Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
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A 54-year-old man of Persian origin presented to our department with a 1-year history of ulcers on the right leg that had been unresponsive to numerous topical treatments, accompanied by lymphedema of the right leg. Medical history included hypergonadotropic hypogonadism, which had not been further investigated. He was treated for 20 years with testosterone IM once monthly, which he stopped a year before the current hospitalization for unclear reasons. The patient reported no congenital lymphedema. Physical examination revealed two deep skin ulcers (Figure 1) on the right leg measuring 10 cm in diameter with raised irregular inflammatory borders and a boggy, necrotic base discharging a purulent hemorrhagic exudate. Bilateral leg pitting edema and right lymphangitis with lymphadenitis were noted. He had low head hair implantment, sparse hair on the body and head, hyperpigmentation on both legs, onychodystrophia of the toenails (mainly the large toe and less prominent on the other toes), which was atrophic lichen-planus-like in appearance and needed no trimming (Figure 2), normal hand nails, oral thrush, and angular cheilitis. Other physical findings were gynecomastia, pectus excavatum, small and firm testicles, long extremities, asymmetrical goiter, systolic murmur 2/6 in left sternal border, and slow and inappropriate behavior. The patient's temperature on admission was 39 degrees C. Blood cultures were negative for bacterial growth. Results of laboratory investigations included hemoglobin (11.2 g/dL), hematocrit (26.8%), normal mean corpuscular volume and mean corpuscular hemoglobin volume, and red blood cell distribution width (16%). Blood smear showed spherocytes, slight hypochromia, anisocytosis, macrocytosis, and microcytosis. Blood chemistry values were taken for iron (4 micro g/dL [normal range 40-150 micro g/dL]), transferrin (193 mg/dL [normal range 220-400 mg/dL]), ferritin (1128 ng/mL [normal range 14-160 ng/mL]), transferrin saturation (1.5% [normal range 20%-55%]), serum folate (within normal limits), and vitamin B12 (within normal limits). Direct Coombs' test equaled positive 2 + IgG. All these values indicated anemia of chronic diseases combined with hemolytic anemia. Further blood work-up tested antinuclear antibody (positive <1:80 homogeneous pattern), rheumatoid factors (143 IU/mL [positive >8.5 IU/mL]), C-reactive protein (286 mg/L [normal range 0-5 mg/L]), anticardiolipin IgM antibody (9.0 monophosphoryl lipid U/mL [normal range 0-7.00 MPL U/mL]) and antithrombin III activity (135% [normal range 74%-114%]). Results of other blood tests were within normal limits or negative, including lupus anticoagulant, beta2 glycoprotein, anticardiolipin IgG Ab, anti-ss DNA Ab, C3, C4, anti-RO, anti-LA, anti-SC-70, anti-SM Ab, P-ANCA, C-ANCA, TSH, FT4, anti-T microsomal, antithyroglobulin, protein C activity, protein S free, cryoglobulins, serum immunoelectrophoresis, VDRL, hepatitis C antibodies, hepatitis B antigen, and human immunodeficiency virus. Endocrinological work-up examined luteinizing hormone (22.9 mIU/mL [normal range for adult men 0.8-6 mIU/mL]), follicle stimulating hormone (49.7 mIU/mL [normal range for adult men 1-11 mIU/mL]), testosterone (0.24 ng/mL [normal range for adult men 2.5-8.0 ng/mL]), bioavailable testosterone (0.02 ng/mL [normal range for adult men >0.6 ng/mL]), and percent bioavailable test (8.1% [normal value >20%]). These results indicate hypergonadotropic hypogonadism. Plasminogen activator inhibitor 1 was 6 U (normal value 5-20 U/mL). Karyotyping performed by G-banding technique revealed a 47 XXY karyotype, which is diagnostic of Klinefelter's syndrome. Doppler ultrasound of the leg ulcers disclosed partial thrombus in the distal right femoral vein. X-rays and bone scan displayed osteomyelitis along the right tibia. Histological examination of a 4-mm punch biopsy from the ulcer border revealed hyperkeratosis, acanthosis, hypergranulosis, and mixed inflammatory infiltrate containing eosinophils compatible with chronic ulcer. Multiple vessels were seen, compatible with a healing process. Direct immunofluorescence of the biopsy revealed granular IgM in the dermo-epidermal junction. Indirect immunofluorescence was negative. Thyroid function tests showed normal thyroid stimulating hormone and free throxine4. Multinodular goiter was seen on thyroid scan and ultrasound. Thyroid fine needle aspiration was compatible with multinodular goiter (normal follicular cells, free colloid, macrophages with pigment). IV treatment with amoxicillin-clavulanic acid 1 g t.i.d. was administered for 2 weeks, with a decrease in temperature and normalization of the leukocyte level. Oral antibiotic treatment with amoxicillin-clavulanic acid was continued for 10 more days, followed by 25 days of ciprofloxacin for the osteomyelitis. Local treatment included saline soakings followed by application of Promogran (Johnson & Johnson, New Brunswick, NJ) and Kaltostat (ConvaTec Ltd., a Bristol-Myers Squibb Company, New York, NY) with slight improvement. At the same time, the patient was treated with warfarin sodium due to deep vein thrombosis under international normalized ratio 2-3. The patient was treated with IM testosterone once monthly for 1 year, which resulted in a reduction in the diameter and depth of the leg ulcers (Figure 3). Blood tests were not performed for follow-up of the immune state.
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PMID:Klinefelter's syndrome presenting with leg ulcers. 1536 65

