1/201. Compound heterozygosity for one novel and one recurrent mutation in a Thai patient with severe protein s deficiency. Homozygous or compound heterozygous protein S (PS) deficiency is a very rare disorder in the anticoagulant system, that can lead to life-threatening thrombotic complications shortly after birth. This report describes the results of the genetic analysis of the PROS 1 genes in a Thai girl patient. She was reported in 1990 as the first case with homozygous PS deficiency and neonatal purpura fulminans. In the present report, we identified the mutations in this patient by direct sequencing of PCR products representing all 15 exons of the PROS 1 gene and their flanking intronic regions. The patient turned out to be compound heterozygous for two null mutations. One allele contained a novel sequence variation, an A-insertion in an A5-tract covering codon 146 and 147, that results in a frameshift and a stop codon (TAA) at position 155. The other allele contained a nonsense mutation in exon 12 by a transition at codon 410 CGA (Arg) to TGA (stop). Cosegregation of PS deficiency with these two genetic defects was observed in her family. ( info) |
2/201. Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis. The 20210A prothrombin mutation has recently been associated with an increased risk of venous thrombosis, but the mechanism of the increased thrombotic risk in affected persons has not been elucidated. We report on a thrombophilic family in which the proband presented with cerebral vein thrombosis and homozygosity for the 20210A prothrombin mutation as her only identifiable risk factor for venous thrombosis. Extended genotyping of family members revealed seven other affected, but asymptomatic, first-degree relatives (one A/A homozygote and six G/A heterozygotes). plasma levels of prothrombin, prothrombin fragments 1 2 and thrombin-antithrombin complexes were highest in A/A homozygotes, intermediate in G/A heterozygotes and lowest in those with the G/G homozygous normal genotype, while D-dimer levels were elevated only in A/A homozygotes. Our results suggest that the 20210A prothrombin mutation is associated with activation of coagulation and increased thrombin generation, not only in patients with a past history of thrombosis but also in otherwise healthy asymptomatic persons. In a similar fashion to the homozygous factor v Leiden mutation, patients with the homozygous 20210A prothrombin mutation could be at highest risk of thrombosis, as suggested by our patient who presented with unusual thrombosis. ( info) |
| budd-chiari syndrome is characterized by hepatic venous outflow obstruction. Although myeloproliferative disorders are usually responsible for this severe thrombotic disorder, deficiency or dysfunction of the natural anticoagulants can be involved. Resistance to activated protein c caused by factor v Leiden mutation has been recently identified as a major cause of thrombophilia. We report 6 patients with budd-chiari syndrome associated with factor v Leiden mutation combined with another acquired thrombophilic state (myeloproliferative disorder and lupus anticoagulant in 3 cases) and without another thrombophilic disorder in the other 3 cases. We conclude that factor v Leiden mutation should be evaluated in any case of hepatic vein occlusion because the prevalence of this mutation in the general population is high. ( info) |
4/201. Resistance to activated protein c as an etiology for stroke in a young adult: a case report. Resistance to activated protein c (R-APC) is an inherited, autosomal dominant, coagulation abnormality that is increasingly recognized as an important etiology for thromboembolic disease and stroke in young adults. This report describes the case of a 27-year-old woman taking oral contraceptives who experienced an acute thrombotic right hemispheric stroke. Three days after rehabilitation admission (33 days after stroke) she developed a left femoral deep venous thrombosis (DVT) despite appropriate prophylaxis. Further diagnostic workup for the stroke and DVT identified R-APC, possibly exacerbated by oral contraceptives, as the etiology. hematology consultation recommended lifetime anticoagulation with warfarin. The patient's family history revealed that a 19-year-old cousin had died of a stroke several years earlier. Several months after discharge, an acute DVT occurred in the patient's 28-year-old brother, who tested positive for factor v Leiden, a genetic abnormality closely associated with R-APC. A thrombotic stroke occurred in her grandfather a few months later, but he was not tested. Her father demonstrated a "borderline" positive R-APC test and probably represents the genetic link. Indications for patient and family screening regarding R-APC and other forms of hereditary thrombophilia and implications for rehabilitation medicine physicians are discussed. ( info) |
5/201. factor v Leiden and antibodies against phospholipids and protein S in a young woman with recurrent thromboses and abortion. We describe the case of a 39-year-old woman who suffered two iliofemoral venous thromboses, a cerebral ischemic infarct and recurrent fetal loss. Initial studies showed high levels of antiphospholipid antibodies (APAs) and a moderate thrombocytopenia. After her second miscarriage, laboratory diagnosis revealed that the woman was heterozygous for the factor v Leiden mutation and had a functional protein s deficiency as well as anti-protein S and anti-beta 2-glycoprotein i antibodies. The impairment of the protein c pathway at various points could well explain the recurrent thromboses in the patient and supports the role of a disturbed protein c system in the pathophysiology of thrombosis in patients with APAs. ( info) |
