Archives of Academic Emergency Medicine. 2021; 9(1): e17 https://doi.org/10.22037/aaem.v9i1.1063 CA S E RE P O RT Rare and Underestimated Association of Pulmonary Em- bolism and Olanzapine Therapy; Report of Two Cases Hammam Rasras1∗, Mustapha Beghi1, Maryem Samti1, Nabila Ismaili1,2, Noha El Ouafi1,2 1. Department of Cardiology, Mohammed VI University Hospital of Oujda, Mohammed First University of Oujda, Morocco. 2. Laboratory of Epidemiology, Clinical Research and Public Health, Faculty of Medicine and Pharmacy, Mohammed the First University of Oujda, Morocco. Received: December 2020; Accepted: December 2020; Published online: 5 February 2021 Abstract: Venous thromboembolic disease (VTD) is a very common and severe pathological condition in which there are many predisposing factors. Olanzapine is a drug frequently used in psychiatric practises; it is thought to increase the risk of VTD. Here, we report two cases, a young man and a woman, with a medical history of schizophrenia treated by olanzapine who developed pulmonary embolism and we did not find any aetiologies of VTD in them. Due to the link between olanzapine and pulmonary embolism, which has been previously described, olanzapine is considered responsible for this problem. Two mechanisms have been reported in the literature in this regard; significant weight gain and lethargy, which are very common side effects of olanzapine. So far, no direct effect of olanzapine on platelet aggregation or coagulation has been found. In patients developing VTD while being treated with olanzapine, discontinuation of olanzapine as a treatment option must be done with an adjustment of antipsychotic treatment and regular monitoring of psychic symptoms. Since the diagnosis of pulmonary embolism is not easy to make in a schizophrenic patient, clinicians should take that in consideration when prescribing these drugs and when facing clinical situations where VTD is suspected. Keywords: Pulmonary embolism; venous thromboembolism; risk factors; antipsychotic agents; olanzapine Cite this article as: Rasras H, Beghi M, Samti M, Ismaili N, El Ouafi N. Rare and Underestimated Association of Pulmonary Embolism and Olanzapine Therapy; Report of Two Cases. Arch Acad Emerg Med. 2021; 9(1): e17. 1. Introduction Venous thromboembolic disease (VTD) is a multifactorial disease, which is represented by two entities: deep venous thrombosis (DVT) or pulmonary embolism (PE). VTD usu- ally develops due to many thromboembolic risk factors, such as old age, context of immobilization, post-surgery or preg- nancy, past history of DVT, neoplasia, certain drugs (oestro- gens, chemotherapy), antiphospholipid syndrome, obesity, sedentarily, and hypercoagulability states, including muta- tion of factor V Leiden or prothrombin (1). Like many dis- eases, VTD has predisposing factors, which are grouped into three categories, termed the Virchow’s triad: endothelial in- jury, stasis of blood flow, and, hypercoagulability (2). It is a major cause of morbidity and mortality among hospitalized patients, with an annual incidence of 1 per 1000 population ∗Corresponding Author: Hammam Rasras; Department of Cardiology, Mo- hammed VI University Hospital of Oujda, Mohammed First University of Ou- jda, Morocco. Tel: 00212762675885, Email: h.rasras@hotmail.com, ORCID: https://orcid.org/0000-0002-7575-9404 (3). Olanzapine is an atypical antipsychotic (AAP) (second- generation antipsychotic), prescribed for schizophrenic pa- tients, especially those with positive symptoms. This thera- peutic class has several side effects, including metabolic syn- drome and diabetes, hyperprolactinemia, sexual dysfunc- tion, and weight gain (4), which is more frequently observed in olanzapine. The incidence of VTD in AAP users is in- creased by 2.20 (95% CI: 1.22-3.95) times (3). We report two cases, a young man and a woman with a his- tory of paranoid schizophrenia, who presented with PE while using olanzapine without inherited risk factors for VTD. We further explored the possible association between olanzap- ine and VTD. Lastly, we took a brief look at and reviewed the potential mechanisms behind this association. 2. Cases presentation 2.1. Case 1 A 28-year old male patient, with no risk factors for VTD, with a medical history of schizophrenia on olanzapine ther- apy, was admitted for an acute onset of hallucinations and This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Rasras et al. 2 Figure 1: Axial cut of thoracic computed tomography angiography showing embolism in right and left pulmonary artery. delirious behaviour with dyspnoea. On admission, he was confused, afebrile, had tachycardia with a blood pressure at 130/50mmHg and normal oxygen saturation in room air. Cardiovascular, respiratory, and abdominal examina- tions’ findings were insignificant. There were no signs of meningism. Blood tests revealed high D-dimer (7.11µg/l), troponin (2928 ng/l) and