fibrin and Hyperhomocysteinemia

We report the case of a 25-year-old man with multiple sclerosis (MS) who had severe headache and unconsciousness. He suffered from optic neuritis that had started at age 6. From the age of 12 years, he had suffered from multiple sclerosis (MS) cerebral lesions that relapsed three times over for 5 years. At age 25, he showed a new lesion in the cerebellar cortex, suggesting an exacerbation of the MS. However, magnetic resonance imaging findings the next day showed cerebral venous sinus thrombosis. His laboratory findings showed low antithrombin activity. Genetic analysis revealed a single-base substitution (C>T) at the codon 359 (Arg to STOP) in the 5th exon portion of the antithrombin gene, heterozygote. In the literature review, 17 cases of multiple sclerosis associated with cerebral venous sinus thrombosis, which occurred after the lumbar puncture and the treatment with high-dose methylpredonisolone in 11 of these cases. In our case, antithrombin deficiency, hyperhomocystinemia, infection, and lumbar puncture were suggested as the risk factors.

Topics: Adult; Antithrombins; Codon, Nonsense; Diffusion Magnetic Resonance Imaging; Fibrin; Heterozygote; Humans; Hyperhomocysteinemia; Male; Methylprednisolone; Multiple Sclerosis; Risk Factors; Sinus Thrombosis, Intracranial; Spinal Puncture

The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease. The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. This review discusses how genetic and environmental factors alter fibrin structure and function and the implications this has for the clinical presentation of vascular disease.

Topics: Afibrinogenemia; Arteriosclerosis; Blood Coagulation; Diabetes Mellitus; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Glycosylation; Humans; Hyperhomocysteinemia; Life Style; Lipoproteins; Polymorphism, Genetic; Protein Conformation; RNA Splicing; Structure-Activity Relationship; Thrombosis

A large body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss early onset preeclampsia, placental abruption, and severe intrauterine growth retardation (IUGR). Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary case-control studies suggest a benefit for prophylaxis with low molecular weight heparins (LMWH), and prospective randomized trials are in progress to define whether LMWH are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.

Topics: Abortion, Habitual; Factor V; Female; Fetal Death; Fibrin; Humans; Hyperhomocysteinemia; Mutation; Placenta; Pregnancy; Pregnancy Complications, Hematologic; Protein C; Prothrombin; Thrombophilia

To critically review the literature regarding inherited thrombophilia and recurrent fetal loss.. English-language literature review.. Women who experienced repeated pregnancy wastage.. Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage.. Live birth, miscarriage, preeclampsia, and pregnancy loss.. Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia.. Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.

Topics: Abortion, Habitual; Antiphospholipid Syndrome; Antithrombin III Deficiency; Female; Fibrin; Humans; Hyperhomocysteinemia; Pregnancy; Protein C; Prothrombin; Thrombophilia

Hyperhomocysteinemia (HHcy) affects haemostasis and shifts its balance in favour of thrombosis. In vitro and in vivo studies suggested that HHcy may impair fibrinolysis either by influencing the plasma levels of fibrinolytic factors or by altering the fibrinogen structure. We investigated the influence of mild HHcy levels on plasma fibrinolytic potential by using clot lysis time (CLT) and fibrin susceptibility to plasmin-induced lysis in 94 patients with previous pulmonary embolism and no pulmonary hypertension. CLT was measured as lysis time of tissue factor induced clots exposed to exogenous tissue plasminogen activator (t-PA). The rate of in vitro plasmin-mediated cleavage of fibrin β-chain was assessed over a 6-h period on fibrin clots, which were obtained by exposition to thrombin of purified fibrinogen. Homocysteine plasma levels were measured by Abbott Imx immunoassay and we considered as altered the values above 15 μmol/L according to the literature. In 68 patients homocysteine levels were below 15 μmol/L (NHcy) and in 26 they were above (HHcy). Significant differences were observed between the two groups regarding plasma fibrinolytic potential (p = 0.016), TAFIact (expressed as clot lysis ratio) (p = 0.02), t-PA (0.008) and PLG (0.037), but not for the other assessed components. The HHcy-patients had a threefold higher risk to have an impaired fibrinolysis. Instead, a multivariate logistic regression analysis adjusted for significances of univariate showed that HHcy (OR 5.2 95% CI 1.7-15.9; p = 0.003) and BMI (OR 5.0 95% CI 1.6-15.9; p = 0.006) resulted independently associated with impaired fibrinolytic activity. HHcy affects TAFI-mediated hypofibrinolysis but not fibrin(ogen) structure or function as documented by fibrin degradation analysis.

