Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
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A 15-year-old woman with a history of transient dysarthria two years before, suddenly developed weakness of right upper extremity, right facial palsy, and dysarthria. She was admitted to our hospital on the third day. She had no hypertension, heart murmur and oedema. On neurological examination, she had mild right hemiparesis including face muscles and mild dysarthria. The right knee jerk was brisk with no Babinski's sign. Ataxia and sensory disturbance were not present. T2-weighted MRI showed a hyperintensity at the posterior limb of the left internal capsule. Cerebral angiography was unremarkable. Ultracardiography and 24-hour electrocardiography were normal. Laboratory data revealed no inflammatory findings, liver dysfunction, hyperglycemia and hyperlipidemia. Antinuclear and anticardiolipin antibodies were negative. Prothrombin time was normal, but activated partial thromboplastin time was slightly prolonged (35.4 sec, normal 25.2-34.4). Protein C, protein S and antithrombin III were normal. Heparin cofactor II (HC II) activity was decreased (44%) with normal HC II antigen (79%) and so she was diagnosed as heparin cofactor II deficiency type II (heparin cofactor II abnormality). Her father manifesting thromboangitis obliterans also had low HC II activity with normal HC II antigen. However, on her genetic analysis, we didn't detect any mutations in the coding region of HC II gene. Until now she has no recurrence of cerebrovascular attacks. On the basis of these results, we suspect that HC II deficiency was a possible risk factor of cerebral infarction in this case because she was so young and had no general risk factors except for HC II. No stroke associated with HC II deficiency type II has been reported up to date. This case is worth considering etiologies of juvenile cerebral infarction.
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PMID:[Juvenile cerebral infarction associated with heparin cofactor II abnormality. A case report]. 1096 62

Inherited gene defects related to the coagulation system have been reported as risk factors for stroke. Recently, a genetic component in the factor V (FV) gene that contributes to activated protein C resistance both in the presence and absence of FV 1691 G-->A was reported. This highly conserved FV gene haplotype was marked as R2 polymorphism, an A to G alteration at position 4070 in exon 13 that predicts the His 1299 Arg substitutions. The aim of this study was to evaluate the role of this mutation in Turkish children with ischemic infarct. The case-control study included 48 patients with cerebral infarction; all were 18 years of age or younger (range: 10 months to 18 years). Ten (20.8%) of the 48 patients were found to carry the FV 1299 His-->Arg mutation, one being homozygous. One patient who had a combination of FV 1691 G-->A and protein C deficiency also carried the FV 4070A mutation. A homozygous FV 1299A patient had a prothrombin (PT) 20210A mutation in the heterozygous state. The cerebral infarct risk for FV 1299 was found to be 2.4 (95% confidence interval 0.9-6.8) for all groups. When underlying conditions were excluded, the incidence of FV 1299 was found to be 8/35 (22.8%), but the risk was almost the same. When two other common thrombophilic mutations (i.e. FV 1691 G-->A and PT 20210 G-->A) were excluded, the incidence of FV 4070 mutation increased to 7/21 (33.3%). The risk also increased to 3.9 (95% confidence interval 1.2-12.3).
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PMID:Factor V (His 1299 Arg) in young Turkish patients with cerebral infarct. 1101 61

Congenital protein C deficiency is now widely recognized as a genetic risk for venous thrombosis. However, it remains uncertain whether this condition also confers risk for arterial thrombosis. We evaluated the association of congenital protein C deficiency with hypertension and silent cerebrovascular disease using brain magnetic resonance imaging (MRI) (T1- and T2-weighted and proton density images) in a large family pedigree of protein C deficiency diagnosed by gene analysis, compared with 46 non-pedigree related control subjects with normal protein C levels (> or = 75%) who were selected from among 55 asymptomatic hypertensive subjects matched for age and cardiovascular risk factors. Of the 58 living subjects in this pedigree, we measured plasma protein C levels in 45 subjects, and found 2 cerebral infarctions in the 24 heterozygotic subjects, whereas there was no stroke in the 21 normal homozygotic subjects. We performed brain MRI in 14 asymptomatic hypertensive subjects without any cardiovascular disease and in two patients with cerebral infarction, and found 28 cerebral infarcts (two corresponded to the patients' neurologic deficits and 26 were silent). All were lacunar infarcts < 10 cm in size. A total of 25 silent lacunar infarcts were found in nine heterozygotic subjects, whereas only one was found in the seven normal homozygotic subjects (2.8 v 0.14 lacunes per person, P = .002). No advanced white matter hyperintense lesions in T2-weighted images were found in either group. The prevalence of silent lacunar infarcts in the heterozygotic subjects was also significantly higher than that in normal control subjects (1.0 per person, P = .01). Concerning the distribution of silent infarcts, the number of lacunes located in the basal ganglia was higher in the heterozygotic subjects (2.3 per person, P < .001) than in the seven normal homozygotic subjects (0.14 per person) or in the control group (0.28 per person), whereas the number of lacunes in the white matter was not different among the groups. In conclusion, congenital protein C deficiency may accelerate the progression of silent cerebral infarct formation in hypertension, particularly in the basal ganglia, and may be a potential risk for stroke or vascularly induced dementia.
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PMID:Silent cerebral infarcts in basal ganglia are advanced in congenital protein C-deficient heterozygotes with hypertension. 1149

