Blood coagulation changes in homocystinuria: Effects of pyridoxine and other specific therapy

Palareti, G; Salardi, S; Piazzi, S.; Legnani, Cristina; Poggi, M; Grauso, F.; Caniato, A; Coccheri, S.; Cacciari, E

doi:10.1016/s0022-3476(86)80284-0

Cited by 48 publications

(23 citation statements)

References 26 publications

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“…Diet-responsive deficiency of factor VII was previously reported in patients who are deficient in cystathione β synthetase. 41 Lentz et al demonstrated a 34% decrease in thrombomodulin anticoagulant activity in the aortas of monkeys with hyperhomocysteinemia. 42 It is generally held that platelet function abnormalities predominate in arterial thrombosis and abnormalities of coagulation and/or fibrinolysis in venous thromboembolism.…”

Section: Discussionmentioning

confidence: 98%

Homocysteine Activates Platelets In Vitro

Mohan

Jagroop

Mikhailidis

et al. 2008

Clin Appl Thromb Hemost

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is very common, and these has been reported to be a risk factor for arterial and venous thromboses. The study of Leiden thrombophilia established hyperhomocysteinemia (above the 90th percentile) as a risk factor for deep-vein thrombosis. 4 A further metaanalysis showed that a 5 μmol/L elevation in HCY was associated with a 27% higher risk of venous thrombosis in prospective studies and 60% higher risk of venous thrombosis in retrospective studies. Genotype studies of the methylenetetrahydrofolate reductase enzyme showed an association of venous thrombosis with hyperhomocysteinemia. 5In 1964, McDonald et al 6 concluded that HCY, both in vivo and in vitro, increased platelet stickiness associated with arterial and venous thrombosis, but this finding was not confirmed. [7][8][9] In studies of platelet kinetics, a direct relationship was found between HCY concentration and platelet survival. 10Harker et al 7 found that increased platelet consumption in homocysteinemia was interrupted by dipyridamole, but not by heparin anticoagulation, and concluded that platelet thrombus formation on arterial surfaces denuded of endothelium, and not enhanced platelet reactivity, increased platelet consumption.H omocysteine (HCY), a sulfur containing amino acid, is a normal by-product of methionine metabolism. Normal levels of plasma HCY in fasting are considered to be between 5 and 15 μmol/L. Moderate, intermediate, and severe hyperhomocysteinemia refer to concentrations between 16 and 30, between 31 and 100, and >100 μmol/L, respectively.1 Homocystinuria is consistent with severe hyperhomocysteinemia. Homozygous cystathione β synthetase deficiency, causing homocystinuria, is associated with a thromboembolic event in 30% of patients by the age of 20 years, 50% of patients by the age of 30 years, and 60% of patients by the age of 40 years.2,3 Mild and moderately elevated HCY levels (hyperhomocysteinemia)The mechanism of thrombogenicity in hyperhomocysteinemia remains controversial. The authors investigated the association between elevated plasma homocysteine levels, platelet function, and blood coagulation. Blood was collected from healthy subjects and patients with critical limb ischemia. Basal platelet counts and platelet aggregation as well as flow cytometry were performed to assess spontaneous-and agonist-induced platelet aggregation as well as P-selectin and Glycoprotein IIb/IIIa expression at different homocysteine concentrations. Thromboelastography was performed, and platelet shape change was assessed, using a channelyzer, by measuring median platelet volume. Lactate dehydrogenase was measured, to indirectly assess red blood cell membrane integrity, after homocysteine exposure. The study results suggest that platelet activation and hypercoagulability occur after exposure to homocysteine, especially in patients with critical limb ischemia. Homocysteine concentrations of approximately 50 μmol/L appear to be the level at which these changes occur in vitro, and this effect on platelets appears to be indirect.

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Section: Discussionmentioning

confidence: 98%

Homocysteine Activates Platelets In Vitro

Mohan

Jagroop

Mikhailidis

et al. 2008

Clin Appl Thromb Hemost

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“…Some hemostatic factors that may contribute to this tendency have been investigated in a large series of studies (5)(6)(7)(8)(9)(10)(11)(12)(13). Plasma coagulation factor VII, platelet survival, and antithrombin III activity have been reported to be abnormal (5)(6)(7)(8)(9)(10). However, these claims have been challenged (1 [1][2][3][4][5][6][7][8][9][10][11][12][13].…”

mentioning

confidence: 99%

“…Plasma coagulation factor VII, platelet survival, and antithrombin III activity have been reported to be abnormal (5)(6)(7)(8)(9)(10). However, these claims have been challenged (1 [1][2][3][4][5][6][7][8][9][10][11][12][13]. Biochemical measurements of urinary TX metabolites and clinical trials with aspirin indicate that enhanced biosynthesis of TXA2 by platelets is an important contributor to the risk of thrombosis associated with several cardiovascular risk factors ( 14).…”

mentioning

confidence: 99%

“…In addition to its role in the conversion of fibrinogen to fibrin, thrombin is a potent inducer of platelet TXA2 biosynthesis. Low levels ofantithrombin III, the major plasma inhibitor of thrombin, have been reported in CBSD patients (6)(7)(8). To examine the possibility that the enhanced excretion of TXA2 metabolites in homocystinuria might be due to high circulating levels of thrombin, we measured several hemostatic variables that reflect a hypercoagulable state.…”

