Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous investigators have postulated that a hypercoagulable state exists in humans for a period of time before the development of thrombotic episodes. A clear biochemical definition of the prethrombotic state, however, has proved elusive due in part to the lack of reliable techniques for monitoring pertinent changes in blood coagulability. Based on recent advances in our knowledge of the biochemistry of the coagulation system, a series of highly sensitive and specific immunochemical tools has been developed that can quantitate the activities of various steps of the hemostatic mechanism in vivo at the subnanomolar level. We have established assays for F1+2 and the protein C activation peptide, which measure the cleavage of the prothrombin molecule by factor Xa and the scission of protein C by the thrombin-thrombomodulin complex, respectively. Nossel and coworkers had previously constructed similar assays for fibrinopeptide A (FPA) and fragment B beta 1-42, which monitor the cleavage of fibrinogen by thrombin and the proteolysis of fibrin I by plasmin, respectively. Substantial elevations in the levels of these markers have been found in patients with disseminated intravascular coagulation and many subjects with acute deep venous thrombosis. The F1+2 and FPA assays have been used to demonstrate that significant increments in factor Xa activity but not thrombin activity regularly occur in the blood of nonanticoagulated individuals with congenital deficiencies of antithrombin or protein C. These two disorders are known to be correlated with the subsequent development of thrombosis. Patients with protein C deficiency have also been noted to have significantly reduced plasma levels of protein C activation peptide. By using the immunoassays for FPA and B beta 1-42 in studies of postoperative patients, it has been shown that an imbalance between the procoagulant action of thrombin and the anticoagulant effect of plasmin on fibrin I polymer may induce an acquired thrombotic diathesis. Finally, we have recently demonstrated that prothrombin activation as measured by the F1+2 assay is suppressed by oral anticoagulants in the blood of patients with thrombotic diatheses. These investigations suggest that these assay techniques can be used to improve our understanding of the hypercoagulable state as well as to develop more effective treatment strategies for the prevention of thromboembolic events.
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PMID:The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. 360 75

We investigated hemostatic abnormalities in 37 patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) (PE patients) and in 40 patients with DVT without PE (DVT patients). Plasma fibrinogen, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex, fibrin-D-dimer, activated protein C (APC)-protein C inhibitor (PCI) complex, von Willebrand factor (vWf), tissue plasminogen activator (t-PA), PA inhibitor-I (PAI-1), and thrombomodulin levels in both PE and DVT patients were significantly increased compared with normal volunteers. Plasma APC-PCI complex, PAI-1, and vWf levels in PE patients were significantly higher than those in DVT patients without PE. These findings indicate that PE patients are more hypercoagulable and hypofibrinolytic than DVT patients. Plasma TAT, APC-PCI complex, PAI-1, and vWf levels were the most sensitive indicators for PE. In these patients, increases in TAT and APC-PCI complex suggest DVT and increased PAI-1 and vWf suggest the risk of onset of PE.
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PMID:Hemostatic abnormalities in patients with pulmonary embolism compared with that in deep vein thrombosis. 856 33

The diagnosis of thromboembolic diseases is still difficult to establish before the occurrence of the pathological event, although it is now known that they are the result of a progressive alteration of the cardiovascular system. Introduction of new diagnostic tools for the evaluation of the thromboresistance capacity of the body or for the measurement of molecular markers allows the testing of the body defenses against thrombosis which is becoming a routine clinical diagnosis. Antithrombin III (AT III), protein C, protein S, and parameters of fibrinolysis have been recognized to be very important anticoagulant proteins and regulators of thrombin formation and thrombus extension. Furthermore, a normal factor V is necessary for the normal function of the protein C pathway. The presence of a factor V mutation leads to the activated protein C resistance syndrome. However, the major incidence of thrombotic events concerns the overall population. It has been epidemiologically related to the existence of risk factors producing blood activation, which progressively saturates the body's thromboresistance. This period is clinically silent for a long time. The new molecular markers recently introduced can show the existence of a preclinical state of blood activation at the plasma level (fibrinopeptide A, thrombin-antithrombin complexes, modified antithrombin III, fragments 1 + 2 of prothrombin, D-dimer) or at the platelet level (B-thromboglobulin, platelet factor 4, and thrombospondin), and promising developments concern the endothelial level (soluble thrombomodulin). The most universally used blood activation test is the D-dimer assay. This analyte has become very popular in past years for its high sensitivity, its long half-life, and its easy detection directly on citrated plasma. Its negative predictive value (in deep venous thrombosis or pulmonary embolism) as well as its use for monitoring of thrombotic risk in the post-operative period have been well documented clinically. New investigations are initiated to find analytes reflecting endothelial damage, an early platelet activation, or the involvement of blood cells (mainly monocytes and neutrophils) in abnormal processes. It also becomes possible to evaluate directly pathological causes inducing blood activation, such as the presence of antiphospholipid antibodies or other autoimmune antibodies.
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PMID:Thromboembolic diseases: biochemical mechanisms and new possibilities of biological diagnosis. 880 28

