Labor analgesia in protein S deficient patient: case report

Abstracts

JUSTIFICATIVA E OBJETIVOS: Na deficiência de proteína S, uma glicoproteína com atividade anticoagulante, o risco de eventos tromboembólicos está aumentado. O objetivo deste relato é abordar o manuseio anestésico em paciente obstétrica portadora desta deficiência. RELATO DO CASO: Paciente com deficiência de proteína S, com 25 semanas de gestação, apresentou os seguintes resultados de exames: INR = 0,9, TTPA = 32 s (controle 25,6), proteína S = 35% (normal = 70% a 130%). Nos dois últimos trimestres de gravidez, fez uso de até 12000 U de heparina, cada 8 horas. Com 38 semanas, foi internada em trabalho de parto. Decorridas 8 horas da interrupção da heparina, já com TTPA 25,8 s (controle 27,8 s), realizou-se anestesia peridural injetando-se 6 ml de bupivacaína a 0,2% e fentanil (20 µg), seguido de infusão contínua. O tempo de infusão foi de 5 horas com dose total de 40 mg de bupivacaína. Não houve intercorrências e, 1 hora após a retirada do cateter, foi reiniciada heparina, por via subcutânea, 10.000 UI, a cada 12 horas. A mãe e o recém-nascido evoluíram bem, recebendo alta no terceiro dia do pós-parto. CONCLUSÕES: Grávidas com deficiência de proteína S devem receber anticoagulantes com o objetivo de manter o TTPA 2 vezes o valor controle. A heparina, por não atravessar a barreira placentária, é o anticoagulante de eleição em obstetrícia. O bloqueio pode ser realizado respeitando um tempo mínimo entre 4 a 6 horas entre a última dose de heparina e a realização da punção lombar, desde que os exames apresentem parâmetros de normalidade. Entretanto, nestes casos, a analgesia peridural pode auxiliar na profilaxia de eventos tromboembólicos.

ANALGESIA, Obstétrica; DOENÇA; TÉCNICAS ANESTÉSICAS, Regional

CLINICAL REPORT

Labor analgesia in protein S deficient patient. Case report^*

Analgesia de parto en paciente portadora de deficiencia de proteína S. Relato de caso

Renato Mestriner Stocche, TSA, M.D.^I; Luis Vicente Garcia, TSA, M.D. ^II; Marlene Paulino dos Reis, M.D.^III; Jyrson Guilherme Klamt, TSA, M.D.^II

^IAssistente do Serviço de Anestesiologia do HC da FMRP-USP

^IIProfessor Assistente Doutor da Disciplina de Anestesiologia da FMRP-USP

^IIIProfessora Associada da Disciplina de Anestesiologia da FMRP-USP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Deficiency in protein S, which is a glycoprotein with anticoagulant activity, increases the risk for thromboembolic events. This report aimed at addressing anesthetic management of protein S deficient obstetric patient.

CASE REPORT: Protein S deficient patient, at 25 weeks gestation, presented the following lab results: INR = 0.9, TTPA = 32 s (control 25.6), protein S = 35% (normal = 70% to 130%). In the last three gestation quarters she has received up to 12,000 IU heparin every 8 hours. With 38 weeks, she was admitted in labor. After 8 uninterrupted heparin hours, already with TTPA of 25.8 s (control 27.8 s) epidural anesthesia was induced with 6 ml of 0.2% bupivacaine and fentanyl (20 µg), followed by continuous infusion. Infusion time was 5 hours with total 40 mg bupivacaine dose. There have been no intercurrences and 1 hour after catheter removal, subcutaneous 10,000 IU heparin were restarted at 12-hour intervals. Patient and neonate evolved well and were discharged 3 days later.

CONCLUSIONS: Protein S deficient pregnant patients should receive anticoagulants to maintain TTPA twice the control value. Heparin, for not crossing placental barrier, is the anticoagulant of choice in obstetrics. Blockade may be induced respecting a minimum period of 4 to 6 hours between last heparin dose and lumbar puncture, provided lab tests are within normal ranges. In these cases, however, epidural analgesia may help in preventing thromboembolic events.

Key Words: ANALGESIA, Obstetric: labor; ANESTHETIC TECHNIQUES, Regional: epidural; DISEASES: protein S deficiency

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: En la deficiencia de proteína S, una glucoproteína con actividad anticoagulante, el riesgo de eventos tromboembólicos está aumentado. El objetivo de este relato es abordar el manoseo anestésico en paciente obstétrica portadora de esta deficiencia.

