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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 343 records · Page 19Linked to original sources
PubMed1986

A low molecular weight heparin alters the fetal coagulation system in the pregnant sheep.

Standard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate; both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.

Animals↗
PubMed1986

Management of anti-thrombin III deficiency during pregnancy without administration of anti-thrombin III.

We report a patient with hereditary antithrombin III deficiency who was successfully treated with heparin throughout pregnancy. Functional antithrombin III levels fell to 0.32 U/ml during heparin treatment, but it was possible to achieve a heparin effect, measured by the activated partial thromboplastin time, thrombin clotting time and heparin assay with subcutaneous heparin in doses of 30,000 U to 35,000 U/24 hours. This achieve an long term heparin effect was obtained without the need for antithrombin III infusions.

Adolescent↗
PubMed1986

The Drosophila virilis dopa decarboxylase gene is developmentally regulated when integrated into Drosophila melanogaster.

The dopa decarboxylase gene (Ddc) has been isolated from Drosophila virilis and introduced into the germ-line of Drosophila melanogaster by P-element mediated transformation. The integrated gene is induced at the correct stages during development with apparently normal tissue specificity, indicating that cis-acting elements required for regulation are functionally conserved between the two species. A comparison of the DNA sequences from the 5' flanking regions reveals a cluster of small (8-16 bp) conserved sequence elements within 150 bp upstream of the RNA startpoint, a region required for normal expression of the D. melanogaster Ddc gene.

Animals↗
PubMed1986

Role of lipoxygenase metabolism in platelet function: effect of aspirin and salicylate.

Aspirin inhibits thromboxane A2 (TxA2) production whereas its salicylate moiety inhibits 12-hydroxy-eicosatetraenoic acid (12-HETE) production in the platelet. The significance of the latter effect on platelet function is unclear. We examined the effects of aspirin and salicylate on (i) platelet/collagen adhesion using 3H-adenine-labelled human platelets and collagen-coated discs, (ii) platelet aggregation induced by thrombin, collagen, ADP and arachidonic acid, and (iii) platelet TxA2 and 12-HETE synthesis as measured by radioimmunoassay and high pressure liquid chromatography respectively. Aspirin (50 uM) decreased platelet aggregation and increased platelet adhesion. The decrease in aggregation was associated with inhibition of TxA2 production and the increase in adhesion was associated with enhanced 12-HETE production. Salicylate had the opposite effects. Platelet aggregation was increased and platelet adhesion decreased. The increased aggregation was associated with enhanced TxA2 production and the decrease in aggregation was associated with inhibition of 12-HETE production. These observations suggest that 12-HETE facilitates platelet adhesion which can be altered by salicylate treatment.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1986

Epidemiology and pathogenesis of venous thrombosis.

Venous thrombi are intravascular deposits composed predominantly of fibrin and red blood cells with a variable platelet and leukocyte component. They frequently arise in large venous sinuses in the calf, in valve cusp pockets either in the deep veins of the calf or thigh or in venous segments that have been exposed to direct trauma. Venous thrombosis can be produced experimentally by a combination of stasis and systemic hypercoagulability or by stasis and endothelial damage. Thrombosis is augmented if the fibrinolytic mechanism is inhibited or defective. A number of clinical conditions and laboratory abnormalities are associated with and predispose to venous thrombosis and, in many of these, it is possible to identify one or more of the thrombogenic factors discussed. Venous thromboembolism (venous thrombosis and pulmonary embolism) is a serious and potentially fatal disorder that usually complicates the course of sick hospitalized patients, but occasionally affects ambulant and otherwise healthy individuals. Screening studies with iodine-125 fibrinogen leg scanning, impedance plethysmography and perfusion lung scanning have shown that the majority of venous thrombi and pulmonary emboli that occur in hospitalized patients are small and asymptomatic, and it is likely that most are clinically insignificant. In bedridden patients, most thrombi commence in the calf and are asymptomatic. When a calf vein thrombus extends into the proximal venous segment, the risk of clinically significant pulmonary embolism increases. Less is known about the incidence and clinical significance in a nonhospital population; although asymptomatic disease occurs, its frequency is unknown. In contrast to the patients with asymptomatic venous thrombosis, symptomatic patients with venous thrombosis usually have large occulsive thrombi localized in their proximal veins.

Blood Circulation↗
PubMed1986

Clinical features and diagnosis of venous thrombosis.

