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Fetal anemia as a response to prophylactic platelet transfusion in the management of alloimmune thrombocytopenia
CASE REPORTS
Fetal anemia as a response to prophylactic platelet transfusion in the management of alloimmune thrombocytopenia John D. Yeast, MD, MSPH, and Frederick Plapp, MD, PhD Kansas City, Mo The antenatal management of alloimmune thrombocytopenia (ATP) frequently requires fetal blood sampling and prophylactic platelet transfusion. A recent case of ATP complicated by associated red blood cell alloimmunization demonstrated severe hemolysis apparently as a result of ABO incompatibility from transfused platelets. (Am J Obstet Gynecol 2003;189:874-6.)
Key words: Alloimmune thrombocytopenia, fetal anemia, fetal hemolysis
A recent complication arose from the antenatal surveillance and treatment of a pregnancy at risk from both neonatal alloimmune thrombocytopenia and red blood cell alloimmunization. Case report The patient was referred during her second pregnancy because of a diagnosis of alloimmune thrombocytopenia (ATP) and sensitization to D and C red blood cell antigens. After an apparently uneventful first pregnancy, her newborn infant was discovered to have petechiae. The infant was severely thrombocytopenic and required platelet therapy. A workup discovered that the patient had HPA-1 (PLA1) antibodies. In addition, the patient was also found to have anti-D and anti-C, in spite of receiving Rh immune globulin at 28 weeks’ gestation. Early in this pregnancy, the father’s blood type was confirmed to be O Rh positive (D, C, c). Maternal blood type was AB, Rh negative. An amniocentesis by the referring physician revealed an Rh phenotype of D, C, c and the presence of HPA-1 antigen (PLA 1 and PLA 2 positive) for the fetus. The karyotype was normal. The patient was at 22 weeks of gestation at referral. An ultrasound confirmed a normally grown infant, but with From the Department of Obstetrics and Gynecology,a and Saint Luke’s Regional Laboratories,b Saint Luke’s Hospital of Kansas City, and the Department of Obstetrics and Gynecology, University of Missouri– Kansas City School of Medicine.c Received for publication September 25, 2002; revised January 9, 2003; accepted January 31, 2003. Reprint requests: John D. Yeast, MD, Department of Obstetrics and Gynecology, Saint Luke’s Hospital of Kansas City, 4401 Wornall Rd, Kansas City, MO 64111. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00229-1
874
a large anterior placenta. An extensive discussion was held with the parents regarding management options. Although optimal management of the ATP could include fetal blood sampling (PUBS) and possible fetal platelet therapy, there was concern that one or more PUBS might exacerbate Rh sensitization. Further, fetal blood sampling for either determination of fetal platelet count or fetal hemoglobin might carry an additional risk of hemorrhage, as a result of possible fetal thrombocytopenia. A plan was developed to attempt conservative management of both fetal risks. It was decided that the risk of fetal anemia would be monitored by weekly ultrasonography, including middle cerebral artery (MCA) peak velocity studies.1 ATP would be managed by the use of maternal infusion of gamma globulin on a weekly basis at a dose of 1 g/kg.2 However, fetal blood sampling would be delayed as long as possible in pregnancy, as long as ultrasound parameters for the fetus remained reassuring.
Table I. MCA peak velocity values Gestational age 22 24 26 27 28 29 30 30 30 31 32
wk wk wk wk wk wk wk wk wk wk wk
1 5 5 5 5 5 2 4 4 4 2
d d d d d d d d (pretransfusion) d (posttransfusion) d d
MCA peak velocity (m/s) 0.30 0.33 0.37 0.37 0.39 0.53 0.66 0.64 0.43 0.60 1.10
Clinical zone* C C C C C B A A C B A
A, Moderate to severe anemia; B, mild anemia; C, no anemia. *See reference 1.
