Biomedical subjects
Publications and source records attributed to J Hirsh.
We performed studies to investigate the effect of protamine sulfate neutralization on both the anticoagulant and hemostatic effects of enoxaparin and heparin. Although the anti-Factor Xa effect of enoxaparin was incompletely neutralized by protamine sulfate in an experimental animal model, protamine sulfate reversed bleeding induced by hemorrhagic doses of enoxaparin.
The monitoring of heparin anticoagulation is fraught with difficulties because of the need for repetitive venipunctures and the vagaries of sample handling and processing. The authors evaluated a new aPTT monitoring system with the potential to eliminate many of these difficulties. The Ciba Corning Diagnostics 512 Coagulation Monitor (CCD monitor) is a hand-held portable instrument that can measure an aPTT from a fingerstick sample of capillary whole blood. Fingerstick aPTTs from 319 subjects (including controls and individuals on heparin and/or warfarin) were compared to venipuncture-derived standard laboratory plasma aPTTs using different aPTT reagents on conventional instruments. The correlation coefficients between fingerstick and standard aPTTs (0.79-0.83) were the same as the correlation coefficient between standard laboratory aPTTs using different reagents (0.79). When venipuncture-derived whole blood was compared to fingerstick samples on the new instrument, the correlation coefficient was excellent (0.93). A high degree of precision, as demonstrated by low coefficients of variations, was shown for within-day and between-day testing using the CCD monitor and normal controls. This capillary whole blood, aPTT system is the first to provide the clinician with a means of rapidly and reliably assessing the anticoagulant response to heparin therapy at the bedside, and its use may ultimately lead to more efficient and effective therapy overall.
A nomogram for the adjustment of heparin dosage was developed to standardize heparin therapy and to reduce delays in achieving and maintaining a therapeutic activated partial thromboplastin time (APTT) result. Fifty consecutive patients with acute venous thromboembolism had their continuous intravenous heparin therapy adjusted according to this heparin nomogram. The effect of the nomogram on heparin therapy in these patients was compared with data from 53 historical control patients. The proportion of patients in the nomogram group who reached a therapeutic APTT at 24 hours after the start of heparin therapy was 66%, which increased to 81% at 48 hours. In contrast, 37% and 58% of the control patients reached a therapeutic APTT at 24 and 48 hours, respectively. The percentage of therapeutic APTT results of the total number of APTT determinations was greater in the nomogram patients than controls. The use of this heparin nomogram resulted in (1) achieving a therapeutic APTT at 24 and 48 hours in a large proportion of patients and (2) reduced periods of inadequate anticoagulation and overanticoagulation during heparin therapy.
We critically evaluated the evidence for an association between venous thromboembolism and impaired fibrinolytic activity, as determined by global tests of fibrinolytic activity or specific tests for tissue plasminogen activator and plasminogen activator inhibitor. A computer-assisted and manual search was performed to retrieve all articles that reported on fibrinolytic activity and venous thromboembolism. The strength of the evidence for an association was assessed by analysis of the design of individual studies with special attention directed to choice of controls and methods of diagnosis of venous thromboembolism. It is concluded that for patients with symptomatic thrombosis the published evidence does not prove an association between impaired fibrinolytic activity and increased risk of thrombosis. In contrast, for postoperative thrombosis there is good evidence for an association between impaired fibrinolytic activity measured either preoperatively or postoperatively and increased risk of postoperative thrombosis. Whether this association is causal or coincidental is unclear, since randomized clinical trials that used interventions to enhance fibrinolytic activity produced inconsistent results.
The risk of pulmonary embolism increases with age. Risk factors in the elderly include stasis caused by immobility and reduced venous tone, the increasing need for operative procedures, particularly orthopedic procedures to hip and knee, and reduced fibrinolytic activity in leg veins. The diagnosis of pulmonary embolism is difficult and is made on the basis of clinical probability, lung scan findings, investigations for deep venous thrombosis and, when indicated, by pulmonary angiography. Effective prophylactic and therapeutic approaches are now available.
