Valproic acid induced coagulopathy
Riten Kumar, MD, MSc, Jorge Vidaurre, MD, Satyanarayana Gedela, MD
PII: S0887-8994(18)30818-X
DOI: https://doi.org/10.1016/j.pediatrneurol.2019.04.019 Reference: PNU 9587
To appear in: Pediatric Neurology
Received Date: 27 July 2018
Revised Date: 21 April 2019
Accepted Date: 24 April 2019
Please cite this article as: Kumar R, Vidaurre J, Gedela S, Valproic acid induced coagulopathy, Pediatric Neurology (2019), doi: https://doi.org/10.1016/j.pediatrneurol.2019.04.019.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Keywords: Valproic acid (VPA), Hemostasis, Coagulopathy, Surgery
Abstract
Background Valproic acid (VPA) is one of the most commonly used anti-seizure medications. Multiple hematological abnormalities have been reported with the use of VPA, which may be particularly relevant in the peri-operative surgical setting. The incidence of these abnormalities, and prevalence of peri-procedure hemorrhage varies significantly in the published literature. In this review article the authors investigate the prevalence and possible etiology of coagulopathy and hemorrhage in patients receiving VPA.
Methods A literature search was completed using “VPA”, “coagulopathy” and “surgery”. The authors reviewed available published data from case reports to large case series.
Results Thrombocytopenia was noted to be the most common laboratory abnormality associated with VPA. An association between VPA and acquired von Willebrand disease has also been suggested. There are case reports describing bleeding in the setting of hypofibrinogenemia and factor XIII deficiency. Peri-operative hemorrhage was reported in pediatric studies of orthopedic procedures, but not in adult cohorts undergoing neuro-surgical interventions.
Conclusion There are no published guidelines on monitoring for potential coagulation abnormalities in patients on VPA scheduled to undergo surgery. More rigorous, prospective trials are needed to assess the association between VPA and clinically-significant coagulopathy. Until such data are available, physicians need to be aware of the potential risk of bleeding in patients receiving VPA. A hemostatic evaluation may be considered in patients on VPA scheduled for surgery. If an abnormality is detected, hematologists should be involved to make recommendation on peri-operative hemostatic strategy.
Introduction
Valproic acid (VPA), a derivative of valeric acid and component of the plant Valeriana officinalis, is widely used for epilepsy treatment. Since the first description by Munier and colleagues on the successful use of VPA for the management of childhood seizures, 1 it has rapidly evolved into a front line anti-epileptic agent for the management of generalized tonic- clonic seizures and focal seizures.2, 3 VPA is also used to treat specific epilepsy syndromes such as Lennox Gastaut encephalopathy with status epilepticus during slow wave sleep and Dravet syndrome2, 4-6. VPA is predominantly metabolized by the liver with a small amount excreted unchanged in urine.7, 8 Metabolism involves cytochrome P450 enzymes, glucuronide conjugation and β-oxidation in mitochondria.9, 10 VPA is highly protein bound with about 95% of the drug bound to albumin. The binding sites saturate with concentrations above 50 mg/L, resulting in a disproportionate increase in unbound concentration.11 Half-life is variable between 4-17 hours, with shorter half-life reported in children and a steady state reached in around 24-48 hours. The mechanism of action for its anticonvulsant effect include GABA potentiation, inhibition of NMDA receptor mediated transmission, sodium and calcium channel blockage and inhibition of histone deacetylases.12
VPA has multiple side effects which may either be dose dependent or part of an idiosyncratic reaction. Herein, we review the existing literature on coagulation abnormalities associated with VPA use, and the potential implications for patients undergoing surgery. Several coagulation abnormalities, namely thrombocytopenia, platelet functional defects, hypofibrinogenemia, factor XIII (FXIII) deficiency and acquired von Willebrand syndrome have been associated with the use of VPA. The incidence on these abnormalities has varied significantly in the published literature13-15 (see table 1 for details). Furthermore, the exact clinical impact of these coagulation abnormalities remains unclear, with some but not all studies documenting an association with increased bleeding symptoms including peri-operative hemorrhage.
