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 Table of Contents  
Year : 2019  |  Volume : 7  |  Issue : 2  |  Page : 70-73

Valproic acid-induced diffuse alveolar hemorrhage: a rare case report from South India

Department of Pulmonary Medicine, SS Institute of Medical Sciences and Research Centre, Davanagere, Karnataka, India

Date of Web Publication20-Jun-2019

Correspondence Address:
Dr. Eti Ajit
Department of Pulmonary Medicine, SS Institute of Medical Sciences and Research Centre, Davanagere
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jacp.jacp_26_18

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Valproic acid (VPA) is an antiepileptic drug that is widely used in various seizure disorders both in adults and in children. Hematological and coagulation abnormality is a well-known adverse effect associated with VPA. However, VPA-induced diffuse alveolar hemorrhage is a rare entity. We are reporting one such case of VPA-associated diffuse alveolar hemorrhage.

Keywords: Alveolar hemorrhage, drug-induced DAH, valproic acid

How to cite this article:
Raykar P, Ajit E, Banur A, Bondade K. Valproic acid-induced diffuse alveolar hemorrhage: a rare case report from South India. J Assoc Chest Physicians 2019;7:70-3

How to cite this URL:
Raykar P, Ajit E, Banur A, Bondade K. Valproic acid-induced diffuse alveolar hemorrhage: a rare case report from South India. J Assoc Chest Physicians [serial online] 2019 [cited 2022 Dec 6];7:70-3. Available from: https://www.jacpjournal.org/text.asp?2019/7/2/70/260588

  Introduction Top

Diffuse alveolar hemorrhage (DAH) syndrome is characterized by bleeding into the alveolar space and is due to disruption of alveolar capillary basement membrane. It is a life-threatening condition characterized by hemoptysis, diffuse alveolar infiltrates, and acute respiratory failure. DAH is caused by a number of clinical conditions. We report a case of drug-induced DAH.

  Case report Top

A 38-year-old male patient was rushed to the emergency department with history of cough, which was predominantly dry, associated with mild-to-moderate hemoptysis and breathlessness without wheeze of 1 week duration. The patient was tachypnoeic and his room air oxygen saturation (SpO2) was 60%. Respiratory system examination showed bilateral crepitations, predominantly on the left side. On admission, SpO2 was 60%, which improved to 90% following administration of 5 L/min of oxygen and noninvasive ventilation. He was a known case of epilepsy and was on oral valproic acid (VPA) 1000 mg and oral clobazam 10 mg daily since 6 years. He was a normotensive, nondiabetic, nonsmoker, and nonalcoholic with no past history of pulmonary tuberculosis. Chest radiograph showed bilateral perihilar infiltrates (left > right) [Figure 1]. Acute pulmonary embolism, lobar pneumonia, and acute left ventricular failure were considered as initial diagnostic possibilities. The patient underwent computed tomography (CT) pulmonary angiography, which revealed air space consolidation with air bronchogram pattern involving superior and posterobasal segments of bilateral lower lobes [Figure 2]. There was no evidence of pulmonary embolism. Echocardiography was normal. Total leukocyte counts and C-reactive protein were within normal limits. Rapid antinuclear antibody enzyme linked immunosorbent assay (ELISA) was negative. Sputum and blood culture showed no growth of organism. Hence, possibility of infection was ruled out. Serial complete blood counts (CBC) showed a decreasing trend of platelets (70k → 60k → 49k), altered coagulation profile (international normalized ratio, INR, of 2.6), and macrocytosis. Based on patient’s clinical presentation, radiological observations, and hematological parameters (thrombocytopenia, altered coagulation profile, and persistent macrocytosis), possibility of VPA-induced DAH was considered. Bronchoscopy was deferred in view of persistent hypoxia and respiratory distress. Neurologist’s opinion was obtained to substitute antiepileptics. VPA was tapered and the patient was initiated on systemic steroids (intravenous methylprednisolone 0.5 mg/kg). Gradual improvement was witnessed in the patient in terms of clinical condition, improving platelet count, and reducing need of supplemental oxygen. The patient was discharged on domiciliary oxygen and was reviewed after 2 weeks. Follow-up CBC revealed improved platelet count of 1.4 lakh/mm3 and normal coagulation profile. Bronchoscopy was done and bronchial wash was sent for acid-fast bacilli stain, gram stain, bacterial culture, and cytology during follow-up. Acid-fast bacilli stain and Gene Xpert test was negative, gram stain and culture were negative, and cytology was negative for hemosiderin-laden macrophages and negative for malignant cells. Over a period of 1 month, VPA was tapered, stopped, and substituted with oral phenytoin 300 mg/day. The patient was off oxygen therapy, maintaining room air SpO2 of above 95%, complete radiological resolution [Figure 3], and platelets of 1.7 lakhs and hemoglobin of 15 g% during 6 weeks of follow-up.
Figure 1 Chest radiograph at presentation showing bilateral nonhomogenous opacities predominantly perihilar and lower zones.