Yeast and Plapp 875
Volume 189, Number 3 Am J Obstet Gynecol
Table II. Infant red blood cell and platelet transfusions Date 8/20/01 8/21/01 8/22/01 8/23/01 8/24/01 9/4/01 9/6/01
Blood component* O neg RBC O pos RDP O neg RBC O pos RDP O pos SDP PLA1 neg O neg RBC O neg RDP O neg RBC
Hemoglobin (g/dL) pretransfusion
Platelet count (103/lL) pretransfusion
40 28 28 50 150
3.6 10.3
258 71
40 50 30
10.6
39
10.1 14.9
300 308
Volume transfused (mL)
65 64
Neg, Rh negative; Pos, Rh positive; RBC, red blood cell; RDP, random donor platelet concentrate; SDP, single donor platelet concentrate; PLA1 neg, PLA1 antigen negative. *All blood components were cytomegalovirus negative and irradiated. Red blood cells and single donor platelets were prestorage leukocyte reduced.
The patient and fetus did well until 29 weeks 5 days of gestation when the MCA peak velocity rose (Table I). In addition, anti-D titer had increased from 1:16 to 1:256 and anti-C titer had increased from 1:1 to 1:4 over a 5-month interval. A repeat value 4 days later revealed a persistent elevation in the MCA peak velocity. A decision was made to proceed with fetal blood sampling and to give a prophylactic platelet infusion after sample acquisition and red blood cell transfusion. Betamethasone was given for 48 hours before PUBS. An uneventful PUBS was performed at the placental cord insertion site. Fetal blood type was B positive. Initial hematocrit was 30%. A rapid quantitative platelet count was not available, but a sample was obtained for initial platelet assessment. A total of 30 mL of O-negative packed red blood cells were transfused, and the posttransfusion hematocrit was 36%. An infusion of 15 mL of O-positive, PLA-1 negative donor platelets was given immediately after the packed red blood cell transfusion. The initial fetal platelet count later returned to 286,000/lL. The MCA peak velocity dropped from 0.64 m/s to 0.40 m/s after the procedure. After the procedure, the patient received her weekly dose of intravenous immune globulin and resumed surveillance. Twelve days later, however, at 32 weeks 2 days of gestation, she was seen for decreased fetal movement, an MCA peak velocity of 1.1 m/s, and a sinusoidal fetal heart rate tracing. A prompt cesarean section was performed. A 1915-g infant was delivered with Apgar scores of 5 at 1 minute and 8 at 5 minutes. Cord pH values were 7.31/7.37. However, the infant’s hemoglobin level was 3.0 g/dL, and the cord bilirubin was 10 mg/dL. The platelet count was 258,000/lL at birth but decreased to 71,000/lL 6 hours later. There was no evidence of fetalmaternal hemorrhage. There was no evidence of retroplacental bleeding, and the amniotic fluid was clear. The infant responded to transfusion of red blood cells and platelets (Table II). Subsequent transfusions of blood products were necessary, and the infant received erythro-
poietin and phototherapy. The infant was hospitalized for 29 days. Neonatal follow-up was arranged to follow hemoglobin levels and platelet counts. No further transfusions of blood products were necessary after discharge. Comment The optimal management of alloimmune thrombocytopenia is still controversial.2-5 Serial fetal blood sampling and use of platelet transfusions carries risk to the fetus of up to 6% mortality. The use of prophylactic gamma globulin therapy does not always prevent fetal thrombocytopenia, although it does appear to reduce the risk of significant fetal hemorrhage. In this case, the additional risk of an Rh antibody anamnestic response led to a unique management plan.6 When fetal blood sampling seemed indicated, it was performed with a presumed risk of both fetal anemia and potential fetal thrombocytopenia. A prophylactic platelet transfusion was given before withdrawal of the sampling needle.7 Although group 0, PLA 1–negative donor platelets were given, the anti-B antibody present in the plasma was incompatible with the group B fetal red blood cells. Subsequently, the fetus became profoundly anemic, presumably the result of hemolysis of its red blood cells by the anti-B antibody present in the platelet transfusion. No group B red cells were detectable at birth because of hemolysis and transfusion with O-negative red blood cells. Therefore, it was not possible to prove that anti-B antibody was the sole cause of hemolysis. In adult patients, ABOincompatible platelets can cause significant hemolytic anemia.8 However, it is theoretically possible that an anamnestic increase in anti-D and anti-C antibodies after fetal sampling may have also contributed to hemolysis. PLA-1–negative donor platelets are often recommended for prophylactic platelet transfusion at initial sampling for a fetus at risk for thrombocytopenia.7 Group O platelets are usually selected for fetal transfusion. Approximately 45% of whites and 49% of African Americans are blood group O. In these cases, transfusion of group O platelets
876 Yeast and Plapp
does not cause hemolysis. However, if the fetus has A, B, or AB red blood cells, transfusion of a relatively large volume of group O platelets could potentially cause hemolysis of fetal red blood cells, especially if the donor has high titers of anti-A or anti-B. The risk of hemolysis is even greater if the fetus has an additional risk of anemia. Based on this case, it may be prudent to attempt to use group AB platelets. However, it may be very difficult to locate platelet donors who are group AB and PLA1 negative. An alternative suggestion would be to use washed group O platelets because washing removes most of the plasma containing anti-A and anti-B. However, platelet numbers and function are somewhat diminished after platelet washing.
