Prevention and management of bleeding complications after thrombolysis

International Journal of Cardiology, 38 (1993) l-6 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0167-5273/93/$06.00

CARD10 01584

Review

Prevention and management of bleeding complications after thrombolysis D.P. de Bono and R.S. More Department of Cardiology, University of Leicester, Clinical Science Wing, Glenfield General Hospital, Leicester, UK

(Received 25 August 1992; accepted 25 August 1992)

Key words: Thrombolysis;

Bleeding; Inhibition of fibrinolysis

In terms of patient numbers treated, coronary thrombolysis has now far outstripped all other forms of thrombolytic therapy. Because of the need for speed in initiating coronary thrombolysis, both the decision to administer such treatment and its supervision are usually in the hands of those trained in general medicine or cardiology rather than haematologists. In general, this policy has led to a widespread but seldom inappropriate use of thrombolysis, and to a very favourable balance between benefits and side effects. Several large controlled trials of thrombolytic therapy have provided data from which the incidence of bleeding complications can be estimated, although the absence of a standardised set of criteria makes cross-trial comparison difficult [1,2]. The most satisfactory definition of a “major” bleeding complication is one which causes death or permanent disability, or which prolongs the patient’s hospital stay. Transfusion requirements are an unsatisfactory criterion, as the indications seem to vary from country to country, and from unit to unit. There is a clear-cut

Correspondence fo: Prof. D.P. de Bono, Dept. of Cardiology, University of Leicester, Clinical Science Wing, Glenfield General Hospital, Leicester LE3 9QP, UK.

distinction between trials which involve arterial intervention (for coronary angiography or angioplasty) and those which do not (Table 1). The average rate of major bleeding complications in the former is around 30%, in the latter less than 5%. The difference is largely accounted for by local bleeding at the puncture site. The average incidence of intracerebral bleeding in several large trials is about 0.8%. The risk of intracerebra1 bleeding is increased by age, hypertension, low body weight, coincident head injury, previous stroke and, curiously, previous coumarin anticoagulation [3,4]. Pooled incidence rates for other types of bleeding are summarised in Table 2. Entry criteria for clinical trials are designed to avoid bleeding complications, and are often more stringent than would necessarily apply in ordinary clinical practice. Whilst there are numerous anecdotal reports of complications when thrombolytic therapy has inadvertently been given to patients with major contraindications, it is difficult to convert these into a true incidence estimate. Analysis of outcome in patients with dissecting aneurysm of the aorta inadvertently given thrombolytic therapy suggests a mortality of 50%, but this has to be set against a mortality of around 30% in such patients correctly diagnosed and not given thrombolysis.

2

TABLE 1 Bleeding complications in coronary thrombolysis trials with and without arterial intervention. Trial

Agent

AntiTotal coagulant bleeding complications (o/o)

Patient numbers

The mechanisms of bleeding in the context of thrombolytic therapy have traditionally been defined as: (i) lysis of a pre-existing haemostatic plug, (ii) direct consequences of fibrinogen depletion, (iii) side effects of continuing anticoagulation [2,5,6]. These now need closer examination.

Lysis of a pre-existing haemostatic plug

Studies involving early angiography

ECSG II r-tPA (0.75 mg/kgI ECSG II SK(1.5 MU) TIMI I SK(1.5 MU) TIMI I r-tPA (40/20/20 mg) ECSG IV r-tPA (100 ms)+ PTCA SWIFT APSAC(30U) + PTCA TAM1 I r-tPA (150 mg)

HW

23

64

HW HW HW

44 47 44

64 122 118

HA

41

183

HW

20

397

HW

42

386

Studies not involving early angiography

GISSI 1 ISIS 2 ISIS 2 ISIS 2 AIMS AIMS ASSET ASSET ISIS 3 ISIS 3 ISIS 3 GISSI 2 GISSI 2

SK(1.5 MU) SK(1.5 MU) SK(1.5 MU) Placebo APSAC(30 U) Placebo r-tPA (100 mg) Placebo SK(1.5 MU) r-tPA (100 mg) APSACOO Ul SK(1.5 MU) r-tPA (100 mg)

U U/A A U HW HW H

3.7 4.0 4.5 1.0 5.4 2.7 7.6

5 860 8490 4 239 4238 502 502 2512

H HA HA

0.8 4.5 5.2

2493 13780 13746

HA HA HA

5.4 7.9 8.5

13 773 6199 6182

H = heparin; W = warfarin; A = aspirin; SK = streptokinase; MU = million units; U = unspecified.

Examples include bleeding from a recent arterial catheterisation site, extension of a haematoma from a recent head injury, and bleeding from a pre-existing ulcer or varices. Gross haematuria may occur in patients with unsuspected bladder or kidney tumours. Such bleeding tends to follow the same time course as therapeutic thrombolysis: it occurs early, and its likelihood, in susceptible patients, parallels the efficacy of the thrombolytic regimen [7]. The main protection against such bleeding is case selection; its management will be discussed below. A special case of this phenomenon is bleeding associated with therapeutic or diagnostic arterial or venous puncture [S]. Unnecessary vascular interventions should be avoided; attention to technique (avoid uncompressible puncture sites, leave in vascular sheaths of appropriate size, repair arteries by direct suture if necessary) minimises the risk of necessary intervention.