B-type natriuretic peptide (BNP) (2415 pg/m) levels. Chest X-ray showed an elevation of the right dome of diaphragm with low abundance pleurisy, whilst his electrocardiogram (ECG) showed sinus tachycar- dia and right bundle branch block with a right axis devi- ation. Computed tomography (CT) pulmonary angiogram revealed an extensive right and left pulmonary embolism (Figure 1). Systolic pulmonary arterial pressure (sPAP) was 41 mmHg, paradoxical septum, and dilated right ventricle (RVD/VG = 1.14) with systolic dysfunction were observed in the transthoracic echocardiography (TTE). The simplified pulmonary embolism severity index (s-PESI) was 1 and the patient was classified as a high intermediate risk patient. In etiological assessment: doppler ultrasound of two legs, tests for thrombophilia (no family history of thrombophilia was found), tumor markers, and thoracic, abdominal, and pelvic CT angiography showed no abnormalities. All of the diagnos- tic tests were normal, and since the only possible risk factor was olanzapine therapy, it was terminated after psychiatric consultation, and then he was put on aripiprazole. Then, he was treated with anticoagulants. 2.2. Case 2 A 68-year old female patient, obese with a medical history of psychotic depression on olanzapine therapy, was admitted for an atypical chest pain and dyspnoea. On admission, she was asthenic, had no fever, heart rate was 111 beats/minute, blood pressure was 100/50 mmHg, and respiratory rate was 28 cycles/minute. Her oxygen saturation level was low (90 % in room air). Physical examination findings were insignif- icant. Blood tests revealed high D-dimer (1.88 µg/l), tro- ponin (7439 ng/l) and BNP (1324 pg/m) levels. Chest X-ray was normal, ECG showed sinus tachycardia. CT pulmonary angiography revealed a bilateral extensive pulmonary em- bolism (Figure 1). TTE showed a dilated right ventricle with systolic dysfunction and a systolic pulmonary arterial pres- sure (sPAP) at 64 mmHg. The s-PESI was 2 and the patient was classified as a high intermediate risk patient. In etio- logical assessment: doppler ultrasound of two legs, tumor markers, gynaecological examination, mammography, and thoracic, abdominal and pelvic CT angiography revealed no anomalies. Then, she was put on heparin therapy with re- lay by vitamin K antagonist until the repeated international normalized ratio (INR) was between 2 and 3. Heparin was stopped on the 9th day, with good evolution. 3. Discussion VTD is a complex disease, involving interaction between ac- quired or inherited predispositions to thrombosis (Throm- bophilia) and environmental exposures (clinical risk factors). Many studies have considered olanzapine as a risk factor that might increase the risk of VTD. This presentation was re- ported for the first time in Germany in 1950s (4). The under- lying mechanism is still unknown. In our study, we are trying to take a brief look at literature and review the hypotheses of the potential mechanisms behind this association. Some clinical and pharmacological studies have been pub- lished in this domain, trying to explain the causality of this association between olanzapine and VTD. In 2002, Hagg et al. (5) found an increased level of antiphospholipid anti- bodies and hyperprolactinemia in patients on olanzapine therapy, and then considered it as an independent risk fac- tor for thromboembolic events. In 2008, Kannan et al. re- ported six cases of fatal PE in six patients who were on olan- zapine therapy for a long period; they showed that olanza- pine binds to serotonin receptors, and then activates sero- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e17 tonergic system, which stimulates platelet aggregation; it can also bind to alpha-receptors, which contributes to the forma- tion thrombosis by causing hypotension and venous blood stasis (1). Some hypotheses were proposed by these two teams and it was suggested that olanzapine can induce hy- perleptinemia, which might lead to abnormalities in fibrinol- ysis, as well as metabolic disorders, such as dyslipidaemia and hyper-homocysteinemia, which play an important role in thrombotic events (1, 5). A retrospective study on the WHO database showed that VTD occurred with a higher fre- quency in patients on olanzapine and clozapine compared to those on other AAPs, and in 60% of cases this event oc- curred within the first 3 months of treatment. Moreover, like other studies, some plausible mechanisms were sug- gested; such as antipsychotic-induced sedation, obesity, hy- perleptinemia, the presence of antiphospholipid antibodies, and enhanced platelet aggregation (6). In 2018, a study was performed by the Netherlands. Pharmacovigilance Centre Lareb on seventeen patients who developed VTD while using olanzapine, and only a few of them had thromboembolism risk factors. This study showed a higher incidence rate of VTD in patients on AAP therapy compared with populations who had predisposing factors of VTD, and that - like other mentioned studies - was explained by the drug’s side effects, causing platelet aggregation and inducing the blockade of histamine-1 receptor and α-1 re- ceptor. It has also been shown that olanzapine and clozap- ine have the most profound impact compared to other AAPs. Moreover, discontinuation of olanzapine has been suggested for those who develop VTD, with a control of psychotic symp- toms and antipsychotic treatment options (3). A pharmaco- logical study performed by Almuqdadi et al. has confirmed that olanzapine could antagonise the serotonin (5-HT2A) re- ceptors; since these receptors are present on platelets, olan- zapine is thought to be a factor influencing platelet aggre- gation (7). Other studies were performed in the same do- main trying to explain the mechanism behind this associa- tion, for instance, Carrizo et al. found increased leptin and Plasminogen Activator Inhibitor-1 (PAI-1) levels in patients treated with olanzapine, and believed that this makes them more exposed to thromboembolic events (8). Both the Dutch website for drug information ‘Farmacothera- peutischKompas’ and the Dutch Summary of Product Char- acteristics (SmPC) indicated that there is no direct relation- ship between olanzapine and VTD and that the underlying cause of VTD are the side effects induced by olanzapine (9, 10). In our cases, no risk factor of VTD was found in the first pa- tient and etiological assessment did not reveal any abnor- malities for any of the patients, and we believe that olanza- pine is the underlying cause of PE, similar to the previously reported cases. No validated risk assessment score is available for identifi- cation of psychiatric patients who might benefit from phar- macological VTD prophylaxis, and we are looking forward to performance of studies that can establish a scoring system for evaluating the risk of thromboembolic events before ini- tiation of therapy with olanzapine or other AAPs. 4. Conclusion Olanzapine is an increasingly prescribed drug for patients with schizophrenia, and like all other drugs, it has side effects that can be banal or potentially serious and life threatening. The incidence rate of VTD in patients treated with olanzap- ine is higher than that of the general population, and despite the absence of studies that confirm the direct link between them, olanzapine is considered to be a factor that can in- crease the risk of thromboembolic events. Further studies, especially pharmacological studies that can confirm the un- derlying cause and find prophylactic treatments, especially for patients who already have thromboembolic risk factors, should be considered. 5. Declarations 5.1. Acknowledgements None. 5.2. Authors contribution All authors passed the criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors. 5.3. Ethical consideration The authors adhered to confidentiality of patients’ profiles and ethical recommendations regarding research in biomed- ical field. 5.4. Conflict of interest The authors declare that there is no conflict of interest re- garding this study. 5.5. Source of financial support No financial support was received for this study. References 1. Kannan R, Molina DK. Olanzapine: a new risk factor for pulmonary embolus? The American journal of forensic medicine and pathology. 2008;29(4):368-70. 2. Esmon CT. Basic mechanisms and pathogenesis of ve- nous thrombosis. Blood reviews. 2009;23(5):225-9. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Rasras et al. 4 3. Dijkstra M, van der Weiden C, Schol-Gelok S, Muller- Hansma A, Cohen G, van den Bemt P, et al. Ve- nous thrombosis during olanzapine treatment: a com- plex association. The Netherlands journal of medicine. 2018;76(6):263-8. 4. Grahmann H. Thombose hazard in chlorpromazine and reserpine therapy of endogenous psychosis. Nervenarzt. 1959;30:224-5. 5. Hagg S, Spigset O. Antipsychotic-induced venous throm- boembolism. CNS drugs. 2002;16(11):765-76. 6. Hagg S, Bate A, Stahl M, Spigset O. Associations be- tween venous thromboembolism and antipsychotics. Drug safety. 2008;31(8):685-94. 7. Almuqdadi A, Bulatova N, Yousef A-M. The effect of atyp- ical antipsychotics on platelet aggregation. Open Journal of Hematology. 2016;7(1). 8. Carrizo E, Fernandez V, Quintero J, Connell L, Ro- driguez Z, Mosquera M, et al. Coagulation and inflam- mation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first- degree relatives. Schizophrenia research. 2008;103(1- 3):83-93. 9. Nederland Z. FarmacotherapeutischKompas [Available from: https://www.farmacotherapeutischkompas.nl/. 10. Dutch SmPC olanzapine Zalasta 2.5/5/7.5/10/15/20 tablets 2012 [26 July 2012:[Available from: https://www.ema.europa.eu/en/documents/product- information/zalasta-epar-product-information_nl.pdf. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Cases presentation Discussion Conclusion Declarations References