Patients with end-stage renal disease are prone to hemorrhagic complications and simultaneously are at risk for a variety of thrombotic complications such as thrombosis of dialysis blood access, the subclavian vein, coronary arteries, cerebral vessel, and retinal veins, as well as priapism. The study was devised for the following purposes: (1) to identify the markers of thrombophilia in hemodialyzed patients, (2) to establish a role for antiphospholipid antibodies in thrombosis of the vascular access, (3) to characterize phospholipid antibodies in hemodialysis patients, and (4) to study the effects of dialysis on coagulation cascade. A group of 20 hemodialysis patients with no thrombotic complications (NTC) and 20 hemodialysis patients with thrombotic complications (TC) were studied along with 400 volunteer blood donors. Patients with systemic lupus erythematosus and those with nephrotic syndrome were excluded. All patients underwent a screening prothrombin time, activated partial thromboplastin time, fibrinogen (Fg), coagulation factors of the intrinsic and extrinsic pathways, antithrombin III (AT-III), protein C (PC), protein S (PS), resistance to activated protein C, prothrombin activation fragment 1+2 (F1+2), plasminogen, tissue type plasminogen activator (t-PA), plasminogen tissue activator inhibitor type-1 (PAI-1), anticardiolipin antibodies type M and G (ACA-IgM and ACA-IgG), lupus anticoagulant antibodies, and antiprothrombin antibodies type M and G (aPT-IgM and aPT-IgG). The study showed that PAI-1, F 1+2, factor VIII, ACA-IgM, and aPT-IgM levels were increased significantly over controls both in TC and NTC, however, they could distinguish patients with thrombotic complications from those without, being increased maximally in the former group. The novelty of the study is represented by the significant aPT increase that was observed in non-systemic lupus erythematosus hemodialysis patients, and particularly in those with thrombotic events. In addition, there was a reduction of factor XII during the treatment. It is possible to assume in the TC group and, to a lesser extent, also in the NTC group that endothelial cells liberate PAI-1 in the vascular lumen, which causes hypofibrinolysis. In addition, an excess of factor VIII is activated by endothelial dysfunction with subsequent activation of the coagulation cascade as shown by increased F1+2 and fibrinogen. ACA-IgM, in turn, is capable of interfering with the system of protein C, a potent anticoagulant factor that inactivates cofactors Va and VIIIa. They also induce the expression of procoagulant factors on the surface of the endothelial cells. In conclusion, the hypercoagulable state caused by alterations of coagulation and fibrinolytic factors is a cause of vascular access dysfunction and thrombosis of other vessels.
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PMID:Plasma levels of plasminogen activator inhibitor type 1, factor VIII, prothrombin activation fragment 1+2, anticardiolipin, and antiprothrombin antibodies are risk factors for thrombosis in hemodialysis patients. 1549 Apr 19

