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)

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).
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PMID:Heparin-induced thrombocytopenia: a ten-year retrospective. 1007 68

The last decade has witnessed substantial progress in the prevention and treatment of venous thromboembolism. However, the risk of deep vein thrombosis remains high in trauma patients and those undergoing orthopaedic surgery despite use of the best available prophylaxis. Existing antithrombotics also carry a significant risk of bleeding and other adverse effects, including heparin-induced thrombocytopenia (HIT). More effective and safer anticoagulants are therefore needed. Current approaches for improving the benefit:risk ratio of antithrombotic therapy include the development of indirect thrombin inhibitors with a high anti-Xa:anti-IIa activity ratio, and the use of direct thrombin inhibitors. Novel indirect thrombin inhibitors under investigation include pentasaccharide and the heparinoid danaparoid. These agents may offer reduced bleeding risk compared with conventional therapies, but there is no evidence of greater antithrombotic efficacy. However, due to low cross-reactivity with anti-heparin-platelet factor 4 antibodies, danaparoid and pentasaccharide may prove valuable in the management of HIT. Theoretically, the antithrombotic effect of direct thrombin inhibitors may be greater than that of indirect inhibitors because direct inhibitors are not dependent on endogenous cofactors and are able to inhibit both free and clot-bound thrombin. Direct inhibitors of the active site of thrombin and recombinant variants of hirudin, originally derived from the medicinal leech, are currently under investigation. Early data on lepirudin and desirudin suggest that recombinant hirudins may have clinical applications in thromboprophylaxis for high-risk patients, acute cardiology indications and HIT.
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PMID:Future prospects of prophylaxis for deep vein thrombosis. 1049 27

A synthetic selective inhibitor of factor Xa, the pentasaccharide SR90107A/Org31540 is in clinical development for the prophylaxis of postsurgical deep vein thrombosis. Another synthetic pentasaccharide with even more sustained inhibition of factor Xa, SanOrg34006, has also been developed. Both of these agents were tested in comparison to unfractionated heparin and a low molecular weight heparin (enoxaparin) for their relative platelet activation potential in heparin-induced thrombocytopenia assays. Sera from patients (n = 30) with heparin-induced thrombocytopenia were pooled and validated for heparin-dependent aggregation responses. Using heparin-platelet factor 4 Sepharose columns, antibodies to heparin-platelet factor 4 were purified from the same pool. The effects of heparin, enoxaparin, SR90107A/Org31540, and San-Org34006 were evaluated in a platelet aggregation assay using platelet donors (n = 10). At comparable concentrations, heparin and enoxaparin consistently produced platelet activation, whereas both pentasaccharides failed to produce a response at a concentration up to 100 micrograms/mL (approximately 50 microM). Similarly, in the 14C-serotonin release and flow cytometric assays, heparin and enoxaparin produced positive responses (n = 30), whereas the two pentasaccharides consistently failed to produce any effect. These observations suggest that the two pentasaccharides with highly selective anti-Xa activity are devoid of generating antiheparin-platelet factor 4 antibody, do not produce heparin-induced thrombocytopenic responses and may inhibit active heparin-induced thrombocytopenia antibody platelet activation.
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PMID:Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. 1072 24

Heparin-induced thrombocytopenia (HIT) is a rare complication of anticoagulative heparin therapy. The more severe HIT type II is defined by peripheral thrombocytopenia combined with thrombotic and thromboembolic events. We report the case of a 24 year old male patient who was admitted to our ICU with thromboembolic obstruction of the right central pulmonary artery, and deep venous thrombosis (DVT) of the right superficial femoral vein. Systemic thrombolytic therapy with urokinase for seven days resulted in nearly complete resolution of the thromboembolic material in the pulmonary arteries. Antithrombotic therapy with intravenous heparin and overlapping oral phenoprocoumon was continued on the regular ward. Six days later, the patient had to be readmitted to the ICU with evidence of hemodynamic compromise due to massive bilateral pulmonary thromboembolism that could be confirmed by CT scan--DVT had extended to the right iliacal vein. Additionally, peripheral thrombocyte counts had markedly declined from 112.000 to 35.000/microliter within 3 days, indicating the presence of a Hit type II. This was verified by positive ELISA testing for antibodies against platelet factor 4 (PF4)-heparin-complex. A filter device was temporarily implanted into the inferior vena cava. The patients condition stabilized upon reinitiated systemic thrombolysis and replacement of heparin therapy against recombinant hirudin. Pulmonary artery pressures normalized. Peripheral thrombocytopenia diminished within three days. HIT type II is a severe complication of anticoagulative therapy with heparin. Here we report a case, and discuss diagnostic procedures as well as differential diagnosis to HIT type I.
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PMID:[Heparin-induced type II thrombocytopenia as the etiology of severe recurrent pulmonary embolism]. 1123 57