RELATO DE CASO: Paciente con deficiencia de proteína S, con 25 semanas de gestación, presentó los siguientes resultados de exámenes: INR = 0,9, TTPA = 32 s (control 25,6), proteína S = 35% (normal = 70% a 130%). En los dos últimos trimestres de embarazo, hizo uso de hasta 12000 U de heparina, cada 8 horas. Con 38 semanas, fue internada en trabajo de parto. Pasadas 8 horas de la interrupción de la heparina, y ya con TTPA 25,8 s (control 27,8 s), se realizó anestesia peridural con inyección de 6 ml de bupivacaína a 0,2% y fentanil (20 µg), seguido de infusión continua. EL tiempo de infusión fue de 5 horas con dosis total de 40 mg de bupivacaína. No hubo intercurrencias y, 1 hora después de la retirada del catéter, fue reiniciada heparina, por vía subcutánea, 10.000 UI, a cada 12 horas. La madre y el recién nacido evoluyeron bien, recibiendo alta en el tercero día del pos-parto.

CONCLUSIONES: Embarazadas con deficiencia de proteína S deben recibir anticoagulantes con el objetivo de mantener el TTPA 2 veces el valor control. La heparina, por no atravesar a barrera placentaria, es el anticoagulante de elección en obstetricia. El bloqueo puede ser realizado respetando un tiempo mínimo entre cuatro a seis horas entre a última dosis de heparina y la realización de la punción lumbar, desde que los exámenes presenten parámetros de normalidad. Entretanto, en estos casos, la analgesia peridural puede auxiliar en la profilaxis de eventos tromboembólicos.

INTRODUCTION

Protein S is a serum glycoprotein dependent on vitamin K, which acts as co-factor of protein C, which has anticoagulant activity ¹. Protein C acts by inactivating coagulation cascade factors Va and VIIIa ². This anticoagulant regulating effect presents as a physiological anti-thrombotic mechanism. So, protein S and/or protein C deficiency, are risk factors for thromboembolic events and are currently classified as thrombophilic diseases ³.

Protein S deficiency may be inherited, with pattern varying from genetic to acquired changes ⁴. Physiological states, such as pregnancy, may decrease plasma protein S levels ⁵. Several diseases have been related to this deficiency, such as multiple myeloma ⁶, HIV ⁷ and varicella ⁸ virus infection, systemic lupus erythematosus ⁹, and nephrotic syndrome ¹⁰, among others.

In general, young protein S deficient patients present with recurrent venous or arterial thrombosis without predisposing factors or in less common sites for their age ^11-13. During pregnancy, there may be repetition abortion, abruption placenta, intra-uterine death and low gestational age weight, all related to multiple placental infarctions ¹⁴. Diagnosis is suspected through history of thromboembolic events, familial history or abrupt pregnancy interruption history ¹⁵. Confirmation is obtained by serum dosage ¹⁶.

This report aimed at addressing coagulation management, thromboembolism and spinal hematoma risks associated to labor analgesia technique in inherited protein S deficient patient.

CASE REPORT

Pregnant patient, 29 years old, with protein S deficiency diagnosed by clinical and lab exams 2 years after presenting lower limbs deep vein thrombosis.

As from the 25^th week of gestation, patient was referred to the high risk and hematology outpatient department for follow up, when she presented the following lab results: PT = 0.9 seconds; INR = 0.9; TTPA = 32 seconds (control 26.6); TT = 8 seconds (control 9.5); Protein S = 35% (normal = 70% to 130%); Antithrombin III = 90% (normal = 70% to 130%); Fibrinogen = 290 mg/dl (normal = 200 to 400); Protein C = 73% (normal = 70% to 130%). As from beginning of prenatal follow-up, she received 10,000 to 12,000 IU subcutaneous heparin every 12 or 8 hours to maintain INR close to 2 (Table I). Hematological exams with hemoglobin and hematocrit count, among others, have remained within normal ranges throughout pregnancy and in the immediate post-delivery period.

