Refractory Thrombocytopenia despite Treatment for Rattlesnake Envenomation
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《新英格兰医药杂志》
To the Editor: In our review article (Aug. 1, 2002, issue),1 we provided an algorithm for the treatment of pit-viper envenomations with Crotalidae Polyvalent Immune Fab — Ovine (CroFab, Protherics). We now must express our concern that treatment based on this algorithm may not reverse the thrombocytopenia frequently associated with timber-rattlesnake envenomation, as suggested by the case described below. Timber-rattlesnake venom was not used as an immunogen in either the old equine antivenom (Antivenin [Crotalidae] Polyvalent, Wyeth Laboratories), which is currently available only in limited quantities, or the new ovine antivenom (CroFab).1
A 38-year-old man was bitten on the left hand by a timber rattlesnake and presented to the emergency department within one hour. He had no underlying medical conditions and no history of snakebite. He had a single fang mark with minimal ecchymosis on the left hand near the second metacarpophalangeal joint. The hand and forearm were swollen, with marked tenderness. Vital signs were within normal limits. Initial laboratory studies included a complete blood count with a differential count, platelet count, coagulation profile (fibrinogen level, prothrombin time, and activated partial-thromboplastin time), creatine kinase measurement, and basic metabolic profile. The platelet count on admission was 157,000 per cubic millimeter. When repeated about five hours later, the platelet count was 28,300 per cubic millimeter.
On the basis of the clinical findings, treatment was initiated with CroFab. Despite treatment with large quantities of antivenom, the patient continued to have thrombocytopenia. On the third hospital day, his platelet count dropped to 590 per cubic millimeter. During his 10-day hospitalization, he received a total of 46 vials of CroFab. At the time of discharge, his platelet count was 26,300 per cubic millimeter. There was never any evidence of spontaneous bleeding or oozing from the venipuncture sites.2 After discharge, the platelet count remained depressed until three weeks after the envenomation, when it rose to 245,000 per cubic millimeter.
Envenomation by the timber rattlesnake commonly causes thrombocytopenia, even in the absence of coagulopathy.3,4 The precise mechanism is unknown. It has been postulated that crotalocytin, a protein component of timber-rattlesnake venom, has the capacity to induce platelet aggregation and release of ATP from the platelets.5
The efficacy of CroFab in reversing the thrombocytopenia associated with timber-rattlesnake envenomation requires further study. Physicians called on to treat envenomations should be cautioned that the algorithm established for the treatment of rattlesnake envenomations with CroFab may not be sufficient to correct the venom-induced thrombocytopenia associated with timber-rattlesnake envenomation.
Barry S. Gold, M.D.
Robert A. Barish, M.D.
University of Maryland School of Medicine
Baltimore, MD 21201
bgold@smail.umaryland.edu
Michael S. Rudman, M.D.
J. Elmer Harp Medical Center
Middletown, MD 21769
References
Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med 2002;347:347-356.
Yip L. Rational use of crotalidae polyvalent immune Fab (ovine) in the management of crotaline bite. Ann Emerg Med 2002;39:648-650.
Bond RG, Burkhart KK. Thrombocytopenia following timber rattlesnake envenomation. Ann Emerg Med 1997;30:40-44.
Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations. 2. Guidelines for clinical management with crotaline Fab antivenom. Ann Emerg Med 2001;37:196-201.
Schmaier AH, Claypool W, Colman RW. Crotalocytin: recognition and purification of a timber rattlesnake platelet aggregating protein. Blood 1980;56:1013-1019.
The above letter was referred to Protherics, the manufacturer of CroFab, which offers the following reply:
To the Editor: We thank Dr. Gold and colleagues for sharing a challenging case of thrombocytopenia. Fortunately, the issue of coagulopathy and thrombocytopenia in crotaline snakebite has been addressed in the medical literature. Currently, there are two antivenoms used in the United States. One — Antivenin (Crotalidae) Polyvalent, made by Wyeth — is available only in very limited quantities, leaving primarily CroFab to meet demand. In 1997, Bond and Burkhart described a case series involving thrombocytopenia resistant to treatment with the Wyeth antivenom in victims of timber-rattlesnake envenomation.1 With regard to the problem of difficult-to-treat thrombocytopenia in the setting of treatment with CroFab, medical opinion has been summarized in articles that independently reached similar conclusions.2,3,4
First, for spontaneous bleeding to occur after snakebite, severe defects in both the platelet count and fibrinogen levels must probably be present to increase substantially the danger of clinically significant bleeding. Even then, clinically important bleeding is rare. Severe abnormalities of either platelets or the coagulation cascade alone rarely cause bleeding.2,3,4 Thus, treatment of thrombocytopenia or coagulopathy may not be required unless severe defects are present in both areas. If severe defects are present in both, treatment is at the discretion of the treating physician. Strategies that have been used include the administration of additional CroFab alone or the infusion of CroFab plus platelets or clotting components, as clinically indicated. In some cases, no additional therapy has been provided, apparently without any adverse outcome.3 All patients with thrombocytopenia or abnormal results on clotting studies should be cautioned to avoid high-risk activities. The appearance of coagulation abnormalities after snake envenomation is an important topic, and we welcome further investigation aimed at optimizing treatment for the uncommon, treatment-resistant cases.
Andrew Heath, M.D., Ph.D.
Protherics
London EC4M 7AA, United Kingdom
References
Bond RG, Burkhart KK. Thrombocytopenia following timber rattlesnake envenomation. Ann Emerg Med 1997;30:40-44.
Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations. 2. Guidelines for clinical management with crotaline Fab antivenom. Ann Emerg Med 2001;37:196-201.