A number of previous studies have shown that anti-phospholipid(aPL) antibodies(Abs) do not bind primarily to the negatively-charged phospholipid itself but rather to complexes of the phospholipid and plasma proteins, and that the most common antigenic targets are beta 2-glycoprotein I recognized by anticardiolipin Abs and prothrombin recognized by most lupus anticoagulants. However, resent studies suggest that other phospholipid-binding proteins, particularly protein C, protein S, and annexin V, may be important targets as well. To clarify the association between the various types of aPL Abs and thrombotic complications in patients with systemic lupus erythematosus(SLE), we examined the prevalence of aPL Abs to various phospholipid-binding proteins(beta 2-glycoprotein I, prothrombin, protein C, protein S, and annexin V). We found that anti-beta 2-glycoprotein I Abs may be associated primarily with cerebral infarction and femoral artery thrombosis, and that anti-protein S Abs may be associated primarily with venous thromboembolism and renal thrombotic microangiopathy. Furthermore, anti-annexin V Abs might be closely related to fetal loss. These findings suggest that thrombotic complications in SLE depend on the antigenic specificities of aPL Abs, alone or in combination.
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PMID:[Association between anti-phospholipid antibodies and thrombotic complications in systemic lupus erythematosus]. 1270 97

This review focuses on the several coagulation disorders (the so called hypercoagulable states) that are associated with cerebral venous thrombosis. Hypercoagulable states likely explain the high percentage of cases of cryptogenic cerebral infarction in young people. The most common of the hereditary defects appear to be deficiency of antithrombin III, protein C or protein S, activated protein C resistance and prothrombin 20211A mutation. In a large majority of cases activated protein C resistance is due to the presence of factor V Leiden. Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) represent an acquired disorder of coagulation. Rare defects include heparin cofactor II (HC II), plasminogen or tissue plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor-1 (PAI-1) and dysfibrinogenemia. Hyperhomocystinemia is responsible for both arterial and venous thrombosis. A work-up to identify one of the recognizable hypercoagulable states is indicated, especially in younger patients with stroke. Laboratory evaluation for hypercoagulable states may also often be indicated in those patients who do not have other obvious risk factors for their stroke. If from clinical history, family history and/or laboratory studies, a patient is felt to have a hypercoagulable state, the decision for long term chronic anticoagulation needs to be individualized. If a hereditary hypercoagulable state is found, it also may be appropriate to recommend screening of other family members.
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PMID:Haematologic disorders and cerebral venous thrombosis. 1718 75

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.
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PMID:Catastrophic antiphospholipid syndrome associated with malignancies (case report and review of the literature). 1728 88

Cerebral infarction is a common cause of seizures in neonates with a prevalence of I in 4000 live births. We report two neonates with different presentations due to cerebral infarction and discuss their etiological and neuroradiological findings in this case report. The initial signs were cyanosis and convulsion. In case 1, tonic convulsion, eye deviation, while case 2 had additionally poor sucking and dehydration as a risk factor. Their evaluation for hereditary causes of thrombosis was unremarkable. With these 2 cases, it is emphasized that neonatal cerebal infarction may be a cause of neonatal convulsion. Hence, neonates with cerebral infarction should be evaluated for hereditary conditions like protein C and S deficiency, anti-thrombin III deficiency, Factor V leiden mutation, prothrombin gene mutation and homocystinuria.
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PMID:Cerebral infarctions manifesting as neonatal seizure. 1790 13

An 84-year-old female patient was scheduled to undergo AVR, CABG, and Maze procedure. She had a history of hypertension, cerebral infarction, and branch retinal vein occlusion. Warfarin was administered preoperatively. Before the cardiopulmonary bypass (CPB), heparin 5,000 units was administered. Activated coagulation times (ACTs) before and after CPB were 123 sec and 157 sec, respectively. Additional heparin of 5,000 units extended ACT to 221 seconds, which was not enough for the CPB. Heparin 10,000 units was added, and ACT was 157 sec. AntithrombinIII (ATIII) and platelet counts were 75% and 270,000 mm(-3), respectively. ATIII 1,500 units was administered. ACT and ATIII became 133 sec and 123%, respectively. Because heparin resistance did not respond to ATIII, the operative method was changed to off-pump CABG. A postoperative examination revealed high factor VIII activity of 263%. Other results were as follows: protein C antigen, 40%; protein S antigen, 65%; factor VII, 50%; platelet factor 4, 12%; heparin cofactor II, 104%; von Willebrand factor antigen, 181%; heparin-PF4-IgG antibody, negative; factor VIII inhibitor, negative. The low values of protein C, protein S, and factor VII may have been caused by warfarin. Other values were normal, except for the von Willebrand factor antigen.
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PMID:[Heparin resistance associated with elevated factor VIII]. 1841 8

A 13-month-old Japanese female with Haemophilus influenzae type b meningitis presented with unusually severe septic shock and cerebral infarction in half a day of fever. The initial therapy of plasma-derived activated protein C (Anact C) led to an impressive effect on the aggressive condition. However, purpura fulminans and the consistent decline of plasma protein C activity (<20%) required prolonged activated protein C therapy and gene analysis. The patient carried a novel heterozygous mutation of PROC (exon 4; 335 GAC>TAC, Asp46Tyr). This is the first report of infectious purpura fulminans in a protein C-deficient heterozygote. The clinical onset and treatment course adequately corroborated the aggravated immune/hemostatic reactions and the cytoprotective effects of activated protein C replacement in human heterozygous protein C deficiency. The monitoring of plasma protein C activity and sufficient administration of activated protein C product could improve the outcome of severe sepsis in children.
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PMID:Fulminant sepsis/meningitis due to Haemophilus influenzae in a protein C-deficient heterozygote treated with activated protein C therapy. 1875 23

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.
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PMID:MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family. 1906 58


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