Herz Giant Thrombus on Apical Wall of Left Ventricle Due to HIT Syndrome After Anterior MI

Transcription

1 Herz Giant Thrombus on Apical Wall of Left Ventricle Due to HIT Syndrome After Anterior MI --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Corresponding Author: HKER-D-1-001R Giant Thrombus on Apical Wall of Left Ventricle Due to HIT Syndrome After Anterior MI Case Report Umit Yasar Sinan, Cardiologist, Instructor Istanbul University, Institute of Cardiology Istanbul, TURKEY Corresponding Author Secondary Information: Corresponding Author's Institution: Istanbul University, Institute of Cardiology Corresponding Author's Secondary Institution: First Author: Umit Yasar Sinan, Cardiologist, Instructor First Author Secondary Information: Order of Authors: Umit Yasar Sinan, Cardiologist, Instructor Ugur Coskun, Cardiologist, Instructor Betul Balaban Kocas, Assistant Nazmi Gultekin, Professor of Cardiology Tevfik Gurmen, Professor of Cardiology Serdar Kucukoglu, Professor of Cardiology Order of Authors Secondary Information: Abstract: ABSTRACT Heparin induced thrombocytopenia (HIT) is the most important and the most frequent drug induced, immune mediated type of thrombocytopenia. It is associated with significant mortality and morbidity if unrecognized. We describe a patient with a giant thrombus on apical wall of left ventricle that occurred due to HIT syndrome after anterior MI. Keywords: HIT syndrome, thrombocytopenia, thrombus Response to Reviewers: see attachment Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

2 Figure 1. Click here to download high resolution image

3 Figure. Click here to download high resolution image

4 title page Click here to download Supplementary Material: title page HIT.doc

5 cover letter Click here to download Supplementary Material: cover letter HIT.doc

6 Revised Manuscript Click here to download Manuscript: Revised manuscript HIT.doc Click here to view linked References Giant Thrombus on Apical Wall of Left Ventricle Due to HIT Syndrome After Anterior MI Umit Yasar Sinan, MD, Ugur Coskun, MD, Betul Balaban Kocas, MD, Nazmi Gultekin, MD, Tevfik Gurmen, MD, Serdar Kucukoglu, MD, Umit Yasar Sinan, MD, Istanbul University Institute of Cardiology Department of Cardiology Cardiologist, Instructor Ugur Coskun, MD, Istanbul University Institute of Cardiology Department of Cardiology Cardiologist, Instructor Betul Balaban Kocas, MD, Istanbul University Institute of Cardiology Department of Cardiology Assistant Nazmi Gultekin, MD, Istanbul University Institute of Cardiology Department of Cardiology Professor of Cardiology Tevfik Gurmen, MD Istanbul University Institute of Cardiology Department of Cardiology Professor of Cardiology Serdar Kucukoglu, MD, Istanbul University Institute of Cardiology Department of Cardiology Professor of Cardiology 1

7 Corresponding author: Umit Yasar Sinan, MD, Cardiologist, Instructor Istanbul University Institute of Cardiology Department of Cardiology Haseki, Aksaray 0 Istanbul/TURKEY Phone: 0()-0 Fax: 0(1)- drumityasar@hotmail.com

8 GIANT THROMBUS ON APICAL WALL OF LEFT VENTRICLE DUE TO HIT SYNDROME AFTER ANTERİOR MI Introduction Mural thrombus on left ventricle is one of the major complications that occur after anterior myocardial infarction (MI). It occurs especially when a large part of the left ventricular wall is affected. The incidence is % after ST elevation myocardial infarction (STEMI) (1). The prognosis is worse when mural thrombus develops after MI and it, also, carries a % risk of systemic embolism (1). After the diagnosis is confirmed by echocardiography heparin therapy is used. Heparin induced thrombocytopenia (HIT) is the most important and the most frequent drug induced, immune mediated type of thrombocytopenia. It is associated with significant mortality and morbidity if unrecognized. % of heparinized patients develop the antibody associated with HIT and that approximately 1-% of patients on heparin progresses to develop HIT with thrombocytopenia (). We describe a patient with a giant thrombus on apical wall of left ventricle that occurred due to HIT syndrome after anterior MI. Case Report A 0 year old man was admitted to our emergency unit with chest pain. It was retrosternal, squeezing and emitted to neck and arm. It had started one hour before and there was no decrease severity of chest pain. There was nothing significant on patient s medical history. On physical examination blood pressure was 0/0 mmhg, heart rate was 0 beats/per minute. 1-lead ECG was performed in ten minutes. The ECG showed mm ST elevation on precordial V1-V and DIaVL derivations and there was reciprocal ST segment depression on inferior derivations. The final diagnosis was acute anterior MI. The patient was taken to catheterization laboratory for primary percutaneous coronary intervention (PCI). 00mg acetylsalicylic acid, 00mg loading dose of clopidogrel were given orally and a bolus of 000 IU enoxaparin (intravenous) was administered

