Editorial I

Is there a bleeding problem with platelet-active drugs?

T. Kövesi and D. Royston

Platelets provide for primary haemostasis by forming a plug at sites of vascular damage. After initial adhesion, platelets aggregate to effect haemostatic plug formation. Platelet aggregation requires active platelet metabolism; stimulation by agonists such as adenosine diphosphate (ADP) or thrombin; divalent cations; specific plasma proteins such as fibrinogen; and a platelet receptor, the glycoprotein IIb/IIIa (GP IIb/IIIa) complex. Activation of the GP IIb/IIIa receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. During aggregation, ADP is released from the platelet to autoactivate its own receptor, thromboxane A2 (TxA2) is synthesized, and preformed serotonin is released to promote microvascular constriction, helping the plug to form a more solid hold on wound edges.

Platelet-active medications have diverse mechanisms of action, pharmacodynamic and adverse effect profiles. All the current drugs can prolong the skin bleeding time. One of the perceived risks of platelet active therapy is thus increased bleeding, especially after operative intervention or trauma. This editorial will address the following questions for each separate class of drug:

Is the risk of spontaneous and operative bleeding increased?

What is that risk, based on current literature?

What will be an appropriate intervention to reduce or prevent that risk?

Non-steroidal anti-inflammatory drugs (NSAIDs)

This class of drug can interfere with platelet function by several mechanisms involving inhibition of cyclooxygenase (COX).

Acetylsalicylic acid (the Bayer pharmaceutical company adopted the trade name Aspirin in 1899) is the only NSAID used therapeutically for its antiplatelet action and is the most widely used antiplatelet agent in clinical practice. Acetylation of platelet prostaglandin (PG) synthase by aspirin is irreversible. Its effects on platelet function and bleeding time recover only with the generation of a new population of platelets. The clinically relevant time to accomplish this is still a matter of debate. There is significant individual variability in the duration of haematological response after withdrawal of aspirin therapy. Two recent studies showed that skin bleeding time1 and platelet aggregation2 were abnormal for at least 48 h and, in some patients, this abnormality could be measured up to 10 days after withdrawal of therapy.

Spontaneous bleeding
Spontaneous gastric perforation, ulceration and bleeding are a major concern in the use of NSAIDs over a prolonged period. A particularly troublesome problem with NSAID gastropathy is that ulceration is often asymptomatic and frequently presents as perforation or haemorrhage. Although this is less of a problem with the newer COX-2 inhibitors, it is still reported to occur.3 Conventional therapies with antacids, histamine H2-receptor antagonists and proton pump inhibitors appear relatively ineffective in preventing NSAID-induced gastropathy. However, tranexamic acid (intravenously or orally) inhibits bleeding and prevents rebleeding.4

Surgical bleeding
Despite numerous studies, no firm conclusions can be drawn regarding an increased risk of surgical haemorrhage in haematologically normal patients given NSAIDs. The bulk of studies reported thus far have discussed the role of aspirin in cardiovascular surgery. Reports from the 1980s, which universally report a positive correlation between aspirin ingestion and increased bleeding, have been followed by studies showing no significant effect of aspirin on postoperative bleeding or the need for transfusion, even in higher-risk surgery.5

Specific therapy to reduce bleeding
On the basis of the duration of abnormality of haematological tests, it would seem prudent to discontinue aspirin within 48 h of elective surgery. If the patient requires more urgent surgery, there is good evidence that high-dose aprotinin will inhibit bleeding6 and that desmopressin (DDAVP)7 may also be useful. Interestingly, a recent meta-analysis showed that the use of systemic tranexamic acid had no effect on reducing transfusion requirements after cardiac surgery in patients who received aspirin.8

Purinergic or adenosine diphosphate receptor blockers

Adenosine 5'-diphosphate (ADP) is a key cofactor of platelet aggregation. Three separate families of membrane-bound ADP receptors (P2 receptors), with differing structures, mechanisms of action and functions, have been proposed. Currently available data are consistent with shape change being mediated by the high-affinity P2Y1 receptor, aggregation requiring the activation of two receptors.9 Each of these receptors appears to be essential, and neither is able to trigger aggregation alone.

