Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematin is clinically useful in the treatment of acute intermittent porphyria. Recently, hematin-induced coagulopathy has been reported, and a patient we treated bled during hematin therapy. On 3 separate occasions, infusions of hematin (4 mg/kg) induced thrombocytopenia, prolongation of the prothrombin time, partial thromboplastin time. Reptilase time, and apparent decreases in fibrinogen and increases in fibrin(ogen) degradation products (FDP). However, fibrinogen assayed by heat precipitation was unchanged, the protamine paracoagulation test was negative, there was no red blood cell fragmentation, and plasminogen and antithrombin III remained normal, excluding the presence of disseminated intravascular coagulation. Furthermore, premedication with heparin, 5000 U i.v., failed to prevent the lengthening of the Reptilase time and exacerbated the thrombocytopenia. In vitro studies revealed that hematin, 0.1 mg/ml, aggregated platelets and induced the release of 14C-serotonin and adenosine triphosphate (ATP). Hematin also aggregated washed or gel-filtered platelets but had no effect on formalin-fixed platelets. Aggregation was inhibited by aspirin (0.12 mg/ml), adenosine triphosphate, and apyrase, suggesting that hematin aggregated platelets by inducing adenosine diphosphate (ADP) release. Hematin (0.07 mg/ml) progressively inactivated thrombin and 0.1 mg/ml prolonged the Reptilase time. Thus, hematin is unique in that it both induces platelet aggregation and inhibits coagulation.
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PMID:Hematin: unique effects of hemostasis. 682 96

Prolonged bleeding by the host after the leech ceases to feed and several reports that the use of leeches restores blood flow in the microcirculation after plastic surgery led us to search for inhibitors of platelet aggregation in Hirudo medicinalis saliva. Dilute leech saliva was collected by phagostimulating starved leeches with a solution of arginine in saline. The saliva is shown to inhibit human platelet aggregation induced by thrombin, collagen, adenosine diphosphate (ADP), epinephrine, platelet activating factor (1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [PAF]), and arachidonic acid. We have isolated the PAF inhibitor and found it to be an amphipathic phosphoglyceride. We have also purified apyrase adenosine triphosphate ([ATP] diphosphohydrolase), which inhibits ADP-induced platelet aggregation, and have described collagenase. Besides well-known hirudin, Hirudo saliva contains a potent inhibitor of coagulation factor Xa. We also report antiaggregant and anticoagulant activities in the crop content of the closely related Nile leech, Limnatis nilotica. Anticoagulants of hematophagous species are surveyed. We have used medicinal leeches in plastic surgery for decompression of skin flaps and in patients with postphlebitic syndrome and peripheral arterial occlusions. Preliminary results indicate certain beneficial effects of leech therapy.
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PMID:Platelet aggregation and coagulation inhibitors in leech saliva and their roles in leech therapy. 883 13

Leeching is considered by many to be a discredited medical relic of the past. This view is not justified, since leeches still play an important part in modern medicine, as in microsurgery and in the treatment of patients with post-phlebitic syndrome. Hirudin, the potent thrombin inhibitor of leech saliva, has been cloned and is used in the treatment of cardiological and hematological disorders. In our search for other antihemostatic factors in Hirudo medicinalis saliva, we found inhibitors of platelet aggregation induced by thrombin, collagen, adenosine 5'-diphosphate, epinephrine, platelet-activating factor and arachidonic acid. We purified apyrase (adenosine 5'-triphosphate diphosphohydrolase), which is a non-specific inhibitor of platelet aggregation by virtue of its action on adenosine 5'-diphosphate. We isolated and characterized the platelet-activating factor antagonist and also identified and recovered an inhibitor of coagulation factor Xa from leech saliva. This report summarizes our findings and those of other investigators, as well as the experience of one of us (A.E.) in leech therapy.
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PMID:The role of the leech in medical therapeutics. 901 16