9 to the patient before procedure. Coronary angiography showed that there was 0% stenosis in left main coronary artery (LMCA), left anterior descending artery (LAD) was totally occluded from the proximal segment.a thrombus in LAD was aspirated than.* mm bare metal stent was placed. After stent implantation thrombolysis in myocardial infarction (TIMI) 1- flow was provided. The patient had dsypnea, hypotension, and oliguri. Cardiogenic shock was diagnosed, intraaortic balloon pump (IABP) was placed and intravenous positive inotropic support was started. Transthoracic echocardiography (TTE) was performed after coronary angiography in the first day of MI to check left ventricular function and if any complications had occurred. There was left ventricular enlargement, anterior segment akinesia and pericardial effusion on TTE. Ejection fraction (EF) was 0%. Also, there was a mural thrombus on apical region of left ventricular cavity (Figure 1). Low molecular weight heparin (LMWH) (enoxaparin) was started twice a day. The platelet count which was 1.000/mm at baseline started to decrease and it was 0.000/mm on the th day of heparin initiation. Echocardiography repeated on the eighth day of MI showed that the thrombus had become bigger (Figure ). Thrombocytopenia was confirmed with peripheral blood smear. Although there were other possible causes of thrombocytopenia, we thought that HIT syndrome had occurred due to enoxaparin and stopped enoxaparin. Fondaparinux was started (.mg qd subcutaneously) for ventricular thrombus since there is 'no cross-reaction of fondaparinux with antibodies generated to the enoxaparin-platelet factor (PF) complex. Although fondaparinux does cause antibody generation to fondaparinux-pf complex, this most often does not result in clinical symptoms of HIT (). On the sixth day of cessation of heparin the platelet count was normalized thus proving the likelihood of our diagnosis of HIT. The patient died due to cardiogenic shock, sepsis and multiple organ failure the twentieth day of hospitalization. Discussion HIT syndrome is an important and frequent drug-related and immune complex mediated syndrome. It raises mortality and morbidity because the diagnosis is missed frequently. Heparin is used for a variety of clinical situations like atrial fibrillation, prophylaxis of deep vein thrombosis, cardiopulmonary surgery, percutaneous coronary intervention. Thrombocytopenia is one of the important complications of heparin after bleeding. HIT is defined as a decrease in platelet count during or shortly following exposure to heparin.