The clinical diagnosis of venous thrombosis is inaccurate because the clinical findings are both insensitive and nonspecific. The sensitivity of clinical diagnosis is low because many potentially dangerous venous thrombi are clinically silent. The specificity of clinical diagnosis is low because the symptoms or signs of venous thrombosis all can be caused by nonthrombotic disorders. For these reasons, a practical approach for the diagnosis of venous thrombosis is important. A current approach to the diagnosis of clinically suspected venous thrombosis favors the use of impedance plethysmography over Doppler ultrasonography as the main test for this disorder. This is because impedance plethysmography is precise and objective, whereas the interpretation of Doppler ultrasonography is subjective and requires considerable skill and experience to form reliable diagnoses. The use of serial impedance plethysmography has been evaluated recently in a prospective study. The rationale of repeated impedance plethysmography evaluation is based on the premise that calf vein thrombi are only clinically important when they extend into the proximal veins, at which point detection with impedance plethysmography is possible. Therefore, by performing repeated examinations with impedance plethysmography in patients with clinically suspected venous thrombosis, it is possible to identify patients with extending calf vein thrombosis who can be treated appropriately. Impedance plethysmography is performed immediately on referral; if it is positive in the absence of clinical conditions that are known to produce falsely positive results, the diagnosis of venous thrombosis is established, and the patient is treated accordingly. If the result of the initial impedance plethysmography evaluation is negative, anticoagulant therapy is withheld, and impedance plethysmography is repeated the following day, again on day 5 to 7 and on day 10 to 14. If impedance plethysmography becomes positive during this time, a diagnosis of venous thrombosis is made and anticoagulant therapy is commenced. Positive impedance plethysmography in the presence of conditions known to produce a false positive result (for example, congestive cardiac failure) should be confirmed by venography. If noninvasive tests for the diagnosis of venous thrombosis are not available, a clinical suspicion of venous thrombosis should be objectively confirmed or excluded by performing ascending venography.

Diagnosis, Differential↗
PubMed1986

Diagnosis of pulmonary embolism.

The clinical diagnosis of pulmonary embolism is highly nonspecific because none of the symptoms or signs of pulmonary embolism is unique and all may be caused by other cardiorespiratory disorders. Thus, objective testing is mandatory to either confirm or exclude a diagnosis of pulmonary embolism. Based on current available information, a diagnostic approach for the management of clinically suspected pulmonary embolism is proposed. After a history and physical examination, electrocardiogram and chest X-ray film, all patients should undergo perfusion lung scanning. The finding of a normal perfusion lung scan rules out clinically significant pulmonary embolism, and anticoagulant therapy is withheld. The management of patients with an abnormal perfusion lung scan is more complex. If this scan demonstrates one or more segmental (or greater) perfusion defects, ventilation lung scanning should be performed because the probability of pulmonary embolism is markedly increased if a mismatch is found, with a high probability scan (positive predictive value 86%) providing an end point for commencing anticoagulant therapy in the majority of patients. In an abnormal ventilation-perfusion study, the presence of a ventilation-perfusion match does not rule out the possibility of pulmonary embolism, and further objective testing is required in these patients with nonhigh probability scans. Similarly, in patients with small perfusion defects (one or more subsegmental defects) or indeterminate lung scan findings (in which the perfusion scan defects correspond to a defect on a chest X-ray film), the predictive values obtained from these ventilation-perfusion scan patterns are not sufficiently high or low to confirm or exclude the presence of pulmonary embolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis, Differential↗
PubMed1986

The haemorrhagic and antithrombotic effects of dermatan sulphate.

Heparin and dermatan sulphate are effective antithrombotic agents but the clinical use of heparin is complicated by haemorrhage. The haemorrhagic effect of dermatan sulphate is unknown. In this study we compared the antithrombotic, haemorrhagic and anticoagulant effects of heparin and dermatan sulphate in rabbits. The antithrombotic effect was measured as prevention of venous thrombus formation. The haemorrhagic effect was measured as 51Cr-blood loss from standardized cuts in rabbit ears. The anticoagulant effect was measured as changes in the APTT, TCT and circulating anti-factor Xa level, and the formation of 125I-thrombin/inhibitor complexes ex vivo. The effect of heparin and dermatan sulphate on collagen-induced platelet aggregation was measured ex vivo. Maximal antithrombotic effects of heparin and dermatan sulphate were achieved with 70 and 500 micrograms/kg respectively. A 20-fold increase in heparin dose caused an 8-fold increase in blood loss and higher doses (40- and 80-fold increases) caused further dose-related increases in blood loss (13- and 35-fold increases respectively). In contrast, a 20- to 40-fold increase in the antithrombotic dose of dermatan sulphate did not increase blood loss and an 80-fold dose increase caused only a 7-fold increase in blood loss. There was no relationship between the antithrombotic and haemorrhagic effects of either heparin or dermatan sulphate and their anticoagulant activities. In contrast, there was a relationship between the dose-related enhancement of blood loss by these glycosaminoglycans and the inhibition of collagen-induced platelet aggregation ex vivo. These results suggest that dermatan sulphate is less haemorrhagic than heparin at equivalent antithrombotic doses, and that the haemorrhagic effect is associated with a glycosaminoglycan-induced platelet defect.