Clopidogrel (Plavix; Sanofi Winthrop/Bristol-Myers Squibb) and ticlopidine (Ticlid; Sanofi Winthrop) are thienopyridine derivatives. Clopidogrel and ticlopidine are licensed for the secondary prevention of vascular events in patients with established atherosclerotic disease (ischaemic stroke, myocardial infarction and peripheral vascular disease).

Neither ticlopidine nor clopidogrel have antiplatelet activity in vitro but require metabolism by the hepatic cytochrome P450-1A system. Although their precise mechanism of action has not been identified, their antiplatelet effect appears to result from non-competitive antagonism of a platelet ADP receptor. About 70% of ADP receptors on the platelet are sensitive to the effects of thienopyridines. These are the low-affinity receptors responsible for platelet aggregation and adenylyl cyclase inhibition. The population of high-affinity receptors, presumed to be P2Y1 receptors, is resistant to treatment with clopidogrel.10 Thromboxane formation is normal, indicating that PG synthase is unaffected. Recovery occurs only with the generation of a new population of platelets, suggesting that antagonism is irreversible.11

Spontaneous bleeding
Spontaneous bleeding requiring hospital admission is less frequent in patients treated with thienopyridines than in those treated with aspirin. In an analysis of patients recruited into the CAPRIE study,12 205 of 9546 patients (2.15%) treated with aspirin and 169 of 9553 (1.77%) treated with clopidogrel had significant bleeding events. The major difference between the two groups was related to gastrointestinal bleeding, with 105 hospital admissions associated with aspirin administration compared with 71 with clopidogrel (P=0.012).

Surgical bleeding
The plasma half-life of ticlopidine is 30–55 h and that of clopidogrel is 20–50 h. These times are 2–3 times longer in the older patient.13 On the basis of this long half-life, it is recommended that clopidogrel is discontinued 7 days and ticlopidine 10–14 days before elective surgery. An increase in postoperative bleeding is reported in patients having cardiac14 or vascular15 surgery.

Specific therapy to reduce bleeding
Animal studies have shown that high-dose corticosteroids13 and aprotinin16 will partially reverse the effects of thienopyridines on the bleeding time. Aprotinin had no effects on the inhibition of thrombus formation by clopidogrel and its effect on the bleeding time was dose-dependent16 (Fig. 1). There is no confirmatory evidence of these effects in humans. There is one report of the correction of bleeding time with desmopressin in a ticlopidine-treated patient.17



View larger version (11K):
[in this window]
[in a new window]
 
Fig 1 Effect of clopidogrel 5 mg kg–1 in increasing bleeding time by 400% and effect of increasing doses of aprotinin on this increase. The line is fitted by least squares regression with y=14.7x+401; r2=0.92. 1 mg aprotinin=7142 kallikrein inhibitor units. Data are from Herbert and colleagues.16

 
Platelet glycoprotein receptor (GPIIb/IIIa) antagonists

Each platelet glycoprotein integrin is composed of an {alpha} and a ß subunit. The GPIIb/IIIa complex is the {alpha}IIb3 integrin. The interest in integrins stems from identification of their adhesion sites, the best characterized of which is the arginine-glycine-aspartate (RGD) motif,18 which is ubiquitous among adhesion molecules. The lysine-glycine-aspartate (KGD) sequence is also associated with adhesion but is specific for the fibrinogen receptor.

Three types of inhibitor of the integrin {alpha}IIb3 are currently available: abciximab, eptifibatide and tirofiban. All of these are given intravenously with a continuous intravenous infusion after a bolus (loading) dose. Results with all agents suggest that monotherapy is not as effective as combination treatment. For example, three randomized, controlled trials with tirofiban showed efficacy with heparin to be significantly greater than with the drug alone.19

Abciximab (c7E3 Fab, ReoPro; Centocor and Eli Lilly) is a non-specific GPIIb/IIIa receptor blocker developed from a mouse-human chimeric 7E3 Fab antibody. The recommended dose regimen produces 80–90% blockade of surface receptors.

