Fetomaternal alloimmune thrombocytopenia presenting as intracerebral bleeding in utero
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《美国医学杂志》
1 Division of Neonatology, Department of Pediatrics, University of Calgary, Canada
2 Department of Maternal and Fetal Medicine, University of Calgary, Canada
Abstract
Feto-maternal alloimmune thrombocytopenia is a serious fetal disorder resulting from platelet antigen incompatibility between the mother and the fetus. Intracranial bleeding is the most serious complication of alloimmune thrombocytopenia and can result in severe disability and death in utero. The authors report a case of intracerebral hemorrhage in utero resulting from alloimmune thrombocytopenia.
Keywords: Intracranial bleed; Alloimmune; Thrombocytopenia
Feto-maternal alloimmune thrombocytopenia (FMAIT) is a disorder caused by fetomaternal platelet incompatibility analogous to that in rhesus hemolytic disease, with maternal antiplatelet antibodies crossing the placenta and destroying the fetal platelets. Intracranial hemorrhage is the most serious complication of FMAIT and can result in severe disability and death in utero.[1] Here is reported a case of intracerebral hemorrhage in utero resulting from alloimmune thrombocytopenia.
Case report
A healthy 21-year-old gravida 2 para 0 woman was referred to the maternal and fetal medicine clinic for an abnormal intracranial fetal ultrasound at 32 weeks, which was done for poor fetal growth. Prior ultrasound scans done at 11 and 19 weeks were normal. Ultrasound revealed an abnormal head size with a large hyper echoic space-occupying lesion measuring 3 X 3.5 cm at the right cerebral hemisphere extending to the posterior horn of lateral ventricle Figure1. Rest of the detail ultrasound revealed no abnormality. Biophysical profile was 8/8. Repeat ultrasound done after one week did not show any change in the size or echogenicity of the mass. Possibility of an intracranial tumor or intracranial bleed was considered.
The patient had spontaneous abortion at 15 weeks in her first pregnancy. She had no history of bleeding or autoimmune disorders in the past. She was not a smoker, did not drink alcohol or use cocaine. There was no family history of bleeding disorders.
Investigation revealed hemoglobin (Hb) of 13.4 gm/dl, with normal white blood cell and platelet counts. Blood group was O-positive. Serology for syphilis, toxoplasma, cytomegalovirus, hepatitis B and human immunodeficiency virus, rubella was negative. In view of the above ultrasound finding, she was further investigated to rule out alloimmune thrombocytopenia. Platelet antigen studies revealed absence of human platelet antigen (HPA-1a). She had antiplatelet antibody against HPA-1a. ELISA done on maternal serum revealed no HLA antibodies. Her husband was investigated and he was homozygous for human platelet (HPA-1a) antigen. HLA typing was not performed during antenatal period. Parental counselling was done; elective cesarean section was planned. She received 2 doses of betamethasone prior to cesarean section. Compatible platelet (HPA-1a antigen negative) was arranged.
A female baby was delivered by elective cesarean section at 34 weeks. She cried soon after birth with Apgars of 8 and 9 at 1 and 5 minutes. The birth weight was 2420 gm (50centile); head circumference of 34.5 cm (>97centile) and length was 49 cm (90 centile). She had a large bruise (3x3 cm) over right parietal region and a small bruise over the suprapubic area. The anterior fontanel was full and both the squamoparietal sutures were separated. Systemic examination was unremarkable. She developed petechial rash all over the back within 1 hour of life.
Investigation showed hemoglobin of 14 gm/dl, total leukocyte count of 15,700/cu.mm and normal differential count. The first platelet count was 3000/cu.mm. Blood group was B-positive and Direct Coomb's test was negative.
She was treated with platelet transfusion (PLA-1a negative) 10 ml/kg and one dose of intravenous immunoglobulin (1 gm/kg) infused over 2 hours. Platelet count was repeated at 6 hours and count improved to 536,000/cu.mm. The platelet counts were monitored 12 hourly for the first 48 hours and daily thereafter. Initially, there was decline in platelet counts, but did not require further platelet transfusion. Platelet count was stabilized by day 10 of life. During the hospital stay, baby also had jaundice and received phototherapy for 96 hours. Ultrasound of brain on the second day of life revealed an intracranial mass of 5 x 3 cm on right cerebral hemisphere with mild midline shift and dilated (L) lateral ventricle. There was no seizure or altered sensorium during hospital stay and she was tolerating oral feeds. Her head circumference was monitored daily and there was no significant increase (>1 cm/wk) in size. Baby was discharged on day 12 of life and the platelet count was 155,000/cu.mm.