Ruha AM, Curry SC, Beuhler M, et al. Initial postmarketing experience with crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation. Ann Emerg Med 2002;39:609-615.
Yip L. Rational use of crotalidae polyvalent immune Fab (ovine) in the management of crotaline bite. Ann Emerg Med 2002;39:648-650.
A 38-year-old man was bitten on the left hand by a timber rattlesnake and presented to the emergency department within one hour. He had no underlying medical conditions and no history of snakebite. He had a single fang mark with minimal ecchymosis on the left hand near the second metacarpophalangeal joint. The hand and forearm were swollen, with marked tenderness. Vital signs were within normal limits. Initial laboratory studies included a complete blood count with a differential count, platelet count, coagulation profile (fibrinogen level, prothrombin time, and activated partial-thromboplastin time), creatine kinase measurement, and basic metabolic profile. The platelet count on admission was 157,000 per cubic millimeter. When repeated about five hours later, the platelet count was 28,300 per cubic millimeter.
On the basis of the clinical findings, treatment was initiated with CroFab. Despite treatment with large quantities of antivenom, the patient continued to have thrombocytopenia. On the third hospital day, his platelet count dropped to 590 per cubic millimeter. During his 10-day hospitalization, he received a total of 46 vials of CroFab. At the time of discharge, his platelet count was 26,300 per cubic millimeter. There was never any evidence of spontaneous bleeding or oozing from the venipuncture sites.2 After discharge, the platelet count remained depressed until three weeks after the envenomation, when it rose to 245,000 per cubic millimeter.
Envenomation by the timber rattlesnake commonly causes thrombocytopenia, even in the absence of coagulopathy.3,4 The precise mechanism is unknown. It has been postulated that crotalocytin, a protein component of timber-rattlesnake venom, has the capacity to induce platelet aggregation and release of ATP from the platelets.5
The efficacy of CroFab in reversing the thrombocytopenia associated with timber-rattlesnake envenomation requires further study. Physicians called on to treat envenomations should be cautioned that the algorithm established for the treatment of rattlesnake envenomations with CroFab may not be sufficient to correct the venom-induced thrombocytopenia associated with timber-rattlesnake envenomation.
Barry S. Gold, M.D.
Robert A. Barish, M.D.
University of Maryland School of Medicine
Baltimore, MD 21201
bgold@smail.umaryland.edu
Michael S. Rudman, M.D.
J. Elmer Harp Medical Center
Middletown, MD 21769
References
Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med 2002;347:347-356.
Yip L. Rational use of crotalidae polyvalent immune Fab (ovine) in the management of crotaline bite. Ann Emerg Med 2002;39:648-650.
Bond RG, Burkhart KK. Thrombocytopenia following timber rattlesnake envenomation. Ann Emerg Med 1997;30:40-44.
Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations. 2. Guidelines for clinical management with crotaline Fab antivenom. Ann Emerg Med 2001;37:196-201.
Schmaier AH, Claypool W, Colman RW. Crotalocytin: recognition and purification of a timber rattlesnake platelet aggregating protein. Blood 1980;56:1013-1019.
The above letter was referred to Protherics, the manufacturer of CroFab, which offers the following reply:
To the Editor: We thank Dr. Gold and colleagues for sharing a challenging case of thrombocytopenia. Fortunately, the issue of coagulopathy and thrombocytopenia in crotaline snakebite has been addressed in the medical literature. Currently, there are two antivenoms used in the United States. One — Antivenin (Crotalidae) Polyvalent, made by Wyeth — is available only in very limited quantities, leaving primarily CroFab to meet demand. In 1997, Bond and Burkhart described a case series involving thrombocytopenia resistant to treatment with the Wyeth antivenom in victims of timber-rattlesnake envenomation.1 With regard to the problem of difficult-to-treat thrombocytopenia in the setting of treatment with CroFab, medical opinion has been summarized in articles that independently reached similar conclusions.2,3,4
First, for spontaneous bleeding to occur after snakebite, severe defects in both the platelet count and fibrinogen levels must probably be present to increase substantially the danger of clinically significant bleeding. Even then, clinically important bleeding is rare. Severe abnormalities of either platelets or the coagulation cascade alone rarely cause bleeding.2,3,4 Thus, treatment of thrombocytopenia or coagulopathy may not be required unless severe defects are present in both areas. If severe defects are present in both, treatment is at the discretion of the treating physician. Strategies that have been used include the administration of additional CroFab alone or the infusion of CroFab plus platelets or clotting components, as clinically indicated. In some cases, no additional therapy has been provided, apparently without any adverse outcome.3 All patients with thrombocytopenia or abnormal results on clotting studies should be cautioned to avoid high-risk activities. The appearance of coagulation abnormalities after snake envenomation is an important topic, and we welcome further investigation aimed at optimizing treatment for the uncommon, treatment-resistant cases.
Andrew Heath, M.D., Ph.D.
Protherics
London EC4M 7AA, United Kingdom
References
Bond RG, Burkhart KK. Thrombocytopenia following timber rattlesnake envenomation. Ann Emerg Med 1997;30:40-44.
Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations. 2. Guidelines for clinical management with crotaline Fab antivenom. Ann Emerg Med 2001;37:196-201.
Ruha AM, Curry SC, Beuhler M, et al. Initial postmarketing experience with crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation. Ann Emerg Med 2002;39:609-615.
Yip L. Rational use of crotalidae polyvalent immune Fab (ovine) in the management of crotaline bite. Ann Emerg Med 2002;39:648-650.