, puerperium, trauma or prolonged immobilization) was reported in 72% of cases. In conclusion, APC resistance is the most frequent coagulation abnormality associated with cerebral venous thrombosis.

Inherited prothrombotic risk factors and cerebral venous thrombosis.

Fifteen patients with cerebral venous thrombosis were ascertained retrospectively. Their case notes were reviewed, and stored or new blood was assayed for factor V Leiden (FVL) mutation, prothrombin gene mutation 20201A, and 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T mutation. A clinical risk factor was identified in 13 patients--the oral contraceptive pill (5), puerperium (1), HRT (1), mastoiditis (1), dehydration (1), lumbar puncture and myelography (1), carcinoma (1), lupus anticoagulant (2). In addition, two patients had the FVL mutation and five (one of whom also had the FVL mutation) were homozygous for the MTHFR mutation. The latter showed a higher than expected frequency compared to 300 healthy controls from South Wales (OR 3.15.95% Cl 1.01-9.83). No patient had the prothrombin 20201A mutation. Two patients died and three had a monocular visual deficit following anticoagulation (13) or thrombolytic (2) treatment, but there was no association between the presence of a primary prothrombotic risk factor and outcome. These results confirm the importance of investigating patients for both clinical predisposing factors and primary prothrombotic states.

Increased rate of factor V Leiden mutation in patients with cerebral venous thrombosis.

We investigated the association between cerebral venous thrombosis and hereditary resistance to activated protein C (APC) in 12 consecutive German patients with non-fatal cerebral venous thrombosis and in 187 controls without a history of thrombotic disorder. Three patients (25%) had a mutation in the factor V Leiden gene against only one subject in the control group. This difference was significant (P < 0.05), with an odds ratio of 11.7 (1.5-87; 95% confidence interval). Two patients carrying the mutation had additional common risk factors for thrombosis, and 2 had a positive family history of thromboembolism. We conclude that inherited APC resistance by a mutation in factor V Leiden is an important risk factor in non-fatal cerebral venous thrombosis. We recommend testing for APC resistance and, if abnormal for factor V Leiden mutation in patients with cerebral venous thrombosis.

Recurrent cerebral thrombosis associated with protein S deficiency in a Chinese female.

A 52-year-old Chinese female with recurrent cerebral thrombosis associated with hereditary protein S deficiency is described. The need to consider clotting disorders in young patients with no known risk factors for stroke is emphasized.