10 Two different types of HIT are recognized. HIT type 1 was known as heparin associated thrombocytopenia formerly. It is a benign form of HIT syndrome since, it does not increase vascular thrombosis risk. The principal mechanism is not known but it seems non-immune mediated. It is probably related to heparin s proaggregan impact. It occurs in % of heparinized patients on the first few days of heparin use. Thrombocytopenia is not serious (platelet count decreases rarely under 0.000/mm ) and temporary.. HIT type is immune mediated and associated with a risk of thrombosis. This type constitutes the majority of HIT syndrome. It is the malign form and the HIT syndrome discussed herein refers to HIT type. % of heparinized patients develop the antibody associated with HIT and approximately 1 to % of these patients developing antibodies progresses to develop HIT with thrombocytopenia (). One third of these patients have arterial or venous thrombosis. Girolami et all reported that of patients taking subcutaneous unfractioned heparin (UFH) had HIT syndrome (). This study showed that HIT related antibodies occur much more in patients who underwent cardiovascular surgery than in patients who underwent orthopedic surgery. Also, these antibodies occured more frequently due to the use of UFH than use of LMWH. But the antibodies developing in patients receiving UFH frequently cross react with LMWH. In a study on patients undergoing elective hip arthroplasty who had been randomized to receive either UFH or LMWH for thrombophylaxis, Warkenitin and colleagues reported that HIT occurred in of patients who received UFH and in none of patients who received LMWH (.% versus 0%, P=0,001) (). HIT syndrome occurs due to antibodies that occur against heparin and platelet factor complex. The immune complex induces platelet aggregation causing thrombocytopenia. Immune complex is also located in endothelium and induces tissue factor. This provokes the occurrence of thrombosis both in arteries and veins. The initiation of HIT syndrome can be early or late. Generally the syndrome occurs or more days after initiation of heparin. But if the patient has been sensitized before it may occur within few days or hours. The diagnosis of HIT remains a clinical one, supported by confirmatory laboratory testing. The criteria include: a) thrombocytopenia (a drop of the platelet count to below 0 /L or a drop of > 0% from the patient's baseline platelet count); b) the exclusion of other causes of thrombocytopenia; c) the resolution of thrombocytopenia after cessation of heparin. As regards the laboratory tests, HIT-antibodies can be demonstrated in vitro by functional tests and immunoassays. Functional tests, which measure platelet activity in the presence of the patient's serum and heparin, include heparin-induced platelet aggregation (HIPA) and the serotonin release assay (SRA) ().

11 Altough functional platelet tests and immunoassays are important for diagnosis of HIT, the T s scoring system allows evaluation of the pre-test probability of HIT. The T s scoring system is based on thrombocytopenia, timing of onset, thrombosis, and absence of other causes (). Patients with low pretest scores (< points) are unlikely to be positive for HIT antibodies (0-1. % confirmed +), whereas patients with intermediate (- points) and high (> points) scores are more likely to test positive (1. % to 0 % confirmed +) (). Our patient score was. When HIT syndrome is suspected cessation of all heparin types must be the first precaution. However, it is not possible to prevent thrombosis at all times, even if heparin is ceased at the earliest moment that the decrease of platelet is recognized (). Harry L. et al. developed a simple scoring system to aid in the early clinical management of patients suspected of HIT with regard to the decisions to decide whether or not to continue with the heparin therapy (). The system was designed to arrive at low (0) or possible (1) probability scores without knowledge of laboratory test results (except platelet counts) to avoid delays (). According to their study if heparin therapy during the first days of therapy did not result in platelet count drop or platelet count did not fall by 0% or there was a significant competing cause for thrombocytopenia (eg recent CABG (- days), sepsis, shock, balloon pump, drugs other then heparin), the score was 0 and the clinical management was to continue heparin therapy if clinically indicated, while waiting for HIT laboratory test results. If thrombocytopenia occured on heparin therapy and there was no significant competing cause for thrombocytopenia and platelet count fell by >0% or there were new thrombosis, the score was 1 heparin was discontinued, while waiting for HIT laboratory test results and an alternative anticoagulant was administered if clinically indicated (). The management is as follows: First we have to stop all types of heparin therapy. Then to prevent thrombosis alternative anticoagulant therapies must be started. Three alternative anticoagulant drugs that do not cross react with heparin are danaparoid, lepirudin and argatroban. Since LMWH cross react with UFH, it is contra-indicated. Treatment duration is uncertain but at least two or three months of anticoagulant therapy with danaparoid, lepirudin or argatroban is necessary. Guidelines from the American College of Chest Physicians recommend the direct thrombin inhibitors as firstline therapy for HIT. Bivalirudin is approved for use in patients with HIT who undergo percutaneous coronary intervention (PCI) (). A novel synthetic heparin pentasaccharide, fondaparinux, which does not cross-react with HIT antibodies, can be successfully used for the treatment of patients with HIT (1). In fact fondaparinux does cause antibody generation to the fondaparinux:pf complex but this most often does not result in clinical symptoms of HIT (). Warfarin may be first treatment choice until the platelet count normalizes. However, use of warfarin alone may increase the risk of thrombosis (skin necrosis and lower extremities gangrene)

12 warfarin must be used together with one of the three drugs (danaparoid, argatroban or lepirudin) for at least days. We had to use fondaparinux (direct Factor X a inhibitor) for our patient because the other three drugs were not available. In this case report we describe a patient with a giant apical left ventricular thrombus after anterior MI who had HIT syndrome following LMWH. Leclerg et al. reported a case about myocardial infarction and masive biventricular thrombosis during thrombocytopenia induced by pentosan polysulfate and heparin (1). Our case is interesting as a case showing growth of a thrombus on apical wall of left ventricle due to HIT syndrome.

