RESUMO
Combined coagulation factor VII (FVII) and factor X (FX) deficiency (combined FVII/FX deficiency) belongs to the group of bleeding disorders in which both factors show reduced plasma activity. It may arise from coincidental inheritance of separate coagulation factor deficiencies or a common cause as large deletions comprising both gene loci. The F7 and F10 genes are located on the long arm of chromosome 13. Here, we describe 10 cases with combined FVII/FX deficiency representing both genetic mechanisms of occurrence. Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation-dependent probe amplification) for detection of heterozygous large deletions. In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13. In the remaining six cases the deficiency resulted from coincidental inheritance of different genetic alterations affecting both genes independently. In most cases, the genetic defects were heterozygous, presenting with prolonged PT, normal aPTT and mild or no bleeding symptoms. Only in one case compound heterozygous mutations were detected in the F10, resulting in prolonged aPTT and a more severe bleeding phenotype. To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal. Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling.
Assuntos
Deficiência do Fator VII/complicações , Deficiência do Fator VII/genética , Fator VII/genética , Deficiência do Fator X/complicações , Deficiência do Fator X/genética , Fator X/genética , Testes de Coagulação Sanguínea , Deleção Cromossômica , Cromossomos Humanos Par 13 , Deficiência do Fator VII/diagnóstico , Deficiência do Fator X/diagnóstico , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , FenótipoRESUMO
Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.
Assuntos
Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/genética , Testes Genéticos/normas , Hematologia/normas , Técnicas de Diagnóstico Molecular/normas , Testes de Função Plaquetária/normas , Guias de Prática Clínica como Assunto , Transtornos Plaquetários/sangue , Alemanha , Humanos , Pediatria/normasRESUMO
Vitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosure of the molecular basis of interaction with VKORC1, the target enzyme of VKA, has helped to better understand coumarin sensitivity and resistance. New oral anticoagulants have now been approved and stimulated expectations in patients and physicians to get rid of the burdening frequent controls of VKA without loss of efficacy and safety. This review will summarize the development and profile of the new substances. Main difference compared to VKA is their direct mode of action against one clotting factor which is factor IIa in dabigatran and factor Xa in rivaroxaban and other "xabanes" currently under intensive investigation. Half lifes of the new anticoagulants are much shorter than that of the mainly used coumarins (phenprocoumon, warfarin), making "anticoagulation bridging" unnecessary before surgery. Therapeutic width of direct thrombin inhibitors and factor Xa inhibitors is broader and they are given at fixed doses. Clinical studies in thromboprophylaxis, thromboembolism and atrial fibrillation indicate at least non-inferiority or even superior efficacy compared with enoxaparin and VKA at comparable safety outcomes. Limitations of the new substances may arise from gastrointestinal side effects, mode of metabolism and route of elimination. Specific antidots are not available for none of them. Undoubtedly, the new oral anticoagulants are very promising. But, although thousands of study patients already have been treated, there are questions to be answered such as treatment adherence in absence of monitoring, safety and efficacy in risk patients, dosage adjustment and interactions with other drugs, before conclusions can be drawn towards their potential to replace VKA.
Assuntos
Anticoagulantes/administração & dosagem , Cumarínicos/administração & dosagem , Heparina/administração & dosagem , Trombose/tratamento farmacológico , Vitamina K/antagonistas & inibidores , HumanosRESUMO
Hyperhomocysteinemia is a risk factor for ischemic stroke. We investigated five functional polymorphisms involved in homocysteine metabolism in each 159 stroke patients and controls. The folate-sensitive polymorphism methylenetetrahydrofolate reductase (MTHFR) c. 677 C > T (A222V) referred a non-significant risk of ischemic stroke (odds ratio: 1.20) in all patients, and homozygosity for MTHFR c. 677 C > T was associated with an earlier onset of stroke selectively in patients younger than 60 years (38 +/- 3 years vs. 45 +/- 1 years; P = 0.043). This study suggests that the investigated polymorphisms are no major risk factors for stroke, although MTHFR c. 677 C > T could be a minor factor of vulnerability especially in young patients (TT genotype), which might be helpful for the clinical work-up of stroke cases and for preventive dietary strategies.
Assuntos
Variação Genética , Homocisteína/genética , Homocisteína/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Acidente Vascular Cerebral/metabolismo , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , Análise Mutacional de DNA/métodos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , RNA Mensageiro/biossíntese , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Acidente Vascular Cerebral/genéticaRESUMO
The authors prospectively studied the risk for immune-mediated heparin-induced thrombocytopenia (HIT) in neurologic patients during administration of low-molecular-weight heparin (LMWH) vs unfractionated heparin (UFH). None of 111 neurologic patients receiving LMWH developed HIT, whereas HIT occurred in 2.5% of 200 patients treated with UFH (p = 0.17). The rate of heparin-induced antibodies in patients treated with LMWH was lower than in patients treated with UFH (1.8 vs 20.5%; p < 0.001).