A 39-year-old white woman presented with a history of aortoiliac occlusive disease diagnosed in 1992 attributed to oral contraceptive use. Shortly thereafter, aortoiliac replacement was performed. Mild hyperlipidemia was diagnosed in 2001. At the current clinic visit, she presented to her primary care physician with a 3-month history of postprandial midepigastric abdominal pain relieved by vomiting and a 30-pound weight loss. Her evaluation included an esophagogastroduodenoscopy, a colonoscopy, and an abdominal ultrasound, all of which were within normal limits. Because of her medical history, the patient underwent an arteriogram, which revealed brachiocephalic stenosis (Figure 1), occlusion of the left subclavian artery (Figures 2a and 2b), and narrowing of the superior and inferior mesenteric arteries (not shown). Since she had discontinued her oral contraceptives in 1992 and her hyperlipidemia was mild, the rheumatology service was consulted to evaluate this patient. On physical examination, she had decreased left brachial and radial pulses and a right carotid bruit. Laboratory evaluation revealed a normal complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, and C - reactive protein. Subsequent testing included a prothrombin time, activated partial thromboplastin time, protein S, protein C, reptilase time, antithrombin III, anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, homocysteine, RPR, and a lipid profile. All test results were within normal limits. Due to the severity of her abdominal pain, the patient underwent superior mesenteric artery (SMA) bypass surgery. Sections from the aorta resected in 1992 are shown in Figures 3 and 4.
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PMID:Pathology case of the month. 39-year-old woman with abdominal pain and weight loss. Takayasu's arteritis (TA). 1555 91

To study the etiological factors and pathogenisis of venous thrombi and their relations with anticoagulation and fibrinolysis, In 47 patients with venous thrombi anticardiolipin antibody (ACA) was detected by ELISA. lupus anticoagulant (LA) and anti-activative protein C resistance (APCR) were examined by coagulation test; factor V Leiden was determined by PCR; activity of anticoagulation and fibrinolysis of antithrombin (AT), protein C (PC), plasminogen (Plg) were detected by chromophore substrate methods. The results showed that ACA and/or LA were positive in 34% of patients with VT, most of which consisted of ACA IgG and LA; Plg was negative in 9.5% of patients; tPAI elevated in 8.3% of patients (much more than control group, P < 0.005); ATIII, PC, tPA were negative in 4.5%, 4.5%, 2.8% of patients, respectively (no significant difference with control groups, P > 0.05); ATIII, PC and Plg were negative constantly in one patient; factor V Leiden was not detected by PCR. There were no significant differences in anticoagulation and fibrinolysis between antiphospholipoprotein antibody (APA) negative subjects and APA positive subjects, 4 patients of which were positive in APCR, 3 patients were positive in ACA and/or LA, two out of three patients didn't achieved APCR reversion after mixing their blood plasma with normal blood plasma. It is concluded that antiphospholipoprotein antibody and abnormal fibrinolysis were the common pathological factors in venous thrombi. LA and/or ACA disturbs the anticoagulation aspect to develop into acquired APCR which may be a possible cause leading to thrombophilia.
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PMID:[Relationship of antiphospholipoprotein antibodies of venous thrombi with anticoagulation and fibrinolysis]. 1563 50

