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Desvenlafaxine as a possible cause of acquired hemophilia
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General Hospital Psychiatry 32 (2010) 646.e13 – 646.e15
Case Report
Desvenlafaxine as a possible cause of acquired hemophilia☆,☆☆ Deepika Shaligram, M.D.⁎, Tahani Alqassem, M.D., Elizabeth Koby, M.D. Department of Psychiatry, St. Elizabeth's Medical Center, Boston, MA 02135, USA Received 4 April 2010; accepted 10 May 2010
Abstract Objective: Acquired hemophilia A (AHA) is characterized by the depletion of Factor VIII mediated by specific autoantibodies. While the cause is unknown in 50% of the cases, an association with malignancy, peripartum period, autoimmune disease and the use of drugs has been described. We report a case of AHA possibly induced by desvenlafaxine. Case report: Mr. P, a 70-year-old Caucasian male with alcohol and opioid dependence in remission, was started on 50 mg of desvenlafaxine for a moderate depressive episode. After 10 weeks, he developed an ecchymosis of the right upper extremity, in the absence of past or family history of bleeding disorder. He had a prolonged activated partial thromboplastin time (74.5 s) not corrected on performing mixing study, decreased Factor VIII activity (b 1%) and detectable Factor VIII inhibitor (30 Bethesda units) confirming a diagnosis of AHA. After all other causes were ruled out, desvenlafaxine was discontinued and the patient was infused with Factor VIIa followed by a 6-week prednisone taper with which he achieved remission. Discussion: While serotonin inhibitors are known to impair platelet aggregation leading to bleeding, abnormalities in the coagulation cascade have not been described so far. Desvenlafaxine appears to be the probable cause of AHA given the temporal association, remission after withdrawal of the drug and the lack of any other probable cause. New-onset abnormalities of the coagulation cascade such as AHA should be considered in the context of bleeding events with desvenlafaxine and perhaps other serotonin inhibitors, given the significant mortality rates when untreated. © 2010 Elsevier Inc. All rights reserved.
1. Background Acquired hemophilia A (AHA) is an uncommon but potentially life-threatening bleeding diathesis associated with significant morbidity and a mortality rate of up to 21%. The hallmark is the depletion of clotting Factor VIII mediated by specific autoantibodies directed against functional epitopes resulting in the neutralization of Factor VIII and/or its accelerated clearance from the plasma [1]. Although the cause is unknown in up to 50% of the cases, an association with an underlying condition such as malignancy, peripartum period, autoimmune disease or the use of a drug has been described in half the cases. Patients with AHA may present with overt hemorrhage or anemia due to occult bleeding. The bleeding manifestations differ from
☆
The manuscript has not been presented at a meeting. The authors report no competing interests. ⁎ Corresponding author. Tel.: +1 617 789 3000. E-mail address: [email protected] (D. Shaligram).
congenital hemophilia in that bleeding commonly occurs in soft tissue, from mucous membranes, or postprocedurally, and hemarthroses are rare [2]. The diagnosis of AHA is based on the demonstration of an isolated prolongation of activated partial thromboplastin time (aPTT) not corrected by incubating the patient's plasma with equal volumes of normal plasma (mixing study), associated with decrease in Factor VIII levels and formal evidence of Factor VIII inhibitor in a patient with no past or family history of bleeding disorder. Drug-induced AHA has been known to occur with antibiotics, anticonvulsants, immunomodulators (fludarabine and interferon-α) and antipsychotics (phenothiazines and thioxanthenes) [3]. We describe a case of AHA possibly induced by desvenlafaxine, a serotonin–norepinephrine reuptake inhibitor (SNRI). 2. Case report
☆☆
0163-8343/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2010.05.001
Mr. P, a 70-year-old Caucasian male with a 10-year history of major depressive disorder, alcohol and opioid
646.e14
D. Shaligram et al. / General Hospital Psychiatry 32 (2010) 646.e13–646.e15
with 60 mg/day for a week with 10 mg/day decrements every week) with which he gradually achieved remission (Fig. 1). On achieving remission, the Factor VIII activity was approximately 55% and the Factor VIII inhibitor level was undetectable. 3. Discussion
Fig. 1. Course of treatment.