Eptifibatide (Integrilin; COR Therapeutics/Schering-Plough) is a synthetic cyclic heptapeptide incorporating the KGD motif. In the UK it is licensed for those with acute coronary syndrome (ACS) in the preceding 24 h who do not fulfil the criteria for thrombolysis. The recommended dose aims to produce a two- to three-fold increase in bleeding time, which is associated with 95% blockade of the GpIIb/IIIa receptor.

The non-peptide inhibitors tested thus far use the RGD peptide sequence incorporated into an extraordinarily diverse range of different chemical entities. Tirofiban (MK-383, Aggrastat; Merck) is derived from tyrosine. The US Food and Drugs Administration approved this agent for treatment of ACS in 1998.

The efficacy of orally active agents reported thus far is less encouraging. For sibrafiban (Xubix; Genentech and Hoffman-La Roche), a recently reported trial showed no significant benefits over the use of aspirin alone in 9233 patients with acute coronary syndrome but major bleeding was more common with high-dose sibrafiban (5.7%) than with aspirin (3.9%).20

Spontaneous bleeding
Unless the patient is also receiving heparin or there is thrombocytopenia, spontaneous bleeding is uncommon. The incidence of intracranial bleeding, recorded in 15 850 patients given glycoprotein IIb/IIIa drugs alone, was similar to that with heparin alone (0.07 vs 0.06%).21 However, the risk of bleeding complications at other sites was increased when these agents were given with heparins. One of the earlier studies investigating abciximab22 reported a two-fold increased risk of major bleeding requiring intervention from sites unrelated to angiography (retroperitoneal, gastrointestinal etc.). However, continued investigation of this agent suggested a lower risk of haemorrhage when a reduced dose of heparin was used (70 U kg–1).23

Thrombocytopenia (platelet count less than 100 000 µl–1) occurs with all three drugs. The incidence was about 1 in 40 patients with abciximab;24 in half of the patients the decrease began 2 h after starting abciximab.22 Profound thrombocytopenia (platelet count less than 20 000 µl–1) within 24 h of treatment was reported in fewer than 1% of patients and improved spontaneously within 5 days after stopping abciximab. Spontaneous bleeding was more common in patients with thrombocytopenia, and mortality in these patients was also increased from 0.6% in patients with with a normal platelet count to 8.4% (P<0.001) in those with a low count.24 It is recommended that a platelet count should be performed within 2–4 h of instituting therapy as well as 12 and 24 h after starting therapy. Spontaneous bleeding and thrombocytopenia with eptifibatide and tirofiban are of equal concern but may be less of a clinical problem because of the more rapid return of platelet function with these agents.

Surgical bleeding
The focus on procedure-associated bleeding followed early reports of increased bleeding and the need for transfusion after cardiac interventions.22 As a result of their very effective inhibition of platelet aggregation, this clinical situation has been viewed with considerable concern, and reports of excessive bleeding and large transfusion requirements have been rumoured, reported25 26 and refuted.27 Why should there be this inconsistent and apparently contradictory literature?

As with the NSAIDs, the risk of increased postoperative bleeding may be related to the time required to reverse the actions of these agents. In addition to having different receptor affinities, the three agents differ in pharmacodynamic and pharmacokinetic profiles. Abciximab is a high-affinity agent with a very short plasma half-life (30 min) but a prolonged duration of action at the platelet target receptor (time to normal platelet aggregation, 48 h). Eptifibatide and tirofiban are low-affinity agents with a longer plasma half-life (about 100 min) but a relatively short duration of action at the target platelet receptor (time to normal platelet aggregation is about 8 h).

The questions are to define the occupancy of GP IIb/IIIa receptors that is ‘safe’ and the time to achieve that occupancy. Studies in the relatives of patients with congenital deficiencies show that, with 50% of normal GP IIb/IIIa, there is no evidence of abnormal platelet function or bleeding tendency.28 Therapeutic intervention aims to achieve 80–90% receptor occupancy, and this is associated with a two- to three-fold prolongation of bleeding time. The ‘safe’ occupancy must be between these figures.