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We evaluated the evidence in support of the suggestion that the risk of deep vein thrombosis after hip surgery is lower with regional than with general anesthesia. A literature search was performed to retrieve all articles which reported on the incidence of postoperative thrombosis in both fractured and elective hip surgery. Articles were included if the method of anesthesia used was reported and if they used mandatory venography. Based upon the quality of study design the level of evidence provided by a study was graded. In patients who did not receive prophylaxis there were high level studies in elective and fractured hip surgery. All studies showed a statistically significantly lower incidence of postoperative deep vein thrombosis with regional anesthesia (relative risk reductions of 46-55%). There were no direct comparative studies in patients who received prophylaxis. However, between study comparisons did not show even a trend towards to lower incidence of postoperative thrombosis with regional anesthesia.
The pattern of clearance of intravenously administered heparin suggests the participation of a saturable mechanism which has been ascribed to heparin binding to the endothelium. Another potential site of heparin binding which may contribute to the saturable mechanism is the red blood cells. We have examined this possibility using unfractionated heparin together with a chemically-modified low affinity heparin labelled with tritium as tracer. Unfractionated heparin and the radioactive tracer were added to pooled plasma at a fixed concentration. The heparinized plasma was mixed with red cells to reconstitute whole blood. After centrifugation, the radioactivity, APTT, anti-Xa and anti-IIa activities were measured in the resultant plasmas. No evidence of significant binding to red cells could be detected even when the hematocrits of the reconstituted whole blood were increased. These results are at variance with those of a previously published report. We conclude that red cell binding does not contribute to the saturable mechanism of heparin clearance.
In order to provide estimates of the risks of symptomatic osteoporosis and reduced bone density in premenopausal women treated with long-term (greater than 1 month) heparin therapy, we evaluated a cohort of 61 consecutive premenopausal women previously treated with long-term heparin (cases) and a group of controls matched for age, parity and duration between the last pregnancy and evaluation. All patients underwent dual photon absorptiometry of the lumbar spine and single photon absorptiometry of the wrist and most cases underwent plain lateral radiography of the thoracolumbar spine in order to exclude silent fractures. Although none of the cases suffered symptomatic fractures (0 of 61, 95% confidence intervals 0.0 to 5.9%), there was a significantly greater proportion of cases than controls with bone density below our pre-defined levels. The long-term implications of our findings are uncertain but because it is possible that the reduction in bone density predisposes women to fractures, this potential risk should be considered when treating women with long-term heparin.
It is common practice to begin anticoagulant treatment of deep-vein thrombosis with a 10-day course of intravenous heparin, with warfarin added on day 5 to 10 and continued for several months. We performed a randomized, double-blind trial comparing a shorter course of continuous intravenous heparin (5 days, with warfarin sodium begun on the first day) with the conventional 10-day course of heparin (with warfarin sodium begun on the fifth day) in the initial treatment of 199 patients with acute proximal venous thrombosis documented by venography. The frequency of objectively documented recurrent venous thromboembolism was low and essentially the same in the two groups (7.1 percent in the short-course group vs. 7.0 percent in the long-course group). Because the observed difference between the groups was 0.1 percent in favor of the long-course group, it is unlikely (P less than 0.05) that a true difference in favor of this group would be greater than 7.5 percent; the difference could be as much as 7.3 percent in favor of the short-course group. Major bleeding episodes were infrequent, and the rate was similar in both groups. We conclude that a five-day course of heparin is as effective as a 10-day course in treating deep venous thrombosis. Furthermore, using the shorter course would permit earlier discharge from the hospital and thus offer substantial cost savings.
