Table of Contents  
CASE REPORT
Year : 2016  |  Volume : 9  |  Issue : 1  |  Page : 117-120  

Atorvastatin induced thrombocytopenia: A case report and review of literature


1 Department of Pulmonary Medicine, Allergy and Asthma Research Centre, Kolkata, West Bengal, India
2 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India
3 Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India

Date of Web Publication22-Dec-2015

Correspondence Address:
Sukanta Sen
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata - 700 073, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.167984

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  Abstract 

A 65-year-old hypertensive male, with co-existing benign prostatic hyperplasia for last 5 years was on tab telmisartan 40 mg and tab tamsulosin 0.4 mg, both once daily. He was found dyslipidemic on a routine investigation and was put on tab atorvastatin 10 mg once daily. The patient developed a petechial rash and bleeding from gums within a week of starting atorvastatin, and his platelet count dropped to 15,000/cmm. Atorvastatin was suspected to be the offender as no other causes of thrombocytopenia could be implicated. Atorvastatin was discontinued and intravenous steroid and platelet transfusion given. Platelet count improved gradually and became normal after 10 days. Causality assessment as per the Naranjo algorithm revealed a "probable association" with atorvastatin therapy.

Keywords: Adverse drug reaction, atorvastatin, causality assessment, drug-induced thrombocytopenia, statins


How to cite this article:
Moitra S, Sen S, Das P, Banerjee I. Atorvastatin induced thrombocytopenia: A case report and review of literature . Med J DY Patil Univ 2016;9:117-20

How to cite this URL:
Moitra S, Sen S, Das P, Banerjee I. Atorvastatin induced thrombocytopenia: A case report and review of literature . Med J DY Patil Univ [serial online] 2016 [cited 2020 Aug 10];9:117-20. Available from: http://www.mjdrdypu.org/text.asp?2016/9/1/117/167984


  Introduction Top


Atorvastatin, a frequently prescribed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin), the rate-limiting enzyme in cholesterol synthesis, is widely used in the treatment of hypercholesterolaemia, which is a key feature of the metabolic syndrome in humans and an important risk factor for the development of cardiovascular diseases, such as myocardial infarction. It is generally well-tolerated and adverse reactions have been mild and transient. It is effective in reducing the risk for cardiovascular disease and stroke in subjects who do not have an adequate reduction in lipid levels after dietary modification. [1] Commonly encountered adverse effects are constipation, flatulence, dyspepsia and abdominal pain. The major adverse events reported with statins are mainly rhabdomyolysis and deranged liver function tests. [2] We present a case of reversible drug-induced thrombocytopenia, attributed to atorvastatin. There have been a very limited number published case reports only a very few case reports of statin-induced thrombocytopenic purpura in the literature. [3],[4],[5]

Drug-induced thrombocytopenia (DITP) is an idiosyncratic immune-mediated reaction. Drug dependent antibodies are an unusual class of antibodies that binds firmly to specific epitopes on platelet surface glycoproteins only in the presence of the sensitizing drug. Drug-induced thrombocytopenia typically appears suddenly, is often severe, and can cause major bleeding and death. [6],[7] Thrombocytopenia defined as the presence of low platelet counts can be either idiopathic or secondary to other causes like drug-induced thrombocytopenia, pregnancy, autoimmune conditions, viral infections, vaccinations, chronic liver disease, malignancy or congenital causes of thrombocytopenia like Von Willibrand's disease. [8]


  Case Report Top


A 65-year-old male was admitted as an emergency to the medical admissions unit with a generalized nonpruritic, purpuric rash and weakness. On examination, he was noted to have a generalized hemorrhagic purpuric rash over his trunk and limbs and bleeding gums. He was otherwise hemodynamically stable, conscious and oriented. Abdominal examination revealed no evidence of any organomegaly. Laboratory tests performed on admission revealed a platelet count of 15,000/cmm, hemoglobin level 9.1 g/dl and a mild neutrophilia. Blood smear and normal range levels of bilirubin and lactate-dehydrogenase excluded microangiopathic hemolytic anemia. There was an elevation in the liver enzymes but not significant. Prothrombin time 14.6 s (9-15 s) and activated partial thromboplastin time 37.9 s (25-38 s) were within the normal range and a direct Coombs test was negative. Ultrasonography of the abdomen and pelvis demonstrated no pathological findings except for mild fatty changes in liver. Electrolytes and renal function were within normal limits. Routine urine examination showed 1+ leucocyte, 1+ blood and was negative for nitrite. There was no evidence of a significant protein abnormality on electrophoresis. Autoantibody screen, including phospholipid antibodies and anticardiolipin immunoglobulin G were negative.