When abciximab was discontinued, a gradual reduction in receptor blockade occurred. Twelve hours after discontinuation of the drug, about 70% of the receptors were still blocked, but a nearly normal bleeding time has been reported at this level.29 This process is accelerated with eptifibatide and tirofiban. The bleeding time returns to normal within 1 h of stopping eptifibatide, although return to 50% of baseline platelet aggregation took about 4 h.30

Gammie and associates highlighted the importance of the time course of return of platelet functions.26 Of the 11 patients detailed in their report, six had required coronary artery bypass grafting within 12 h of abciximab treatment. None of the patients died but some did have ‘substantial transfusion requirements and, at times, massive coagulopathies’. Median per patient values for blood product transfusions were as follows: red blood cells, 6 units; platelets, 20 units; frozen plasma, 4 units. In contrast, patients who received eptifibatide and required urgent surgery had blood loss and transfusion requirements similar to those of patients who received placebo.31 This supports the notion of time to recovery of haemostatic function as the principal risk factor.

In order to minimize the risk of bleeding, it would seem logical to allow an appropriate time between discontinuing abciximab and performing surgery. Unfortunately, there is great interpersonal variability in recovery of platelet function.32 This may also explain some of the differences between the reports of preoperative bleeding in the literature. The residual effects of abciximab can be measured by platelet aggregometry. If this test is abnormal or a further delay is not feasible because of the clinical need of the patient, then what other strategies may be of benefit?

Specific therapy to reduce bleeding
Reduction in the heparin dose, as with invasive cardiology,23 would seem appropriate for most interventions. There are no reports that confirm this approach as effective or safe during a period of extracorporeal circulation. Low-dose aprotinin therapy did not show efficacy in one report.25 The therapy with the best supporting literature, according to observations in non-human primates, is to administer platelets. Although free abciximab may not be circulating, that bound to the native platelets redistributes among the total pool, both native and donor, resulting in an overall smaller percentage of blocked receptors. In monkeys, infusion of platelets produced a normal bleeding time within 1 h of the infusion.27 Clinical experience with routine platelet administration supports the recommendation to administer platelets as an antidote to counteract the effect of recently administered abciximab.27 To avoid subjecting the donor platelets to the adverse effects of cardiopulmonary bypass, the platelet transfusion should be given after the administration of protamine.

In summary, the evidence for increased risk of spontaneous or perioperative bleeding is not consistent or universal. Withdrawal of therapy before surgery appears to be the only dependable method of reducing any apparent risk. If this is not feasible, certain haemostatic drugs have proven benefits in controlling bleeding associated with NSAIDs and thienopyridines. Administration of platelets appears to be the only intervention likely to be of benefit in patients given GPIIb/IIIa receptor blockers.

T. Kövesi

D. Royston

Department of Anaesthesia

Royal Brompton and Harefield NHS Trust

Harefield Hospital

Middlesex UB9 6HJ

UK

References

1 Sonksen JR, Kong KL, Holder R. Magnitude and time course of impaired primary haemostasis after stopping chronic low and medium dose aspirin in healthy volunteers. Br J Anaesth 1999; 82: 360–5[Abstract/Free Full Text]

2 Gibbs NM, Weightman WM, Thackray NM, Michalopoulos N, Weidmann C. The effects of recent aspirin ingestion on platelet function in cardiac surgical patients. J Cardiothorac Vasc Anesth 2001; 15: 55–9[ISI][Medline]

3 Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment. Br J Rheumatol 1998; 37: 937–45[ISI][Medline]

4 vonHolstein CC, Eriksson SB, Kallen R. Tranexamic acid as an aid to reducing blood transfusion requirements in gastric and duodenal bleeding. Br Med J 1987; 294: 7–10[ISI][Medline]

5 Tuman KJ, McCarthy RJ, O’Connor CJ, McCarthy WE, Ivankovich AD. Aspirin does not increase allogeneic blood transfusion in reoperative coronary artery surgery. Anesth Analg 1996; 83: 1178–84[Abstract]