Discussion
Alloimmune thrombocytopenia is reported to occur in 1 per 1000 to 1 per 5000 live births.[2], [3] Several platelet specific antigens have been implicated, but human platelet antigen 1a (PLA 1a) is the most common and is responsible for 65-90 % of all cases.[4], [5] The ability of HPA-1a negative mother to form anti HPA-1a is controlled by HLA DR52a allele.[6] The risk of a severely affected child (platelet count <50,000 mm3) in a DR 52a positive individual is 1 in 15.
The important finding in this index case was a well-defined hyper-echoic space-occupying lesion in the brain, which did not change in echogenicity over a week's time. The differential diagnosis of a well-defined hyper-echogenic mass in utero includes intracranial tumors (such as teratoma, astrocytoma, choroid plexus papilloma and lipoma), intracranial hemorrhage or cerebral infarction. Intracranial tumor during fetal life is extremely rare and reported incidence of 0.34 per million live births.[7] The more common diagnosis is intracranial bleed. Intracranial bleed normally shows some changes in the echogenicity over the course of time.
Intracranial hemorrhage (ICH) has been reported to occur in 10-20% of newborns with FMAIT.[5],[6],[8] Mueller-Eckhardt et al reported that 12/88 (14%) neonates with alloimmune thrombocytopenia had intracranial hemorrhage. Of the 12 babies, 11 had intracerebral hemorrhage; of which 5 occurred in utero. Only one baby had subarachnoid bleeding.[5] Intracranial hemorrhage in the utero can occur as early as 16 weeks but the majority occurred at 35-37 weeks of gestation. Intracranial hemorrhage in alloimmune thrombocytopenia is typically intraparenchymal, unlike ICH due to prematurity, which is characterized by intraventricular bleed.[9] The most common site for intracranial hemorrhage is beneath the cerebral cortex, with expansion to a subarachnoid bleed and dissection through the brain reaching ventricles.[10] Intracranial hemorrhage can lead to death or permanent neurological sequelae, such as seizures, learning disabilities, cerebral palsy, hypotonia, cortical blindness, developmental delay, seizures, and psychomotor retardation.[1]
The diagnosis of FMAIT is confirmed by demonstrating antibodies in maternal serum that react with both father's and child's platelets and not with mother's platelets. Antenatal management of fetal alloimmune thrombocytopenia is controversial and includes a combination of maternal intravenous gamma globulin (IVIG) administration, intrauterine platelet transfusion and corticosteroid therapy, while monitoring fetal platelet count closely throughout the course of pregnancy. Antenatal treatment of alloimmune thrombocytopenia with weekly gamma globulin effectively improves the fetal platelet count and prevents intracranial hemorrhage.[11] In a series of 54 women with thrombocytopenic fetus, given IVIG weekly, no intracranial hemorrhage occurred and 20% showed no increase in platelet count with therapy.[12]
Postnatally, the treatment of choice for alloimmune thrombocytopenia is administration of maternal (or compatible) platelets.[11] Maternal platelets for transfusion must be washed and free from antibody containing plasma and resuspended in AB plasma. It is preferable to arrange the platelets before delivery of the baby. Other treatment options are intravenous immunoglobulin with or without steroids. When matched platelets are not available in an emergency situation, IV immunoglobulin 1 gm/kg/dose for two days have shown to be effective in cases with severe thrombocytopenia. Steroids have been tried in situations with continued low platelet count and bleeding.[11]
The natural history of FMAIT is one of the progressive worsening of the disease in subsequent pregnancies. Previous antenatal intracranial hemorrhage is a reliable predictor of severely low platelet counts and intracranial hemorrhage in the subsequent affected fetus.
