How to Manage Bleeding following Thrombolysis?

CHAPTER 16Uday B Khanolkar, Rajkumar Annamalai

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INTRODUCTIONBesides primary angioplasty, fibrinolytic agents have been the backbone of management of acute myocardial infarction (AMI).1,2 Although major hemorrhage is infrequent with use of fibrinolytic drugs, management of bleeding is difficult and individualized, especially due to lack of large scale data. Severe bleeding could be associated with high morbidity and mortality. Hence, risks and benefits should be carefully considered prior to administering these drugs. Fibrinolytic therapy is an attractive option when primary percutaneous coronary intervention (PPCI) is not available in patients presenting with STEMI and onset of ischemic symptoms within the previous 12 hours (class I), for patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia within 12–24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability (class II) and for those presenting with true posterior wall MI.2-5 Most critically, fibrinolytic therapy should be administered within 30 minutes of arrival.6 Even when PPCI is superior to fibrinolytic therapy, it is important to recognize that the strategy may not be applicable for all patients especially in India. In these situations, TNK-tPA may be a better alternative reperfusion therapy, considering age, the infarct-related artery or delays in the system of activating the catheterization laboratory.6,7

FIBRINOLYTIC AGENTS AND IMPLICATION ON BLEEDINGThe fibrinolytic agents currently approved for use are strepto kinase, urokinase, alteplase, tenecteplase, and reteplase.2 All these agents act indirectly by promoting generation of plasmin, which then mediates clot lysis. The plasma half life, metabolism and clearence of fibrinolytic agents are variable. Alteplase has a half life of 4–8 minutes and is metabolized by the liver. Tenectaplase has a longer half-life of about 20 minutes and is also metabolized by the liver. It has a higher fibrin specificity.8 Reteplase causes a greater systemic reduction in fibrin than alteplase. It has a half life of about 15 minutes and is metabolized by liver and kidney. Streptokinase binds plasminogen converting it into a compound to activate other free plasminogen molecules. Hence, even though the plasma half life is 20–40 minutes, the half life of antithrombotic effect of streptokinase is about 80 minutes. Urokinase, a direct plasminogen activator with a half life of 20 minutes is metabolized by the liver. Hence, the half life of these agents may be prolonged due to liver and/or kidney derangement (Table 1). Although the half lives of these drugs is short, their effect on the coagulation cascade is much longer. After alteplase administration for myocardial infarction, fibrinogen is lowest at 2–3 hours, remains low for 24 hours and normalizes after 48 hours.8

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Bleeding after treatment with fibrinolytic drugs may occur due to various mechanisms such as plasmin-mediated lysis of the fibrin clot and antiplatelet action along with plasminemia, fibrinogenemia and reduction of other factors such as factor V.8,9 However, the management of fibrinogen and factor V reduction does not correlate with frequency of intracerebral hemorrhage.10

CLASSIFICATION OF SEVERITY OF BLEEDINGThere is a need for an appropriate definition of the severity of bleeding in the current era. The criteria used for bleeding severity defined by TIMI investigators and the GUSTO investigators originated from fibrinolytic trials.

Bleeding was defined as severe if it causes substantial hemodynamic compromise that requires intervention or treatment and moderate if transfusion alone was sufficient (Table 2).

BLEEDING AFTER THROMBOLYSIS IN PRIOR TRIALS The fibrinolytics therapy trialist (FTT) collaborative group18 evaluated nine trials including 58,600 patients randomized to thrombolytic therapy versus control therapies is acute myocardial infarction. In thrombolytic group, the incidence of major noncerebral bleeding was 1.1% versus

Table 1 Fibrinolytic agents and their implication on bleeding

Fibrinolytic agent Dose Fibrin specificity* Fibrinogen depletion Antigenic Patency Rate (90-min TIMI 2 or 3 flow)