Overview of Hemostasis
Hemostasis refers to the arrest of bleeding at the site of vessel wall injury and is traditionally divided into primary and secondary hemostasis (see figure 1 for details).16 Primary hemostasis initiates immediately following endothelial damage and comprises of four sequential but overlapping phases, namely (i) vasospasm, (ii) platelet adhesion to the underlying collagen mediated by the large multimeric glycoprotein – von Willebrand factor (VWF), (iii) platelet activation and (iv) platelet aggregation.16 The final end-product of primary hemostasis is the formation of a platelet plug. A quantitative deficiency or qualitative defect in either platelets or VWF may result in a bleeding disorder. Disorders of primary hemostasis are typically characterized by muco-cutaneous bleeding symptoms – epistaxis, easy bruising, petechiae, menorrhagia and bleeding after surgical or dental interventions. Congenital von Willebrand disease (VWD) is the most common bleeding diathesis with an estimated prevalence of 1:1000 individuals.17 Common laboratory tests used to investigate the primary hemostatic pathway include complete blood count (to evaluate platelet count), platelet function analysis closure times (PFA-100® CT), platelet aggregation and von Willebrand panel (including von Willebrand antigen [VWF:Ag], von Willebrand ristocetin cofactor function [VWF:RCo], Factor VIII [FVIII] activity and VWF multimer analysis).
Secondary hemostasis involves the sequential interaction of serine protease zymogens and their cofactors via the coagulation pathway and comprises of three overlapping phases: initiation, amplification and propagation. Secondary hemostasis results in the formation of covalently cross-linked fibrin that stabilizes the primary platelet plug.16 Details of the coagulation pathway are elaborated elsewhere.16 Disorders of secondary hemostasis are less common – hemophilia A (X-linked congenital deficiency of FVIII) has an estimated prevalence of 1:5000 males,17 whereas congenital FXIII deficiency has an estimated prevalence of 1:2,000,000 individuals.18 Disorders of secondary hemostasis typically present with deep bleeds into muscles, hemarthrosis and intracranial hemorrhage. The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time are commonly used to screen for disorders of secondary hemostasis (see figure 2 for details). In the case of abnormal results, individual levels of clotting proteins (e.g. FVIII, FIX etc.) can be obtained to help identify the exact disorder.
Impact of Valproic acid on Laboratory Markers of Coagulation
In a cohort of 385 pediatric patients treated with VPA, Gerstner and colleagues identified clinically significant coagulopathies in eight patients; seven additional patients were found to have a coagulopathy based on pre-operative testing.19 They estimated the cumulative incidence of coagulation abnormalities associated with VPA to be 4%, which likely represents an underestimation as all patients were not screened.
Thrombocytopenia is the most common laboratory abnormality associated with VPA use, with most, but not all studies demonstrating this association. 13, 20 In general, the incidence of VPA associated thrombocytopenia in published literature has ranged from 3-40%, with clinically significant thrombocytopenia developing in about 10%.19-25 While the exact mechanism of VPA mediated thrombocytopenia remains unclear, immune mediated destruction of platelets and direct toxicity to the bone marrow have both been hypothesized as possible etiologies. Studies have also demonstrated a negative correlation between VPA dosing/serum concentration and platelet count.21, 22, 24 The largest pediatric study investigating the association between VPA and thrombocytopenia was reported by Delgado and colleagues.23 Of the 306 children investigated, 64 (21%) developed thrombocytopenia and 21 (10.5%) developed clinically significant thrombocytopenia, defined as a platelet count below 100,000/cu mm. Average time for thrombocytopenia to develop was 7.5 months. Of note, only eight patients (2.6%) had bleeding symptoms. Their median platelet count was 50,000/cu mm (range: 19,000 – 68,000/cu mm).