It has been suggested that protamine sulfate is a poor antidote for the bleeding side-effects of low molecular weight heparins (LMWHs) in vivo, since protamine sulfate does not completely neutralize the anti-factor Xa activity of LMWHs in vitro or ex vivo. Therefore, we performed experiments to compare directly the abilities of protamine sulfate to neutralize the anticoagulant activities of the LMWH, enoxaparine, and unfractionated heparin ex vivo, with its ability to neutralize the bleeding side-effects of both compounds in vivo. Bleeding was measured as the amount of blood lost from 5 cuts made in rabbits ears before and after treatment with enoxaparine or unfractionated heparin +/- protamine sulfate. Plasma anti-factor Xa and anti-thrombin activities ex vivo, were measured chromogenically. Doses of 400 and 1,500 anti-factor Xa U/kg of heparin and enoxaparine, respectively, were required to enhance blood loss to the same extent. Protamine sulfate completely neutralized blood loss induced by both compounds, but did not neutralize the anti-factor Xa nor antithrombin activities ex vivo. We conclude that protamine sulfate is an effective antidote for the bleeding side-effects of enoxaparine and unfractionated heparin, despite its inability to completely neutralize their anticoagulant activities.
Venous thrombosis and pulmonary embolism are closely related disorders. As many as 70 to 80% of patients with pulmonary embolism have associated proximal deep venous thrombosis. The clinical diagnosis alone of both venous thrombosis and pulmonary embolism is inaccurate because of the insensitivity and nonspecificity of findings, a problem that also occurs with a variety of other disorders. Invasive, objective tests are still the reference standard, but they are not always easy to perform, they cannot be used for a considerable number of very ill patients, and they create some patient discomfort. There is an increasing trend toward using noninvasive methods, either alone or in combination. These methods entail less risk, can be performed more quickly and conveniently, and are usually more cost-effective. Practical approaches to diagnosing venous thrombosis and pulmonary embolism in the clinical setting are discussed.
We performed studies to determine the relationship between injured vessel wall thrombogenicity, vessel wall 13-hydroxyoctadecadienoic acid (13-HODE) synthesis and cAMP levels in rabbit treated with salicylate or dipyridamole. Injured vessel wall thrombogenicity was measured as the number of 3H-adenine labelled platelets adhered to the subendothelial basement membrane exposed by air injury in carotid arteries of rabbits treated orally with salicylate or dipyridamole. Vessel wall 13-HODE was measured by HPLC and vessel wall cAMP was measured by RIA. Vessel wall thrombogenicity was increased two-fold in rabbits treated with salicylate and decreased by half in rabbits treated with dipyridamole. The levels of vessel wall cAMP levels were correlated both with the plasma dipyridamole levels and increases in 13-HODE synthesis. cAMP levels were unaffected by salicylate treatment, but 13-HODE synthesis was decreased. We conclude that there is a significant relationship between vessel wall cAMP levels and 13-HODE synthesis, which in turn, influences subsequent vessel wall thrombogenicity.
Several genes have been identified that affect the specification of unique neuronal identities during development of the Drosophila central nervous system. At least two of these genes, fushi tarazu (ftz) and even-skipped (eve) share a common structural motif, the homoeobox, which encodes a sequence-specific DNA-binding domain (homoeodomain). A family of related proteins has been recently characterized in mammals and nematodes that contain a diverged homoedomain as part of a structure referred to as a POU domain. Mammalian genes encoding POU domains have region-specific patterns of expression in the central nervous system, indicating a potential role for them in the regulation of neuronal development. The nematode POU-domain gene, unc-86, is involved in the determination of neuroblast lineages leading to serotonergic and dopaminergic neurons. We have now identified a Drosophila gene, Cfla, encoding a sequence-specific DNA-binding protein containing a highly conserved POU domain. The Cfla gene product binds to a DNA element required for expression of the dopa decarboxylase gene (Ddc) in selected dopaminergic neurons, implying that it functions as a neuron-specific transcription factor.