The frequency of heparin-induced thrombocytopenia (HIT) varies between different clinical treatment settings and remains unknown for patients treated with unfractionated (UFH) or low-molecular-weight heparin (LMWH) because of deep vein thrombosis. In this multicentre, open-label study, 1137 patients with deep vein thrombosis were randomly assigned to UFH for 5-7 d, reviparin, a LMWH, for 5-7 d (short-treated group) or reviparin for 28 d (long-treated group). Heparin-platelet factor 4 antibodies (HPF4-A) were determined on d 5-7 and d 21. Heparin-induced thrombocytopenia was defined by clinical evaluation. Two patients in the UFH group (incidence: 0.53%, 95% confidence interval (CI): 0.06-1.91) and two patients in the long-treated LMWH group (incidence: 0.53%, 95% CI: 0.06-1.92) had HIT, while no HIT was observed in the short-treated LMWH group. Pulmonary embolism developed in one of the HIT-patients, who had HPF4-A and was treated with UFH. On d 5-7 the incidence of HPF4-A was 9.1% in the UFH group, 2.8% in the short-treated LMWH group and 3.7% in the long-treated LMWH group, with a significant increase to 20.7% in the UFH group and to 7.5% in the long-treated LMWH group on d 21. Therefore the incidence of HPF4-A and heparin-induced thrombocytopenia was lower in patients treated with LMWH compared with UFH for the same duration of treatment.
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PMID:Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin. 1219 98

Fondaparinux (Org-31540 / SR-90107A) is a new drug chemically synthesized for treatment and prophylaxis of thromboembolic disease. Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models. Phase I trials have shown a 100% bioavailability after subcutaneous (s.c.) administration, a rapid onset of action and an approximate half-life of 13.5 h. Fondaparinux is cleared as an active substance by the kidneys. In elderly patients, renal clearance is reduced and the half-life is longer. The phase II Pentathlon trial demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism in total hip-replacement patients and the optimal dose was determined to be 2.5 mg s.c./24 h. Four phase III trials have evaluated fondaparinux starting 6 hours after surgery compared with enoxaparin for prevention of venous thromboembolism following orthopedic surgery in 7,344 patients. The risk of thrombosis was reduced by 50% with fondaparinux and no differences were observed in death or severe bleeding. In a phase II trial, similar efficacy and incidence of major bleeding were seen with fondaparinux s.c. compared with dalteparin s.c. in the treatment of deep venous thrombosis. In patients with acute myocardial infarction, the efficacy of fondaparinux during fibrinolytic therapy was assessed in 326 patients who had acute coronary syndromes of less than a 6 hour duration, showing a slight but statistically not significant advantage for fondaparinux over unfractionated heparin in the coronary angiographies. There is currently no antidote for fondaparinux.
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PMID:Fondaparinux sodium. 1253 74

We report a patient with diabetic endstage renal disease with an initial platelet count of 17.6 x 10(4)/mm3 who developed type-II heparin-induced thrombocytopenia (HIT) during the induction period of hemodialysis (HD) when unfractionated heparin was used. Because the recognition of the condition and the treatment of this patient with HIT was unsatisfactory, she developed deep venous thrombosis, myocardial infarction, and occlusion of vascular access, at times of platelet counts of 4.1 x 10(4), 7.7 x 10(4), and 6.4 x 10(4)/mm3, respectively, with antibodies to heparin/platelet factor 4 complex. Unfortunately, we misjudged in our belief that the thromboembolic events might be associated with an underlying procoagulant state in diabetic nephrotic syndrome, rather than being associated with the clinical picture of HIT. This case report suggests that the clinician must consider HIT in the differential diagnosis for thromboembolic complications during the induction period of HD, because unfractionated heparin is the major anticoagulant used in HD.
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PMID:Deep venous thrombosis, myocardial infarction, and occlusion of vascular access associated with heparin-induced thrombocytopenia in a diabetic hemodialysis patient. 1471 62