dependence in remission, had had multiple failed trials of antidepressants, when he was started on 50 mg of desvenlafaxine for a moderate depressive episode in February 2009. His medical history was significant for hypertension, benign prostatic hypertrophy and gastroesophageal reflux disease. After 10 weeks of treatment, he developed an enlarging circumferential swelling and ecchymosis of the right forearm from the base of the fingers to beyond the elbow associated with numbness and tingling over a period of 1 week. There was no history of local trauma or use of anticoagulants or nonsteroidal antiinflammatory drugs (NSAIDs). Furthermore, he did not have a personal or family history of bleeding tendency. Deep vein thrombosis was ruled out on ultrasound examination. An orthopedic consult was obtained to rule out compartment syndrome. Liver function test results were within normal limits, and colonoscopy showed no evidence of an occult bleed. The patient had a normal prothrombin time of 13.1 s (normal=12–15 s), a prolonged aPTT of 74.5 s (normal=25–35 s), which was not corrected on performing mixing studies, a Factor VIII activity b1% (normal N50%), and a Factor VIII inhibitor level of 30 Bethesda units (normal=0) confirming a diagnosis of AHA. His Factor IX, XI and von Willebrand factor levels were unremarkable. A thorough evaluation and follow-up by the hematology– oncology service over a period of 1 year did not reveal an underlying solid tumor, lymphoproliferative or autoimmune process. The patient had been on valsartan, amlodipine, tamsulosin, gabapentin, mirtazapine, sucralfate and omeprazole for about 5 years without adverse effects, thus making these drugs an unlikely cause of AHA. Desvenlafaxine was discontinued on clinical suspicion, and the patient was given an intravenous infusion of Factor VIIa at a dose of 3800 μg for acute control of bleeding. This was followed by a 6-week course of prednisone taper (starting
Desvenlafaxine is the active metabolite of venlafaxine. It has relatively greater norepinephrine transporter (NET) inhibition than venlafaxine but still has less potent actions on NET than on the serotonin transporter [4]. The most commonly observed adverse reactions in patients taking desvenlafaxine vs. placebo were nausea (22% vs. 10%), dizziness (13% vs. 5%), hyperhidrosis (10% vs. 4%), constipation (9% vs. 4%) and decreased appetite (5% vs. 2%). It is noteworthy that specific serotonin reuptake inhibitors (SSRIs) and SNRIs including desvenlafaxine may increase the risk of bleeding events, especially so with the concomitant use of NSAIDs (like aspirin), warfarin and other anticoagulants. While the prescribing information for desvenlafaxine [5] states that “drugs which inhibit serotonin uptake in platelets may lead to abnormalities in platelet aggregation and thus predispose to bleeding”, thus far, abnormalities in the coagulation cascade have not been implicated as a cause of bleeding with SSRIs or SNRIs. As per the Adverse Drug Reaction Probability Scale [6], desvenlafaxine appears to be the probable cause of AHA in this patient given the temporal association, remission after withdrawal of the drug and the lack of any other probable cause. A PubMed search from 1960 to 2010 with search terms psychotropics, antidepressants, SSRIs, SNRIs, desvenlafaxine, venlafaxine and acquired hemophilia retrieved no studies. To the best of our knowledge, this is the first reported case of AHA with desvenlafaxine. Bleeding events hitherto reported with venlafaxine and other antidepressants seem to be correlated with the degree of serotonin inhibition. The proposed mechanisms include impaired platelet function (aggregation) [7] and a decrease in the number of platelets (drug-induced thrombocytopenia) [8]. It is important to consider new-onset abnormalities of the coagulation cascade like AHA, in the context of bleeding events with desvenlafaxine and perhaps other serotonin inhibitors, given the significant mortality rates when untreated and the good prognosis for remission on withdrawal of the inciting agent or after immunosuppressive therapy. References [1] Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, et al. Acquired hemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003;121(1):21–35. [2] Bitting RL, Bent S, Li Y, et al. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis 2009;20:517–23.
D. Shaligram et al. / General Hospital Psychiatry 32 (2010) 646.e13–646.e15 [3] Franchini M, Capra F, Nicolini N, et al. Drug-induced anti-factor VIII antibodies: a systematic review. Med Sci Monit 2007;13(4):RA55–61. [4] Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. New York: Cambridge University Press; 2008. [5] Pristiq (Desvenlafaxine) Prescribing Information, Wyeth Pharmaceuticals Inc 2009.
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[6] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2): 239–45. [7] Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007;9(1):47–59. [8] Andersohn F, Konzen C, Bronder E, et al. Citalopram-induced bleeding due to severe thrombocytopenia. Psychosomatics 2009;50(3):297–8.