Snake venom toxins affecting haemostasis have facilitated extensively the routine assays of haemostatic parameters in the coagulation laboratory. Snake venom thrombin-like enzymes (SVTLE) are used for fibrinogen/fibrinogen breakdown product assay and for the detection of fibrinogen dysfunction. SVTLE are not inhibited by heparin and can thus can be used for assaying antithrombin III and other haemostatic variables in heparin-containing samples. Snake venoms are a rich source of prothrombin activators and these are utilised in prothrombin assays, for studying dysprothrombinaemias and for preparing meizothrombin and non-enzymic forms of prothrombin. Russell's viper (Daboia russelli) venom (RVV) contains toxins which have been used to assay blood clotting factors V, VII, X, platelet factor 3 and, importantly, lupus anticoagulants (LA). Other prothrombin activators (from the taipan, Australian brown snake and saw-scaled viper) have now been used to assay LA. Protein C and activated protein C resistance can be measured by means of RVV and Protac, a fast acting inhibitor from Southern copperhead snake venom and von Willebrand factor can be studied with botrocetin from Bothrops jararaca venom. The disintegrins, a large family of Arg-Gly-Asp (RGD)-containing snake venom proteins, show potential for studying platelet glycoprotein receptors, notably, GPIIb/IIIa and Ib. Snake venom toxins affecting haemostasis are also used in the therapeutic setting: Ancrod (from the Malayan pit viper, Calloselasma rhodostoma), in particular, has been used as an anticoagulant to achieve 'therapeutic defibrination'. Other snake venom proteins show promise in the treatment of a range of haemostatic disorders.
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PMID:Practical applications of snake venom toxins in haemostasis. 1592 82

Thromboembolic events during the perinatal period are responsible for irreversible brain damage owing to cerebral hypoxia and neuronal necrosis. We investigated the presence of thrombophilia risk factors in children with congenital neurologic disorders. Nineteen children (9 males and 10 females), aged 1 to 14 years (median 4.5 years), who had presented with symptoms and signs of congenital neurologic disorders were studied. Thirty-five age-matched healthy children recruited from the same geographic area served as controls. Three patients of 19 (15.8%) were carrying the factor V Leiden mutation compared with 2 children among the controls (5.7%). One patient was heterozygous for the prothrombin G20210A variant (5.2%) compared with one child who was heterozygous among the controls. Three patients were homozygous (15.8%) and 11 were heterozygous (57.9%) for the C677T 5,10-methylenetetrahydrofolate reductase gene mutation compared with 4 (11.5%) and 18 (51.4%), respectively, among the controls. Three patients of 19 (15.8%) were carrying more than one mutation. We found 18 mutations in 79% (15/19) of the patients and 25 mutations in 69% (24/35) of the healthy children. Among the individuals carrying the homozygous 677TT 5,10-methylenetetrahydrofolate reductase genotype, we found 7 mutations in 32% (6/19) of the patients and 7 mutations in 20% (7/35) of the healthy children (P > .05). In one patient, lupus anticoagulant and antiphospholipid antibodies of IgG isotype were detected. Reduced activities of protein C, protein S, or antithrombin III were not observed in either the patient or the control group. Although, among our cases, we found some well-known risk factors associated with thrombosis in adults, the pathogenesis of these clinical entities remains obscure.
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PMID:Genetic risk factors associated with thrombosis in children with congenital neurologic disorders. 1599

We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common significant cause of sporadic first trimester miscarriage. We compared thrombophilia and hypofibrinolysis in 92 women (85 white, 5 black, 2 other) with 1 or more pregnancies and 1 miscarriage (143 live births, 92 miscarriages) (cases) and in 380 female controls (355 white, 21 black, 4 other) with 1 or more pregnancies and 0 miscarriages (964 live births). We used polymerase chain reaction techniques to characterize thrombophilic gene mutations (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic gene mutations (plasminogen activator inhibitor [PAI-1] activity 4G4G). We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]). Of the 380 controls, 6 (1.6%) had FV heterozygosity vs 12 heterozygous and 2 homozygous FV cases (15.2% [14/92]; P < .0001). Plasminogen activator inhibitor activity was high (> or =21.1 U/mL) in 21 (33%) of 63 cases vs 27 (18%) of 152 controls (P = .013). Factor VIII was high (>150%) in 15 (31%) of 48 cases vs 19 (18%) of 103 controls (P = .079). By logistic regression, with age and factor VIII (categorical [< or =150%, >150%]) as explanatory variables and group (cases, controls) as the dependent variable, after adjusting for age, high factor VIII was a significant predictor for miscarriage (odds ratio, 3.28; 95% confidence interval, 1.34-8.04; P = .01). There were no other group differences (P > .05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic first trimester miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and factor VIII, etiologies for sporadic miscarriage.
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PMID:The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage. 1615 34