September 2003 Am J Obstet Gynecol
2. 3.
4.
5.
6.
7. REFERENCES 1. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell
8.
alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9-14. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmune thrombocytopenia. N Engl J Med 1997;1997:22-6. Giers G, Hoch J, Bauer H, et al. Therapy with intravenous immunoglobulin G (ivIgG) during pregnancy for fetal alloimmune (HPA-Ia(Zwa)) thrombocytopenic purpura. Prenat Diagn 1996;16: 495-502. Dickinson JE, Marshall LR, Phillips JM, et al. Antenatal diagnosis and management of fetomaternal alloimmune thrombocytopenia. Am J Perinatol 1995;12:333-5. Overton TG, Duncan KR, Jolly M, et al. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 2002;186: 826-31. Radder CM, Brand A, Kanhai HHH. A less invasive treatment strategy to present intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia. Am J Obstet Gynecol 2001;185: 683-8. Silver RM, Porter FT, Branch W, et al. Neonatal alloimmune thrombocytopenia: antenatal management. Am J Obstet Gynecol 2000;182:1233-8. Larsson LG, Welsh VJ, Ladd DJ. Acute intravascular hemolysis secondary to out of group platelet transfusion. Transfusion 2000;40:902-6.
Fetal anemia as a response to prophylactic platelet transfusion in the management of alloimmune thrombocytopenia John D. Yeast, MD, MSPH, and Frederick Plapp, MD, PhD Kansas City, Mo The antenatal management of alloimmune thrombocytopenia (ATP) frequently requires fetal blood sampling and prophylactic platelet transfusion. A recent case of ATP complicated by associated red blood cell alloimmunization demonstrated severe hemolysis apparently as a result of ABO incompatibility from transfused platelets. (Am J Obstet Gynecol 2003;189:874-6.)
Key words: Alloimmune thrombocytopenia, fetal anemia, fetal hemolysis
A recent complication arose from the antenatal surveillance and treatment of a pregnancy at risk from both neonatal alloimmune thrombocytopenia and red blood cell alloimmunization. Case report The patient was referred during her second pregnancy because of a diagnosis of alloimmune thrombocytopenia (ATP) and sensitization to D and C red blood cell antigens. After an apparently uneventful first pregnancy, her newborn infant was discovered to have petechiae. The infant was severely thrombocytopenic and required platelet therapy. A workup discovered that the patient had HPA-1 (PLA1) antibodies. In addition, the patient was also found to have anti-D and anti-C, in spite of receiving Rh immune globulin at 28 weeks’ gestation. Early in this pregnancy, the father’s blood type was confirmed to be O Rh positive (D, C, c). Maternal blood type was AB, Rh negative. An amniocentesis by the referring physician revealed an Rh phenotype of D, C, c and the presence of HPA-1 antigen (PLA 1 and PLA 2 positive) for the fetus. The karyotype was normal. The patient was at 22 weeks of gestation at referral. An ultrasound confirmed a normally grown infant, but with From the Department of Obstetrics and Gynecology,a and Saint Luke’s Regional Laboratories,b Saint Luke’s Hospital of Kansas City, and the Department of Obstetrics and Gynecology, University of Missouri– Kansas City School of Medicine.c Received for publication September 25, 2002; revised January 9, 2003; accepted January 31, 2003. Reprint requests: John D. Yeast, MD, Department of Obstetrics and Gynecology, Saint Luke’s Hospital of Kansas City, 4401 Wornall Rd, Kansas City, MO 64111. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00229-1
874
a large anterior placenta. An extensive discussion was held with the parents regarding management options. Although optimal management of the ATP could include fetal blood sampling (PUBS) and possible fetal platelet therapy, there was concern that one or more PUBS might exacerbate Rh sensitization. Further, fetal blood sampling for either determination of fetal platelet count or fetal hemoglobin might carry an additional risk of hemorrhage, as a result of possible fetal thrombocytopenia. A plan was developed to attempt conservative management of both fetal risks. It was decided that the risk of fetal anemia would be monitored by weekly ultrasonography, including middle cerebral artery (MCA) peak velocity studies.1 ATP would be managed by the use of maternal infusion of gamma globulin on a weekly basis at a dose of 1 g/kg.2 However, fetal blood sampling would be delayed as long as possible in pregnancy, as long as ultrasound parameters for the fetus remained reassuring.