Fibrin specific

Tenecteplase (TNK) Single IV weight-based bolus1

++++ Minimal No 85%

Reteplase (r-PA) 10 units + 10-unit IV bolues given 30 minute apart

++ Moderate No 84%

Alteplase (t-PA) 90-minute weight-based infusion2

++ Mild No 73–84%

Nonfibrin specific

Streptokinase3 1.5 million units IV given over 30–60 minute

No Marked Yes4 60–68%

* Strength of fibrin specificity: ++++ is stronger; ++ is less strong.1 Bolus of 30 mg for weight less than 60 kg, 35 mg for 60–69 kg, 40 mg for 70–79 kg, 45 mg for 80–89 kg, and 50 mg for 90 kg or greater.2 Bolus of 15 mg, infusion of 0.75 mg/kg for 30 minutes (maximum, 50 mg), then 0.5 mg/kg (maximum, 35 mg) over the next 60 minutes; the

total dose not to exceed 100 mg.3 Streptokinase is no longer marketed in the United States but is available in other countries.4 Streptokinase is highly antigenic and absolutely contraindicated within 6 months of previous exposure because of the potential for serious

allergic reaction.Abbreviations: r-PA, reteplase plasminogen activator; t-PA, tissue plasminogen activator.Source: From O’Gara PT, Kushner FG, Ascheim DD, et al: 2013 ACCFIAHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 61:e78, 2013.

Table 2 Definitions used to define bleeding events in ACS11-17

Trials Severity Criteria used

TIMI Major Intracranial bleeding.Overt bleeding with a decrease in hemoglobin ≥3 g/dL or decrease in hematocrit ≥5%

Minor Spontaneous gross hematuria. Spontaneous hematemesis. Observed bleeding with decrease in hemoglobin ≥ 3 g/dL but hematocrit <15%

Insignificant Blood loss insufficient to meet criteria listed above

GUSTO Severe Morbid bleeding. Intracerebral bleeding or substantial hemodynamic compromise requiring treatment

Moderate Bleeding requiring transfusion

Mild Other bleeding not requiring transfusion or causing hemodynamic compromise

Other classifications in use are PLATO, ACUITY, GRACE, STEEPLE and BARC

0.4% in control subjects (P<0.0001). The combined data from GISI and ISIS revealed that major bleeding rates were higher for streptokinase than TPA (0.9% versus 0.7%; P <0.05) and for associated subcutaneous heparin than

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no heparin (1% versus 0.7%; P <0.00001). Regardless of thrombolytic assignment, higher bleeding rates were associated with higher aPTT. However for a given aPTT, the risk of bleeding was higher for streptokinase-assigned patients than for TPA-assigned patients. Worsening of killip class was associated with higher incidence of bleeding complications. In addition, higher incidence of bleeding events was strongly related to associated invasive procedures, e.g swan-ganz catheter placement, insertion of pacemaker, balloon pump, angiography, angioplasty or bypass surgery.

RISK FACTORS FOR BLEEDINGIt is imperative to recognize the preexisting clinical risk factor19 for bleeding after thrombolytic therapy such as advanced age, female sex, renal insufficiency, coadministration of anti throm botic agents, hepatic impairment, etc. The detailed list of absolute and relative contraindications are enumerated in Table 3.

CLINICAL IMPACT OF BLEEDING COMPLICATIONSAll bleeding events are not necessarily life-threatening. However, major bleeding events are associated with higher in hospital and 1-year mortality compared to minor bleeding. Bleeding complications also prolong hospital stay and cost of treatment. In Grace registry, patients with STEMI who developed major bleeding had maximum mortality (22.8% vs 7%) as compared to NSTEMI. Major bleeding was associated with increased risk of ischemic events (20% with bleeding and 5% without bleeding) due to hemodynamic instability, hyperadrenergic state, exaggeration of inflammatory response and discontinuation of antithrombotic therapy. The creation of torrential nature of hemorrhage (gastrointestinal, retroperitoneal or intracranial) may result in death. The discontinuation of antithrombotic treatment is one of the main links between bleeding events and ischemic mortality as shown by Grace investigators.

