Recombinant Factor Viia Use to Overcome Massive Fatal Postpartum Hemorrage

Recombinant Factor VIIa Use to Overcome Massive Fatal Postpartum Hemorrhage- Our Experience

S. Segal1,3, IY. Shemesh1,3, R.Blumental1,3, B. Yoffe1,3, N. Laufer2, D. Mankuta2, M. Mazor3, S. Zohar4, E. Shiff6, O. Ben-Tal5, D. Pauzner5 and

U. Martinowitz6,7

Barzilai Medical Center, Ashkelon1, Hadassah University Hospital, Jerusalem2, Ben-Gurion University, Beer-Sheva3, Ziv Medical Center, Zefat4, Sourasky Medical Center, Tel-Aviv5, Sheba Medical Center6, The National Hemophilia Center, Tel-Hashomer7, Israel.

Massive postpartum hemorrhage (MPPH) that might be fatal, is seen with uterine rupture, placental abruption, uterine atony, placenta accreta, placenta

praevia, retained placenta, coagulation defects and trauma to the genital tract. Excessive uterine bleeding seen vaginally or concealed placental abruption with large clot formation may lead to consumptive coagulopathy and disseminated intravascular coagulation (DIC).

Conditions that predispose and worsen obstetrical hemorrhage belong to 4 main groups: a. placenta accreta/ increta/ percreta, placental abruption and placenta praevia. b. trauma during labor and delivery, uterine rupture, high parity, hyperstimulation, obstructed labor and cervical rupture, c. uterine atony, overdistended uterus, exhausted myometrium and prolonged labor, d. coagulation defects, placental abruption, severe preeclampsia, amniotic fluid embolism, intrauterine fetal death, sepsis, massive transfusion and congenital coagulopathies (1). In a study of 763 pregnant women, who died due to hemorrhage, 141(19%) had placental abruption, 125 (16%) uterine rupture, 115 (15%) uterine atony, 108(14%) coagulopathies, 50 (7%) placenta praevia, 44(6%) placenta accreta, 44(6%) uterine bleeding and 32(4%) retained placenta (2).

Massive postpartum hemorrhage (MPPH) was defined as a blood loss in excess of 1500ml, with a drop in hemoglobin concentration of ≥4 g/dl and the need of ≥ 4 units of blood (3). The complications of MPPH include hypovolemic shock, disseminated intravascular coagulopathy (DIC) renal failure, hepatic failure and adult respiratory distress syndrome (ARDS) (4). Factors influencing the outcome are: underestimation of blood loss, late diagnosis of uterine rupture, undiagnosed concealed abruption, late diagnosis of retroperitoneal or intraabdominal bleeding, rapid changes of coagulation events, inability to accurately diagnose the severity of DIC and the lack of ideal hospital facilities.

Dilemmas include: a hysterectomy in a young parturient and the preferred order of procedure: hysterectomy, ligation of the internal iliac arteries, arterial embolization, etc.

Consumptive coagulopathy and DIC: The control of the haemostatic system is done by the vascular integrity, platelet function, coagulation system and clot lysis. Platelets play an important role in clot formation. They adhere to damaged endothelium, release ADP recruiting more thrombocytes.

Beyond the damage, prostacyclin is secreted inhibiting further aggregation. Aggregated platelets and injured tissue activate coagulation factors. Fibrin is produced clot lysis is controlled by activated plasminogen and plasmin. Activation of coagulation cascade is cause by large amounts of tissue phospholipids causing DIC, as in abruption, dead fetus and amniotic fluid embolism. These tissue phospholipids utilize large amounts of clotting factors leading to consumptive coagulopathy. Once this happens the lythic process starts, with degradation of fibrin. Production of fibrin split products (FDP) in large amounts inhibit fibrinogen cross linking and cause platelet dysfunction.

Recombinant activated factor VII (rFVIIa) has been shown to correct severe coagulopathy and control life threatening bleeding (5, 6). rFVIIa – NovoSeven® by Novo Nordisk, Denmark, has been also used in obstetrics with encouraging results (7-13). During the years 2000-2004, NovoSeven® was used in 13 patients with massive postpartum hemorrhage, in several institutions in Israel. Ten patients of this group were studied and their results previously published (9). The patients were treated by surgery, as hysterectomy, uterine artery ligation, internal iliac arteries ligation, pelvic packing and arterial embolization. The coagulopathy was corrected with packed cells, fresh frozen plasma, cryoprecipitate and platelets. All patients received recombinant activated factor VII (rFVIIa) intravenously, at doses of 90 to 100 mcg/kg and total doses of 7.2-19mg.