General Hospital Psychiatry 32 (2010) 646.e13 – 646.e15
Case Report
Desvenlafaxine as a possible cause of acquired hemophilia☆,☆☆ Deepika Shaligram, M.D.⁎, Tahani Alqassem, M.D., Elizabeth Koby, M.D. Department of Psychiatry, St. Elizabeth's Medical Center, Boston, MA 02135, USA Received 4 April 2010; accepted 10 May 2010
Abstract Objective: Acquired hemophilia A (AHA) is characterized by the depletion of Factor VIII mediated by specific autoantibodies. While the cause is unknown in 50% of the cases, an association with malignancy, peripartum period, autoimmune disease and the use of drugs has been described. We report a case of AHA possibly induced by desvenlafaxine. Case report: Mr. P, a 70-year-old Caucasian male with alcohol and opioid dependence in remission, was started on 50 mg of desvenlafaxine for a moderate depressive episode. After 10 weeks, he developed an ecchymosis of the right upper extremity, in the absence of past or family history of bleeding disorder. He had a prolonged activated partial thromboplastin time (74.5 s) not corrected on performing mixing study, decreased Factor VIII activity (b 1%) and detectable Factor VIII inhibitor (30 Bethesda units) confirming a diagnosis of AHA. After all other causes were ruled out, desvenlafaxine was discontinued and the patient was infused with Factor VIIa followed by a 6-week prednisone taper with which he achieved remission. Discussion: While serotonin inhibitors are known to impair platelet aggregation leading to bleeding, abnormalities in the coagulation cascade have not been described so far. Desvenlafaxine appears to be the probable cause of AHA given the temporal association, remission after withdrawal of the drug and the lack of any other probable cause. New-onset abnormalities of the coagulation cascade such as AHA should be considered in the context of bleeding events with desvenlafaxine and perhaps other serotonin inhibitors, given the significant mortality rates when untreated. © 2010 Elsevier Inc. All rights reserved.
1. Background Acquired hemophilia A (AHA) is an uncommon but potentially life-threatening bleeding diathesis associated with significant morbidity and a mortality rate of up to 21%. The hallmark is the depletion of clotting Factor VIII mediated by specific autoantibodies directed against functional epitopes resulting in the neutralization of Factor VIII and/or its accelerated clearance from the plasma [1]. Although the cause is unknown in up to 50% of the cases, an association with an underlying condition such as malignancy, peripartum period, autoimmune disease or the use of a drug has been described in half the cases. Patients with AHA may present with overt hemorrhage or anemia due to occult bleeding. The bleeding manifestations differ from
☆
The manuscript has not been presented at a meeting. The authors report no competing interests. ⁎ Corresponding author. Tel.: +1 617 789 3000. E-mail address: [email protected] (D. Shaligram).
congenital hemophilia in that bleeding commonly occurs in soft tissue, from mucous membranes, or postprocedurally, and hemarthroses are rare [2]. The diagnosis of AHA is based on the demonstration of an isolated prolongation of activated partial thromboplastin time (aPTT) not corrected by incubating the patient's plasma with equal volumes of normal plasma (mixing study), associated with decrease in Factor VIII levels and formal evidence of Factor VIII inhibitor in a patient with no past or family history of bleeding disorder. Drug-induced AHA has been known to occur with antibiotics, anticonvulsants, immunomodulators (fludarabine and interferon-α) and antipsychotics (phenothiazines and thioxanthenes) [3]. We describe a case of AHA possibly induced by desvenlafaxine, a serotonin–norepinephrine reuptake inhibitor (SNRI). 2. Case report
☆☆
0163-8343/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2010.05.001
Mr. P, a 70-year-old Caucasian male with a 10-year history of major depressive disorder, alcohol and opioid
646.e14
D. Shaligram et al. / General Hospital Psychiatry 32 (2010) 646.e13–646.e15
with 60 mg/day for a week with 10 mg/day decrements every week) with which he gradually achieved remission (Fig. 1). On achieving remission, the Factor VIII activity was approximately 55% and the Factor VIII inhibitor level was undetectable. 3. Discussion
Fig. 1. Course of treatment.