6 Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth 1992; 6: 76–100[Medline]

7 Mannucci PM. Hemostatic drugs. N Engl J Med 1998; 339: 245–53[Free Full Text]

8 Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg 1997; 85: 1258–67[Abstract]

9 Park HS, Hourani SM. Differential effects of adenine nucleotide analogues on shape change and aggregation induced by adenosine 5-diphosphate (ADP) in human platelets. Br J Pharmacolol 1999; 127: 1359–66[Abstract/Free Full Text]

10 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667–72[Abstract/Free Full Text]

11 Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998; 129: 394–405[Abstract/Free Full Text]

12 Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am Heart J 2000; 140: 67–73[ISI][Medline]

13 Desager JP. Clinical pharmacokinetics of ticlopidine. Clin Pharmacokinet 1994; 26: 347–55[ISI][Medline]

14 Criado A, Juffe A, Carmona J, Otero C, Avello F. Ticlopidine as a hemorrhagic risk factor in coronary surgery. Drug Intell Clin Pharm 1985; 19: 673–6[ISI][Medline]

15 Nevelsteen A, Mortelmans L, Van de Cruys A, Merckx E, Verhaeghe R. Effect of ticlopidine on blood loss, platelet turnover and platelet deposition on prosthetic surfaces in patients undergoing aorto-femoral bypass grafting. Thromb Res 1991; 64: 363–9[ISI][Medline]

16 Herbert JM, Bernat A, Maffrand JP. Aprotinin reduces clopidogrel-induced prolongation of the bleeding time in the rat. Thromb Res 1993; 71: 433–41[ISI][Medline]

17 Calenda E, Papion H, Borg JY, et al. [Correction of bleeding time after administration of desmopressin in a woman treated with ticlopidine]. Presse Med 1988; 17: 2143[ISI][Medline]

18 Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science 1987; 238: 491–7[ISI][Medline]

19 Theroux P. Antiplatelet therapy: do the new platelet inhibitors add significantly to the clinical benefits of aspirin? Am Heart J 1997; 134: S62–70[ISI][Medline]

20 SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The SYMPHONY Investigators. Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes. Lancet 2000; 355: 337–45

21 Memon MA, Blankenship JC, Wood GC, Frey CM, Menapace FJ. Incidence of intracranial hemorrhage complicating treatment with glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of major clinical trials. Am J Med 2000; 109: 213–7[ISI][Medline]

22 EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330: 956–61[Abstract/Free Full Text]

23 EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. N Engl J Med 1997; 336: 1689–96[Abstract/Free Full Text]

24 Kereiakes DJ, Berkowitz SD, Lincoff AM, et al. Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade. Am Heart J 2000; 140: 74–80[ISI][Medline]

25 Alvarez JM. Emergency coronary bypass grafting for failed percutaneous coronary artery stenting: increased costs and platelet transfusion requirements after the use of abciximab. J Thorac Cardiovasc Surg 1998; 115: 472–3.[Free Full Text]

26 Gammie JS, Zenati M, Kormos RL, et al. Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998; 65: 465–9.[Abstract/Free Full Text]

27 Lemmer JH Jr. Clinical experience in coronary bypass surgery for abciximab-treated patients. Ann Thorac Surg 2000; 70: S33–7.[Abstract/Free Full Text]

28 George JN, Pickett EB, Saucerman S, et al. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 1986; 78: 340–8[ISI][Medline]

29 Coller BS. GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemost 1997; 78: 730–5.[ISI][Medline]

30 Tcheng JE, Harrington RA, Kottke-Marchant K, et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators. Circulation 1995; 91: 2151–7[Abstract/Free Full Text]

31 Tardiff BE, Califf RM, Tcheng JE, et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. IMPACT-II Investigators. Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II. J Am Coll Cardiol 1999; 33: 88–96[ISI][Medline]

32 Steinhubl SR, Kottke-Marchant K, Moliterno DJ, et al. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation 1999; 100: 1977–82.[Abstract/Free Full Text]