Topics: Adult; Aged; Aged, 80 and over; Female; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Hyperhomocysteinemia; Male; Middle Aged; Proteolysis; Pulmonary Embolism; Risk Factors

Essentials Evidence suggests a comorbidity between hyperhomocysteinemia (HHC) and Alzheimer's disease (AD). Homocysteine (HC) could affect the β-amyloid (Aβ)-fibrinogen interaction in AD pathology. AD patients with concomitant HHC have increased fibrin and Aβ deposits in their brains. HC contributes to AD pathology via the Aβ-fibrinogen interaction.. Background Accumulating clinical evidence suggests that hyperhomocysteinemia (HHC) is correlated with Alzheimer's disease (AD) and vascular dementia. Objective This study was carried out to elucidate the specific role of elevated homocysteine (HC) levels in AD pathophysiology. Methods Immunohistochemistry was used to examine β-amyloid (Aβ) deposition along blood vessels, also known as cerebral amyloid angiopathy (CAA), fibrin(ogen) deposition, and their correlation to each other in the brains of AD patients with and without HHC. To study AD-HHC co-morbidity in detail, an AD mouse model was administered a high methionine diet for several months. Parenchymal Aβ plaques, CAA-positive vessels and fibrin deposits were then assessed by immunohistochemistry at different stages of AD progression. Memory deficits were evaluated with contextual fear conditioning and the Barnes maze. Additionally, the effect of HC and its metabolite, homocysteine thiolactone (HCTL), on the Aβ-fibrinogen interaction was analyzed by pull-down, ELISA and fibrin clot formation and fibrinolysis assays in vitro. Results We found increased fibrin(ogen) levels and Aβ deposits in the blood vessels and brain parenchyma of AD patients with HHC. We demonstrate that HC and HCTL enhance the interaction between fibrinogen and Aβ, promote the formation of tighter fibrin clots and delay clot fibrinolysis. Additionally, we show that diet-induced HHC in an AD mouse model leads to severe CAA and parenchymal Aβ deposition, as well as significant impairments in learning and memory. Conclusions These findings suggest that elevated levels of plasma HC/HCTL contribute to AD pathology via the Aβ-fibrin(ogen) interaction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biotinylation; Brain; Cerebral Amyloid Angiopathy; Dementia, Vascular; Disease Models, Animal; Disease Progression; Fibrin; Fibrinogen; Fibrinolysis; Humans; Hyperhomocysteinemia; Immunohistochemistry; Maze Learning; Memory; Methionine; Mice; Mice, Transgenic; Plaque, Amyloid; Protein Binding

Mechanisms involved in the relationship between hyperhomocysteinemia and thrombosis are still unclear. In previous reports we have shown that high homocysteine concentrations led to more compact and branched fibrin networks than controls. These clots showed an impaired lysis associated to their architecture. The aim of this study was to evaluate the effects of homocysteine on permeation of clots obtained from plasma and purified systems. Fibrin gels were prepared with normal plasma incubated with homocysteine and, in the purified systems, with fibrinogen and factor XIII treated with the amino acid. Permeability constants (K(s)) were determined through flow measurements. Linear regression curve between K(s) values and homocysteine levels in the plasmatic assays showed a negative correlation coefficient, r = -0.997 (p = 0.003). K(s) of fibrin gels obtained from purified systems with fibrinogen incubated with homocysteine was (7.07 ± 0.27) × 10(-9) cm(2), control was (11.40 ± 0.37) × 10(-9) cm(2) (n = 3; p < 0.01). K(s) of fibrin gels obtained with factor XIII treated with homocysteine was (1.47 ± 0.17) × 10(-9) cm (2), and control was (3.31 ± 0.31) × 10(-9) cm(2) (n = 3; p<0.01). Plasma incubated with high homocysteine concentrations produced fibrin clots significantly less permeable than controls in a dose dependent manner, and the results showed that fibrinogen and factor XIII were involved in that detrimental effect. These findings might explain the impaired fibrinolysis related to increased homocysteine levels and contribute to understanding the association between the amino acid and thrombosis.