dependence in remission, had had multiple failed trials of antidepressants, when he was started on 50 mg of desvenlafaxine for a moderate depressive episode in February 2009. His medical history was significant for hypertension, benign prostatic hypertrophy and gastroesophageal reflux disease. After 10 weeks of treatment, he developed an enlarging circumferential swelling and ecchymosis of the right forearm from the base of the fingers to beyond the elbow associated with numbness and tingling over a period of 1 week. There was no history of local trauma or use of anticoagulants or nonsteroidal antiinflammatory drugs (NSAIDs). Furthermore, he did not have a personal or family history of bleeding tendency. Deep vein thrombosis was ruled out on ultrasound examination. An orthopedic consult was obtained to rule out compartment syndrome. Liver function test results were within normal limits, and colonoscopy showed no evidence of an occult bleed. The patient had a normal prothrombin time of 13.1 s (normal=12–15 s), a prolonged aPTT of 74.5 s (normal=25–35 s), which was not corrected on performing mixing studies, a Factor VIII activity b1% (normal N50%), and a Factor VIII inhibitor level of 30 Bethesda units (normal=0) confirming a diagnosis of AHA. His Factor IX, XI and von Willebrand factor levels were unremarkable. A thorough evaluation and follow-up by the hematology– oncology service over a period of 1 year did not reveal an underlying solid tumor, lymphoproliferative or autoimmune process. The patient had been on valsartan, amlodipine, tamsulosin, gabapentin, mirtazapine, sucralfate and omeprazole for about 5 years without adverse effects, thus making these drugs an unlikely cause of AHA. Desvenlafaxine was discontinued on clinical suspicion, and the patient was given an intravenous infusion of Factor VIIa at a dose of 3800 μg for acute control of bleeding. This was followed by a 6-week course of prednisone taper (starting
Desvenlafaxine is the active metabolite of venlafaxine. It has relatively greater norepinephrine transporter (NET) inhibition than venlafaxine but still has less potent actions on NET than on the serotonin transporter [4]. The most commonly observed adverse reactions in patients taking desvenlafaxine vs. placebo were nausea (22% vs. 10%), dizziness (13% vs. 5%), hyperhidrosis (10% vs. 4%), constipation (9% vs. 4%) and decreased appetite (5% vs. 2%). It is noteworthy that specific serotonin reuptake inhibitors (SSRIs) and SNRIs including desvenlafaxine may increase the risk of bleeding events, especially so with the concomitant use of NSAIDs (like aspirin), warfarin and other anticoagulants. While the prescribing information for desvenlafaxine [5] states that “drugs which inhibit serotonin uptake in platelets may lead to abnormalities in platelet aggregation and thus predispose to bleeding”, thus far, abnormalities in the coagulation cascade have not been implicated as a cause of bleeding with SSRIs or SNRIs. As per the Adverse Drug Reaction Probability Scale [6], desvenlafaxine appears to be the probable cause of AHA in this patient given the temporal association, remission after withdrawal of the drug and the lack of any other probable cause. A PubMed search from 1960 to 2010 with search terms psychotropics, antidepressants, SSRIs, SNRIs, desvenlafaxine, venlafaxine and acquired hemophilia retrieved no studies. To the best of our knowledge, this is the first reported case of AHA with desvenlafaxine. Bleeding events hitherto reported with venlafaxine and other antidepressants seem to be correlated with the degree of serotonin inhibition. The proposed mechanisms include impaired platelet function (aggregation) [7] and a decrease in the number of platelets (drug-induced thrombocytopenia) [8]. It is important to consider new-onset abnormalities of the coagulation cascade like AHA, in the context of bleeding events with desvenlafaxine and perhaps other serotonin inhibitors, given the significant mortality rates when untreated and the good prognosis for remission on withdrawal of the inciting agent or after immunosuppressive therapy. References [1] Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, et al. Acquired hemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003;121(1):21–35. [2] Bitting RL, Bent S, Li Y, et al. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis 2009;20:517–23.
D. Shaligram et al. / General Hospital Psychiatry 32 (2010) 646.e13–646.e15 [3] Franchini M, Capra F, Nicolini N, et al. Drug-induced anti-factor VIII antibodies: a systematic review. Med Sci Monit 2007;13(4):RA55–61. [4] Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. New York: Cambridge University Press; 2008. [5] Pristiq (Desvenlafaxine) Prescribing Information, Wyeth Pharmaceuticals Inc 2009.
646.e15
[6] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2): 239–45. [7] Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007;9(1):47–59. [8] Andersohn F, Konzen C, Bronder E, et al. Citalopram-induced bleeding due to severe thrombocytopenia. Psychosomatics 2009;50(3):297–8.