In the present index case, the father was homozygous for platelet antigen. Therefore, there is 100% recurrent risk in future pregnancy. Parents have been counselled regarding the need for antenatal therapy with repeated platelet transfusion or weekly immunoglobulins therapy in subsequent pregnancies.
This case is reported to consider and to have a high index of suspicion for alloimmune thrombocytopenia in a differential diagnosis of a fetus presenting with hyperechoic intracerebral mass in utero.
References
1. Sharif U, Kuban K. Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 2001; 16 : 838-842.
2. Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993;329 : 1463-1466
3. Williamson LM, Hackett G, Rennie J et al. The natural history of feto-maternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood 1998; 92 : 2280-2287.
4. Bussel JB, Zabusky MR, Berkowitz RL, McFarland JG. Fetal alloimmune thrombocytopenia. N Engl J Med 1997; 337 : 22-26
5. Mueller-Eckhardt C, Kiefel V, Grubert A et al. 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 1989; 1: 363-366.
6. Bussel J, Kaplan C, McFarland J. Recommendations for the evaluation and treatment of neonatal autoimmune and alloimmune thrombocytopenia. Thromb Haemost 1991; 65: 631-634
7. Jooma R, Kendall BE, Hayward RD. Intracranial tumors in neonate. Report of seventeen cases. Surg Neurol 1984; 21:165-170
8. Herman JH, Jumbelic MI, Ancona RJ, Kickler TS. In utero cerebral hemorrhage in alloimmune thrombocytopenia. Am J Pediatr Hematol Oncol 1986; 8 : 312-317.
9. Naidu S, Messmore H, Caserta V, Fine M. CNS lesions in neonatal isoimmune thrombocytopenia. Arch Neurol 1983; 40: 552-554.
10. Govaert P, Bridger J, Wigglesworth J. Nature of the brain lesion in fetal alloimmune thrombocytopenia. Dev Med Child Neurol 1995; 37: 485-495
11. Lynch L, Bussel JB, McFarland JG, Chitkara U, Berkowitz RL. Antenatal treatment of alloimmune thrombocytopenia. Obstet Gynecol 1992; 80: 67-71.
12. Bussel JB, Berkowitz RL, Lynch L et al. Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol 1996;174 : 1414-1423.(Singh Soraisham Amuchou, )
2 Department of Maternal and Fetal Medicine, University of Calgary, Canada
Abstract
Feto-maternal alloimmune thrombocytopenia is a serious fetal disorder resulting from platelet antigen incompatibility between the mother and the fetus. Intracranial bleeding is the most serious complication of alloimmune thrombocytopenia and can result in severe disability and death in utero. The authors report a case of intracerebral hemorrhage in utero resulting from alloimmune thrombocytopenia.
Keywords: Intracranial bleed; Alloimmune; Thrombocytopenia
Feto-maternal alloimmune thrombocytopenia (FMAIT) is a disorder caused by fetomaternal platelet incompatibility analogous to that in rhesus hemolytic disease, with maternal antiplatelet antibodies crossing the placenta and destroying the fetal platelets. Intracranial hemorrhage is the most serious complication of FMAIT and can result in severe disability and death in utero.[1] Here is reported a case of intracerebral hemorrhage in utero resulting from alloimmune thrombocytopenia.
Case report
A healthy 21-year-old gravida 2 para 0 woman was referred to the maternal and fetal medicine clinic for an abnormal intracranial fetal ultrasound at 32 weeks, which was done for poor fetal growth. Prior ultrasound scans done at 11 and 19 weeks were normal. Ultrasound revealed an abnormal head size with a large hyper echoic space-occupying lesion measuring 3 X 3.5 cm at the right cerebral hemisphere extending to the posterior horn of lateral ventricle Figure1. Rest of the detail ultrasound revealed no abnormality. Biophysical profile was 8/8. Repeat ultrasound done after one week did not show any change in the size or echogenicity of the mass. Possibility of an intracranial tumor or intracranial bleed was considered.
The patient had spontaneous abortion at 15 weeks in her first pregnancy. She had no history of bleeding or autoimmune disorders in the past. She was not a smoker, did not drink alcohol or use cocaine. There was no family history of bleeding disorders.
