Accepted Manuscript Thrombocytopenia in Acute Coronary Syndromes: Etiologies and Proposed Management Abhinav Sharma, MD, Craig Ferguson, BSc, Kevin R. Bainey, MD, MSc PII:
S0828-282X(15)00026-4
DOI:
10.1016/j.cjca.2014.12.034
Reference:
CJCA 1533
To appear in:
Canadian Journal of Cardiology
Received Date: 6 October 2014 Revised Date:
18 December 2014
Accepted Date: 20 December 2014
Please cite this article as: Sharma A, Ferguson C, Bainey KR, Thrombocytopenia in Acute Coronary Syndromes: Etiologies and Proposed Management, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2014.12.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Thrombocytopenia in Acute Coronary Syndromes:
RI PT
Etiologies and Proposed Management
Abhinav Sharma MD, Craig Ferguson BSc, Kevin R. Bainey MD, MSc
SC
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
Word Count: 1361 (From introduction to end of discussion)
M AN U
Running title: Thrombocytopenia in ACS
TE D
Funding: None
Correspondence:
EP
Kevin R. Bainey MD, MSc Division of Cardiology
AC C
Mazankowski Alberta Heart Institute University of Alberta Edmonton, Canada
[email protected]
1
ACCEPTED MANUSCRIPT
Brief Summary:
Thrombocytopenia in acute coronary syndrome (ACS) can arise from a variety of
RI PT
etiologies. We present a case of profound thrombocytopenia due to administration of a glycoprotein IIb/IIIa receptor antagonist, eptifibatide, following percutaneous coronary intervention (PCI). We review the major causes and suggest an approach for diagnosis
AC C
EP
TE D
M AN U
SC
and management of thrombocytopenia in ACS.
2
ACCEPTED MANUSCRIPT
Abstract
Thrombocytopenia in acute coronary syndromes (ACS) can arise from a variety of
RI PT
etiologies. Glycoprotein IIb/IIIa receptor antagonists (GPRA) have improved clinical outcomes in ACS (1) however profound thrombocytopenia can occur with use of these agents (2). We present a case of profound thrombocytopenia due to administration of a
SC
GPRA, eptifibatide, following percutaneous coronary intervention (PCI) for an inferior ST elevation myocardial infarction (STEMI). We review the major causes and suggest an
AC C
EP
TE D
M AN U
approach for diagnosis and management of thrombocytopenia in ACS.
3
ACCEPTED MANUSCRIPT
Introduction:
Thrombocytopenia in acute coronary syndromes (ACS) can arise from a variety of
RI PT
etiologies. Glycoprotein IIb/IIIa receptor antagonists (GPRA) have improved clinical outcomes in ACS (1) however profound thrombocytopenia can occur with use of these agents (2). We present a case of profound thrombocytopenia due to administration of a
SC
GPRA, eptifibatide, following percutaneous coronary intervention (PCI) for an inferior ST elevation myocardial infarction (STEMI). We review the major causes and suggest an
M AN U
approach for diagnosis and management of thrombocytopenia in ACS.
Case Report:
TE D
A 47-year-old male with no previous medical history presents to a non-PCI community hospital with two hours of chest pain. The initial electrocardiogram demonstrated ST elevation in the inferior leads. The patient was given a loading dose of
EP
aspirin, 300 mg of clopidogrel, and intravenous unfractionated heparin (5000 units) and
AC C
transferred to a tertiary center for primary PCI.
During the PCI, a radial artery approach was utilized with an additional 1000 units of heparin along with 200ug of nitroglycerin given via the radial sheath. A completely occluded dominant right coronary artery was identified. PCI was performed with a drug eluting stent (DES). Peri-procedurally, he was started on eptifibatide and was stable on transfer to the coronary care unit.
4
ACCEPTED MANUSCRIPT
An initial complete blood count (CBC) performed at time of transfer demonstrated a platelet count of 201,000/µL. Four hours post PCI, the platelet count dropped to
RI PT
5,000/µL. A repeat CBC done immediately thereafter was confirmatory. A peripheral smear did not reveal any clumping, schistocytes, helmet cells, or toxic vacuoles. An enzyme-linked immunosorbent assays (ELISA) for heparin induced thrombocytopenia
SC
(HIT) was negative. At the six-hour mark aspirin, clopidogrel, and eptifibatide were
discontinued and one adult unit of platelets was administered. The platelet count rose to
M AN U
34,000/µL within 9 hours post-eptifibatide discontinuation. The count stayed at this level until the 36 hours mark, hence aspirin 81mg and clopidogrel 75 mg were restarted at the next scheduled dose. The platelet count normalized at 67 hours. There was no bleeding complications or acute stent thrombosis when dual anti-platelet therapy
TE D
(DAPT) was held. The patient was subsequently given a medical alert bracelet indicating adverse reaction to GPRAs and was discharged home in stable condition.