He was hypertensive, with benign prostatic hyperplasia for last 5 years for which he was on tab telmisartan 40 mg once daily and tab tamsulosin 0.4 mg once daily. He was a nonsmoker and nonalcoholic with no history of drug allergy. On routine blood investigation (07/06/2013), he was found to be dyslipidemic for which he was advised tab atorvastatin 10 mg at bedtime on 08/06/13. Other routine hematological tests were within normal limits, including platelet count (1,75,000/cmm). He noticed a generalized nonpruritic, petechial rash on the dorsum aspect of his hands on 13/06/2013 following which he developed a generalized petechial rash all over his body and become weak. There was neither any history of the seasonal flu, vaccination or blood transfusion in recent past. There was no history of any bleeding problems with prior dentistry or trauma and no history of any known malignancy. He had no positive family history of ischemic heart disease, familial hypercholesterolemia, and any bleeding disorders. There was no history of taking any anti-platelet medications in the recent past. Other causes of thrombocytopenia were ruled out, and administration of atorvastatin was stopped on 14/06/2013.

Treatment was initiated with intravenous steroids and platelet transfusions. His platelet level improved and become normal after 10 days of stopping atorvastatin. The steroids were tapered gradually, and he remained well with no further episodes of thrombocytopenia. He is still actively being followed up by treating physician. No new oral hypolipidemic was advised after this episode, and he was on strict dietary control for dyslipidemia.


  Discussion Top


Our patient developed symptoms 6 th day after starting atorvastatin. The temporal relation between the initiation of therapy of atorvastatin and the onset of petechial rashes and bleeding gums, along with the exclusion of other etiologies, suggests a cause-and-effect relationship. The causality assessment was done by the Naranjo probability scale [9] [Table 1] and the same was corroborated with World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale (WHO Collaborating Centre for International Drug Monitoring, the UMC). [10] In both the scale, the drug event relationship were found to be "probable." No other underlying illness was found, and there was a rapid recovery after discontinuation of the drug.
Table 1: Naranjo ADR probability scale-items and score and the present case

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The miscellaneous pathophysiologic mechanisms of drug-induced thrombocytopenia can be divided into two major categories :

  1. Decreased platelet production via marrow suppression and
  2. Peripheral platelet clearance, usually by one of the several possible immune mechanisms. [11]
The diagnostic approach must include the differentiation of drug-induced thrombocytopenia from idiopathic thrombocytopenic purpura because the latter diagnosis requires the exclusion of other causes of thrombocytopenia [8],[12] [Table 2].
Table 2: Criteria for assessing reports of drug-induced thrombocytopenia and levels of evidence for a causal relationship of the drug to thrombocytopenia

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Drug-induced thrombocytopenia (DITP) can be confirmed by the demonstration of drug-dependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. [13] Immunofluorescence by flow cytometry is the most sensitive method available for detection of drug-dependent platelet antibodies. In this process, patient serum is incubated with normal Group O target platelets in both the presence and absence of drug and bound immunoglobulin is detected. Fluorescence values obtained in the presence and absence of drug are compared. [14]

The diagnosis of thrombotic thrombocytopenic purpura was excluded as the patient was conscious, oriented, no associated fever, renal, and neurological dysfunction. As in other causes of drug-induced thrombocytopenia, statin-induced thrombocytopenia affects only a small fraction of patients taking these medications. On extensive literature search we come across some statin-induced thrombocytopenia case reports and co-related with our present case study [Table 3]. [3],[5],[15],[16],[17],[18]
Table 3: Cases with statin-induced thrombocytopenia reported in the literature

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  Conclusion Top


Statins have pleiotropic effects, including immunomodulatory, anti-inflammatory and antiproliferative properties. [19] Statins affect coagulation by decreasing platelet aggregation, adhesion and its activity by its actions through nitric oxide synthase activity and also by direct inhibition of platelets. [20] It is well-known that the effects of statins on platelet function is time and dose dependent and is more likely to occur soon after the initiation of statin treatment and may be a class-effect. [21]

Our patient had been on atorvastatin for 6 days prior to the development of thrombocytopenia, which points to an idiosyncratic reaction being the most likely cause. Physicians must have a high degree of suspicion and should remain cautious and warn patients to report any symptoms of thrombocytopenia after the inception of this group of drugs for the management of dyslipidemia.