Most patients had complete recovery of platelet counts within 1-week of stopping VPA. Additionally, platelet functional abnormalities, independent of thrombocytopenia, including impaired platelet aggregation with agonists like collagen and ADP have also been described. 13, 14 The association between VPA and VWD is less clear. In a case-control study of 30 children on VPA and 43 children with congenital type 1 VWD, Kreuz and colleagues classified 67% of the children receiving VPA as having type I VWD.26 However, the exact cutoff of VWF:Ag or VWF:RCo used for making the diagnosis was not elaborated. In another retrospective analysis of 29 children receiving VPA for at least six months, six (21%) developed low VWF:RCo levels (median 33.05 %; range: 11.5-39.7%). In a prospective trial of 23 children, coagulation parameters were obtained at baseline, six weeks and six months after starting VPA. A significant decrease was appreciated in both VWF:Ag and VWF:RCo, with eight patients (35%) developing clinical VWD. 14 These initial observations, however, were not confirmed in a recently published, prospective multicenter trial.27 Eberl and colleagues investigated 40 consecutive patients, and obtained coagulation specimens before, one week, two, three and six months after starting VPA. No significant alterations were appreciated in either VWF:RCo or FVIII activity. While a slight decrease was seen in the VWF:Ag results, no patient developed pathological levels (defined as <50% VWF:Ag; personal communication with Dr. Wolfgang Eberl, Klinikum Braunschweig, Germany). Several case reports of bleeding in the setting of hypofibrinogenemia have been described in patients receiving VPA.28, 29 Causality between hypofibrinogenemia and VPA therapy was suggested based on the fact that fibrinogen levels rapidly corrected after cessation of therapy. In the above mentioned prospective study by Koenig and colleagues, 12/23 (57%) of patients developed hypofibrinogenemia, defined as a fibrinogen level below 150 mg/dL.14 Similarly, in the prospective multicenter trial reported by Eberl and colleagues, 9/40 (23%) developed pathological fibrinogen concentrations within six months of starting therapy with VPA (defined as <180 mg/dL fibrinogen level; personal communication with Dr. Wolfgang Eberl, Klinikum Braunschweig, Germany).27 There also exist case reports of FXIII deficiency associated with VPA therapy.15, 30 While the exact etiology is unclear, VPA mediated hepatotoxicity (fibrinogen and FXIII are both synthesized in the liver) is postulated to be responsible for these specific deficiencies. Perioperative hemorrhage in the setting of valproic acid use Bleeding complications in the operating room can impose major challenges for surgeons. At this time, there are no published guidelines regarding monitoring of potential coagulation abnormalities in patients on VPA scheduled to undergo surgical interventions. While there are several publications investigating the impact of VPA on platelet count and platelet function (table 1),31 there are few case reports or case series reporting the hemorrhagic side effects of VPA on patients undergoing surgery (table 2A-B). Interestingly, despite the high incidence of reported abnormalities in the coagulation system, the risk of peri-surgical bleeding, particularly in adults undergoing neuro-surgical interventions appear to be low.32, 33 Winter and colleagues first published the impact of VPA on post-operative bleeding in 139 children undergoing posterior spinal fusion. At the time of surgery 22 subjects were receiving VPA. Use of VPA was associated with increased need for peri-operative blood transfusion.34 In a subsequent study from the Children’s Hospital of San Diego, Chambers and colleagues investigated 114 patients with cerebral palsy undergoing spine surgery for progressive paralytic scoliosis. Of these 114 patients, 18 were receiving VPA monotherapy and 44% of patients on VPA had prolonged bleeding times. Patients on VPA had increased blood loss and required more red blood cell infusions compared to patients on other anti-epileptic agents.35 These initial observations were confirmed in a recent retrospective study of 29 children undergoing bilateral femoral osteotomy. VPA use was associated with increased peri-operative blood loss and need for transfusion.36 In stark contrast to these observations in children undergoing orthopedic procedures, studies investigating adults undergoing neuro-surgical procedures have not consistently identified an association between VPA use and peri-operative hemorrhage.33, 37-39 In a retrospective review of 87 consecutive patients undergoing temporal lobectomy, Ward and colleagues did not find any difference in the estimated blood loss and need for post-operative blood transfusion between patients who were on VPA, and those who were not.39 In a subsequent retrospective review of 313 patients undergoing cortical resection, Anderson and colleagues studied 111 patients on VPA and 202 controls who were on anti-epileptic drugs other than VPA. While platelet counts and fibrinogen levels were lower in patients on VPA, there was no significant difference in the estimated peri-operative blood loss between the two groups.37 More recently, Kurwale and colleagues investigated 169 patients with drug-resistant epilepsy undergoing neurosurgical interventions. 