EP
Discussion:
AC C
Thrombocytopenia is a rare adverse event of GPRA use which includes abciximab, eptifibatide, and tirofiban (2). Thrombocytopenia can be classified as a platelet count of < 100,000/µL; severe thrombocytopenia < 50,000/µL; and profound thrombocytopenia< 20,000/µL (2). Severe thrombocytopenia occurs in less than 1.6% of all patients using GPRA and a platelet count < 100,000/µL occurs in less than 6% of all patients (2). The clinical presentation occurs most commonly in the first 24 hours but has been reported
5
ACCEPTED MANUSCRIPT
up to 7 days later (2,3). When a GPRA is administered, it binds to platelets, causing a conformational change, exposing neoepitopes, which are recognized by preformed antibodies (4). In one study, such antibodies were identified in all patients who
RI PT
developed profound thrombocytopenia and were not seen in healthy controls (4).These preformed antibodies induce an immune mediated thrombocytopenia response,
SC
although the exact mechanism is poorly understood (4).
Given the differences in management, it is important to understand the distinction
M AN U
between GPRA induced thrombocytopenia and HIT (Table 1). There are two distinct types of HIT (5). HIT type 1 typically presents within 2 days and is usually mild (> 100,000/µL and/or 50% from baseline value). The platelet count normalizes with heparin discontinuation. This is a non-immune disorder resulting from heparin directly activating
TE D
platelets. HIT type 2 is immune-mediated and occurs approximately 4-10 days after exposure to heparin (although it may present later in the context of concomitant surgery). Heparin binds to platelet factor 4 (PF4) (a cytokine released by platelets
EP
during aggregation) and an antibody forms (HIT antibody) leading to platelet activation, consumption and thrombocytopenia. The platelet count is reduced on average by 50%
AC C
but is typically greater than 20,000/µL. Earlier onset may be seen if the patient has heparin exposure one to three months prior to the event. To objectively assess the pretest probability of HIT, the 4T score can be utilized (5). Serologically, the ELISA based HIT test is sensitive but lacks specificity (5). The serotonin-release-assay (SRA) and Heparin Induced Platelet Activation (HIPA) tests are more sensitive and specific (5) but are not as widely available. The time course of HIT is different than with GPRA
6
ACCEPTED MANUSCRIPT
induced thrombocytopenia; HIT has a slower onset unless exposed to heparin previously (2,5).
RI PT
Another important etiology to exclude is thienopyridine-derivative (ticlopidine,
clopidogrel, and prasugrel) induced thrombotic thrombocytopenia purpura (TTP).
Ticlopidine induced TTP is well documented but is now rarely used in clinical practice.
SC
Clopidogrel induced TTP is a syndrome characterized by microangiopathic hemolytic anemia, jaundice and schistocytes on blood film. In addition, these patients may have
M AN U
neurological symptoms including hallucinations, abdominal pain, nausea, vomiting, confusion, fever, and renal injury (online reference 1). Prasugrel-associated TTP has been reported and as of 2011, the Food and Drug Administration has received 14 cases of prasugrel associated TTP (online reference 2). To date, no concerns with ticagrelor,
TE D
a non-thienopyridine reversible adenosine diphosphate receptor antagonist currently being used in the treatment of ACS, have been reported. In addition, clopidogrelinduced TTP takes days to weeks to occur, unlike the rapid onset of GPRA induced
EP
thrombocytopenia. Clopidogrel-induced TTP typically does not resolve with removing the offending agent, requires plasma exchange for treatment, and takes weeks for
AC C
resolution (online reference 1). Our patient did not have these symptoms or schistocytes on his blood film, making clopidogrel-induced TTP extremely unlikely.