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Figure 2 CT thorax depicting bilateral lower lobes airspace consolidation.

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Figure 3 Complete resolution of chest radiograph at 6-week follow-up.

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  Discussion and review of literature Top

VPA is an anticonvulsant drug used in the treatment of epilepsy with generalized or focal seizures, bipolar disorders, neuropathic pain, and prophylaxis for migraine in both pediatric patients and adults.[1] Various drugs can cause DAH that include amiodarone, crack cocaine, nitrofurantoin, penicillamine, propylthiouracil, sirolimus, and trimellitic anhydride.[2],[3] As such, VPA-associated DAH is very rare, and till now only four cases are reported in the literature worldwide. To the best of our knowledge, this is the first case to be reported from India.

DAH secondary to VPA is explained by various coagulation abnormalities associated with it. Thrombocytopenia is a known complication that occurs at a frequency of 5% to 60%.[4] The possibility of thrombocytopenia is due to dose-dependent suppression of bone marrow production of platelets or antiplatelet antibody production either by drug itself or its metabolite.[5] VPA-induced thrombocytopenia was associated with inverse relation between platelet count and antiplatelet immunoglobulin levels.[6] In few articles by Sandler et al.[7] and Morris et al.,[8] it was suggested that immune thrombocytopenia is due to structural similarities between VPA and fatty acid components of cell membranes of platelet. Kishi et al.[9] have shown that high plasma concentration of VPA is associated with bone marrow suppression. Hence, thrombocytopenia due to VPA is explained both by concentration dependent as well as by immune-mediated platelet destruction.

VPA is also associated with other coagulation abnormalities like prolonged prothrombin time/INR, acquired Von–Willebrand factor deficiency, hypofibrinogenemia, and hematological abnormalities like macrocytosis.[10] Exact mechanism behind these abnormalities is not clear. DAH-associated VPA is due to either thrombocytopenia or other related coagulation abnormalities.

Bleeding into the alveolar spaces characterizes the syndrome of DAH. Causes of DAH can be classified into immune and nonimmune. More than half of cases of DAH are of nonimmune origin. The most frequent causes of immune DAH are small vessel vasculitis (microscopic polyangitis, granulamatosis polyangitis, systemic lupus erythamatosis, and Goodpasture’s syndrome). The most frequent nonimmune causes of DAH are heart disease (mainly left ventricular failure and mitral stenosis), infections, drug, and coagulation disorders.[11],[12]

Pulmonary capillaritis, diffuse alveolar damage, and bland pulmonary hemorrhage are three different histological pattern associated with DAH. Bland pulmonary hemorrhage is histological pattern seen in cases of DAH due to drugs, coagulopathy, and left heart failure in which case red blood cells leak into the alveoli without evidence of inflammation or destruction of alveolar capillaries, venules, and arterioles.[13]

Chest radiograph usually shows bilateral symmetrical opacities but asymmetrical or unilateral involvement may sometimes occur. High-resolution CT thorax shows ground glass opacities or consolidation with predominant central involvement and sparing of the lung periphery. Blood tests should include CBC, coagulation profile, determination of autoantibodies including antineutrophil cytoplasmic antibody, antibasement membrane antibody, and antibodies associated with connective tissue diseases. Fiber optic bronchoscopy is indicated in all suspected cases of DAH. It helps in ruling out a bleeding of bronchial origin, establishing diagnosis of DAH and searching for infectious agents. Transbronchial biopsy is not recommended in all cases. A hemorrhagic bronchoalveolar lavage sample, with successive aliquots showing increased blood content, is considered diagnostic of acute DAH. Alveolar macrophages convert hemoglobin into hemosiderin in 36 to 72 hours after bleeding episode. Hemosiderin-laden macrophages reside in lungs for 4 to 8 weeks. DAH can be diagnosed with hemosiderin-laden macrophages constituting more than 20% to 30% of total macrophage count or with a GOLD score above 100 with or without blood cells. GOLD score is a semiquantitative assessment, which assess both the percentage of macrophages containing hemosiderin as well as intensity of staining between 0 and 4. The score result may vary between 0 and 400.[14]