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.
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PMID:Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men. 1624 70

The role of thrombophilia in the pathogenesis of preeclampsia is controversial. The aim of this case-controlled study was to determine whether thrombophilia increases the risk of preeclampsia or interferes with its clinical course. A total of 808 white patients who developed preeclampsia (cases) and 808 women with previous uneventful pregnancies (controls) matched for age and parity were evaluated for inherited and acquired thrombophilia (factor V Leiden; factor II G20210A; methylenetetrahydrofolate reductase C677T; protein S, protein C, and antithrombin III deficiency; anticardiolipin antibodies; lupus anticoagulant; and hyperhomocysteinemia). Odds ratios (ORs) with 95% confidence intervals (CIs) for risk of being carriers of thrombophilia in cases compared with controls and for risk of maternal life-threatening complications and adverse perinatal outcomes in preeclamptic patients with or without thrombophilia were calculated. Women with severe preeclampsia (406 cases) had a higher risk (OR, 4.9; 95% CI, 3.5 to 6.9) of being carriers of either an inherited or acquired thrombophilic factor, except for protein S, protein C, and antithrombin deficiency. In women with mild preeclampsia (402 cases), only prothrombin and homozygous methylenetetrahydrofolate reductase gene mutations were significantly more prevalent than in the controls. Thrombophilic patients with severe preeclampsia are at increased risk of acute renal failure (OR, 1.8; 95% CI, 1.5 to 2.2), disseminated intravascular coagulation (OR, 2.7; 95% CI, 1.1 to 6.4), abruptio placentae (OR, 2.6; 95% CI, 1.2 to 6.0) and perinatal mortality (OR, 1.7; 95% CI, 1.5 to 2.2) compared with nonthrombophilic preeclamptic patients. Our study demonstrates a significant association between maternal thrombophilia and severe preeclampsia in white women. Thrombophilia also augments the risk of life-threatening maternal complications and adverse perinatal outcomes in preeclamptic patients.
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PMID:Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. 1628 82

Familial Mediterranean fever (FMF) patients in clinical remission are reported to have increased baseline inflammation. Normal function of the natural anticoagulant pathways is particularly needed in diminishing inflammatory responses. In the presence of subclinical inflammation, natural anticoagulant response may be exaggerated. We aimed to observe the anticoagulant-procoagulant status in attack-free FMF patients. Twenty-seven FMF patients diagnosed in accordance with Tel-Hashomer criteria, and 26 healthy controls were included. All patients were attack-free under regular colchicine treatment. Amyloidosis, autoimmunity, accompanying liver and renal disease, and vasculitis were excluded. Predisposing factors for thrombosis were not present. Acute phase reactants (APRs), anticardiolipin antibody positivity, prothrombin time (PT), activated prothrombin time, thrombin time (TT) and d-dimer, protein C activity, activated protein C resistance, free protein S, antithrombin, lupus anticoagulant, human prothrombin fragment F 1 + 2, and human thrombin/antithrombin III complex were analyzed for all subjects. APRs were comparable with controls. Autoimmune markers were negative in all. Anti-streptolysin titers were significantly different than the control group. PT, TT, protein C activity, and F 1 + 2 levels were significantly different from those of healthy controls. Shortened PT and TT, decreased protein C activity vs increased levels of F 1 + 2 suggested a hypercoagulable state in our patients. The hypercoagulable state detected in FMF patients suggests that screening with abnormal coagulation tests may be beneficial for tracing the future consequences of subclinical inflammation in these patients. Studies covering larger groups of patients are needed to verify the currently observed hypercoagulable status in FMF.
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PMID:Hypercoagulability: interaction between inflammation and coagulation in familial Mediterranean fever. 1672 92


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