Assuntos
Anticoagulantes/efeitos adversos , Transtornos Cerebrovasculares/tratamento farmacológico , Heparina de Baixo Peso Molecular/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Esquema de Medicação , Feminino , Heparina/administração & dosagem , Heparina/efeitos adversos , Heparina/imunologia , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/imunologia , Humanos , Doença Iatrogênica/prevenção & controle , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombocitopenia/epidemiologiaRESUMO
BACKGROUND: Glutathione S-transferase omega-1 (GSTO1) protects from oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia (VaD), and stroke. Polymorphisms in GSTO1 might influence the function of the protein and thus the risk of AD, VaD, and stroke. METHODS: The GSTO1 gene was screened for variations. The effect of the detected polymorphisms on the risk of AD, VaD, and stroke was evaluated. CSF levels of cholesterol and plasma homocysteine levels were compared according to the GSTO1 genotype. RESULTS: Two missense polymorphisms in exon 4 of GSTO1 (Ala140Asp and Glu155DeltaGlu) were detected and tested for their association with AD, VaD, and stroke. The Asp/Asp and Ala/Asp genotypes increased the risk of stroke (p = 0.003, OR = 2.1), and the Asp/Asp genotype increased the risk of VaD (p = 0.02, OR = 2.2). GSTO1 polymorphisms did not influence the risk of AD, but the Asp allele influenced the age at onset (p = 0.05). In nondemented probands CSF levels of cholesterol were increased in carriers of the Asp/Asp genotype (p = 0.004); however, in patients with manifest dementia the authors found decreased CSF levels of cholesterol in carriers of the Asp/Asp genotype (p = 0.028). Serum homocysteine levels in stroke patients were higher in carriers of at least one Asp allele (p = 0.011). CONCLUSION: The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.
Assuntos
Doença de Alzheimer/genética , Substituição de Aminoácidos , Demência Vascular/genética , Glutationa Transferase/genética , Mutação de Sentido Incorreto , Mutação Puntual , Polimorfismo Genético , Acidente Vascular Cerebral/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/epidemiologia , Sequência de Aminoácidos , Sequência de Bases , Colesterol/líquido cefalorraquidiano , Demência Vascular/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Glutationa Transferase/fisiologia , Homocisteína/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Acidente Vascular Cerebral/epidemiologiaRESUMO
The risk for immune-mediated heparin-induced thrombocytopenia (HIT) in neurologic patients receiving unfractionated heparin (UFH) is not known. In a prospective study of 200 patients, the authors found a 2.5% rate of HIT and a 2% rate of HIT-associated thromboses, suggesting that neurologic patients treated with UFH are at considerable risk for development of HIT and its complications. Prevalence of heparin-induced antibodies was 20.5% and was dependent on heparin dose. It was higher in cerebrovascular than in noncerebrovascular (29.4% versus 11.2%, p < 0.01) patients.
Assuntos
Heparina/efeitos adversos , Doenças do Sistema Nervoso/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Adulto , Idoso , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/imunologia , Feminino , Heparina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/imunologia , Prevalência , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/epidemiologia , Púrpura Trombocitopênica Idiopática/imunologia , Risco , Trombose/epidemiologia , Trombose/etiologiaRESUMO
We report the case of a 46-year old man who developed an unexpected fatal cardiac failure during liver transplantation. Attempts at resuscitation were unsuccessful. At necropsy the lungs showed numerous microthrombi occluding small lung vessels and pulmonary capillaries. Thrombi were not found in other organs. The source of this extensive thrombus formation is not known. The thrombi could have been developed within the liver, the venous blood stream between liver and lungs or the pulmonary capillaries. In our experience, this complication is very rare, and a risk profile is not known.
Assuntos
Insuficiência Cardíaca/patologia , Complicações Intraoperatórias/patologia , Embolia Pulmonar/patologia , Disfunção Ventricular Direita/patologia , Capilares/patologia , Evolução Fatal , Parada Cardíaca/patologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: Thrombophilic mutations may play a role in the pathogenesis of the juvenile osteonecrosis of the femoral head, Perthes' disease. We investigated whether children with Perthes' disease have an increased incidence of mutations of factor V (Leiden) and prothrombin (G2O210A), which predispose to thrombosis. METHODS: For this pilot study, we analysed the data of twenty consecutive children (16 boys, 4 girls, mean age at diagnosis 6.4 years). According to Catterall's classification of severity, 2 children were in group 1, 7 in group 2, 8 in group 3, and 3 were in the most severe group 4. Mutations of factor V and prothrombin were identified in EDTA-blood by PCR amplification, digestion with restriction enzymes, and gel electrophoresis. RESULTS: Heterozygoty for the factor V mutation was detected in two children, for the prothrombin mutation in one child. Both results did not differ significantly from the incidence in Germany, which is 0.05 for factor V mutations and 0.04 for prothrombin mutations. CONCLUSIONS: For the presented group of children with Perthes' disease, we did not find an increased rate of factor V or prothrombin mutations compared to the natural incidence. In accordance to other recent studies, our results do not support a link between inherited thrombophilic mutations and Perthes' disease.