91 patients were on VPA and 78 patients were on other anti-epileptic drugs. All patients had normal pre-operative labs including platelet counts, bleeding time, prothrombin time and activated partial thromboplastin time. Average blood loss was not significantly different in the two cohorts.33 Conclusion VPA is a widely used antiepileptic drug with a broad spectrum of efficacy. Multiple hematological abnormalities have been reported with this medication. The incidence of these abnormalities and their association with peri-operative hemorrhage has varied significantly in the published literature. This may in part be explained by differences in study design (retrospective versus prospective), and criteria used to diagnose a bleeding diathesis. For instance, using a VWF:RCo cutoff of 70% to diagnose VWD,26 or a FXIII cutoff of 70% to diagnosed FXIII deficiency,14 may not have clinical relevance since most patients do not develop bleeding symptoms until these values are much lower. It is also unclear if these effects are dose-related or idiosyncratic with the exception of thrombocytopenia which appears to be dose dependent. The discrepancy in peri-operative hemorrhage may in part be explained by the type of surgery – orthopedic surgeries are typically associated with more bleeding compared to neurosurgical procedures. More rigorous, prospective trials are needed to assess the clinical burden of VPA associated coagulopathy. Until such data are available, surgeons, neurologists, hematologists and anesthesiologists need to be aware of the potential risk of bleeding in patients receiving VPA. A full hemostatic evaluation, including platelet count, PT, APTT, fibrinogen level, VWF:Ag, VWF:RCo and FXIII levels may be considered in patients on VPA therapy scheduled to undergo major surgical interventions. If any abnormality is detected, hematologists, should be involved to make recommendations on peri-operative hemostatic strategies. In some cases, and in the setting of significant coagulopathy, it may be reasonable to substitute VPA with another anti-epileptic drug, postpone surgery by 1-2 weeks from the last dose of VPA and repeat the assays. The risks of VPA discontinuation should be weighed against risks of peri operative hemorrhage. When urgent surgical interventions are required in patients receiving VPA, we recommend getting a complete blood count, APTT, PT and fibrinogen activity. These laboratory assays can be performed emergently in most hospitals. There are no evidence-based guidelines for peri- procedure transfusion of platelets and plasma products (i.e. fresh frozen plasma, cryoprecipitate) in this cohort. However, reasonable goals for such patients would be to maintain platelet counts > 50 x109/L (100 x 109/L for neurosurgical procedures). 40 Prospective, adequately powered, multicenter cohort studies would be ideal, but difficult to undertake. In the interim, gathering well defined data from retrospective studies or registries will be useful.
References
1. Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M. [Pharmacodynamic properties of N-dipropylacetic acid]. Therapie 1963;18:435-438.
2. Tomson T, Battino D, Perucca E. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol 2016;15:210-218.
3. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 1992;327:765-771.
4. Caraballo RH, Fejerman N. Dravet syndrome: a study of 53 patients. Epilepsy Res 2006;70 Suppl 1:S231-238.
5. Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Saf 2000;22:467-477.
6. Veggiotti P, Pera MC, Teutonico F, Brazzo D, Balottin U, Tassinari CA. Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update. Epileptic Disord 2012;14:1-11.
7. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev 2003;9:199-216.
8. Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 2008;22:27-47.
9. Nakajima Y, Ito T, Maeda Y, et al. Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS. Brain Dev 2011;33:816-823.
10. Silva MF, Aires CC, Luis PB, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 2008;31:205-216.
11. Methaneethorn J. A systematic review of population pharmacokinetics of valproic acid.Br J Clin Pharmacol 2018;84:816-834.
12. Ghodke-Puranik Y, Thorn CF, Lamba JK, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2013;23:236-241.
13. Zighetti ML, Fontana G, Lussana F, et al. Effects of chronic administration of valproic acid to epileptic patients on coagulation tests and primary hemostasis. Epilepsia 2015;56:e49-52.
14. Koenig S, Gerstner T, Keller A, Teich M, Longin E, Dempfle CE. High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study. Blood Coagul Fibrinolysis 2008;19:375-382.
15. Teich M, Longin E, Dempfle CE, König S. Factor XIII deficiency associated with valproate treatment. Epilepsia 2004;45:187-189.
16. Kumar R, Carcao M. Inherited abnormalities of coagulation: hemophilia, von Willebrand disease, and beyond. Pediatr Clin North Am 2013;60:1419-1441.
17. Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost 2012;38:727-734.
18. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008;14:1190-1200.
19. Gerstner T, Teich M, Bell N, et al. Valproate-associated coagulopathies are frequent and variable in children. Epilepsia 2006;47:1136-1143.