13 References 1. Braunwald s Heart Disease : A Textbook of Cardiovascular Medicine (Eight Edition).. Franchini M (00) Heparin-induced thrombocytopenia: an update Massimo Franchini. Thrombosis Journal :1.. Greinacher A (0) Immunogenic but effective : the HIT-fondaparinux brain puzzler. J Thromb Haemost Dec;(1):-.. Girolami B, Prandoni P, Stefani PM, et al (00) The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 1:-.. Warkentin TE, Levine MN, Hirsh J, et al (1) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med :-1.. Warkentin TE (00) Heparin-induced thrombocytopenia: Diagnosis and management. Circulation 1:-.. Warkentin TE, Heddle NM (00) Laboratory diagnosis of immune heparin-induced thrombocytopenia.curr Hematol Rep :1-1.. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A (00) Evaluation of pretest clinical score ( T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost :-.. Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF (1) Failure of early heparin cessation as treatment for heparininduced thrombocytopenia. Am J Med :-.. Harry L. Messmore, Nancy Fabrini, Mary L. Bird et al (0) Simple scoring system for early management of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 1: Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al (00) ACC/AHA/SCAI 00 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation : Kuo KHM, Kovacs MJ (00) Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost : Leclerg C, de Place C, Rioux C, Mabo P, Paillard F, Daubert JC () Myocardial infarction and massive biventricular thrombosis during thrombocytopenia induced by

14 pentosan polysulfate and heparin. Arch Mal Coeur Vaiss (1):-. Figure Legends: Figure 1: Huge left ventricular cavity thrombus in apical two chamber echocardiographic view. Figure : Huge left ventricular cavity thrombus in apical four chamber echocardiographic view.

15 Authors' Response to Reviewers' Comments Click here to download Authors' Response to Reviewers' Comments: RESPONSE LETTER.doc List of revisions Dear Editor, According to the advices of the editor and reviewers we tried to reply all proposals one by one as much as possible. We highlighted the changes we have performed in the manuscript. We hope this revised form may be suitable for the journal. Kind regards Reviewers' comments: Reviewer #1: This paper has been improved upon in this revision. It is now more clear. However two very important points remain that need to be addressed. 1. The diagnosis of HIT in this case study cannot be definitely ruled as HIT. There were no lab tests performed, either immunological or platelet function, to provide assurance of the diagnosis. Secondly, it is not definitive that 'other' reasons for thrombocytopenia were ruled out since this patient had sepsis, shock, an IABP, and consumption of platelets by the thrombus, all of which can lead to thrombocytopenia in the same time frame. All of this should be included in the case presentation. State if any testing for DIC (another cause of thrombocytopenia) was performed and if this was ruled out too. It would be more appropriate to state it as a likely diagnosis of HIT.. The English has to be corrected. In addition it is not good form to copy word for word a reviewer's comment directly into the paper (English errors and all).

16 1.In our case report there were no lab tests performed, either immunological or platelet function, to serve as an evidence for the diagnosis. However, as we mentioned in the case report, altough functional platelet tests and immunoassays are important for diagnosis of HIT, the T s scoring system allows evaluation of the pre-test probability of HIT. Our patient score was significantly high. We did not performe laboratory tests because the lab tests required for the diagnosis of HIT are not available in our hospital. There were the other reasons for thrombocytopenia but on the sixth day of cessation of heparin the platelet count was normalized thus proving the likelihood of our diagnosis of HIT. If thrombocytopenia was to develop due to the other causes, platelet count would not have been normalized.. We have revised the English and made the necessary corrections.