The treatment of DAH primarily involves supportive treatment of respiratory failure and control of hemoptysis. Nonimmune DAH should be treated according to the underlying pathophysiology and immune-mediated DAH should be treated with steroids, immune-suppressive agents, and plasmapheresis.[15] In case of drug-induced DAH, simple treatment such as reversal of a coagulation defect or withdrawal of drugs can reverse life-threatening situation. Depending on the severity, drug withdrawal may not be sufficient and corticosteroid treatment is recommended in few cases.[16]

  Conclusion Top

The high index of suspicion of DAH is required in patient with epilepsy who are on VPA presenting with hemoptysis. It is crucial to elicit proper drug history in every patient suspected with diffuse pulmonary hemorrhage after ruling out other most common causes. In majority of the cases, stopping drug with or without systemic steroids results in complete resolution of disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Zawab A, Carmody J. Safe use of sodium valproate. Aust Prescr 2014;37:187.  Back to cited text no. 1
Vlahkis NE, Rickman OB, Morgenthaler T. Sirolimus associated diffuse diffuse alveolar haemorrhage. Mayo Clin Proc 2004;79:541-5.  Back to cited text no. 2
Zeiss CR, Wolkonsky P, Chacon R, Tuntland PA, Levitz D, Prunzansky JJ et al. Syndromes in workers exposed to trimellitic anhydride. A longitudinal clinical and immunological study. Ann Intern Med 1983;98:8-12.  Back to cited text no. 3
Inzirillo F, Giorgetta C, Ravalli E, Pona CD. Diffuse alveolar damage due to valproic acid: case report and review of literature. Lung India 2015;32:175-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
Nasreddine W, Beydon A. Valproate induced thrombocytopenia: a prospective monotherapy study. Epilepsia 2008;49:438-45.  Back to cited text no. 5
Barr RD, Copeland SA, Stockwell ML, Morris N, Kelton JC. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982;57:681-4.  Back to cited text no. 6
Sandler RM, Emberson C, Roberts GE, Voak D, Darnborough J, Heeley AF. IgM platelet antibody due to sodium valproate. Br Med J 1978;2:1683-4.  Back to cited text no. 7
Morris N, Barr RD, Pai KR, Kelton JG. Valproic acid and thrombocytopenia. Can Med Assoc J 1981;125:63-4.  Back to cited text no. 8
Kishi T, Fujita N, Kawaguchi H, Ishimae M, Watanabe K, Tanaka T. Bone marrow suppression induced by high dose dose valproaic acid. Arch Dis Child 1994;71:153-5.  Back to cited text no. 9
Koenig S, Gerstner T, Keller A, Teich M, Longin E, Dempfle CE. High incidence of valproate induced coagulation disorders in children receiving valproic acid: a prospective study. Blood Coagul Fibrinolysis 2008;19:375-82.  Back to cited text no. 10
Picard C, Cadranel J, Porcher R, Prigent H, Levy P, Fartoukh M et al. Alveolar haemorrhage in the immunocompetent host: a scale for early diagnosis of an immune cause. Respiration 2010;80:313-20.  Back to cited text no. 11
de Prost N, Parrot A, Cuquemelle E, Picard C, Antoine M, Fleury-Feith J. Diffuse alveolar haemorrhage: factor associated with in −hospital and long term mortality. Eur Respir J 2010;35:298-300.  Back to cited text no. 12
Park MS. Diffuse alveolar haemorrhage. Tuberc Respir Dis (Seol) 2013;74:151-62.  Back to cited text no. 13
Aasarod K, Bostad L, Hammerstrom J. Renal histopathology and clinical course in 94 patients with Wegeners granulomatosis. Nephrol Dial Transplant 2001;16:953-60.  Back to cited text no. 14
Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W. Eular recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310-7.  Back to cited text no. 15
Schwarz M, Fontenot AP. Drug induced diffuse alveolar haemorrhage and vasculitis. Clin Chest Med 2004;25:133-40.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3]

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