We examined hemostatic molecular markers in various thrombotic disorders. The efficacy of treatment in relation to the disseminated intravascular coagulation (DIC) score when the treatment was begun showed that greater efficacy was achieved in Pre-DIC than in DIC patients. The outcome was poorer with increasing DIC score, suggesting that early treatment is important. The sensitivity in some of molecular markers was high for both DIC and Pre-DIC. Receiver operating characteristic analysis suggest that soluble fibrin monomer level could be the most useful marker for the diagnosis of DIC. In examination of these markers in deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and cerebral infarction, plasminogen activator inhibitor-1 and activated protein C-protein C inhibitor complex were useful marker for the diagnosis. Increased plasma GMP-140 was suggested to be the activation of platelets. The patients with high levels of plasma thrombomodulin (TM) considered to be a marker of vascular endothelial injuries became poor outcome. We will term these patients with high TM as systemic vascular endothelium injuries syndrome, and treat those by protecting the vascular endothelium.
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PMID:[Study of hemostatic molecular marker]. 913 93

The increased risk for deep vein thrombosis (DVT) after orthopaedic surgery has been well documented as well as hypercoagulable state during both total hip arthroplasty (THA) and total knee replacement (TKR). To investigate the influence of the surgical procedure [posterolateral (PL) or lateral (L) approach for THA, use of tourniquet (TQ) or not use of TQ for TKR] on the hypercoagulability and the role of extrinsic pathway activation and endothelial stimulation during orthopaedic surgery we have examined 40 patients (20 patients undergoing primary THA--10 with PL approach and 10 with L approach--and 20 patients undergoing TKR--10 with TQ application and 10 without TQ). Thrombin-antithrombin complexes (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM) and von Willebrand factor antigen (vWF:Ag) were analyzed before and during the orthopaedic surgery. During THA, TAT plasma levels increased more markedly in patients assigned to the L than PL approach (p <0.05); during TKR an elevation of TAT of higher degree (p <0.05) was observed when TQ was not applicated. Blood clotting activation was significantly (p <0.001) more relevant during THA than TKR. No changes in TF and vWF:Ag plasma levels were observed in all patients undergoing THA and TKR. TFPI plasma levels significantly (p <0.05) decreased 1 h after the end of the THA in group PL and group L, whereas they remained unaffected in the two groups of patients undergoing TKR. Similarly TM plasma levels significantly decreased during THA, but not during TKR. In conclusion, these results show that: 1) the site of surgical procedures and the type of approach affect the degree of hypercoagulability, 2) the blood clotting activation takes place in the early phases of orthopaedic surgery, without signs of extrinsic pathway and endothelial activation.
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PMID:Procedure-dependence and tissue factor-independence of hypercoagulability during orthopaedic surgery. 1040 60

Protein C (PC) is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating blood coagulation and fibrinolysis by inhibiting not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). In this study, it was reported that the antithrombotic effect of a human APC product (designated as CTC-111) compared with that of heparin and human PC on the deep venous thrombosis (DVT) model induced in mice by stasis caused by inferior vena cava ligation and operative invasion. Drugs were injected into a tail vein at -2, 30, 60, and 120 min after the inferior vena cava ligation. One-fifth amount of the total dosage of a given drug was injected at each time point. The wet weight of thrombus formed was reduced by APC or heparin administration, however, PC, which was equal to APC in protein amount, did not show any antithrombotic effect. To confirm whether human PC could be activated by mouse thrombin, PC was treated with mouse or human thrombin to measure the amount of APC formed. Mouse thrombin could activate human PC at a similar activation rate as human thrombin. These results suggest that externally administrated PC cannot exhibit antithrombotic effect in this DVT model due to slow activation rate to APC and that APC is a better antithrombic agent than PC for treating thrombotic diseases.
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PMID:Effect of activated human protein C on experimental venous thrombosis induced by stasis with operative invasion in mice. 1099 52