Investigation revealed hemoglobin (Hb) of 13.4 gm/dl, with normal white blood cell and platelet counts. Blood group was O-positive. Serology for syphilis, toxoplasma, cytomegalovirus, hepatitis B and human immunodeficiency virus, rubella was negative. In view of the above ultrasound finding, she was further investigated to rule out alloimmune thrombocytopenia. Platelet antigen studies revealed absence of human platelet antigen (HPA-1a). She had antiplatelet antibody against HPA-1a. ELISA done on maternal serum revealed no HLA antibodies. Her husband was investigated and he was homozygous for human platelet (HPA-1a) antigen. HLA typing was not performed during antenatal period. Parental counselling was done; elective cesarean section was planned. She received 2 doses of betamethasone prior to cesarean section. Compatible platelet (HPA-1a antigen negative) was arranged.
A female baby was delivered by elective cesarean section at 34 weeks. She cried soon after birth with Apgars of 8 and 9 at 1 and 5 minutes. The birth weight was 2420 gm (50centile); head circumference of 34.5 cm (>97centile) and length was 49 cm (90 centile). She had a large bruise (3x3 cm) over right parietal region and a small bruise over the suprapubic area. The anterior fontanel was full and both the squamoparietal sutures were separated. Systemic examination was unremarkable. She developed petechial rash all over the back within 1 hour of life.
Investigation showed hemoglobin of 14 gm/dl, total leukocyte count of 15,700/cu.mm and normal differential count. The first platelet count was 3000/cu.mm. Blood group was B-positive and Direct Coomb's test was negative.
She was treated with platelet transfusion (PLA-1a negative) 10 ml/kg and one dose of intravenous immunoglobulin (1 gm/kg) infused over 2 hours. Platelet count was repeated at 6 hours and count improved to 536,000/cu.mm. The platelet counts were monitored 12 hourly for the first 48 hours and daily thereafter. Initially, there was decline in platelet counts, but did not require further platelet transfusion. Platelet count was stabilized by day 10 of life. During the hospital stay, baby also had jaundice and received phototherapy for 96 hours. Ultrasound of brain on the second day of life revealed an intracranial mass of 5 x 3 cm on right cerebral hemisphere with mild midline shift and dilated (L) lateral ventricle. There was no seizure or altered sensorium during hospital stay and she was tolerating oral feeds. Her head circumference was monitored daily and there was no significant increase (>1 cm/wk) in size. Baby was discharged on day 12 of life and the platelet count was 155,000/cu.mm.
Discussion
Alloimmune thrombocytopenia is reported to occur in 1 per 1000 to 1 per 5000 live births.[2], [3] Several platelet specific antigens have been implicated, but human platelet antigen 1a (PLA 1a) is the most common and is responsible for 65-90 % of all cases.[4], [5] The ability of HPA-1a negative mother to form anti HPA-1a is controlled by HLA DR52a allele.[6] The risk of a severely affected child (platelet count <50,000 mm3) in a DR 52a positive individual is 1 in 15.
The important finding in this index case was a well-defined hyper-echoic space-occupying lesion in the brain, which did not change in echogenicity over a week's time. The differential diagnosis of a well-defined hyper-echogenic mass in utero includes intracranial tumors (such as teratoma, astrocytoma, choroid plexus papilloma and lipoma), intracranial hemorrhage or cerebral infarction. Intracranial tumor during fetal life is extremely rare and reported incidence of 0.34 per million live births.[7] The more common diagnosis is intracranial bleed. Intracranial bleed normally shows some changes in the echogenicity over the course of time.