In recent years there has been an explosion of clinical trials evaluating low molecular weight (LMW) heparin both in the prevention of venous thrombosis and in the treatment of established venous thrombosis. Results to date would indicate that LMW heparin is an effective method of prophylaxis and has a negligible risk of bleeding, provided the anti-factor Xa levels 4-6 h after injection do not exceed 0.2 units/ml. There is suggestive evidence that, if LMW heparin is given in doses which produce anti-factor Xa levels of more than 0.4 units/ml, there is an increased risk of perioperative bleeding in surgical patients. Although three studies have reported that LMW heparin is more effective than standard unfractionated low dose heparin in the prevention of venous thrombosis, further studies evaluating risks and benefits are required. The promising experimental findings that LMW heparin produces less bleeding for equivalent antithrombotic efficacy has yet to be established in man. Results of clinical trials in neurosurgical patients, patients undergoing knee surgery and patients undergoing cardiac surgery may establish whether LMW heparin is advantageous in such patients at very high risk for bleeding. Finally, the early results from randomized trials suggest that LMW heparins are effective in the treatment of established venous thrombosis, but further trials are required.
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Propagation of venous thrombi or rethrombosis after coronary thrombolytic therapy can occur despite heparin administration. To explore potential mechanisms, we set out to determine whether clot-bound thrombin is relatively protected from inhibition by heparin-antithrombin III but susceptible to inactivation by antithrombin III-independent inhibitors. Using plasma fibrinopeptide A (FPA) levels as an index of thrombin activity, we compared the ability of thrombin inhibitors to block FPA release mediated by fluid-phase thrombin with their activity against the clot-bound enzyme. Incubation of thrombin with citrated plasma results in concentration-dependent FPA generation, which reaches a plateau within minutes. In contrast, there is progressive FPA generation when fibrin clots are incubated with citrated plasma. Heparin, hirudin, hirudin dodecapeptide (hirugen), and D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (PPACK) produce concentration-dependent inhibition of FPA release mediated by fluid-phase thrombin. However, heparin is much less effective at inhibiting thrombin bound to fibrin because a 20-fold higher concentration is necessary to block 70% of the activity of the clot-bound enzyme than is required for equivalent inhibition of fluid-phase thrombin (2.0 and 0.1 U/ml, respectively). In contrast, hirugen and PPACK are equally effective inhibitors of fluid- and solid-phase thrombin, while hirudin is only 50% as effective against the clot-bound enzyme. None of the inhibitors displace bound 125I-labeled thrombin from the clot. These studies indicate that (a) clot-bound thrombin is relatively protected from inhibition by heparin, possibly because the heparin binding site on thrombin is inaccessible when the enzyme is bound to fibrin, and (b) clot-bound thrombin is susceptible to inactivation by antithrombin III-independent inhibitors because the sites of their interaction are not masked by thrombin binding to fibrin. For these reasons, antithrombin III-independent inhibitors may be more effective than heparin in certain clinical settings.
Although recombinant tissue-type plasminogen activator (rt-PA) has the potential to induce thrombolysis without producing a generalized coagulopathy, the dosage regimens in present use induce a plasma fibrinolytic state and are associated with bleeding. Animal experiments have demonstrated that rt-PA produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is increased and bleeding is reduced when rt-PA is administered over a short time period. To determine whether a short course regimen of rt-PA has potential in man, we gave a bolus injection of rt-PA (0.6 mg/kg) concurrently with heparin to five patients with venous thromboembolism. Three patients with angiographically proven pulmonary embolism had marked improvement of the perfusion defects when lung scans were repeated 24 h after rt-PA administration. In one of two patients with thrombosis of the deep veins of the upper extremity the venographic defect resolved completely. In three of four patients there was a mild decrease in fibrinogen and a moderate decrease in alpha 2-antiplasmin levels. There was no excessive bleeding. These results suggest that a bolus injection regimen of rt-PA has considerable potential in the treatment of thromboembolic disease.