Assuntos
Fator V/genética , Doença de Legg-Calve-Perthes/genética , Mutação/genética , Protrombina/genética , Trombofilia/genética , Alelos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Alemanha , Humanos , Incidência , Doença de Legg-Calve-Perthes/sangue , Doença de Legg-Calve-Perthes/cirurgia , Masculino , Projetos Piloto , Reação em Cadeia da Polimerase , Trombofilia/sangueRESUMO
OBJECTIVE: To evaluate neurologic complications in patients with immune-mediated heparin-induced thrombocytopenia (HIT) with respect to incidence, clinical characteristics, outcome, and therapy. METHODS: One hundred and twenty consecutive patients with immune-mediated HIT were recruited over a period of 11 years and studied retrospectively for the occurrence of neurologic complications. Diagnosis of HIT was based on established clinical criteria and confirmed by detection of heparin-induced antibodies using functional and immunologic tests. RESULTS: Eleven of the 120 patients (9.2%) presented with neurologic complications; 7 suffered from ischemic cerebrovascular events, 3 from cerebral venous thrombosis, and 1 had a transient confusional state during high-dose heparin administration. Primary intracerebral hemorrhage was not observed. The relative mortality was much higher (Chi-square test, p < 0.01) in HIT patients with neurologic complications (55%) as compared to patients without neurologic complications (11%). The mean platelet count nadir in neurologic patients was 38 +/- 25 x 10(9)/l on average, and was lower in patients with fatal outcome compared to those who survived (21 +/- 13 x 10(9)/l versus 58 +/- 21 x 10(9)/l; p < 0.05, Wilcoxon test). In three patients neurologic complications preceded thrombocytopenia. There was a high coincidence of HIT-associated neurologic complications with other HIT-associated arterial or venous thrombotic manifestations. CONCLUSION: Neurologic complications in HIT are relatively rare, but associated with a high comorbidity and mortality. HIT-associated neurologic complications include cerebrovascular ischemia and cerebral venous thrombosis. They may occur at a normal platelet count.
Assuntos
Heparina/efeitos adversos , Doenças do Sistema Nervoso/complicações , Trombocitopenia/complicações , Trombocitopenia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Trombocitopenia/sangue , Fatores de TempoRESUMO
We report the case of a 55-year-old man who developed heparin-induced thrombocytopenia II after a vertebral fracture. Autopsy revealed segmental hepatic vein thrombosis of the right lobe with subacute congestion and an activation of hepatic stellate cells. This case shows that heparin-induced thrombocytopenia II is a possible cause of the Budd-Chiari syndrome.
Assuntos
Anticoagulantes/efeitos adversos , Síndrome de Budd-Chiari/etiologia , Heparina/efeitos adversos , Fígado/patologia , Trombocitopenia/induzido quimicamente , Biomarcadores/análise , Síndrome de Budd-Chiari/patologia , Veias Hepáticas/patologia , Humanos , Imuno-Histoquímica , Fígado/irrigação sanguínea , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.
