Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Appropriate laboratory testing for the platelet-type bleeding disorders hinges on an adequate assessment in the history and physical examination. Patients with histories and screening laboratory results consistent with coagulation disorders (hemophilia, disseminated intravascular coagulation) are not appropriate candidates for platelet function testing. In contrast, patients with a lifelong history of platelet-type bleeding symptoms and perhaps a positive family history of bleeding would be appropriate for testing. Figure 6 depicts one strategy to evaluate these patients. Platelet morphology can easily be evaluated to screen for two uncommon qualitative platelet disorders: Bernard-Soulier syndrome (associated with giant platelets) and gray platelet syndrome, a subtype of storage pool disorder in which platelet granulation is morphologically abnormal by light microscopy. If the bleeding disorder occurred later in life (no bleeding with surgery or trauma early in life), the focus should be on acquired disorders of platelet function. For those patients thought to have an inherited disorder, testing for vWD should be done initially because approximately 1% of the population has vWD. The complete vWD panel (factor VIII coagulant activity, vWf antigen, ristocetin cofactor activity) should be performed because many patients will have abnormalities of only one particular panel component. Patients diagnosed with vWD should be classified using multimeric analysis to identify the type 1 vWD patients likely to respond to DDAVP. If vWD studies are normal, platelet aggregation testing should be performed, ensuring that no antiplatelet medications have been ingested at least 1 week before testing. If platelet aggregation tests are normal and if suspicion for an inherited disorder remains high, vWD testing should be repeated. The evaluation of thrombocytopenia may require bone marrow examination to exclude primary hematologic disorders. If future studies with thrombopoietin assays confirm preliminary results, however, the bone marrow examination of certain patients may be replaced by a thrombopoietin level.
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PMID:Overview of platelet physiology and laboratory evaluation of platelet function. 1037 Aug 53

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.
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PMID:Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. 1046 79

Hemophilia A is the most severe of the inherited bleeding disorders. Otolaryngologists are frequently asked to assist in the care of a patient with this disorder who has intractable bleeding from sites in the head and neck. This disorder is transmitted in an X-linked recessive manner and results from factor VIII deficiency. Factor replacement therapy has contributed much to the management of acute bleeding episodes and the prevention of long-term sequelae in patients with hemophilia. A consequence of factor replacement therapy that occurs in as much as 16% of patients is the development of antibodies to the exogenous factor. These antibodies inactivate any supplemental factor VIII, resulting in continued bleeding despite attempts at replacement therapy. This poses an extremely challenging clinical problem because other standard therapies have had limited usefulness. Activated prothrombin complex has been shown to be efficacious in the treatment of patients with inhibitors. This has led to the production of factor VIII inhibitor bypassing activity (FEIBA), which contains activated forms of factors II, VII, IX, and X. The mechanism of action of this preparation remains unknown, but it seems to bypass the need for factor VIII in the clotting cascade. Factor VIII inhibitor bypassing activity is not as effective as factor VIII concentrates in patients with normally responsive hemophilia, and patients with low inhibitor levels may be given larger doses of factor VIII. Disseminated intravascular coagulation is most often mentioned as a potential complication of the administration of factor VIII inhibitor bypassing activity, although it has been rarely reported. Otolaryngologists should be familiar with this clinical phenomenon and understand its implications. Two patients with bleeding diatheses were recently treated at our institution.
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PMID:Manifestations of factor VIII inhibitor in the head and neck. 1055 99

To examine the safety profile of products used to treat inhibitor patients unresponsive to factor VIII, a review of published clinical experience was performed. The products evaluated were activated prothrombin complex concentrates (aPCCs), such as AUTOPLEX T, porcine factor VIII and recombinant activated factor VII (rVIIa). Safety characteristics included potential for transmission of infectious agents, anamnesis, thrombogenicity, thrombocytopenia and allergic reactions. While viral transmission has been virtually eliminated, the risk is theoretically higher with plasma-derived products such as aPCC and porcine factor VIII than with rVIIa, although contamination of cultured cells is a concern. Anamnesis occurs with aPCCs and porcine factor VIII, and may induce resistance to further therapy with porcine factor VIII. Thrombosis and disseminated intravascular coagulation are very infrequently reported in patients exposed to aPCCs and rVIIa, and never with porcine factor VIII. The latter is occasionally associated with thrombocytopenia, but this uncommonly limits treatment with this agent. Lastly, allergic reactions occur with about equal frequency with all products, but anaphylaxis is mainly a concern after administration of porcine factor VIII. In conclusion, products currently available are reasonably safe. Considerations such as efficacy, availability, ease of administration and cost must also be considered in making treatment choices.
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PMID:Complications associated with the treatment of haemophiliacs with inhibitors. 1059 83