The causes of bleeding in the 13 patients were: placenta accreta: 4(31%), ruptured uterus: 4(31%) and uterine atony: 4(31%). Hysterectomy was done in 10(77%) women and repeated surgery in 9 (69%). The procedures for uterine atony and bleeding were oxytocin and prostaglandin application and laparotomy and uterine artery ligation, when needed. Cases of placenta accreta and bleeding ended with hysterectomy with or without ligation of the iliac arteries. Many of them were expected due to anterior placenta praevia and repeated cesarean sections. When the bleeding continued, NovoSeven® was given. Uterine rupture of cervix or lower segment was treated by hysterectomy with or without ligation of iliac arteries. Patients with uterine rupture, retroperitoneal bleeding and tissue damage which continued to bleed, underwent repeated explorations with hemostasis and pelvic packing. Massive postpartum bleeding led to DIC in 8 (68%) patients. The extreme cases required massive transfusions of 44 to 100 units of packed cells, 24 to 50u. of fresh frozen plasma, 50-54u. of cryoprecipitate and 50-60 units of platelets.

NovoSeven® was used and is indicated with massive postpartum hemorrhage: 1) in a fatal situation when no other treatment is available, 2) in a young bleeding parturient before the decision of hysterectomy and 3) for a temporary decrease of bleeding to achieve better surgical hemostasis. Massive postpartum hemorrhage is an active and progressive process. The coagulopathy and the degree of irreversibility of this complicated process are difficult to evaluate as is the danger to the patient. The detrimental effect of the tissue factors on coagulation enhanced by repeated and prolonged surgery can be diminished and prevented by the use of rFVIIa. Should NovoSeven® be used prophylactically or only therapeutically, needs further elucidation. When arterial embolization is not available as an emergency procedure, NovoSeven® can be used to decrease bleeding and achieve better surgical hemostasis. The drug is quite expensive and its cost is of concern. With accumulation of data on its clinical advantage more accurate indications could be provided.

Reference:

1. CUNNINGHAM FG, GANT NF, LEVENO KJ, GILSTRAP III LC, HAUTH JC, WENSTRON KD. Obstetrical hemorrhage. Williams Obstetrics. 21st ed. New-York: McGraw-Hill, 619-669, 2001.
   
2. CHICHAKLI LO, ATRASH HK, MACKAY AP, MUSANI AS, BERG BJ, Pregnancy-related mortality in the United Stats due to hemorrhage: 1979-1992. Obstet. Gynecol 94; 721, 1999.
   
3. WATERSTONE M, BEWLEY S, WOLFE C. Incidence and predictors of severe obstetric morbidity: case-control study. Brit. Med. J. 322:1089-1094, 2001.
   
4. BONNAR J, Massive obstetric hemorrhage. Bailieres Best. Pract. Res. Clin Obstet Gynecol. 14; 1-8, 2001.
   
5. HEDNER U, Recombinant activated factor VII as a universal haemostatic agent. Blood Coagul Fibrinolysis. 9; S147-152, 1998.
   
6. MARTINOWITZ U,KENET G, SEGAL E, LUBOSHITZ J, LUBETSKY A, INGERSLEV J, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 51; 431-439, 2001.
   
7. SEGAL S, SHEMESH IY, BLUMENTAL R, YOFFE B, LAUFER N, EZRA Y, LEVY I, MAZOR M and MARTINOWITZ U. in The 2nd world Congress on Controversies in Obstetrics Gynecology & Infertility, ed. Ben-Rafael Z, Shoham Z and Frydman R, Monduzzi Editore, Vol 2, p. 43-46, 2001.
   
8. SEGAL S, SHEMESH IY, BLUMENTAL R, YOFFE B, LAUFER N, EZRA Y, LEVY I, MAZOR M and MARTINOWITZ U. Treatment of obstetric hemorrhage with recombinant activated factor VII (rFVIIa). Arch. Gynecol. Obstet. 268; 266-267, 2003.
   
9. SEGAL S, SHEMESH IY, BLUMENTAL R, YOFFE B, LAUFER N, MANKUTA D, MAZOR M, ZOHAR S, SCHIFF E and MARTINOWITZ U. The use of recombinant factor VII in severe postpartum hemorrhage. Acta Obstet. Gynecol Scand. 83, 2004.
   
10. MOSCARDO F, PEREZ F, DE LA RUBIA J, BALERDI B, LORENZO J, SENET ML, AZNAR I, CARCELLER S, SANZ MA. Successful treatment of severe intraabdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII. Brit. J. Hemat. 113; 174-176, 2001.
    
11. BREBOROWICZ GH, SOBIESZCZYK S, SZYMANKIEWICZ M. Efficacy of recombinant activated factor VII (rFVIIa, NovoSeven®) in prenatal medicine. Arch. Perinatal Med. 8 (2); 21-27, 2002.
    
12. ZUPANICIC SALEK S, SOKOLIC V, VISKOVIC T, SANJUG J, SIMIC M, KASTELAN M, Successful use of recombinant factor VIIa for massive bleeding after cesarean section due to HELLP syndrome. Acta Hematol 108; 162-163, 2002.
    
13. BOUWMEESTER FW, JONKHOFF AR, VERHEIJEN RHM, VAN GEIJN HP, Successful treatment of life threatening postpartum hemorrhage with recombinant activated factor VII. Obstet. Gynecol. 101; 1174-1176, 2003.