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confidence: 99%

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Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

Minno¹,

Davı̀²,

Margaglione³

et al. 1993

J. Clin. Invest.

151

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IntroductionHomocystinuria due to homozygous cystathionine tl-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 1 1-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724±828 pg/mg creatinine, mean±SD, in patients vs. 345±136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 1i-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation. (J. Clin. Invest.

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“…O diagnóstico precoce de homocistinúria pode ser feito por screening neonatal, e o tratamento com piridoxina e dieta pobre em metionina deve ser iniciado precocemente pois há relatos de prevenção do retardo mental, das alterações do cristalino, das crises convulsivas e de retardo do aparecimento de eventos tromboembó-licos em pacientes tratados 6,10 . Em nosso caso, apesar do diagnóstico tardio, a terapêutica com vitamina B6 foi instituida pois a literatura demonstra benefícios, principalmente quanto a prevenção da ocorrência de complicações trombóticas.…”

Section: Discussionunclassified

Trombose venosa cerebral e homocistinúria: relato de caso

Silva

Almeida

Félix

et al. 2001

Arq. Neuro-Psiquiatr.

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RESUMO -Homocistinúria apresentando-se como trombose venosa cerebral é incomum. Relatamos o caso de um adolescente com características fenotípicas de homocistinúria que foi admitido por cefaléia intensa, vômitos e sonolência. Investigação diagnóstica com tomografia computadorizada de crânio, ressonância magnética e angiorressonância foi compatível com trombose dos seios transversos e sigmóides. Altos níveis de homocisteína foram detectados no sangue e na urina. Apresentamos os aspectos clínicos e radiológicos deste caso discutindo a controversa fisiopatologia da tendência trombofílica associada a homocistinúria. PALAVRAS-CHAVES: trombose venosa cerebral, homocistinúria.Cerebral venous thrombosis and homocystinuria: case report ABSTRACT -Homocystinuria presenting as cerebral venous thrombosis is not usual. We report on a 13-yearold boy who was admitted to the hospital due to severe headache, nausea, vomiting and fever (38ºC). The patient was Marfan like and presented left hemiparesis and meningeal irritation sings. He was mentally retarded, had severe myopia, and had right lens dislocation one month before. Cranial CT scan was suggestive of cerebral venous infarct. MRI and magnetic resonance angiography showed venous infarcts more prominent in the right thalamic projection with hemorrhagic transformation and multiple foci of cortical (occipital and parietal bilaterally) deep parietal and left capsular bleeding, secondary of thrombosis of the transverse and sigmoid venous sinuses. High levels of homocysteine were detected in the blood and urine. Homocystinuria is an autossomal recessive inborn error of methionine metabolism caused by cystathione-ß-synthase defect in most cases. We discuss the clinical and radiological findings in this patient, analyzing the pathophysiology of the thrombotic events related to homocystinuria. Trombose venosa cerebral (TVC) tem sido reconhecida mais frequentemente nas últimas décadas devido à melhora na qualidade dos exames de neuroimagem, apesar de sua incidência real permanecer desconhecida por falta de estudos epidemiológicos específicos 1 . TVC costuma ser relacionada a alguns fatores de risco como uso de hormônios estrogênicos, período peri-parto, infecções contíguas, estados trombofílicos, entre outros. A proporção de casos de etiologia incerta (idiopáticos) ainda permanece em torno de 20 a 35% 1 . A incidência de tromboflebite séptica vem diminuindo em países desenvolvidos, permanecendo em torno de 7 a 17% em algumas séries 2 . Homocistinúria apresentando-se com TVC é rara, no entanto participa do diagnóstico diferencial, particularmente em pacientes jovens com características marfanóides 3,4 . Relataremos o caso de um adolescente que teve homocistinúria diagnosticada por ocasião de trombose venosa dos seios transversos e sigmóide. CASOPaciente masculino de 13 anos, foi admitido ao hospital por cefaléia holocraniana súbita, intensa, acompanhada de náuseas e vômitos. Apresentava antecedentes de retardo do desenvolvimento neuropsicomotor, miopia grave e cirurgia por subluxação d...

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Blood coagulation changes in homocystinuria: Effects of pyridoxine and other specific therapy

Cited by 48 publications

References 26 publications

Homocysteine Activates Platelets In Vitro

Homocysteine Activates Platelets In Vitro

Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

Trombose venosa cerebral e homocistinúria: relato de caso

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