Table I. MCA peak velocity values Gestational age 22 24 26 27 28 29 30 30 30 31 32
wk wk wk wk wk wk wk wk wk wk wk
1 5 5 5 5 5 2 4 4 4 2
d d d d d d d d (pretransfusion) d (posttransfusion) d d
MCA peak velocity (m/s) 0.30 0.33 0.37 0.37 0.39 0.53 0.66 0.64 0.43 0.60 1.10
Clinical zone* C C C C C B A A C B A
A, Moderate to severe anemia; B, mild anemia; C, no anemia. *See reference 1.
Yeast and Plapp 875
Volume 189, Number 3 Am J Obstet Gynecol
Table II. Infant red blood cell and platelet transfusions Date 8/20/01 8/21/01 8/22/01 8/23/01 8/24/01 9/4/01 9/6/01
Blood component* O neg RBC O pos RDP O neg RBC O pos RDP O pos SDP PLA1 neg O neg RBC O neg RDP O neg RBC
Hemoglobin (g/dL) pretransfusion
Platelet count (103/lL) pretransfusion
40 28 28 50 150
3.6 10.3
258 71
40 50 30
10.6
39
10.1 14.9
300 308
Volume transfused (mL)
65 64
Neg, Rh negative; Pos, Rh positive; RBC, red blood cell; RDP, random donor platelet concentrate; SDP, single donor platelet concentrate; PLA1 neg, PLA1 antigen negative. *All blood components were cytomegalovirus negative and irradiated. Red blood cells and single donor platelets were prestorage leukocyte reduced.
The patient and fetus did well until 29 weeks 5 days of gestation when the MCA peak velocity rose (Table I). In addition, anti-D titer had increased from 1:16 to 1:256 and anti-C titer had increased from 1:1 to 1:4 over a 5-month interval. A repeat value 4 days later revealed a persistent elevation in the MCA peak velocity. A decision was made to proceed with fetal blood sampling and to give a prophylactic platelet infusion after sample acquisition and red blood cell transfusion. Betamethasone was given for 48 hours before PUBS. An uneventful PUBS was performed at the placental cord insertion site. Fetal blood type was B positive. Initial hematocrit was 30%. A rapid quantitative platelet count was not available, but a sample was obtained for initial platelet assessment. A total of 30 mL of O-negative packed red blood cells were transfused, and the posttransfusion hematocrit was 36%. An infusion of 15 mL of O-positive, PLA-1 negative donor platelets was given immediately after the packed red blood cell transfusion. The initial fetal platelet count later returned to 286,000/lL. The MCA peak velocity dropped from 0.64 m/s to 0.40 m/s after the procedure. After the procedure, the patient received her weekly dose of intravenous immune globulin and resumed surveillance. Twelve days later, however, at 32 weeks 2 days of gestation, she was seen for decreased fetal movement, an MCA peak velocity of 1.1 m/s, and a sinusoidal fetal heart rate tracing. A prompt cesarean section was performed. A 1915-g infant was delivered with Apgar scores of 5 at 1 minute and 8 at 5 minutes. Cord pH values were 7.31/7.37. However, the infant’s hemoglobin level was 3.0 g/dL, and the cord bilirubin was 10 mg/dL. The platelet count was 258,000/lL at birth but decreased to 71,000/lL 6 hours later. There was no evidence of fetalmaternal hemorrhage. There was no evidence of retroplacental bleeding, and the amniotic fluid was clear. The infant responded to transfusion of red blood cells and platelets (Table II). Subsequent transfusions of blood products were necessary, and the infant received erythro-