Topics: Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Homocysteine; Humans; Hyperhomocysteinemia; Linear Models; Permeability

When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 muM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed "A2") is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the "tail" domain of A2. We also demonstrated that fibrinolysis and angiogenesis are severely impaired in A2-deficient mice. We now report here that, although hyperhomocysteinemic mice had a normal coagulation profile and normal platelet function, fibrin accumulated in their tissues due to reduced perivascular fibrinolytic activity and angiogenesis was impaired. A2 isolated from hyperhomocysteinemic mice failed to fully support TPA-dependent plasmin activation. However, infusion of hyperhomocysteinemic mice with fresh recombinant A2, which localized to neoangiogenic endothelial cells, resulted in normalization of angiogenesis and disappearance of peri- and intravascular fibrin. We therefore conclude that hyperhomocysteinemia impairs postnatal angiogenesis by derivatizing A2, preventing perivascular fibrinolysis, and inhibiting directed endothelial cell migration. These findings provide a mechanistic explanation for microvascular dysfunction and macrovascular occlusion in individuals with hyperhomocysteinemia.

Topics: Animals; Annexin A2; Cell Movement; Corneal Neovascularization; Diet; Endothelial Cells; Fibrin; Fibrinolysis; Homocysteine; Hyperhomocysteinemia; Male; Methionine; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Recombinant Proteins

Topics: Blood Coagulation; Factor XIII; Fibrin; Fibrinogen; Homocysteine; Humans; Hyperhomocysteinemia

We have previously shown functional differences in fibrinogen from hyperhomocysteinemic rabbits compared to that in control rabbits. This acquired dysfibrinogenemia is characterized by fibrin clots that are composed of abnormally thin, tightly packed fibers with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with primary amines. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We now demonstrate that the reaction of Hcys thiolactone with purified fibrinogen in vitro produces fibrinogen (Hcys fibrinogen) with functional properties that are strikingly similar to those we have observed in homocysteinemic rabbits. Fibrinogen purified from homocysteinemic rabbits and Hcys fibrinogen are similar in that (1) they both form clots composed of thinner, more tightly packed fibers than their respective control rabbit and human fibrinogens; (2) the clot structure could be made to be more like the control fibrinogens by increased calcium; and (3) they both form clots that are more resistant to fibrinolysis than those formed by the control fibrinogens. Further characterization of human fibrinogens showed that Hcys fibrin had similar plasminogen binding to that of the control and an increased capacity for binding tPA. However, tPA activation of plasminogen on Hcys fibrin was slower than that of the control. Mass spectrometric analysis of Hcys fibrinogen revealed twelve lysines that were homocysteinylated. Several of these are close to tPA and plasminogen binding sites. Lysines are major binding sites for fibrinolytic enzymes and are also sites of plasmin cleavage. Thus, modification of lysines in fibrinogen could plausibly lead to impaired fibrinolysis. We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia.

Topics: Amino Acid Sequence; Blood Coagulation; Dose-Response Relationship, Drug; Fibrin; Fibrinogen; Fibrinolysis; Homocysteine; Humans; Hyperhomocysteinemia; Lysine; Models, Biological; Molecular Sequence Data; Plasminogen; Protein Binding; Radiation-Protective Agents; Structure-Activity Relationship; Thrombosis; Tissue Plasminogen Activator

Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects.. We studied healthy men not taking any medication (n=76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n=33), men with diabetes mellitus diagnosed recently (median hemoglobin A(1c) 7.65%; n=16), and patients with isolated hypercholesterolemia (>7.0 mmol/L; n=15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R2=0.88, P<0.0001 and R2=0.54, P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R2=0.84; P<0.0001) than was fibrinogen alone (R2=0.66; P<0.0001), whereas tHcy was the only predictor of lysis time (R2=0.69; P<0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P=0.0002) and shorter lysis time (P<0.0001).. Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.