All patients receiving a GPRA should have platelet levels assessed prior to administration and at least once during the first 2-6 hours. In the event of thrombocytopenia (120,000-100,000/µL), pseudothrombocytopenia and dilutional
7
ACCEPTED MANUSCRIPT
thrombocytopenia should first be ruled out (Table 2). In this platelet range, either HIT type 1, type 2 or GPRA induced thrombocytopenia can be the culprit. With platelet levels between 50,000-100,000/µL, GPRA discontinuation should strongly be
RI PT
considered, particularly if there is bleeding or continual drop in platelet count. For
platelet levels
S0828-282X(15)00026-4
DOI:
10.1016/j.cjca.2014.12.034
Reference:
CJCA 1533
To appear in:
Canadian Journal of Cardiology
Received Date: 6 October 2014 Revised Date:
18 December 2014
Accepted Date: 20 December 2014
Please cite this article as: Sharma A, Ferguson C, Bainey KR, Thrombocytopenia in Acute Coronary Syndromes: Etiologies and Proposed Management, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2014.12.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Thrombocytopenia in Acute Coronary Syndromes:
RI PT
Etiologies and Proposed Management
Abhinav Sharma MD, Craig Ferguson BSc, Kevin R. Bainey MD, MSc
SC
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
Word Count: 1361 (From introduction to end of discussion)
M AN U
Running title: Thrombocytopenia in ACS
TE D
Funding: None
Correspondence:
EP
Kevin R. Bainey MD, MSc Division of Cardiology
AC C
Mazankowski Alberta Heart Institute University of Alberta Edmonton, Canada
[email protected]
1
ACCEPTED MANUSCRIPT
Brief Summary:
Thrombocytopenia in acute coronary syndrome (ACS) can arise from a variety of
RI PT
etiologies. We present a case of profound thrombocytopenia due to administration of a glycoprotein IIb/IIIa receptor antagonist, eptifibatide, following percutaneous coronary intervention (PCI). We review the major causes and suggest an approach for diagnosis
AC C
EP
TE D
M AN U
SC
and management of thrombocytopenia in ACS.
2
ACCEPTED MANUSCRIPT
Abstract
Thrombocytopenia in acute coronary syndromes (ACS) can arise from a variety of
RI PT
etiologies. Glycoprotein IIb/IIIa receptor antagonists (GPRA) have improved clinical outcomes in ACS (1) however profound thrombocytopenia can occur with use of these agents (2). We present a case of profound thrombocytopenia due to administration of a
SC
GPRA, eptifibatide, following percutaneous coronary intervention (PCI) for an inferior ST elevation myocardial infarction (STEMI). We review the major causes and suggest an
AC C
EP
TE D
M AN U
approach for diagnosis and management of thrombocytopenia in ACS.
3
ACCEPTED MANUSCRIPT
Introduction:
Thrombocytopenia in acute coronary syndromes (ACS) can arise from a variety of
RI PT
etiologies. Glycoprotein IIb/IIIa receptor antagonists (GPRA) have improved clinical outcomes in ACS (1) however profound thrombocytopenia can occur with use of these agents (2). We present a case of profound thrombocytopenia due to administration of a
SC
GPRA, eptifibatide, following percutaneous coronary intervention (PCI) for an inferior ST elevation myocardial infarction (STEMI). We review the major causes and suggest an
M AN U
approach for diagnosis and management of thrombocytopenia in ACS.
Case Report:
TE D
A 47-year-old male with no previous medical history presents to a non-PCI community hospital with two hours of chest pain. The initial electrocardiogram demonstrated ST elevation in the inferior leads. The patient was given a loading dose of
EP
aspirin, 300 mg of clopidogrel, and intravenous unfractionated heparin (5000 units) and
AC C
transferred to a tertiary center for primary PCI.
During the PCI, a radial artery approach was utilized with an additional 1000 units of heparin along with 200ug of nitroglycerin given via the radial sheath. A completely occluded dominant right coronary artery was identified. PCI was performed with a drug eluting stent (DES). Peri-procedurally, he was started on eptifibatide and was stable on transfer to the coronary care unit.
4
ACCEPTED MANUSCRIPT
An initial complete blood count (CBC) performed at time of transfer demonstrated a platelet count of 201,000/µL. Four hours post PCI, the platelet count dropped to
RI PT
5,000/µL. A repeat CBC done immediately thereafter was confirmatory. A peripheral smear did not reveal any clumping, schistocytes, helmet cells, or toxic vacuoles. An enzyme-linked immunosorbent assays (ELISA) for heparin induced thrombocytopenia
SC
(HIT) was negative. At the six-hour mark aspirin, clopidogrel, and eptifibatide were
discontinued and one adult unit of platelets was administered. The platelet count rose to
M AN U
34,000/µL within 9 hours post-eptifibatide discontinuation. The count stayed at this level until the 36 hours mark, hence aspirin 81mg and clopidogrel 75 mg were restarted at the next scheduled dose. The platelet count normalized at 67 hours. There was no bleeding complications or acute stent thrombosis when dual anti-platelet therapy
TE D
(DAPT) was held. The patient was subsequently given a medical alert bracelet indicating adverse reaction to GPRAs and was discharged home in stable condition.