6/201. Hematologic effects of thrombophilia. The hematologic effects of thrombophilia are subtle, and when recognized may provide clues for the diagnosis of hypercoagulation in patients. This article identifies aberrant, routine test results associated with the diagnosis of thrombophilia. The future expansion of laboratory testing for thrombophilia detection is presented in summation. ( info) |
| prothrombin G20210A is a newly described common mutation that is associated with an increased risk of arterial and venous thrombosis. We describe a healthy child heterozygous for this prothrombin mutation who had a spinal cord infarct with no other prothrombotic risk factors. ( info) |
| The causes of budd-chiari syndrome (BCS) comprise several diseases leading to thrombophilia. One of the most common thrombophilic disorders is resistance against activated protein c, caused by a single point mutation of the factor v gene. In December 1993, a 22-year-old patient was given a diagnosis of subacute BCS with occlusion of all major hepatic veins. Placement of a transjugular intrahepatic portosystemic stent shunt led to rapid disappearance of ascites and hepatic encephalopathy. During the following two years, recurrent partial occlusions of the shunt were treated by balloon angioplasty. The cause of the BCS still being unknown, in October 1996 we performed extensive laboratory investigations concerning states of thrombophilia and found moderately elevated IgG anticardiolipin antibodies (19.7 U/ml) and a resistance against activated protein c caused by heterozygosity for a point mutation of the factor v gene (1691G-->A; factor v Leiden). As a consequence, oral anticoagulation with coumarin was initiated. In October 1997, elective liver transplantation was performed which led to disappearance of APC resistance. Moreover, IgG anticardiolipin antibodies have been negative since then. If BCS is caused by APC resistance, liver transplantation not only treats the chronic liver disease but also cures the state of thrombophilia since factor v is mainly synthesized in the liver. ( info) |
9/201. Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism. BACKGROUND AND OBJECTIVE: A new genetic risk factor for venous thromboembolism has recently been described which involves a G to A transition at position 20210 in the 3' untranslated region of the prothrombin gene. To date, only a few homozygotes for this mutation have been reported and in most of cases, they suffered from thrombotic disease. Here, we describe a pedigree including both heterozygous and homozygous subjects for prothrombin (PT) 20210 A. DESIGN AND methods: This family was recruited in 1996 as part of our gait (Genetic Analysis of Idiopathic thrombophilia) project. To qualify for the gait study, a pedigree was required to have at least 10 living individuals in three or more generations (i.e. extended pedigree). The pedigrees were selected through probands with idiopathic thrombophilia. A complete set of plasma and dna determinations related to hemostasis was performed on this family. RESULTS: The plasma studies yielded normal results in all of the individuals. The family members who had a history of thromboembolism were heterozygous carriers of the PT 20210 A variant. In addition, 4 relatives who were heterozygous, and two who were homozygous for this A allele, failed to show clinical manifestations. These two homozygotes were 51 and 19 years old. INTERPRETATION AND CONCLUSIONS: This case exemplifies the complexity of thrombotic disease since individuals homozygous for a mutant gene do not exhibit symptoms while heterozygous individuals often do exhibit the disease. This case suggests that the new genetic risk factor for thrombosis (i.e. PT 20210 A) may not be as strong as most of the previously described genetic risk factors. ( info) |
| Malignancies, antiproliferative drug treatment, cancer-related conditions like immobilization, perioperative status and radiotherapy are risk factors for hypercoagulability. Setting aside mass or invasion-related venous thrombosis, the differential diagnosis regarding the etiopathogenesis (paraneoplastic syndrome or antiproliferative treatment) is usually problematic. The authors report a case of combined malignant hemangiopericytoma and recurrent deep venous thrombosis in the right inferior limb. Through a literature review, the following issues are discussed: 1) the criteria for cyto-histopathologic assessment; 2) the involvement of pericytes both in coagulation and platelet aggregation; 3) the importance of discriminating true paraneoplastic syndromes from other tumor-related clinical manifestations; 4) the response to external radiotherapy of malignant hemangiopericytoma as limited disease; 5) the poor results of doxorubicin-ifosfamide polychemotherapy and dacarbazine monochemotherapy in metastatic disease. Although doxorubicin-ifosfamide treatment was in progress in the reported case, the authors conclude that the recurrent deep venous thrombosis is likely to be paraneoplastic, even if such a diagnosis has not been previously reported in the literature. ( info) |