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

The Shwartzman reaction is a classic biologic response in which the coagulation system is activated in vivo. Cellular initiation of the extrinsic coagulation protease cascade can be mediated by one or more limbs of the lymphoid response to diverse biological stimuli. The T cell-instructed monocyte and macrophage responses that have been implicated are mediated by a number of different cellular pathways and are elicited not only by antigens and allogeneic cells but also by other stimuli such as immune complexes and the lipid A moiety of bacterial lipopolysaccharide (LPS). The latter response has been implicated in the pathogenesis of the disseminated intravascular coagulation associated with bacterial infection. In the rapid collaborative cellular pathway response to LPS, we have described a relatively rigorous requirement for T helper cells in induction of the biosynthesis of tissue factor and Factor VII by monocytes. To elucidate potential regulatory aspects of this cellular procoagulant response, we provide the first evidence for the existence of T suppressor cells for the cellular procoagulant response to LPS by the rapid T cell-instructed pathway. Human peripheral blood lymphocytes were separated by cytoaffinity into Fc gamma-positive and Fc mu-positive cells and were characterized for their functional properties in the procoagulant response. T mu cells mediated the monocyte response, consistent with their identity with instructor cells. T gamma cells suppressed the response of monocytes to LPS in the presence of T mu cells, suggesting that they possess suppressor function for this response. The T gamma suppressor cells required stimulation by LPS to express their suppressor function and they exerted their suppressive effect directly on the monocyte. The existence and participation of LPS-responsive T suppressor cells on the cellular procoagulant response in vitro add a new dimension to the complexity of the rapid pathway of the collaborative cellular procoagulant response and may be important in the pathogenesis of disseminated intravascular coagulation.
 ...
PMID:Regulatory roles of T mu and T gamma cells in the collaborative cellular initiation of the extrinsic coagulation pathway by bacterial lipopolysaccharide. 316 8

Heparin-induced thrombocytopenia/thrombosis (HITP) is thought to be mediated by immunoglobulins that activate platelets in the presence of pharmacologic concentrations of heparin, but the molecular basis for this relatively common and often serious complication of heparin therapy has not been established. We found that plasma from each of 12 patients with HITP contained high titer (> or = 1:200) antibodies that reacted with immobilized complexes of heparin and platelet factor 4 (PF4), a heparin-binding protein contained in platelet alpha-granules. Recombinant human PF4 behaved similarly to PF4 isolated from platelets in this assay system. Complexes formed at an apparent heparin/PF4 molecular ratio of approximately 1:2 (fresh heparin) and approximately 1:12 (outdated heparin) were most effective in binding antibody. Immune complexes consisting of PF4, heparin, and antibody reacted with resting platelets; this interaction was inhibited by a monoclonal antibody specific for the Fc gamma RII receptor and by excess heparin. Human umbilical vein endothelial cells, known to express heparin-like glycosaminoglycan molecules on their surface, were recognized by antibody in the presence of PF4 alone; this reaction was inhibited by excess heparin, but not by anti-Fc gamma RII. Antibodies reactive with heparin/PF4 were not found in normal plasma, but IgG and IgM antibodies were detected at dilutions of 1:10 (IgG) and 1:50 (IgM) in 3 of 50 patients (6%) with other types of immune thrombocytopenia. These findings indicate that antibodies associated with HITP react with PF4 complexed with heparin in solution or with glycosaminoglycan molecules on the surface of endothelial cells and provide the basis for a new hypothesis to explain the development of thrombocytopenia with thrombosis or disseminated intravascular coagulation in patients sensitive to heparin.
 ...
PMID:Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. 828 25

Heparin-induced thrombocytopenia is an uncommon but potentially dangerous adverse effect of heparin therapy. Late onset thrombocytopenia is usually observed several days after initiating treatment and can be distinguished from early-onset benign thrombocytopenia which is more moderate and transitory and which results from a direct interaction between heparin and platelet membrane proteins which potentialize ADP-induced aggregation. Severe late-onset thrombocytopenia clearly results from an immunological mechanism due to the development of heparin-independent antiplatelet antibodies, often IgGs. These antibodies do not cause cell lysis but have a platelet-activating effect with release of the contents of the dense alpha granulations. This cell activation requires the formation of a heparin-dependent antibody-platelet complex. In most cases, platelet factor 4, an alpha granule protein, would be implicated. The antibody-platelet interaction has an activating effect following binding of the IgG Fc fragment to the Fc gamma RII receptor. The antibodies could also bind, favoring the development of thrombosis. The diagnosis of heparin-induced thrombocytopenia is evidenced by a platelet count under 100 Giga/l, usually from the 5th to 20th week of heparin therapy. Occasionally, the only sign is the low platelet count (drop of over 40% from pretreatment levels). Coagulation activation can lead to diffuse consumption coagulopathy in about 25% of the cases. Clinically, thrombosis is observed in about one half of the cases. Arterial thrombosis is the most characteristic and concerns the aorta and its branches as well as cerebral, coronary, mesenteric, renal and upper limb arteries. Venous thrombosis may be underestimated as they often occur as paradoxical recurrence after heparin therapy. Hemorrhage is much less frequent (less than 20% of cases) and often benign. To diagnose heparin-induced thrombocytopenia, one must eliminate other potential causes (infection, drug...), observe complete normalization of platelet count after heparin withdrawal, and demonstrate heparin-dependent antibodies in the plasma or serum. Different laboratory tests are quite helpful but have variable sensitivity. The incriminated heparin must be discontinued immediately. Use of low-molecular-weight heparins, even when cross-reactivity is not demonstrated in vitro, is not recommended. Other compound however, such as Orgaran 10,172 (or Lomoparan, appear to be the best choice. The action of antivitamin K agents is delayed and, due to the early dissociated drop in protein C at the beginning of treatment further raise the major risk of thrombosis. Classic antiplatelet agents such as aspirin are ineffective if used alone. More powerful compounds such as Ilomedine, are not available for this indication and are difficult to titrate. Part of the therapeutic problem with heparin-induced thrombocytopenia may be resolved with the advent of molecules with a direct antithrombin effect such as hirudine or its analogues. As suggested by a recent study, widespread use of low-molecular-weight heparin will undoubtedly have a highly significant effect on reducing the number of cases of severe thrombocytopenia.
 ...
PMID:[Thrombopenia induced by heparin. From physiopathology to treatment]. 923 38