Topics: Acute Disease; Adult; Aged; Blood Coagulation; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus; Drug Resistance; Fibrin; Fibrinolytic Agents; Folic Acid; Hematinics; Homocysteine; Humans; Hypercholesterolemia; Hyperhomocysteinemia; Male; Middle Aged; Permeability; Recombinant Proteins; Tissue Plasminogen Activator

Elevated plasma homocysteine is associated with an increased risk of atherosclerosis and thrombosis. However, the mechanisms by which homocysteine might cause these events are not understood. We hypothesized that hyperhomocysteinemia might lead to modification of fibrinogen in vivo, thereby causing altered fibrin clot structure. New Zealand White rabbits were injected intraperitoneally (i.p.) every 12 h through an indwelling catheter with homocysteine or buffer for 8 weeks. This treatment raised the plasma homocysteine levels to about 30 micro mol L(-1) compared with 13.5 micro mol L(-1) in control rabbits by the end of the treatment period. The fibrinogen levels were 3.2 +/- 0.6 in homocysteine-treated and 2.5 +/- 1.1 mg mL(-1) in control rabbits. The reptilase time was prolonged to 363 +/- 88 for plasma from homocysteine-treated rabbits compared with 194 +/- 48 s for controls (P < 0.01). The thrombin clotting time (TCT) for the homocysteine-treated rabbits was significantly shorter, 7.5 +/- 1.7 compared with 28.6 +/- 18 s for the controls (P < 0.05). The calcium dependence of the thrombin clotting time was also different in homocysteinemic and control plasmas. Clots from plasma or fibrinogen of homocysteinemic rabbits were composed of thinner fibers than control clots. The clots formed from purified fibrinogen from homocysteine-treated rabbits were lyzed more slowly by plasmin than comparable clots from control fibrinogen. Congenital dysfibrinogenemias have been described that are associated with fibrin clots composed of thin, tightly packed fibers that are abnormally resistant to fibrinolysis, and recurrent thrombosis. Our results suggest that elevated plasma homocysteine leads to a similar acquired dysfibrinogenemia. The formation of clots that are abnormally resistant to fibrinolysis could directly contribute to the increased risk of thrombosis in hyperhomocysteinemia.

Topics: Animals; Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysin; Homocysteine; Hyperhomocysteinemia; In Vitro Techniques; Microscopy, Electron, Scanning; Rabbits; Thrombosis

A total of 260 consecutive patients, referred for hypercoagulable assessment, was included in this study. Four coagulation activation markers were utilized to assess these patients [enzyme-linked immunosorbent assays for soluble fibrin polymer (TpP), prothrombin fragment 1.2, thrombin-antithrombin complex, and D-dimer]. The mean levels of the activation markers directly correlated with the number of hypercoagulable abnormalities. The percentage of patients with increased TpP levels for each group was lower than the other activation markers. The findings indicate that activation markers reflect the number of underlying thrombophilic abnormalities. Our data suggest that there is a utility in performing a panel of coagulation activation markers to assess the thrombotic risk. The measurement of soluble fibrin polymer may be more reflective of an impending vascular event.

Topics: Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Antiphospholipid Syndrome; Antithrombin III; Antithrombin III Deficiency; Autoimmune Diseases; Biomarkers; Enzyme-Linked Immunosorbent Assay; Factor V; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Hyperhomocysteinemia; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Protein C Deficiency; Protein S Deficiency; Prothrombin; Risk; Solubility; Thrombophilia

The incidence of placental thrombotic lesions in early onset preeclampsia (PE) and/or intrauterine growth restriction (IUGR) were compared between women with and without thrombophilia or hyperhomocysteinemia.. Matched case-control study. 183 women with a history of early onset PE and/or IUGR were tested for thrombophilia and hyperhomocysteinemia. From the 66 women with a thrombophilic factor the placental histological slides were available in 47 women. These were matched for maternal condition (PE and/or IUGR), gestational age at delivery, parity and maternal age, to 47 women with no thrombophilic factor. All slides were revised for lymphohistiocytic villitis, fetal thrombosis and fibrin depositions.. There were no significant differences between the placentas of the matched groups with and without a thrombophilic factor.. Placental thrombotic and inflammatory lesions associated with early onset PE and/or IUGR do not occur more often in women with compared to women without thrombophilia or hyperhomocysteinemia.

Topics: Case-Control Studies; Female; Fetal Growth Retardation; Fibrin; Humans; Hyperhomocysteinemia; Inflammation; Placenta; Pre-Eclampsia; Pregnancy; Thrombophilia; Thrombosis