Variability of thrombotic disease among individuals homozygous for factor V Leiden has been described. It has been shown that some thrombotic patients carry an additional genetic risk factor such as protein C, protein S, antithrombin deficiency or the G20210A mutation on the prothrombin gene. The occurrence of a deep vein thrombosis during enoxaparin prophylactic treatment in a pregnant woman homozygous for factor V Leiden, without other known prothrombotic genetic factors, led us to investigate her thrombomodulin gene. We found that the patient was heterozygous for the previously described G127-->A mutation, which results in an Ala25-->Thr substitution. Furthermore, for this patient, the allelic combination at the 1418 polymorphic site was C/T, which predicts an Ala455-->Val replacement. Although larger studies are required, this case report suggests that thrombomodulin gene mutations could be an additional genetic risk factor for thrombosis in carriers of the factor V Leiden mutation.
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PMID:Deep vein thrombosis during enoxaparin prophylactic treatment in a young pregnant woman homozygous for factor V Leiden and heterozygous for the G127-->a mutation in the thrombomodulin gene. 1113 55

Since the first patient with antithrombin deficiency was reported, various hereditary thrombophilia have been discovered. However, we experienced a family line of multiple thrombosis in which known hereditary thrombophilia were all refuted. Case 1 died of inferior vena cava thrombosis at the age of 56 days. Case 2, the elder sister of Case 1, developed deep vein thrombosis of the left leg at age 2. She was started on warfarin but contracted deep vein thrombosis of the right leg at the age of 7. In the family of these cases there have been another five cases of thrombosis, spanning three generations, giving a total of seven cases. Six of the cases developed at an early age, below 50 years. Antithrombin, protein C, protein S, heparin cofactor II, soluble thrombomodulin, plasminogen, alpha 2 plasminogen inhibitor, and tissue factor pathway inhibitor were measured but there were no abnormalities, nor was there any resistance to activated protein C. The onset of thrombosis in this family is becoming younger with the passing of generations, and clinical symptoms have been showing a worsening tendency.
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PMID:[A family with multiple thrombosis including infancy occurrence]. 1157 53

Unfractionated heparin, low molecular weight heparin and vitamin K antagonists are anticoagulants currently used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Considerable limitations of these agents, such as a narrow therapeutic window, a variable dose response or lack of oral bioavailability, created the need for new anticoagulants. Numerous new compounds with different mechanisms of action have been developed and some have been already approved for clinical use. Quite recently, fondaparinux, an indirect anti-factor Xa inhibitor, has been licensed in Europe and in the US for prevention of VTE in patients undergoing hip or knee replacement surgery. In addition, lepirudin, a recombinant hirudin derivative, and the heparinoid danaparoid, have been approved in Austria for treatment of heparin-induced thrombocytopenia. Recombinant nematode anticoagulant protein c2, the orally available thrombin inhibitor ximelagatran and ART-123, a recombinant soluble thrombomodulin, are in advanced stages of clinical development. This article reviews mechanisms and sites of action, and the current state of preclinical and clinical research of these and various other agents with respect to the prevention and treatment of venous thromboembolism).
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PMID:Novel anticoagulants for the prevention and treatment of venous thromboembolism. 1464 23

Deep venous thrombosis (DVT) has been variably reported in multiple myeloma patients during treatment with thalidomide alone or in combination with chemotherapy or dexamethasone. With the aim of investigating this complication, we performed, on a cohort of 13 relapsed refractory MM patients treated with low-dose thalidomide (100 mg/day) and dexamethasone (20 mg p.o./day for 4 days every 2 weeks), a serial evaluation of different laboratory parameters implicated in DVT. No significant abnormalities in all genetic, serologic, or plasmatic parameters studied were registered, apart from thrombomodulin which showed significant variations between baseline and 1st-month values and 1st- and 3rd-month values. In conclusion, the evidence of significant variations of thrombomodulin values in the 1st month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.
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PMID:Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone. 1523 49


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