In 1967 we reported for the first time five cases of an acquired bleeding disorder in humans which developed after contact with saturnidae caterpillars. Since that time, other cases have been reported in Brazil, French Guyana, Peru, Paraguay and Argentina. The caterpillars have been identified as Lonomia achelous (LA) in Venezuela and northern Brazil and as Lonomia obliqua (LO) in southern Brazil. All patients present pain and a burning sensation at the site of contact. Within a few hours hematomas and hematuria are seen in combination with intracerebral and intraperitoneal hemorrhage (in some cases also renal failure). Hematological tests show: mild anemia with leucocytosis; prolonged PT, PTT and ThT; decreased fibrinogen, factor V, factor XIII, plasminogen and alpha2-antiplasmin levels; increased factor VIII:c, von Willebrand factor, and FDPs/D-dimers levels with normal ATIII and platelets. Factor VII, factor II and PC levels varied. Several activities similar to or directed against blood clotting factors have been identified in LA: fibrinolytic enzymes, which degrade fibrinogen producing abnormal FDPs; prothrombin activators: one direct and one factor Xa-like; a thermostable factor V activator; a thermolabile factor V inhibitor; a factor XIII proteolytic/urokinase-like activity; and a kallikrein-like activitiy. In LO three activities have been described: a prothrombin activator called 'Lonomia obliqua prothrombin activator protease' (LOPAP); a factor X activator; and a phospholipase A(2)-like activity called Lonomiatoxin. No fibrinolytic activity has been described in LO. Subcutaneous injection of crude hemolymph and some chromatographic fractions of LA induce a decrease in fibrinogen, plasminogen and factor XIII. Intravenous injection of factor XIII proteolytic/urokinase-like activity induce a dose-dependent thrombolysis with a decrease in plasmatic factor XIII without hemorrhagic manifestations. Intradermal injection of LO bristle extracts in rats and rabbits produce incoagulability whereas intravenous injection of LOPAP induced DIC in mice.
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PMID:Lonomia genus caterpillar toxins: biochemical aspects. 1108 23

To ascertain the time course of prolonged coagulation time and the coagulation factors that were consumed preferentially after injection of Escherichia coli endotoxin (ETX, 3 mg/kg, intravenously) in rats, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured. Using aPTT and PT, the residual levels of the major coagulation factors were quantified by partial replacement of ETX-injected rat plasma with individual factor-deficient human plasma. The residual levels of prekallikrein and high molecular weight (HMW) kininogen were also measured. After ETX injection, aPTT and PT showed gradual increasing prolongation, which was marked at 3-5 h after the injection. The residual level of fibrinogen was markedly reduced between 1 and 3 h after ETX injection and dropped to the determination limit 7 h after the injection. Ratios of the consumed coagulation factors, prekallikrein, and HMW kininogen in rat plasma collected 7 h after intravenous injection of ETX were obtained as follows: prekallikrein (18.0 +/- 4.8%), HMW kininogen (36.2 +/- 1.9 %), factor XII (54.0 +/- 0.7%), factor VIII (86.1 +/- 1.8%), factor VII (35.6 +/- 7.7%), factor V (90.6 +/- 0.8%), and factor I (fibrinogen) (>89.6 +/- 0.0%). Thus, coagulation factor I (fibrinogen) and factors V and VIII (cofactors) were consumed preferentially. The extrinsic coagulation pathway was dominantly activated, whereas the intrinsic coagulation pathway, including plasma kallikrein-kinin system, played less important role in the ETX-induced consumption coagulopathy in rat.
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PMID:Preferential consumption of coagulation factors I, V, and VIII in rat endotoxemia. 1109 86

We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.
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PMID:Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome. 1119 24