Arthropods in at least 23 different families or orders, distributed between two classes (Insecta and Arachnida), feed on vertebrate blood. They are able to do this despite constraints imposed by a sophisticated array of hemostatic defenses, due to the presence of a wide range of antihemostatic molecules in their saliva, including vasodilators, antiplatelet factors, and anticoagulants. Vasodilators include amines, prostaglandins, peptides, proteins, and even a mechanism to store large amounts of nitric oxide and deliver it into the skin. Platelet aggregation inhibitors include nitric oxide, prostaglandins, apyrase, molecules that sequester ADP, and a range of peptides and proteins that interact specifically with integrin receptors. Anticoagulants include a wide variety of inhibitors that target thrombin and factor Xa, as well as proteins that disrupt the "tenase", prothrombinase, and tissue factor/FVIIa complexes. The potential complexity of saliva is illustrated with the example of Rhodnius prolixus, which contains a large array of compounds, many of which affect more than one target in the hemostatic process. Finally a brief discussion of a new approach (sialomics) to the discovery of pharmacological agents in arthropod saliva is presented.
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PMID:Antihemostatic strategies of blood-feeding arthropods. 1557 59

The activities of NTPDase (EC 3.6.1.5, apyrase, CD39) and 5'-nucleotidase (EC 3.1.3.5, CD73) enzymes were analyzed in platelets from breast cancer patients. Initially, patients were compared in terms of length (years) of tamoxifen use. The following groups were studied: breast cancer patients who did not use tamoxifen, patients using tamoxifen for 1-48 months, patients using tamoxifen for 49-84 months, and controls (healthy subjects). Results demonstrated that adenosine triphosphate (ATP) hydrolysis was enhanced (F(3,114)=8.53; P<0.001) and adenosine diphosphate (ADP) hydrolysis was reduced (F(3,106)=5.09, P=0.002) as a function of tamoxifen use, while adenosine monophosphate (AMP) hydrolysis was unchanged. Next, patients were compared statistically according to disease stage, determined by the tumor-node-metastasis (TNM) staging system for classifying breast tumor. ATP hydrolysis was significantly elevated in patients with stage I and II breast cancer (F(4,113)=4.35; P=0.003), but was normal in patients with stage III and IV cancer. ADP hydrolysis was reduced in stages II to IV (F(4,105)=3.88, P=0.006) and AMP hydrolysis was elevated in stage II (F(4,105)=3.45 P=0.01), but was normal in stages III and IV. Platelet aggregation time was similar in all patients regardless of tamoxifen use or disease stage. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were also within the normal range and similar among all groups. Similarly, fibrinogen and fibrin degradation product (FDP) were unchanged in all groups. In conclusion, our study demonstrated for the first time that hydrolysis of adenine nucleotides is modified in platelets from breast cancer patients taking tamoxifen.
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PMID:Enzymes that hydrolyze adenine nucleotides in platelets from breast cancer patients. 1594 10

It is widely accepted that shear stress activates platelets. However, this may have two linked but separate causes: a direct effect of shear stress on individual platelets, and secondary inter-platelet activation dependent on the release of agonists caused by shear. Gel-filtered platelets were exposed to intermittent low shear at 20,000 and 200,000 platelets/microl and their activation was measured with a prothrombinase-based assay. At the lower count, activation was slow and essentially linear, but at the higher count, it rose exponentially with time, leading to 3-fold more prothrombinase activity. Inclusion of apyrase and/or prostaglandin I(2) slightly reduced activation at high platelet counts, but did not abolish the nonlinear kinetics, and antibodies against von Willebrand factor had no significant effect. The contributions of anionic phospholipid and factor Va to the prothrombinase activity were assessed by measurements in the presence of exogenous factor Va. The results strongly suggest that anionic phospholipid appearance is caused directly by shear exposure, but that factor Va release from the alpha-granules is a secondary event and largely the result of platelet-platelet signaling.
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PMID:The extent of platelet activation under shear depends on platelet count: differential expression of anionic phospholipid and factor Va. 1677 36