Assuntos
Oxigenases de Função Mista/genética , Deficiência de Vitamina K/etiologia , Fatores de Coagulação Sanguínea/metabolismo , Carbono-Carbono Ligases/genética , Saúde da Família , Feminino , Genes Recessivos , Hemorragia/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Oxigenases de Função Mista/efeitos adversos , Linhagem , Fenótipo , Análise de Sequência , Vitamina K/farmacocinética , Deficiência de Vitamina K/congênito , Deficiência de Vitamina K/genética , Vitamina K Epóxido RedutasesAssuntos
Isquemia Encefálica/etiologia , Heparina/efeitos adversos , Embolia e Trombose Intracraniana/etiologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We report one patient who presented with a spontaneous bleeding complication under phenprocoumon therapy. Oral anticoagulation was initiated due to deep-vein thrombosis which was attributed to an antiphospholipid antibody syndrome. Coagulation analysis revealed a strong and selective reduction of factor IX (F IX) activity to 1%, whereas the other vitamin K-dependent factors (II, VII, X), the prothrombin time and International Normalized Ratio (INR) were within the therapeutic range. After withdrawal of phenprocoumon, all vitamin K-dependent factors including F IX normalized. Because the patient suffered from a recurrence of thrombotic events, he was re-exposed to phenprocoumon and the disproportionate decline of F IX was observed again. These findings indicate an increased sensitivity of F IX to vitamin K antagonists, representing an uncommon mechanism associated with bleeding complications under oral anticoagulant treatment.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Anticoagulantes/efeitos adversos , Transtornos da Coagulação Sanguínea/induzido quimicamente , Fator IX/efeitos dos fármacos , Femprocumona/efeitos adversos , Trombose/tratamento farmacológico , Trombose/imunologia , Adulto , Transtornos da Coagulação Sanguínea/sangue , Fatores de Coagulação Sanguínea/efeitos dos fármacos , Humanos , Masculino , Tempo de Protrombina , Fatores de TempoRESUMO
Bleeding complications are the most common and unwanted side-effect of oral anticoagulant therapy. We report three patients in whom mutations in the factor IX (FIX) propeptide were found to cause severe bleeding during coumarin therapy. Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (INR). In all three patients coumarin therapy caused an unusually selective decrease of FIX activity (FIX:C) to levels below 1-3%. Upon withdrawal of coumarin, FIX:C increased to subnormal or normal values of 55%, 85% and 125%, respectively. Analysis of the FIX gene revealed two different missense mutations affecting the Ala-10 residue in the propeptide coding region: Ala[GCC] to Val[GTC] in two patients and Ala[GCC] to Thr[ACC] in one patient. No further mutation was detected by screening 195 random blood donors for mutations at Ala-10, thus excluding a frequent polymorphism at this position. The mutation in the FIX propeptide at a position which is essential for the carboxylase recognition site causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction which is decisively triggered by the vitamin K concentration. Determination of FIX and APTT in addition to PT and INR is therefore recommended in coumarin-treated patients with an uncommon bleeding pattern.
Assuntos
Anticoagulantes/efeitos adversos , Fator IX/genética , Hemorragia/genética , Mutação , Administração Oral , Adulto , Idoso , Éxons/genética , Hemorragia/induzido quimicamente , Humanos , Fragmentos de Peptídeos/genéticaRESUMO
Hereditary Factor VII deficiency is one of the rare congenital coagulopathies. Prolonged prothrombin time (PT) with normal partial prothrombin time (PTT) may be an indicator for Factor VII deficiency. A family with hereditary heterozygous Factor VII deficiency is presented in whom no symptoms of a bleeding disorder were clinically detectable. A discussion of the therapeutic options follows.
Assuntos
Deficiência do Fator VII/genética , Heterozigoto , Testes de Coagulação Sanguínea , Criança , Deficiência do Fator VII/sangue , Feminino , Transtornos Hemorrágicos/sangue , Transtornos Hemorrágicos/genética , HumanosRESUMO
Vasodilator substances released in the blood vessel wall, such as the endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2), may participate in the regulation of arterial blood pressure. However, their role in the pathogenesis of human essential hypertension to date remains unclear. For some of these factors affecting vascular smooth muscle cells, blood platelets represent a second target tissue. Thus, EDRF and PGI2 inactivate platelets by stimulation of cyclic guanosine-5'-monophosphate (cGMP) and cyclic adenosine-5'-monophosphate (cAMP) synthesis, respectively. In the present study, platelet cAMP (n = 68) and cGMP (n = 60) were determined in a control group of healthy subjects (C) and in 12 patients with untreated essential hypertension (EH). In the control group, platelet cAMP and cGMP content averaged 13.52 +/- 0.38 and 1.48 +/- 0.06 pmol/10(9) platelets and no dependence of either variable on sex or age could be established. Furthermore, cGMP levels were similar in EH as compared to the control group (1.38 +/- 0.11 pmol/10(9) platelets). However, intracellular concentrations of cAMP were significantly lower in EH as compared to C (11.22 +/- 1.37 pmol/10(9) platelets; P < .01). In addition, we investigated the stimulatory effect on cAMP of the stable PGI2 analog iloprost (10(-9), 5 x 10(-9), 10(-8), 5 x 10(-8) mol/L) in the platelets of 12 control subjects (C12) and EH.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Plaquetas/metabolismo , AMP Cíclico/sangue , GMP Cíclico/sangue , Hipertensão/sangue , Adulto , Idoso , Feminino , Humanos , Iloprosta/farmacologia , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Valores de ReferênciaRESUMO
Pathogenesis of Budd-Chiari-syndrome, under treatment e.g. of malignant melanoma with DTIC (dacarbacin) is still unknown. In our investigations we could not find any hint for the hypothesis that Budd-Chiari-syndrome under DTIC is caused by hemostaseological impairment.