Apart from inadequate surgical haemostasis, postoperative bleeding can be related to acquired disorders of platelet number, platelet function or coagulation proteins (e.g. Vitamin K deficiency, DIC or liver injury). We highlight our experience with three patients who suffered life-threatening bleeding in the postoperative setting. The three patients - a 47-year-old man and 70- and 74-year-old women -- all had negative histories for excessive bleeding with prior surgeries, and all had normal preoperative PT and aPTT tests. Surgeries were resection of ischaemic bowel, cholecystectomy and coronary artery bypass grafting. All patients experienced unexpected bleeding within the first few postoperative days requiring multiple red cell transfusions and surgical re-explorations. Evaluations within the first 4--7 days after surgery revealed that these three patients had developed prolonged aPTT due to demonstrable factor VIII antibodies initially at low titre. One patient was treated with high doses human factor VIII, corticosteroids, intravenous gammaglobulin and plasma exchanges. The inhibitor was no longer demonstrable after 6 weeks of such therapy, and he has remained in remission without therapy. The second patient was initially treated with high-dose human factor VIII infusions. Five months later, prednisone and 6-mercaptopurine were begun for worsening inhibitor titre and diffuse purpura and subcutaneous haematomas. The factor inhibitor remitted, but the patient died from liver failure related to post-transfusion hepatitis. The third patient was initially managed with high-dose human factor VIII. Two months later, worsening inhibitor titre and tongue haematoma was treated with activated prothrombin complex, corticosteroids and cyclophosphamide. Eight years later, she is on no therapy, demonstrates a mild bleeding tendency and has a stable low-titre inhibitor. There have been a few case reports of inhibitors to coagulation factors including factor VIII becoming manifest in the postoperative setting but surgery has not been widely recognized as an underlying cause for acquired haemophilia. This paper speculates on pathogenesis and reviews treatment options. This syndrome is remarkable for its abrupt onset in the first few postoperative days and for its substantial morbidity. The problem is potentially reversible with immunosuppressive therapy. Clinicians should be aware of this syndrome, considering acquired haemophilia in patients with unexpected postoperative bleeding.
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PMID:Surreptitious bleeding in surgery: a major challenge in coagulation. 1125 54

The management of unexpected bleeding must be directed at the specific abnormality identified, as there is no universally effective and safe procoagulant product. Where practical, a purely pharmaceutical approach obviates the residual risks of exposure to plasma-derived products. Desmopressin is often effective in bleeding due to mild haemophilia A, Type I von Willebrand's disease and some platelet function disorders. Where replacement therapy is necessary, it should be as specific as possible, preferably using purified components singly or in combination. Recombinant proteins provide the greatest margin of safety, but it must be borne in mind that these are biologicals, and that they may contain human and animal plasma-derived proteins. Where specific replacement is unavailable or impractical, plasma or crudely fractionated plasma derivatives may be used. In the case of inhibitor antibodies to factor VIII, high dose human factor VIII or porcine factor VIII may be used. Where replacement therapy is impossible due to a high inhibitory titre, it may be necessary to bypass the specific haemostatic defect using activated prothrombin complex concentrates or recombinant activated factor VIIa. The latter product is being studied in patients with various disorders of platelet function, and in the more global haemostatic failure that accompanies end-stage liver disease. Ancillary methods are often of great value in securing haemostasis. These may be derived from pharmacological or biological sources, and their sites of action may be systemic or topical. Examples include antifibrinolytic lysine analogues, corticosteroids where inflammation accompanies bleeding, and the topical application of fibrin sealants or thrombin. Simple physical measures such as pressure, ice, or splinting are also valuable adjunctive measures. Finally, it must be emphasized that the ultimate control of bleeding often depends upon effective management of the inciting cause, such as eliminating the trigger for DIC, or suppressing the causative antibody of ITP. These principles will be presented using a practical algorithmic approach. The initial question when considering treatment should be whether or not the patient is acutely unstable. Instability may be due to one of two causes: the volume of blood loss leading to a compromised cardio-vascular status, or the site of the bleed. The relevance of the site of the bleed is independent of the volume of blood loss, so for example, a closed bleed into CNS will cause critical functional compromise even though the volume of bleeding may be minimal. Similarly bleeding into a compartment, such as into a forearm or a calf will cause critical functional compromise irrespective of the volume of bleeding.
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PMID:Unexpected bleeding disorders: Algorithm for approach to therapy. 1125 56

Monoclonal antibody therapies have conducted to not only hematologic malignancies but also disorders of hemostasis and coagulation. This article describes the recent advances of monoclonal antibody therapy for bleeding disorders such as idiopathic thrombocytopenic purpura(ITP), hemophilia A, disseminated intravascular coagulation(DIC), and thrombosis. Rituximab, chimeric anti-CD20 monoclonal antibody treatment has a valuable effect in the patients with ITP, and clinical trials using anti-CD40 ligand monoclonal antibody for ITP are underway. Anti-CD40 ligand monoclonal antibody can be an alternative therapy for hemophilia A patients with inhibitors to factor VIII. In thrombosis, anti-tissue factor monoclonal antibody and anti-factor IX(a) monoclonal antibody were established as novel anticoagulant regents. Plasminogen activator inhibitor-1(PAI-1) increases in endotoxin-induced DIC and many thrombotic diseases such as myocardial infarction, type 2 diabetes mellitus, and hyperlipidemia. Anti-PAI-1 monoclonal antibody reduced fibrin deposition in DIC mouse model. Treatment of these monoclonal antibodies for the molecules regulating coagulation-fibrinolysis system may be utilized for acute coronary syndrome and venous thrombosis.
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PMID:[Monoclonal antibody therapy for disorders of hemostasis and coagulation]. 1190 68


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