20. De Berardis D, Campanella D, Matera V, et al. Thrombocytopenia during valproic acid treatment in young patients with new-onset bipolar disorder. J Clin Psychopharmacol 2003;23:451-458.
21. Allarakhia IN, Garofalo EA, Komarynski MA, Robertson PL. Valproic acid and thrombocytopenia in children: a case-controlled retrospective study. Pediatr Neurol 1996;14:303- 307.
22. Conley EL, Coley KC, Pollock BG, Dapos SV, Maxwell R, Branch RA. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy 2001;21:1325-1330.
23. Delgado MR, Riela AR, Mills J, Browne R, Roach ES. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol 1994;9:311-314.
24. Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia 2008;49:438-445.
25. Neophytides AN, Nutt JG, Lodish JR. Thrombocytopenia associated with sodium valproate treatment. Ann Neurol 1979;5:389-390.
26. Kreuz W, Linde R, Funk M, et al. Valproate therapy induces von Willebrand disease type I. Epilepsia 1992;33:178-184.
27. Eberl W, Budde U, Bentele K, et al. Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare. Hamostaseologie 2009;29:137-142.
28. Chen HF, Xu LP, Luo ZY, et al. Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review. Drug Des Devel Ther 2013;7:767-770.
29. Karakayalı B, Onsal Ozturk D, Yazar AS, Guven S, Islek I. Hypofibrinogenemia and intra-articular hemorrhage due to valproic acid. Pediatr Int 2016;58:1358-1359.
30. Pohlmann-Eden B, Peters CN, Wennberg R, Dempfle CE. Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding. Acta Neurol Scand 2003;108:142-145.
31. Verrotti A, Greco R, Matera V, Altobelli E, Morgese G, Chiarelli F. Platelet count and function in children receiving sodium valproate. Pediatr Neurol 1999;21:611-614.
32. Kumar S. Valproate-induced bleeding: report of two cases and review of literature. Indian Pediatr 2005;42:833-834.
33. Kurwale N, Garg K, Arora A, Chandra PS, Tripathi M. Valproic acid as an antiepileptic drug: Is there a clinical relevance for the epilepsy surgeon? Epilepsy Res 2016;127:191-194.
34. Winter SL, Kriel RL, Novacheck TF, Luxenberg MG, Leutgeb VJ, Erickson PA. Perioperative blood loss: the effect of valproate. Pediatr Neurol 1996;15:19-22.
35. Chambers HG, Weinstein CH, Mubarak SJ, Wenger DR, Silva PD. The effect of valproic acid on blood loss in patients with cerebral palsy. J Pediatr Orthop 1999;19:792-795.
36. Carney BT, Minter CL. Is operative blood loss associated with valproic acid? Analysis of bilateral femoral osteotomy in children with total involvement cerebral palsy. J Pediatr Orthop 2005;25:283-285.
37. Anderson GD, Lin YX, Berge C, Ojemann GA. Absence of bleeding complications in patients undergoing cortical surgery while receiving valproate treatment. J Neurosurg 1997;87:252-256.
38. Psaras T, Will BE, Schoeber W, Rona S, Mittelbronn M, Honegger JB. Quantitative assessment of postoperative blood collection in brain tumor surgery under valproate medication. Zentralbl Neurochir 2008;69:165-169.
39. Ward MM, Barbaro NM, Laxer KD, Rampil IJ. Preoperative valproate administration does not increase blood loss during temporal lobectomy. Epilepsia 1996;37:98-101.
40. R K, M S. Acquired Bleeding Disorders in Children. In: VS B, VR B, S R-V, eds.SickKids Handbook of Pediatric Thrombosis and Hemostasis: Basel, Karger, 2013: 105-123.
41. Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia 2008;49:438-445.
42. Serdaroglu G, Tütüncüoglu S, Kavakli K, Tekgül H. Coagulation abnormalities and acquired von Willebrand’s disease type 1 in children receiving valproic acid. J Child Neurol 2002;17:41-43.
43. Manohar C, Avitsian R, Lozano S, Gonzalez-Martinez J, Cata JP. The effect of antiepileptic drugs on coagulation and bleeding in the perioperative period of epilepsy surgery: the Cleveland Clinic experience. J Clin Neurosci 2011;18:1180-1184.