Direct consequences of fibrinogen depletion In the early part of our current experience with thrombolysis, it seems in retrospect that we overrated the importance of fibrinogen depletion as a primary cause of bleeding. Because strepto-

TABLE 2 Combined data from ISIS-3 and GISSI-2 on non-cerebral bleeds associated with use of thrombolytic agents and heparin.

?Z=

SK 19 979

r-tPA 19 928

APSAC 13 773

Heparin 26 831

No heparin 26 849

Total bleeds (%I Major bleed (%I

5.6 0.9

6.2 0.7

5.4 1.0

7.3 1.0

4.3 0.8

3

kinase and anistreplase both cause major fibrinogen depletion, and tissue plasminogen activator does not, it was inferred that tissue plasminogen activator would cause less haemorrhage than streptokinase [5,9]. This has not, in general, been confirmed in clinical studies [lO,lll. Although one early trial did appear to show fewer minor bleeding complications with tissue plasminogen activator [12], there has been no consistent difference with respect to major bleeding complications, or even in some trials, a higher cerebral bleed rate with tissue plasminogen activator [ll]. Factors which may be relevant to this observation are: (i) measured circulating fibrinogen concentration, especially if chemical precipitation techniques are used, may be measuring haemostatically ineffective fibrinogen [13]; (ii) low fibrinogen concentrations (for example, when associated with hereditary afibrinogenaemia) are not necessarily associated with a marked increase in bleeding risk [14]; (iii) platelet associated fibrinogen may be as important, haemostatically, as free circulating fibrinogen. It is simplistic to separate fibrinolytic activity from platelet function. Both platelet activation and inhibition have been reported in association with fibrinolytic therapy, but with different time courses. Platelet activation tends to be seen early after the administration of thrombolytic agents, while platelet inhibition predominates later 1153. Thrombolytic agents have little effect on established platelet thrombi, but addition to plasminogen-sufficient platelet rich plasma inhibits subsequent thrombin induced aggregation. Suggested mechanisms of platelet activation include thrombin or plasmin-mediated aggregation [161. Alternatively the platelet proaggregant effect may represent idiosyncratic, possibly antibody mediated, reactions analogous in mechanism to heparin induced platelet aggregation and thrombocytopenia [171. Conversely, persisting circulatory fibrinolytic activity is associated with a prolonged cutaneous bleeding time in man [18], and in animal models [19]. We have shown that in rats human tissue plasminogen activator infusion causes a marked prolongation of bleeding time which is correctable with plasmin inhibitors such as aprotinin

PI.

Several mechanisms have been proposed to explain platelet inhibition by fibrinolytic agents. These include inhibition of platelet arachidonic acid metabolism by low dose plasmin, and selective lysis of fibrinogen bound to the platelet surface. In addition, the products of fibrin and fibrinogen degradation released during fibrinolysis may interfere with fibrinogen binding to platelet [ 161. Platelet aggregation is primarily dependent on the glycoprotein IIb/IIIa receptor for which fibrinogen or fibrin are important ligands [21]. Covalent conjugates of urokinase and a monoclonal antibody to the IIb/IIIa receptor cause more inhibition of adenosine diphosphate-induced platelet aggregation in vitro than either antibody or urokinase alone [22]. There is strong clinical evidence that the risk of bleeding from initially “normal” vessels increases as a function of time for which thrombolysis has been continued (this parallels clinical experience with severe thrombocytopenia). The major clinical use of thrombolytic therapy, for the treatment of coronary thrombosis, actually involves a relatively short duration of circulatory thrombolytic activity, and there is a strong correlation between the adoption of a “short-term high dose” approach to thrombolysis and a reduction in bleeding complications [231. Recently, the policy of “short-term high dose” thrombolysis has also been shown to be effective in the management of pulmonary embolism [24]. Prolonged thrombolytic therapy is still required in the treatment of peripheral arterial thrombosis, and this use is still accompanied by a relatively high risk of bleeding, exacerbated by the need for arterial puncture to perform angiography [25].