poietin and phototherapy. The infant was hospitalized for 29 days. Neonatal follow-up was arranged to follow hemoglobin levels and platelet counts. No further transfusions of blood products were necessary after discharge. Comment The optimal management of alloimmune thrombocytopenia is still controversial.2-5 Serial fetal blood sampling and use of platelet transfusions carries risk to the fetus of up to 6% mortality. The use of prophylactic gamma globulin therapy does not always prevent fetal thrombocytopenia, although it does appear to reduce the risk of significant fetal hemorrhage. In this case, the additional risk of an Rh antibody anamnestic response led to a unique management plan.6 When fetal blood sampling seemed indicated, it was performed with a presumed risk of both fetal anemia and potential fetal thrombocytopenia. A prophylactic platelet transfusion was given before withdrawal of the sampling needle.7 Although group 0, PLA 1–negative donor platelets were given, the anti-B antibody present in the plasma was incompatible with the group B fetal red blood cells. Subsequently, the fetus became profoundly anemic, presumably the result of hemolysis of its red blood cells by the anti-B antibody present in the platelet transfusion. No group B red cells were detectable at birth because of hemolysis and transfusion with O-negative red blood cells. Therefore, it was not possible to prove that anti-B antibody was the sole cause of hemolysis. In adult patients, ABOincompatible platelets can cause significant hemolytic anemia.8 However, it is theoretically possible that an anamnestic increase in anti-D and anti-C antibodies after fetal sampling may have also contributed to hemolysis. PLA-1–negative donor platelets are often recommended for prophylactic platelet transfusion at initial sampling for a fetus at risk for thrombocytopenia.7 Group O platelets are usually selected for fetal transfusion. Approximately 45% of whites and 49% of African Americans are blood group O. In these cases, transfusion of group O platelets
876 Yeast and Plapp
does not cause hemolysis. However, if the fetus has A, B, or AB red blood cells, transfusion of a relatively large volume of group O platelets could potentially cause hemolysis of fetal red blood cells, especially if the donor has high titers of anti-A or anti-B. The risk of hemolysis is even greater if the fetus has an additional risk of anemia. Based on this case, it may be prudent to attempt to use group AB platelets. However, it may be very difficult to locate platelet donors who are group AB and PLA1 negative. An alternative suggestion would be to use washed group O platelets because washing removes most of the plasma containing anti-A and anti-B. However, platelet numbers and function are somewhat diminished after platelet washing.
September 2003 Am J Obstet Gynecol
2. 3.
4.
5.
6.
7. REFERENCES 1. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell
8.
alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9-14. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmune thrombocytopenia. N Engl J Med 1997;1997:22-6. Giers G, Hoch J, Bauer H, et al. Therapy with intravenous immunoglobulin G (ivIgG) during pregnancy for fetal alloimmune (HPA-Ia(Zwa)) thrombocytopenic purpura. Prenat Diagn 1996;16: 495-502. Dickinson JE, Marshall LR, Phillips JM, et al. Antenatal diagnosis and management of fetomaternal alloimmune thrombocytopenia. Am J Perinatol 1995;12:333-5. Overton TG, Duncan KR, Jolly M, et al. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 2002;186: 826-31. Radder CM, Brand A, Kanhai HHH. A less invasive treatment strategy to present intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia. Am J Obstet Gynecol 2001;185: 683-8. Silver RM, Porter FT, Branch W, et al. Neonatal alloimmune thrombocytopenia: antenatal management. Am J Obstet Gynecol 2000;182:1233-8. Larsson LG, Welsh VJ, Ladd DJ. Acute intravascular hemolysis secondary to out of group platelet transfusion. Transfusion 2000;40:902-6.