There should be provisions for early withdrawing the offending drug and supportive therapy to lower the intensity of this unexpected potential life threatening drug-induced complication.

 
  References Top

1.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S) Lancet 1994;344:1383-9.  Back to cited text no. 1
    
2.
Malinowski JM. Atorvastatin: A hydroxymethylglutaryl-coenzyme a reductase inhibitor. Am J Health Syst Pharm 1998;55:2253-67.  Back to cited text no. 2
    
3.
González-Ponte ML, González-Ruiz M, Duvós E, Gutiérrez-Iñiguez MA, Olalla JI, Conde E. Atorvastatin-induced severe thrombocytopenia. Lancet 1998;352:1284.  Back to cited text no. 3
    
4.
Narayanan D, Kilpatrick ES. Atorvastatin-related thrombocytopenic purpura. BMJ Case Rep. 2010 May 19; 2010. pii: bcr0120102614. doi: 10.1136/bcr.01.2010.2614.  Back to cited text no. 4
    
5.
Vrettos I, Papageorgiou S, Economopoulou C, Pappa V, Tsirigotis P, Tountas N, et al. Rosuvastatin-induced thrombocytopenia. South Med J 2010;103:676-8.  Back to cited text no. 5
    
6.
Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580-7.  Back to cited text no. 6
    
7.
Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: Pathogenesis, diagnosis, and management. J Thromb Haemost 2009;7:911-8.  Back to cited text no. 7
    
8.
George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, et al. Drug-induced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886-90.  Back to cited text no. 8
    
9.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 9
[PUBMED]    
10.
The Use of the WHO-UMC System for Standardized Case Causality Assessment. Available from: http://www.WHO-UMC.org/graphics/4409.pdf. [Last accessed on 2014 Dec 04].  Back to cited text no. 10
    
11.
Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med 2009;133:309-14.  Back to cited text no. 11
    
12.
George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3-40.  Back to cited text no. 12
    
13.
Arnold DM, Kukaswadia S, Nazi I, Esmail A, Dewar L, Smith JW, et al. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013;11:169-76.  Back to cited text no. 13
    
14.
McFarland JG. Laboratory investigation of drug-induced immune thrombocytopenias. Transfus Med Rev 1993;7:275-87.  Back to cited text no. 14
    
15.
Groneberg DA, Barkhuizen A, Jeha T. Simvastatin-induced thrombocytopenia. Am J Hematol 2001;67:277.  Back to cited text no. 15
    
16.
Possamai G, Bovo P, Santonastaso M. Thrombocytopenic purpura during therapy with simvastatin. Haematologica 1992;77:357-8.  Back to cited text no. 16
    
17.
Yamada T, Shinohara K, Katsuki K. Severe Thrombocytopenia Caused by Simvastatin in which Thrombocyte Recovery was Initiated after Severe Bacterial Infection. Clin Drug Investig 1998;16:172-4.  Back to cited text no. 17
    
18.
Ames PR. Simvastatin-induced thrombocytopaenia: A further case and a brief on its clinical relevance. Ann Hematol 2008;87:773-4.  Back to cited text no. 18
[PUBMED]    
19.
Werner N, Nickenig G, Laufs U. Pleiotropic effects of HMG-CoA reductase inhibitors. Basic Res Cardiol 2002;97:105-16.  Back to cited text no. 19
    
20.
Ray JG, Mamdani M, Tsuyuki RT, Anderson DR, Yeo EL, Laupacis A. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001;161:1405-10.  Back to cited text no. 20
    
21.
Pedersen-Bjergaard U, Andersen M, Hansen PB. Drug-induced thrombocytopenia: Clinical data on 309 cases and the effect of corticosteroid therapy. Eur J Clin Pharmacol 1997;52:183-9.  Back to cited text no. 21
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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