MANAGEMENT OF BLEEDINGManaging bleeding in patients after thrombolytic therapy is tricky and challenging. There are no specific guidelines for treatment and therapy should be individualized in majority of the situations. Patients having minor bleeding may not need much attention but should be monitored for any subsequent need for de-escalation of therapy. Close monitoring of hemodynamic and coagulation parameters is essential in care of major bleeding.

Table 3 Contraindications to fibrinolytic therapy2

Absolute contraindications

Any prior ICH

Known structural cerebral vascular lesion (e.g. arteriovenous malformation)

Known malignant intracranial neoplasm (primary or metastatic)

Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours

Suspected aortic dissection

Active bleeding or bleeding diathesis (excluding menses)

Significant closed-head or facial trauma within 3 months

Intracranial or intraspinal surgery within 2 months

Severe uncontrolled hypertension (unresponsive to emergency therapy)

For streptokinase, prior treatment within the previous 6 months

Relative contraindications

Significant hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)

History of prior ischemic stroke >3 months

Dementia

Known intracranial pathology not covered in absolute contraindications

Traumatic or prolonged (>10 minute) CPR

Major surgery (>3 weeks)

Recent (within 2–4 weeks) internal bleeding

Noncompressible vascular punctures

Pregnancy

Active peptic ulcer

Oral anticoagulant therapy

Thrombolytic therapy along with associated antiplatelet and anticoagulation therapy should be temporarily or permanently discontinued unless bleeding is adequately controlled by specific hemostatic interventions.8

General principles to stop bleeding are enumerated in (Table 4). Blood transfusion may have deleterious effect on outcome of such patients. Blood transfusion has impact on oxygen delivery, proinflammatory effects, prothrombotic effects, transfusion-related immunomodulation and issues related to blood storage, all of which contribute to adverse events.20,21 In patients evaluated in GUSTO IIb trial, death at 30 days (13.7 v/s 0.5%), 6 months (19.7% vs 6.9%) and 1 year (21.8% vs 8.7%) was significantly higher for transfused patients than for nontransfused patients, respectively. On the basis of present data, arbitrary cut-off (hemoglobin of <8 g/dL) to trigger transfusion should be avoided in most circumstances, unless associated with hemodynamic

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compromise. In patients of low hemoglobin, who exhibit evidence of ischemia despite successful revascularization, there is clear potential benefit of blood transfusion. Patients without clear evidence of ongoing ischemia are predominantly predisposed to adverse effects of transfusion.

BLEEDING RELATED TO SPECIFIC SYSTEMS

Symptomatic Intracranial Hemorrhage

Development of symptomatic intracranial hemorrhage (sICH) is associated with worse outcome. There is no evidence-based guidelines that address manage ment of thrombolytic–associated sICH. AHA empirically suggests therapies to replace clotting factors and platelets, but acknowledge the lack of evidence to support any specific therapy. 40% of patients with CT-scans following lysis showed evidence of ICH expansion. A similar frequency of hematoma expansion has been noted in nonthrombolysis-associated ICH, and clinical trials have demonstrated that hemostatic therapy may reduce risk of hematoma expansion. However, the choice of hemostatic therapy in thrombolysis-associated sICH is controversial. Thrombolytic agents convert plas minogen to plasmin, which degrades fibrin at the site of thrombus formation. Antifibrinolytics such as aminocaproic acid seem to be the logical antidote to fibrinolytic therapy and have been proposed as aggressive means of limiting intracranial bleeding.8

Goldstein et al. reported 20/352 patients who developed ICH after thrombolytic therapy. None had fibrinogen levels <1 g/liter and only 11 received therapy which included FFP, cryoprecipitate, vitamin K, platelet and aminocaproic acid.8 However, it is not possible to assess the benefits of these therapies due to small numbers in each group. Hence, it may be suggested from expert opinion, rather

than hard core clinical data, that the following treatment measures could be attempted for managing major bleeding within 48 hours of administration of fibrinolytic drugs:8

• Stop infusion of fibrinolytic drug and other antithrombotic drugs (1C)8

• Administer FFP 12 mL/kg (2C)8

• Administer intravenous tranexamic acid 1g tds (2C)8

• If there is depletion of fibrinogen then, administer cryo-precipitate or fibrinogen concentrate (2C)8

• Further therapy should be guided by results of coagulation profile.