Animals↗
PubMed1986

Mechanisms for inhibition of the generation of thrombin activity by sulfated polysaccharides.

Three mechanisms by which sulfated polysaccharides act as anticoagulants and possibly as antithrombotic agents have been described. These are the two heparin cofactor-dependent mechanisms involving the catalysis of the inhibition of various proteases of coagulation by either antithrombin III or heparin cofactor II. The third is a heparin cofactor-independent mechanism involving the inhibition of formation of prothrombinase and tenase complexes. Four sulfated polysaccharides previously shown to have anticoagulant and antithrombotic effects were assessed to determine which of the three mechanisms operate in the expression of their anticoagulant effects. To do this, [125I]prothrombin was added to undiluted human plasma, and the inhibition of [125I]prothrombin activation, or the catalysis of the formation of thrombin-inhibitor complexes was determined in plasma containing one of the four sulfated polysaccharides. Prothrombin activation was demonstrated by the formation of [125I]prothrombin fragment 1.2 and [125I]thrombin. The effect of the thrombin-specific inhibitor, D-Phe-L-Pro-L-ArgCH2Cl (PPACK), on prothrombin activation was also investigated to determine the role of thrombin-dependent feedback reactions on efficient prothrombin activation. Use of PPACK with sulfated polysaccharides also facilitated estimation of the role of the heparin cofactor-independent effects of sulfated polysaccharides on prothrombin activation. Three concentrations of each of the sulfated polysaccharides were used: 0.66, 6.6, and 66 micrograms/ml of plasma. PPACK (1.0 X 10(-6)M) completely inhibited both intrinsic and extrinsic prothrombin activation. The inhibition of prothrombin activation caused by PPACK was abolished when thrombin was added to the plasma before PPACK. These observations indicate that the presence of trace thrombin activity is critical for efficient prothrombin activation by both the intrinsic and extrinsic pathways. All three concentrations of standard heparin completely inhibited the intrinsic activation of prothrombin. This inhibition was only partially abolished when thrombin was added to the plasma before heparin, indicating that heparin inhibits prothrombin activation both by catalyzing the inhibition of thrombin activity and by a heparin cofactor-independent mechanism. Heparan sulfate did not inhibit intrinsic prothrombin activation but catalyzed the inhibition of the thrombin generated by the formation of thrombin-antithrombin III complex. Dematan sulfate inhibited intrinsic prothrombin activation only at the highest concentration. At the two lower concentrations, dermatan sulfate catalyzed formation of thrombin-heparin cofactor II.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Chloromethyl Ketones↗
PubMed1986

Delimiting regulatory sequences of the Drosophila melanogaster Ddc gene.

We delimited sequences necessary for in vivo expression of the Drosophila melanogaster dopa decarboxylase gene Ddc. The expression of in vitro-altered genes was assayed following germ line integration via P-element vectors. Sequences between -209 and -24 were necessary for normally regulated expression, although genes lacking these sequences could be expressed at 10 to 50% of wild-type levels at specific developmental times. These genes showed components of normal developmental expression, which suggests that they retain some regulatory elements. All Ddc genes lacking the normal immediate 5'-flanking sequences were grossly deficient in larval central nervous system expression. Thus, this upstream region must contain at least one element necessary for this expression. A mutated Ddc gene without a normal TATA boxlike sequence used the normal RNA start points, indicating that this sequences is not required for start point specificity.

Alcohol Dehydrogenase↗
PubMed1986

In vivo effects of low molecular weight heparins on experimental thrombosis and bleeding.

Recent studies with heparin fractions indicate that it is possible to dissociate the antithrombotic and hemorrhagic effects of heparin and so improve its therapeutic potential. Heparin inhibits blood coagulation by 3 independent mechanisms by augmenting the effect of antithrombin III (the major effect), by augmenting the inhibitory effect of thrombin or heparin cofactor II, and by disrupting the activation of blood coagulation on the platelet surface; it has an additional effect on hemostasis through its interaction with blood platelets. Some insight into the mechanism of heparin-induced bleeding has been provided by studies with low molecular weight heparins. These heparins have reduced antithrombin activity but retain anti-Xa activity and have antithrombotic properties in animals with a reduced risk of bleeding. There is evidence that the reduction in the bleeding risk is unrelated to the anticoagulant effect of these low molecular weight heparins, but that it may be related to the observation that they inhibit platelet function less than standard heparin. The very low molecular weight heparins (molecular weight 3,000 daltons), have virtually no anti-IIa activity and are relatively weaker antithrombotic agents than low molecular weight heparins of 5,000 daltons. A minimal amount of anti-IIa activity is required for full expression of the antithrombotic activities of these low molecular weight heparins.

Animals↗