EP
Discussion:
AC C
Thrombocytopenia is a rare adverse event of GPRA use which includes abciximab, eptifibatide, and tirofiban (2). Thrombocytopenia can be classified as a platelet count of < 100,000/µL; severe thrombocytopenia < 50,000/µL; and profound thrombocytopenia< 20,000/µL (2). Severe thrombocytopenia occurs in less than 1.6% of all patients using GPRA and a platelet count < 100,000/µL occurs in less than 6% of all patients (2). The clinical presentation occurs most commonly in the first 24 hours but has been reported
5
ACCEPTED MANUSCRIPT
up to 7 days later (2,3). When a GPRA is administered, it binds to platelets, causing a conformational change, exposing neoepitopes, which are recognized by preformed antibodies (4). In one study, such antibodies were identified in all patients who
RI PT
developed profound thrombocytopenia and were not seen in healthy controls (4).These preformed antibodies induce an immune mediated thrombocytopenia response,
SC
although the exact mechanism is poorly understood (4).
Given the differences in management, it is important to understand the distinction
M AN U
between GPRA induced thrombocytopenia and HIT (Table 1). There are two distinct types of HIT (5). HIT type 1 typically presents within 2 days and is usually mild (> 100,000/µL and/or 50% from baseline value). The platelet count normalizes with heparin discontinuation. This is a non-immune disorder resulting from heparin directly activating
TE D
platelets. HIT type 2 is immune-mediated and occurs approximately 4-10 days after exposure to heparin (although it may present later in the context of concomitant surgery). Heparin binds to platelet factor 4 (PF4) (a cytokine released by platelets
EP
during aggregation) and an antibody forms (HIT antibody) leading to platelet activation, consumption and thrombocytopenia. The platelet count is reduced on average by 50%
AC C
but is typically greater than 20,000/µL. Earlier onset may be seen if the patient has heparin exposure one to three months prior to the event. To objectively assess the pretest probability of HIT, the 4T score can be utilized (5). Serologically, the ELISA based HIT test is sensitive but lacks specificity (5). The serotonin-release-assay (SRA) and Heparin Induced Platelet Activation (HIPA) tests are more sensitive and specific (5) but are not as widely available. The time course of HIT is different than with GPRA
6
ACCEPTED MANUSCRIPT
induced thrombocytopenia; HIT has a slower onset unless exposed to heparin previously (2,5).
RI PT
Another important etiology to exclude is thienopyridine-derivative (ticlopidine,
clopidogrel, and prasugrel) induced thrombotic thrombocytopenia purpura (TTP).
Ticlopidine induced TTP is well documented but is now rarely used in clinical practice.
SC
Clopidogrel induced TTP is a syndrome characterized by microangiopathic hemolytic anemia, jaundice and schistocytes on blood film. In addition, these patients may have
M AN U
neurological symptoms including hallucinations, abdominal pain, nausea, vomiting, confusion, fever, and renal injury (online reference 1). Prasugrel-associated TTP has been reported and as of 2011, the Food and Drug Administration has received 14 cases of prasugrel associated TTP (online reference 2). To date, no concerns with ticagrelor,
TE D
a non-thienopyridine reversible adenosine diphosphate receptor antagonist currently being used in the treatment of ACS, have been reported. In addition, clopidogrelinduced TTP takes days to weeks to occur, unlike the rapid onset of GPRA induced
EP
thrombocytopenia. Clopidogrel-induced TTP typically does not resolve with removing the offending agent, requires plasma exchange for treatment, and takes weeks for
AC C
resolution (online reference 1). Our patient did not have these symptoms or schistocytes on his blood film, making clopidogrel-induced TTP extremely unlikely.
All patients receiving a GPRA should have platelet levels assessed prior to administration and at least once during the first 2-6 hours. In the event of thrombocytopenia (120,000-100,000/µL), pseudothrombocytopenia and dilutional
7
ACCEPTED MANUSCRIPT
thrombocytopenia should first be ruled out (Table 2). In this platelet range, either HIT type 1, type 2 or GPRA induced thrombocytopenia can be the culprit. With platelet levels between 50,000-100,000/µL, GPRA discontinuation should strongly be
RI PT
considered, particularly if there is bleeding or continual drop in platelet count. For
platelet levels