Intracranial hemorrhage (ICH) has been reported to occur in 10-20% of newborns with FMAIT.[5],[6],[8] Mueller-Eckhardt et al reported that 12/88 (14%) neonates with alloimmune thrombocytopenia had intracranial hemorrhage. Of the 12 babies, 11 had intracerebral hemorrhage; of which 5 occurred in utero. Only one baby had subarachnoid bleeding.[5] Intracranial hemorrhage in the utero can occur as early as 16 weeks but the majority occurred at 35-37 weeks of gestation. Intracranial hemorrhage in alloimmune thrombocytopenia is typically intraparenchymal, unlike ICH due to prematurity, which is characterized by intraventricular bleed.[9] The most common site for intracranial hemorrhage is beneath the cerebral cortex, with expansion to a subarachnoid bleed and dissection through the brain reaching ventricles.[10] Intracranial hemorrhage can lead to death or permanent neurological sequelae, such as seizures, learning disabilities, cerebral palsy, hypotonia, cortical blindness, developmental delay, seizures, and psychomotor retardation.[1]
The diagnosis of FMAIT is confirmed by demonstrating antibodies in maternal serum that react with both father's and child's platelets and not with mother's platelets. Antenatal management of fetal alloimmune thrombocytopenia is controversial and includes a combination of maternal intravenous gamma globulin (IVIG) administration, intrauterine platelet transfusion and corticosteroid therapy, while monitoring fetal platelet count closely throughout the course of pregnancy. Antenatal treatment of alloimmune thrombocytopenia with weekly gamma globulin effectively improves the fetal platelet count and prevents intracranial hemorrhage.[11] In a series of 54 women with thrombocytopenic fetus, given IVIG weekly, no intracranial hemorrhage occurred and 20% showed no increase in platelet count with therapy.[12]
Postnatally, the treatment of choice for alloimmune thrombocytopenia is administration of maternal (or compatible) platelets.[11] Maternal platelets for transfusion must be washed and free from antibody containing plasma and resuspended in AB plasma. It is preferable to arrange the platelets before delivery of the baby. Other treatment options are intravenous immunoglobulin with or without steroids. When matched platelets are not available in an emergency situation, IV immunoglobulin 1 gm/kg/dose for two days have shown to be effective in cases with severe thrombocytopenia. Steroids have been tried in situations with continued low platelet count and bleeding.[11]
The natural history of FMAIT is one of the progressive worsening of the disease in subsequent pregnancies. Previous antenatal intracranial hemorrhage is a reliable predictor of severely low platelet counts and intracranial hemorrhage in the subsequent affected fetus.
In the present index case, the father was homozygous for platelet antigen. Therefore, there is 100% recurrent risk in future pregnancy. Parents have been counselled regarding the need for antenatal therapy with repeated platelet transfusion or weekly immunoglobulins therapy in subsequent pregnancies.
This case is reported to consider and to have a high index of suspicion for alloimmune thrombocytopenia in a differential diagnosis of a fetus presenting with hyperechoic intracerebral mass in utero.
References
1. Sharif U, Kuban K. Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 2001; 16 : 838-842.
2. Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993;329 : 1463-1466
3. Williamson LM, Hackett G, Rennie J et al. The natural history of feto-maternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood 1998; 92 : 2280-2287.
4. Bussel JB, Zabusky MR, Berkowitz RL, McFarland JG. Fetal alloimmune thrombocytopenia. N Engl J Med 1997; 337 : 22-26
5. Mueller-Eckhardt C, Kiefel V, Grubert A et al. 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 1989; 1: 363-366.
6. Bussel J, Kaplan C, McFarland J. Recommendations for the evaluation and treatment of neonatal autoimmune and alloimmune thrombocytopenia. Thromb Haemost 1991; 65: 631-634
7. Jooma R, Kendall BE, Hayward RD. Intracranial tumors in neonate. Report of seventeen cases. Surg Neurol 1984; 21:165-170
8. Herman JH, Jumbelic MI, Ancona RJ, Kickler TS. In utero cerebral hemorrhage in alloimmune thrombocytopenia. Am J Pediatr Hematol Oncol 1986; 8 : 312-317.
9. Naidu S, Messmore H, Caserta V, Fine M. CNS lesions in neonatal isoimmune thrombocytopenia. Arch Neurol 1983; 40: 552-554.
10. Govaert P, Bridger J, Wigglesworth J. Nature of the brain lesion in fetal alloimmune thrombocytopenia. Dev Med Child Neurol 1995; 37: 485-495
11. Lynch L, Bussel JB, McFarland JG, Chitkara U, Berkowitz RL. Antenatal treatment of alloimmune thrombocytopenia. Obstet Gynecol 1992; 80: 67-71.
12. Bussel JB, Berkowitz RL, Lynch L et al. Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol 1996;174 : 1414-1423.(Singh Soraisham Amuchou, )