A 30-year-old female with severe factor XI deficiency of 0-2% acquired factor XI inhibitor following many infusions for fresh frozen plasma (FFP) for surgical procedures starting at 4 years of age. Seven months before this inhibitor was diagnosed, surgery was complicated by prolonged bleeding resistant to FFP, requiring epsilon aminocaproic acid (EACA) and surgical packing. The inhibitor was measured at 2.2 Bethesda units, 7 months since the last FFP. The inhibitor was confirmed as specific anti-XI and anti-XIa binding by patient's IgG to immobilized factor XI and factor XIa from whole plasma and purified IgG. For repair of a painful anterior cruciate ligament (ACL) defect she was given recombinant factor VIIa (rVIIa) at 90 mug kg(-1), starting one-half hour preoperatively and continued every 2 h for 8 h when haemostasis was complete. Thereafter the rVIIa was given every 3 h for two doses, and then every 4 h for four doses at which time she was discharged on EACA which was continued for 6 days. There was excellent haemostasis during and following the surgery. There was no evidence of consumptive coagulopathy, with no change in the fibrinogen, platelet count, or D-D dimer; and no increase of platelet factor 4, beta-thromboglobulin, or prothrombin fragment F 1.2. The thrombin-antithrombin complex increased over baseline after 24 h. There was no postoperative deep vein thrombosis or pulmonary embolus. In this patient with a factor XI inhibitor, the recombinant factor VIIa was effective and safe, ensuring adequate haemostasis with no thrombotic complications. This product which was designed for patients with inhibitors to factor VIII or factor IX, and factor VII deficiency, has now been given successfully to four patients with factor XI inhibitors.
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PMID:Treatment of factor XI inhibitor using recombinant activated factor VIIa. 1566 Sep 84

Argatroban, a synthetic peptidomimetic antithrombin agent, is the first clinical anticoagulant solely to target thrombin. For some time, this drug has been used in Japan for the management of thromboembolic disorders. Recently, it has been approved in Japan for use in thrombotic and ischaemic stroke. Despite a large number of preclinical studies on the pharmacology of this agent, clinical trials in Europe and North America were only initiated in 1996. Argatroban produces anticoagulant effects comparable to therapeutic heparinisation at concentrations of approximately 1 microg/ml. At concentrations of 5-10 microg/ml, this agent produces adequate anticoagulation for inteventional cardiovascular procedures and prolongs the activated clotting time (ACT) to 400-600 s. The predictable anticoagulant effect of this agent is relatively short lasting, and may not warrant pharmacologic neutralisation in the majority of patients. However, patients with hepatic dysfunction may need some means of neutralisation. Unlike heparin, this drug produces its anticoagulant effects by direct inhibition of thrombin and thrombin-mediated processes. This agent is not influenced by endogenous factors such as platelet factor 4 and other proteins which bind heparin. Argatroban's use does not lead to the formation of antiplatelet antibodies. Thus, this drug is useful in the management of heparin induced thrombocytopenic (HIT) patients. Although argatroban was initially developed for the management of deep vein thrombosis (DVT), based on its pharmacologic properties, it can be developed for safer anticoagulation in such indications as acute coronary syndromes, as an adjunct to thrombolytics, thrombotic and ischaemic stroke and inflammatory diseases resulting in thrombotic complications.
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PMID:Pharmacology of argatroban. 1599 20

A 45-year-old man presented with deep vein thrombosis of the right leg and bilateral pulmonary embolism. Heparin was administered on the initial one and a half days. On the 3rd day, an inferior vena cava (IVC) filter was placed with a heparin flush, after which massive IVC thrombosis developed. The platelet count was 221000/mm3, decreased 42% from the initial level, but remained within the normal range. Heparin was replaced by argatroban on the 13th day. The platelet count increased to 355000/mm3 on the 15th day. The patient was positive for antibody against complexes of heparin and platelet factor 4, and was diagnosed as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). When thrombosis develops during heparin treatment, it is important to suspect HITTs and to assay for the associated antibodies, regardless of the actual platelet count.
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PMID:Heparin-induced thrombocytopenia complicated with massive thrombosis of the inferior vena cava after filter placement. 1635 99


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