However, there is a risk of prothrombotic activity. In addition, if tPA induces systemic fibrinolysis, fibrinogen replacement in the form of fresh frozen plasma or cryo-precipitate would be the logical choice for patients with low fibrinogen levels. Often patients do not develop low fibrinogen levels of less than 100 mg/dL, suggesting a limited benefit of such therapy.8 Clot lysis releases D-dimer, which can exert an antiplatelet effect by binding to platelet- fibrinogen receptor. So, there is a theoretical basis for platelet transfusion as rescue therapy. However, this hypothesis has not yet been tested. Finally, thrombolytic agents may affect a number of processes independent of clot disruption, including extracellular matrix degradation and cell signalling. Intervention aimed at reversing these effects may offer promising avenues for research.8,20

The decision to surgically evacuate intracranial hemor-rhage is delicate. In Gusto trial, 268 patients with ICH were analysed.8 In-hospital mortality was 60% with only 13% of patients discharged with minor or no disability. 47 had neurosurgical interventions. Overall prognosis was poor regardless of treatment strategy, but surgical evacuation was associated with higher likelihood of ‘‘survival without disability.’’ Neurosurgical intervention may be considered in case of large cerebellar ICH or lobar ICH with mass effect. Surgical evacuation may be performed once coagulopathy is corrected. There are certain palliative measures in the management of sICH, which are being regularly followed (Table 5). These measures can be extrapolated to patients in the post-thrombolysis scenarios due to paucity of specific data in this segment of patients.

GASTROINTESTINAL BLEEDINGGastric interventions are safe provided that the patients are hemodynamically stable. A case control study of patients who underwent gastroscopy at a median of 9.1 days post-MI had significantly higher rate of serious complications than control group (7.5 vs 15%).25-27 However, those with

Table 4 General measures to stop bleeding

•  Stop the fibrinolytic agent

•   Document the timing and amount of fibrinolytic drug and presence of preexisting hepatic and renal derangement

•  Estimate the ½ life and functional defect induced by the drug

•  Assess the source of bleeding 

•   Assess full blood count, prothrombin time, APTT, TT, fibrinogen concentration, creatinine concentration

•   Correct hemodynamic compromise with IV fluids and red cell transfusion

•  Apply mechanical pressure, if possible 

•   Use endoscopic, radiological and surgical measures as and when necessary

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complications typically had hemodynamic instability and higher APACHE II severity score, highlighting the need for adequate pre gastroscopy hemodynamic stability. Accordingly, patients who have a GI bleeding should undergo diagnostic and thera peutic gastroscopy within 24 hours, ideally after adequate hemodynamic stabilization. Given its safety, the threshold of gastroscopy should be low. An early gastroscopy allows the clinician to potentially control the source of bleeding and arrest hemorrhage as well as providing information that assist in estimation of mortality and risk of further bleeding.25-27

In those considered high risk for rebleeding or those suffering from ongoing bleeding, a repeat endoscopy may be considered within days after index bleeding, which allow further endoscopy attempts at arresting hemorrhage and reassessment of bleeding risk. This may allow the appropriate reintroduction of antiplatelet agents, thereby reducing ischemic risk.

CONCLUSIONThere is a significant paucity of data regarding definitive guidelines for management of bleeding after thrombolysis. Some of the information provided here have been extra-polated from different scenarios. More studies and rando-mized trials are needed to formulate definitive guide-lines and recommendations for management of bleeding complications after thrombolysis. In this current era of primary PCI, it may be highly unlikely to obtain such data even in future. Hence, each complication has to be indivi-dualized and managed accordingly with available data and information.