Brazilian Journal of Anesthesiology, 2004; 54: 1: 68 - 72

Labor analgesia in protein S deficient patient. Case report

Renato Mestriner Stocche; Luis Vicente Garcia; Marlene Paulino dos Reis; Jyrson Guilherme Klamt

Pregnancy has evolved without severe events and with controlled coagulopathy. Four ultrasounds were performed and have not evidenced fetal or placental abnormalities.

With 38 weeks and 6 days of amenorrhea, patient was admitted in labor with 4 cm dilatation and dynamic of 2 contractions in 10 minutes. After admission, the case was discussed with hematologist, anesthesiologist and obstetrician who decided to withdraw heparin and administer protamine if necessary. The option has been vaginal delivery with early delivery epidural analgesia. After previous activated coagulation time test resulting in 105 seconds and TTPA close to control (25.6 seconds) epidural puncture and catheter insertion were performed. Initial 6 ml of 0.2% bupivacaine associated to 20 µg fentanyl were administered followed by 0.2% bupivacaine and fentanyl (1 µg.ml^-1) continuous infusion until second labor stage completion, with no need for additional doses. Delivery was helped by forceps 1 hour after total cervical dilatation. Total infusion time was 5 hours, with total 40 mg bupivacaine and 34 µg fentanyl doses. Epidural catheter was removed immediately after delivery and, 1 hour later, 10,000 IU subcutaneous heparin were restarted every 12 hours. Patient and neonate evolved without postoperative complications and were discharged 3 days after delivery.

DISCUSSION

Protein S deficiency associated to gestational hypercoagulability and labor stress highly increases the risk for intravascular thrombosis during pregnancy and in the peri-delivery period, thus requiring thromboembolism prophylaxis ^14,15. Heparin poses less fetal risk as compared to cumarin agents and should be used throughout pregnancy and in the immediate post-delivery period. In our case, and according to the literature, TTPA was twice the control time ¹⁵. There is heparin action resistance during pregnancy and this was apparent in our case where heparin dose had to be increased and intervals decreased to maintain INR in 2 (Table I).

Vaginal delivery seems to be the method of choice because bleeding risk in C-section is higher, as well as stress and endocrine-metabolic and immune changes duration, which could result in increased risk for thrombotic events ¹⁵.

However, labor stress triggers neuroendocrine and metabolic response similar to surgical stress, resulting in hypothalamohypophysial axis activation and consequent hypercoagulability ^17-19. So, anesthetic technique in this case should aim at maternal comfort and fetal wellbeing in addition to attenuating labor stress response. It is known that spinal analgesia is more effective in attenuating neuroendocrine and metabolic response to labor than systemic analgesia ^20,21, justifying the choice of epidural analgesia with continuous infusion. Mechanisms by which spinal blocks modulate coagulation are not well defined; however other factors, different from neuroendocrine response decrease to maternal stress, are involved, including: increased blood flow in the blocked region ²², increase in fibrinolytic activity ²³ via prevention of plasma plasminogen inhibiting factor increase ¹⁹ and decrease in platelet aggregation and blood viscosity. On the other hand, other factors involved in hypercoagulability, such as increased IL1, IL6 and tumor necrosis factor ²⁴, are not influenced by current labor analgesic techniques.

Heparin should be withdrawn during labor because the risk for bleeding and hemorrhagic emergencies is increased. In general, neuraxis may be blocked respecting a minimum interval of 4 to 6 hours between last heparin dose and lumbar puncture, provided exams are within normal ranges. In our case, heparin was withdrawn 8 hours before epidural puncture, which was enough to normalize TTPA.

Initial bolus infusion followed by continuous infusion was the technique of choice to obtain deep and constant analgesia, decrease total anesthetic dose and labor stress response. Thromboembolism prophylaxis with heparin should be reintroduced in the post-delivery period; however, epidural catheter should be removed before starting prophylaxis because its removal may lead to epidural hematoma in patients receiving heparin. Studies have shown that heparin may be safely restarted one hour after epidural catheter insertion and it is possible that the same time interval should be respected for catheter removal ²⁵.