Interactions with continuing anticoagulant therapy The necessity for continuing anticoagulant therapy to reap the full benefits of thrombolysis continues to be controversial. The ISIS-3 trial suggested that high dose subcutaneous heparin had no significant effect on 35-day survival, although at an earlier stage patients receiving heparin appeared to have fewer reocclusion episodes [ll]. The European cooperative study group trial

4

of tissue plasminogen activator thrombolysis with or without concomitant heparin showed significantly better coronary patency in the heparin-receiving group [26]. Some years ago we found that recurrent ischaemia in patients given anistreplase and heparin (but not aspirin) was more common at the time when the heparin infusion was terminated, and this has recently been echoed in a study on patients with unstable angina [27,28]. There is a definite trend towards increased bleeding in patients given heparin, and this appears to parallel the level of anticoagulation achieved as measured by the activated partial thromboplastin time. In patients who have received streptokinase or anistreplase the anticoagulant effect of fibrin degradation products will also prolong the activated partial thromboplastin time or thrombin time [13] but reptilase time estimation may help to determine the cause. The use of platelet antiaggregants such as acetylsalicylic acid to enhance thrombolytic efficacy has been virtually universal in myocardial infarct management since the ISIS-2 trial [21. There is little evidence that aspirin in the context of short-term thrombolysis seriously worsens bleeding risk, but studies with other platelet antiaggregants in the context of longer-term fibrinolytic therapy indicate an increase both in functional thrombolytic activity and in bleeding complications [29]. Experience is still limited with very potent platelet inhibitors such as monoclonal antibody to GPIIa/IIIb [30]. Most platelet inhibitors are not pharmacologically reversible, and substitution of fresh platelets would be the only effective means of reversing the coagulation defect.

Investigations in patients with thrombolysis-associated bleeding problems Virtually by definition, serious bleeding problems require rapid reaction, and sophisticated but time-consuming tests are pointless. Moreover, most thrombolytic therapy takes place in district general hospitals without sophisticated coagulation facilities. The objectives are: (i) to decide whether there is residual thrombolytic activity, (ii> to evaluate the nature of any consequential coag-

TABLE 3 Plasma half-life of thrombolytic agents.

Agent r-tPA

Clearance half-life (min) 2-7

Prolonged thrombolytic activity may occur in thrombus

Urokinase

10

Persistence of thrombolysis may be less than with SK

Streptokinase

25

Effective fibrinolysis may persist 4-6 h May vary with antibody level

APSAC

SO-90

Long half-life may aid thrombolysis

ulation defect, (iii) to monitor the correction of the defect. Classically, residual thrombolytic activity was monitored using the euglobulin lysis time [31], but this is time consuming and requires careful standardisation. Chromogenic substrate assays for tissue plasminogen activator or for plasmin activity are simpler and quicker, but may not be universally available [321. Extensive data are available on plasma halflives of thrombolytic agents (Table 3) and this information is useful in assessing the likelihood of residual thrombolytic activity; however, there is evidence for the persistence of thrombolytic activity within thrombi after it has been cleared from plasma, and it may be prudent to assume the persistence of some fibrinolytic activity up to 24 h after discontinuation of therapy. Measurement

of the haemostatic

defect

A prolonged skin bleeding time, or continuous bleeding from skin punctures, indicates a severe haemostatic defect, and probably continuing fibrinolysis. Very low plasma fibrinogen is usual after streptokinase or anistreplase, but “low normal” values after tissue plasminogen activator should also be regarded with suspicion. Prothrombin time ratio measurements are unhelpful,

but thrombin time, activated partial thromboplastin time and reptilase time measurements are useful. Correction

of haemostatic

defect

The first step is to discontinue administration of the thrombolytic agent and any concomitant anticoagulants. Since plasminogen activation is the final common pathway for fibrinolysis it is logical to use plasmin inhibition as a major strategy in reversing thrombolysis associated bleeding. Both aprotinin and tranexamic acid are effective plasmin inhibitors in vitro and in vivo. Clinical interest has centred on aprotinin because of the by now extensive experience of high dose aprotinin in cardiac surgery and liver transplantation [33]. Aprotinin is well tolerated, though there is some risk of anaphylaxis after repeated exposure. There have now been several reports of the use of aprotinin to reverse thrombolytic activity, most commonly in patients requiring major cardiac or vascular surgery. Typical doses are an initial loading dose of 2 million Kallikrein inhibitory units over 10 min, followed by 70,000 units per hour until haemostasis is secured. There has been less reported clinical experience with tranexamic acid, though in an animal model we found it more effective than aprotinin in preventing cerebral bleeding during tissue plasminogen activator infusion [20]. As a smaller molecule, it may diffuse into haematomata more readily than aprotinin; conversely it is more rapidly excreted and perhaps more likely to cause haemodynamic disturbances. The second priority after inhibiting plasmin is to replace fibrinogen, with fresh frozen plasma, fibrinogen concentrate or blood depending on the clinical and haemodynamic state of the patient. Fibrinogen replacement inevitably involves plasminogen repletion, so administration of plasmin inhibitors should continue, and fibrinogen levels need to be monitored. Overcorrection should be avoided, partly because it may induce coronary rethrombosis, and partly because post infarct patients are sensitive to volume overload. In conclusion: Serious bleeding complications are thankfully a rare complication of thrombolytic

therapy. Careful case selection and meticulous invasive techniques are important contributors to this. Early recognition of bleeding, prompt termination of thrombolysis, administration of plasmin inhibitors and fibrinogen repletion are the major steps in correcting the haemostatic defect.

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