REFERENCES 1. Collen D, Lijnen HR. The tissue-type plasminogen activator

story. Arterioscler Thromb Vasc Biol. 2009;29(8):1151-5. 2. American College of Emergency Physicians, Society for

Cardiovascular Angiography and Interventions, O’Gara, et al. 2013 ACC/AHA guidelines for the management of ST-elevation myocardial infarction; a report of the American

College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-140.

3. Goodman SG, Menon V, Cannon CP, et al. Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence–Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):708S-775S.

4. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol. 2007;50(10):917-29.

5. O’gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation Myocardial Infarction. Circulation. 2013;127(4):e362-425.

6. Gibson CM, Pride YB, Frederick PD, et al. Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1999 to 2006. Am Heart J. 2008;16(6):1035-44.

7. Sathyamurthy I, Srinivasan KN, Jayanthi K, et al. Efficacy and safety of tenecteplase in Indian patients with ST-segment elevation myocardial infarction. Indian Heart J. 2008;60(6): 554-7.

8. Mike Makris, Joost J. Van Veen, Campbell R. Tait, Andrew D. Mumford and Mike Laffan on behalf of the British Committee for Standards in Haematology, Guideline on the management of bleeding in patients on antithrombotic agents, British Journal of Haematology. 2012;160:35-46.

9. Halvorsen S, Huber K. The role of fibrinolysis in the era of primary percutaneous coronaryintervention. Thromb Haemost. 2011;105:390.

10. Erlemeier HH1, Zangemeister W,Bleeding after thrombolysis in acute myocardial infarction,Eur Heart J. 1989;10(1):16-23.

11. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial infarction (TIMI) Trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1998;11:1-22.

12. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med. 1993;329:673-82.

13. Stone GW, McLaurin BT, Cox DA, et al; ACUITY investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-16.

14. Wallentin L, Becker RC, Budaj A, et al. The PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2009;361:1045-57.

15. Steinhubl SR, Kastrati A, Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J. 2007;154:3-11.

Table 5 Palliative therapy of sICH

Palliative therapy of sICH is focused on early intensive BP lower-ing treatment which is expected to attenuate the hematoma expansion22

However, low BP could lead to worsening of cerebral infarction or perihematoma ischemia23

Blood pressure should not be lowered beyond a cerebral perfusion pressure of 60 mm Hg24

Anticerebral edema measures have not been conclusively proven to be of benefit in sICH

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16. Schulman S, Kearon C. On behalf of the subcommittee on control of the scientific and standardization committee of the international society of Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medical products in non-surgical patients. J Thrombosis and haemostasis. 2005;3:692-4.

17. Mehran R, Rao SV, Bhatt DL, et al. Standardized Bleeding Definitions for Cardiovascular Trials: A Consensus Report from the Bleeding Academic Research Consortium (BARC). Circulation. 2011;123:2736-47.

18. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet. 1994;343:311-22.

19. Moscucci M, Fox KA, Connon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003;24:1815-23.

20. Doyle BJ, Rihal CS, Gastineau DA, et al. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervension. J Am Coll Cardiol. 2009;53:2019-27.

21. Shishebor MH, Madhwal S, Rajagopal V, et al. Impact of blood transfusion, on short- and long-term mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol Interv. 2009;2:46-53.

22. J Neurology Neurosurgery Psychiatry: 10:1136/jaap-2016-313246 for INTERACT 2 Investigators.

23. Stroke Vasc Neurol. 2016;1:72-82. 24. Guideline for management of Spontaneous ICH, Stroke

April Vol. 30 no. 4 905-15. 25. Capelle M, et al. AM J Med. 1999;106(1)29-35. 26. Chin WS, et al. AM J. Gastroenterology. 2007;102(11):2411-

16. 27. Banadrian, et al. AM J. Gastroenterology. 2004;99(4):619-

22.