REFERENCES

Submitted for publication March 10, 2003

Accepted for publication May 14, 2003

• 01. Yamazaki T - Molecular biological analysis of hereditary thrombophilia-genetic characterization of protein S deficiency. Rinsho Ketsueki, 1995;36:299-302.
• 02. Dahlbäck B, Wiedmer T, Sims PJ - Binding of anticoagulant vitamin K-dependent protein S to platelet-derived microparticles. Biochemistry, 1992;31:12769-12777.
• 03. Faioni EM, Valsecchi C, Palla A et al - Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost, 1997; 78:1343-1346.
• 04. Formstone CJ, Wacey AI, Berg LP et al - Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy. Blood, 1995;86:2632-2641.
• 05. Lefkowitz JB, Clarke SH, Barbour LA - Comparison of protein S functional and antigenic assays in normal pregnancy. Am J Obstet Gynecol, 1996;175:657-660.
• 06. Deitcher SR, Erban JK, Limentani AS - Acquired free protein S deficiency associated with multiple myeloma: a case report. Am J Hematol, 1996;51:319-323.
• 07. Sugerman RW, Church JA, Goldsmith JC et al - Acquired protein S deficiency in children infected with human immunodeficiency virus. Pediatr Infect Dis J, 1996;15:106-111.
• 08. Levin M, Eley BS, Louis J et al - Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr, 1995;127:355-363.
• 09. Ginsberg JS, Demers C, Brill Edwards P et al - Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus. Am J Med, 1995;98:379-383.
• 10. Hanevold CD, Lazarchick J, Constantin MA et al - Acquired free protein S deficiency in children with steroid resistant nephrosis. Ann Clin Lab Sci, 1996;26:279-282.
• 11. Simioni P, Sanson BJ, Prandoni P et al - Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost, 1999;81:198-202.
• 12. Ganesan V, McShane MA, Liesner R et al - Inherited prothrombotic states and ischaemic stroke in childhood. J Neurol Neurosurg Psychiatry, 1998;65:508-511.
• 13. Siqueira Neto JI, Santos AC, Fábio SR et al - Cerebral infarctions in young patients related to deficiency of natural anticoagulants. Protein C and protein S. Arq Neuropsiquiatr, 1996;54:590-594.
• 14. Arias F, Romero R, Joist H et al - Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med, 1998;7: 277-286.
• 15. Bonnar J, Green R, Norris L - Inherited thrombophilia and pregnancy: the obstetric perspective. Semin Thromb Hemost, 1998;24:(Suppl1):49-53.
• 16. Tripodi A, Bertina RM, Conard J et al - Multicenter evaluation of three commercial methods for measuring protein S antigen. Thromb Haemost, 1992;68:149-154.
• 17. Rosenfeld BA, Beattie C, Christopherson R et al - The perioperative ischemia randomized anesthesia trial study group: the effects of different anesthetic regimens on fibrinolysis and development of postoperative arterial thrombosis. Anesthesiology, 1993;79:435-443.
• 18. Breslow MJ, Parker SD, Frank SM et al - Determinants of catecholamine and cortisol response to lower-extremity revascularization. Anesthesiology, 1993;79:1202-1209.
• 19. Rosenfeld BA, Faraday N, Campbell D et al - Hemostatic effects of stress hormone infusion. Anesthesiology, 1994;81: 1116-1126.
• 20. Hoffmann R - The thrombo-embolic risk in surgery. Hepatogastroenterology, 1991;38:272-278.
• 21. Liu S, Carpenter RL, Neal JM - Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology, 1995;82:1474-1505.
• 22. Modig J, Malberg P, Karlstrom G - Effect of peridural versus general anaesthesia on calf blood flow. Acta Anaesthesiol Scand, 1980;24:305-309.
• 23. Donadoni R, Baele G, Devulder J et al - Coagulation and fibrinolytic parameters in patients undergoing total hip replacement: Influence of anaesthesia technique. Acta Anaesthesiol Scand, 1989;33:588-589.
• 24. Bateman A, Singh A, Kral T et al - The immune-hypothalamic-pituitary-adrenal axis. Endocrine Rev, 1989;10:92-112.
• 25. Rao TLK, El-Etr AA - Anticoagulation following placement of epidural and subarachnoid catheters: an evaluation of neurologic sequelae. Anesthesiology, 1981;55:293-296.

Correspondence to

Dr. Renato Mestriner Stocche

Address: Rua Afolfo Serra, 237 Alto da Boa Vista

ZIP: 14025-520 City: Ribeirão Preto, Brazil

*

Received from Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP USP), Ribeirão Preto, SP

Publication Dates

• Publication in this collection
  06 May 2004
• Date of issue
  Feb 2004

History

• Accepted
  14 May 2003
• Received
  10 Mar 2003