- Email: [email protected]
ADAMTS13 deficiency, an important cause of thrombocytopenia during pregnancy
International Journal of Obstetric Anesthesia (2009) 18, 73–77 0959-289X/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2008.07.009
CASE REPORT
www.obstetanesthesia.com
ADAMTS13 deficiency, an important cause of thrombocytopenia during pregnancy R. Kato, A. Shinohara, J. Sato Department of Anesthesiology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan
ABSTRACT We present the case of a woman with congenital ADAMTS13 deficiency and discuss peripartum management of her fourth pregnancy. All four pregnancies were complicated by significant thrombocytopenia. Her first pregnancy ended with fetal demise ascribed to HELLP syndrome and placental abruption. During her second pregnancy, she was diagnosed with idiopathic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura and congenital ADAMTS13 deficiency were diagnosed during the third pregnancy. She had recurrent thrombotic thrombocytopenic purpura during the fourth pregnancy and responded to treatment with fresh frozen plasma, with a successful outcome. The need for accurate diagnosis to ensure appropriate treatment is emphasized. c 2008 Elsevier Ltd. All rights reserved.
Keywords: ADAMTS13; Thrombotic thrombocytopenic purpura; Pregnancy; Cesarean delivery; Spinal anesthesia
Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease characterized by microangiopathic hemolytic anemia and consumptive thrombocytopenia leading to disseminated microvascular thrombosis. This results in a variety of signs and symptoms from organ ischemia. The etiology of TTP had remained unclear until ADAMTS13 (a disintegrin-like and metalloproteinase domain with thrombospondin type I motifs 13) was shown to be involved in its pathogenesis in the late 1990s. ADAMTS13 is a specific von Willebrand factor (VWF)-cleaving metalloprotease found in plasma. This protease limits admission and persistence of unusually large VWF multimers in the circulation, where they form abnormally large thrombi in the microvasculature. When ADAMTS13 activity is reduced, TTP develops. ADAMTS13 deficiency can be either congenital or acquired. Congenital deficiency is caused by reduced synthesis of ADAMTS13 due to genetic defect. This type shows autosomal recessive inheritance and accounts for only 2–4% of all TTP cases. Acquired TTP is, at least in part, caused by inactivation and removal of ADAMTS13 from plasAccepted July 2008 Correspondence to: Dr. Rie Kato, Department of Anesthesiology, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan. E-mail address: [email protected]
ma due to the development of anti-ADAMTS13 autoantibodies.1–3 We present the anesthetic management of a parturient with congenital ADAMTS13 deficiency and a complex obstetric history.
Case report A 36-year-old woman (G4, P3) known to have congenital ADAMTS13 deficiency, was referred to our hospital at 26 weeks of gestation for specialized hematologic and obstetric care. She was 162 cm tall and weighed 57 kg. Her obstetric history was complex. Her first pregnancy occurred at 28 years of age and was uneventful until 28 weeks when she noted lack of fetal movement. Obstetric evaluation that same day revealed intrauterine fetal demise, and she was diagnosed with HELLP (hemolytic anemia, elevated liver enzymes, low platelets) syndrome and placental abruption. Cesarean section was performed under general anesthesia. She became pregnant again the following year. At 28 weeks of gestation, her platelet count decreased to 88 · 109/L. Her hemoglobin (Hb) was 11.8 g/dL and lactate dehydrogenase (LDH) 510 units/L. At 36+5 weeks, platelets, Hb and LDH were 15 · 109/L, 10.8 g/dL and 1021 units/L, respectively. At this time, she had 2+ proteinuria. However, her blood pressure, renal function and liver enzymes remained normal throughout
74
ADAMTS13 deficiency (TTP) in pregnancy
the pregnancy. She was diagnosed with idiopathic thrombocytopenic purpura (ITP) and treated with prednisolone and immunoglobulin until 37+3 weeks, at which time her platelet count was 23 · 109/L. Due to lack of improvement in her thrombocytopenia despite treatment, cesarean section was performed the next day following a 5-unit platelet transfusion, which increased the platelet count to 96 · 109/L. She gave birth to a healthy baby. Pathological examination of the placenta showed partial placenta abruption and chorioamnionitis. Her postoperative course was uneventful. The platelet count was 92 · 109/L the following day and recovered rapidly to 268 · 109/L on the fourth day postpartum. The patient became pregnant for the third time at 32 years of age. In the intervening months since the second pregnancy, her sister had been diagnosed with TTP. She developed purpura and proteinuria at 17 weeks of gestation, followed by multi-system organ failure and eventual intrauterine fetal demise at 20 weeks. Due to her sister’s diagnosis of TTP, our patient was put on lowdose aspirin from 9 weeks of gestation onwards. At 36 weeks the platelet count was 94 · 109/L and LDH was 489 units/L. Cesarean section was performed at 37 weeks because of worsening thrombocytopenia and previous cesarean delivery, delivering a healthy baby under spinal anesthesia. Platelets were 67 and 245 · 109/L on the 3rd and 8th postoperative days. Because of repeated thrombocytopenia during pregnancy and her sister’s history of TTP, the patient was suspected of having familial TTP. Further testing showed that both she and her sister had very low (<3% of normal) activity of ADAMTS13 and no
Plt Hb (g/dL) (109/L)
12
300
11
200
2 1
ADAMTS13 inhibitor. Defects of genes responsible for ADAMTS13 were also confirmed. Consequently the patient and her sister were diagnosed with congenital ADAMTS13 deficiency. The clinical course of our patient’s fourth pregnancy is summarized in Fig. 1. At her initial visit at 26 weeks of gestation there were no remarkable findings. Her medication included aspirin 81 mg per day and her platelet count was 179 · 109/L. At 35+6 weeks, the platelet count had dropped to 78 · 109/L, though there were no associated symptoms. Aspirin was stopped. One week later the patient complained of hematuria and a tendency to bruise easily. Her blood pressure was 99/58 mmHg and her platelet count had fallen to 15 · 109/L. She had 3+ hematuria and 1+ proteinuria. Her LDH was 455 units/L. Laboratory data, including a full blood count, biochemistry and coagulation studies were otherwise normal. She was admitted to the hospital and treated with fresh frozen plasma (FFP). After transfusion of FFP 1-2 units/day for 3 days, at 37+2 weeks of gestation her platelet count was 71 · 109/L and her Hb 9.5 g/dL. Cesarean section was performed under spinal anesthesia on the same day. One unit of FFP was administered preoperatively. Standard monitoring including ECG, non-invasive blood pressure and pulse oximetry were started in the operating room. An 18-gauge intravenous line was in placed. Spinal anesthesia was administered in the right lateral position at the L3/4 interspace on the first attempt with a 27-gauge pencil-point needle. Hyperbaric bupivacaine 0.5% 2.4 mL with fentanyl 10 lg and morphine 0.15 mg was given intrathecally. Sensory block to T5 assessed by pin-prick was achieved. A healthy
2.5 units/ day
FFP
LDH un its/ L
Pl t Hb LDH
400
300
c- section
10
100
9
0
200
100 26w 31w 33w 35w 36w 37w 37w 37w 1d 2d 3d 4d 5d 33d 6d 6d 6d 0d 1d 2d post partum gestation
Fig. 1
Clinical course during pregnancy and post partum. LDH: lactate dehydrogenase; FFP: fresh frozen plasma; