http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, Early Online: 1–2 ! 2014 Informa UK Ltd. DOI: 10.3109/09537104.2014.898263
CASE REPORT
Synthetic marijuana ‘‘K2’’ induced ITP Erman O¨ztu¨rk1, Alihan Oral2, Melek O¨zdemir2, & Nail Bambul2 Department of Hematology, Istanbul Medeniyet University, Go¨ztepe Training and Research Hospital, Istanbul, Turkey, and 2Department of Internal Medicine, Istanbul Medeniyet University, Go¨ztepe Training and Research Hospital, Istanbul, Turkey
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1
Abstract
Keywords
Immune thrombocytopenia (ITP) is a heterogeneous disease which can be primary or secondary due to other conditions such as drugs. CB2 receptors (CB2R) also have a role in the ITP pathogenesis as CB2 receptor gene (CNR2) polymorphisms are associated with chronic immune thrombocytopenia and autoimmune diseases. K2 is synthetic marijuana which acts on cannabinoid receptors that are found on immune cells and thrombocytes. Here, we present a case who presented with ITP secondary to K2 usage and was successfully treated with 1 mg/kg prednisolone. This is the first ITP case in the literature due to K2. It is important in the era of the new drugs development of the CB2R mimetics.
Cannabinoid, ITP, K2, marijuana, thrombocytopenia
Introduction Immune thrombocytopenia (ITP) is an acquired autoimmune disease mediated by platelet antibodies that accelerate platelet destruction and inhibit their production. Most cases are considered primary, whereas others are attributed to coexisting conditions known as secondary ITP. ITP is best characterized as a syndrome sharing the common clinical phenotype of immune-mediated thrombocytopenia [1]. ITP patients may have defects in immune self-tolerance with autoreactive cytotoxic CD8-expressing T-lymphocyte clones against platelets and possibly megakaryocytes [1, 2]. Drugs are well known causes of thrombocytopenia by inducing immune mechanisms. Several drugs have been demonstrated to cause ITP [3]. ‘‘K2’’ drugs represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana. The psychoactive effect of marijuana is mainly exhibiting partial agonistic activity both in central nervous system via CB1 cannabinoid receptors and in the periphery via CB2 receptors (CB2R) [4]. Marijuana abuse is common but marijuana related thrombocytopenia has not been reported. Here, we report of a case of synthetic marijuana (K2) induced ITP.
Case report A 23-year-old male was admitted to the hospital with complaints of bleeding, e.g. epistaxis and petechial rashes on both legs. There was no history of any chronic disease and family history for thrombocytopenia. He was not on any regular medications but he was addicted to K2 drugs. On clinical examination, there were oropharyngeal petechiae, epistaxis and peripheral ecchymoses.
¨ ztu¨rk, Department of Hematology, Istanbul Correspondence: Erman O Medeniyet University, Goztepe Egitim ve Arastirma Hastanesi, Kadikoy/ Istanbul, Turkey. Tel: +90 216 5709281. Fax: +90 216 5709281. E-mail: [email protected]
History Received 11 December 2013 Revised 16 February 2014 Accepted 23 February 2014 Published online 18 April 2014
He did not have any fever, lymphadenopathy or hepatosplenomegaly and neurological examination was normal. On the full blood count, his WBC: 11 000/mm3, Neu: 6500/mm3, Hb: 14.2 g/dl, Hct: 42.4%, Plt: 8000/mm3, absolute reticulocyte count 60.000/ml (25 000–75 000), LDH: 538 IU/l (135–214). PT: 13.1 seconds (10–14), aPTT: 31.3 seconds (22–35), Cr: 0.91 mg/dl (0.5–1.4), total bilirubin: 0.57 mg/dl (0.7–1.2), sedimentation rate: 12 mm/h and alanine aminotransferase and aspartate aminotransferase were normal. Peripheral blood smear confirmed thrombocytopenia with large thrombocytes. There were no other abnormalities on blood smear such as atypical cells or schistocytes. Thrombotic thrombocytopenic purpura (TTP)/ hemolytic uremic syndrome (HUS) were considered for differential diagnosis but the absence of diarrhea, fever, neurologic findings, schistocytes on blood film and normal renal functions ruled out both diseases. The patient was negative for hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human immune deficiency virus (HIV). Antinuclear antibody (ANA) was also negative. Recently, he was not on any medications but he reported that he had been addicted to the synthetic marihuana, K2. He had been using K2 for 1 year and the last dose was 4 days before the bleeding occurred. Platelet transfusion was given because of his symptomatic bleeding. His platelet count was 12.000/mm3 1 hour after the transfusion. Therefore the patient was diagnosed as ITP and was given prednisolone with a dose of 1 mg/kg/day. On the follow-up, LDH values decreased constantly and thrombocyte levels rose with treatment. On the sixth day of the steroid therapy, the patient was discharged with a platelet count of 48 000/mm3. Three weeks after the steroid treatment his platelet count was 245 000/mm3 and prednisolone dose was tapered off. After 6 months of the presentation, he was still in remission without being under any treatment and does not use any K2 drugs.
Discussion It is important to define the etiology of the thrombocytopenia in the emergency room. Differential diagnosis of the
Platelets Downloaded from informahealthcare.com by University of Toronto on 08/10/14 For personal use only.
2
¨ ztu¨rk et al. E. O
thrombocytopenia with high LDH levels includes TTP and HUS. In our case, the absence of the classical pentad of TPP/HUS, persistence of the thrombocytopenia after transfusion of thrombocyte and good response to the steroid therapy TTP and HUS were ruled out and he was diagnosed as ITP. In primary ITP, LDH values are usually within normal limits but can be elevated in secondary ITP due to the underlying disease. Elevation of LDH in our patient is probably not due to the hemolysis of erythrocytes. LDH is an enzyme that exists in many tissues such as brain, liver or muscle and tissue damage with the use of synthetic marijuana could have increased the LDH levels in our patient. Unfortunately, we could not identify the sub-groups of LDH and where was originated from. We think the decrease of the LDH levels in our patient is either due to the discontinuation of K2 drugs or due to the steroid therapy. Drugs are important causes in the etiology of ITP. The usage of synthetic marijuana ‘‘K2’’ is increasing progressively mainly because of its psychosomatic effects. There are three case reports in the literature with marijuana associated thrombocytopenia which are not ITP but associated with the toxicity of the marijuana [5–7]. While marijuana acts on the cannabinoid receptors, synthetic marijuana, like K2, has strong activity and affinity on CB2R [8]. CB2R and ligands are found primarily in immune cells and has effects on immune modulation [9]. CB2 receptor gene (CNR2) polymorphism is associated with chronic immune thrombocytopenia and autoimmune diseases [10]. Therefore, we hypothesize that K2, which is a strong stimulator of CB2R may cause to ITP by modifying its effects on immunomodulation. In our case, ITP was considered to be secondary to the K2 and remission was achieved by steroid therapy. This case is important as K2 addiction is increasing and as more CB1R and CB2R mimetics drugs are on the way.
Platelets, Early Online: 1–2
Declaration of interest The authors declare that they have no conflict of interest.
References 1. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood 2009;113: 6511–6521. 2. Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B, Carlsson LM, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003;9: 1123–1124. 3. George JN, Aster RH. Drug-induced thrombocytopenia: Pathogenesis, evaluation, and management. ASH Education Program Book 2009;1:153–158. 4. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuro Psychopharmacol Biol Psychiatry 2012;39:234–243. 5. Payne Rj BSN. THe toxicity of intravenously used marihuana. JAMA 1975;233:351–354. 6. Farber Sj HVE. Intravenously injected marihuana syndrome. Arch Intern Med 1976;136:337–339. 7. Vaziri ND, Thomas R, Sterling M, Seiff K, Pahl MV, Davila J, et al. Toxicity with intravenous injection of crude marijuana extract. Clin Toxicol 1981;18:353–366. 8. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33:195–209. 9. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, et al. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74:486–496. 10. Rossi F, Mancusi S, Bellini G, Roberti D, Punzo F, Vetrella S, et al. CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 2011;96:1883–1885.
CASE REPORT
Synthetic marijuana ‘‘K2’’ induced ITP Erman O¨ztu¨rk1, Alihan Oral2, Melek O¨zdemir2, & Nail Bambul2 Department of Hematology, Istanbul Medeniyet University, Go¨ztepe Training and Research Hospital, Istanbul, Turkey, and 2Department of Internal Medicine, Istanbul Medeniyet University, Go¨ztepe Training and Research Hospital, Istanbul, Turkey
Platelets Downloaded from informahealthcare.com by University of Toronto on 08/10/14 For personal use only.
1
Abstract
Keywords
Immune thrombocytopenia (ITP) is a heterogeneous disease which can be primary or secondary due to other conditions such as drugs. CB2 receptors (CB2R) also have a role in the ITP pathogenesis as CB2 receptor gene (CNR2) polymorphisms are associated with chronic immune thrombocytopenia and autoimmune diseases. K2 is synthetic marijuana which acts on cannabinoid receptors that are found on immune cells and thrombocytes. Here, we present a case who presented with ITP secondary to K2 usage and was successfully treated with 1 mg/kg prednisolone. This is the first ITP case in the literature due to K2. It is important in the era of the new drugs development of the CB2R mimetics.
Cannabinoid, ITP, K2, marijuana, thrombocytopenia
Introduction Immune thrombocytopenia (ITP) is an acquired autoimmune disease mediated by platelet antibodies that accelerate platelet destruction and inhibit their production. Most cases are considered primary, whereas others are attributed to coexisting conditions known as secondary ITP. ITP is best characterized as a syndrome sharing the common clinical phenotype of immune-mediated thrombocytopenia [1]. ITP patients may have defects in immune self-tolerance with autoreactive cytotoxic CD8-expressing T-lymphocyte clones against platelets and possibly megakaryocytes [1, 2]. Drugs are well known causes of thrombocytopenia by inducing immune mechanisms. Several drugs have been demonstrated to cause ITP [3]. ‘‘K2’’ drugs represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana. The psychoactive effect of marijuana is mainly exhibiting partial agonistic activity both in central nervous system via CB1 cannabinoid receptors and in the periphery via CB2 receptors (CB2R) [4]. Marijuana abuse is common but marijuana related thrombocytopenia has not been reported. Here, we report of a case of synthetic marijuana (K2) induced ITP.
Case report A 23-year-old male was admitted to the hospital with complaints of bleeding, e.g. epistaxis and petechial rashes on both legs. There was no history of any chronic disease and family history for thrombocytopenia. He was not on any regular medications but he was addicted to K2 drugs. On clinical examination, there were oropharyngeal petechiae, epistaxis and peripheral ecchymoses.
¨ ztu¨rk, Department of Hematology, Istanbul Correspondence: Erman O Medeniyet University, Goztepe Egitim ve Arastirma Hastanesi, Kadikoy/ Istanbul, Turkey. Tel: +90 216 5709281. Fax: +90 216 5709281. E-mail: [email protected]
History Received 11 December 2013 Revised 16 February 2014 Accepted 23 February 2014 Published online 18 April 2014
He did not have any fever, lymphadenopathy or hepatosplenomegaly and neurological examination was normal. On the full blood count, his WBC: 11 000/mm3, Neu: 6500/mm3, Hb: 14.2 g/dl, Hct: 42.4%, Plt: 8000/mm3, absolute reticulocyte count 60.000/ml (25 000–75 000), LDH: 538 IU/l (135–214). PT: 13.1 seconds (10–14), aPTT: 31.3 seconds (22–35), Cr: 0.91 mg/dl (0.5–1.4), total bilirubin: 0.57 mg/dl (0.7–1.2), sedimentation rate: 12 mm/h and alanine aminotransferase and aspartate aminotransferase were normal. Peripheral blood smear confirmed thrombocytopenia with large thrombocytes. There were no other abnormalities on blood smear such as atypical cells or schistocytes. Thrombotic thrombocytopenic purpura (TTP)/ hemolytic uremic syndrome (HUS) were considered for differential diagnosis but the absence of diarrhea, fever, neurologic findings, schistocytes on blood film and normal renal functions ruled out both diseases. The patient was negative for hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human immune deficiency virus (HIV). Antinuclear antibody (ANA) was also negative. Recently, he was not on any medications but he reported that he had been addicted to the synthetic marihuana, K2. He had been using K2 for 1 year and the last dose was 4 days before the bleeding occurred. Platelet transfusion was given because of his symptomatic bleeding. His platelet count was 12.000/mm3 1 hour after the transfusion. Therefore the patient was diagnosed as ITP and was given prednisolone with a dose of 1 mg/kg/day. On the follow-up, LDH values decreased constantly and thrombocyte levels rose with treatment. On the sixth day of the steroid therapy, the patient was discharged with a platelet count of 48 000/mm3. Three weeks after the steroid treatment his platelet count was 245 000/mm3 and prednisolone dose was tapered off. After 6 months of the presentation, he was still in remission without being under any treatment and does not use any K2 drugs.
Discussion It is important to define the etiology of the thrombocytopenia in the emergency room. Differential diagnosis of the
Platelets Downloaded from informahealthcare.com by University of Toronto on 08/10/14 For personal use only.
2
¨ ztu¨rk et al. E. O
thrombocytopenia with high LDH levels includes TTP and HUS. In our case, the absence of the classical pentad of TPP/HUS, persistence of the thrombocytopenia after transfusion of thrombocyte and good response to the steroid therapy TTP and HUS were ruled out and he was diagnosed as ITP. In primary ITP, LDH values are usually within normal limits but can be elevated in secondary ITP due to the underlying disease. Elevation of LDH in our patient is probably not due to the hemolysis of erythrocytes. LDH is an enzyme that exists in many tissues such as brain, liver or muscle and tissue damage with the use of synthetic marijuana could have increased the LDH levels in our patient. Unfortunately, we could not identify the sub-groups of LDH and where was originated from. We think the decrease of the LDH levels in our patient is either due to the discontinuation of K2 drugs or due to the steroid therapy. Drugs are important causes in the etiology of ITP. The usage of synthetic marijuana ‘‘K2’’ is increasing progressively mainly because of its psychosomatic effects. There are three case reports in the literature with marijuana associated thrombocytopenia which are not ITP but associated with the toxicity of the marijuana [5–7]. While marijuana acts on the cannabinoid receptors, synthetic marijuana, like K2, has strong activity and affinity on CB2R [8]. CB2R and ligands are found primarily in immune cells and has effects on immune modulation [9]. CB2 receptor gene (CNR2) polymorphism is associated with chronic immune thrombocytopenia and autoimmune diseases [10]. Therefore, we hypothesize that K2, which is a strong stimulator of CB2R may cause to ITP by modifying its effects on immunomodulation. In our case, ITP was considered to be secondary to the K2 and remission was achieved by steroid therapy. This case is important as K2 addiction is increasing and as more CB1R and CB2R mimetics drugs are on the way.
Platelets, Early Online: 1–2
Declaration of interest The authors declare that they have no conflict of interest.
References 1. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood 2009;113: 6511–6521. 2. Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B, Carlsson LM, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003;9: 1123–1124. 3. George JN, Aster RH. Drug-induced thrombocytopenia: Pathogenesis, evaluation, and management. ASH Education Program Book 2009;1:153–158. 4. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuro Psychopharmacol Biol Psychiatry 2012;39:234–243. 5. Payne Rj BSN. THe toxicity of intravenously used marihuana. JAMA 1975;233:351–354. 6. Farber Sj HVE. Intravenously injected marihuana syndrome. Arch Intern Med 1976;136:337–339. 7. Vaziri ND, Thomas R, Sterling M, Seiff K, Pahl MV, Davila J, et al. Toxicity with intravenous injection of crude marijuana extract. Clin Toxicol 1981;18:353–366. 8. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33:195–209. 9. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, et al. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74:486–496. 10. Rossi F, Mancusi S, Bellini G, Roberti D, Punzo F, Vetrella S, et al. CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 2011;96:1883–1885.
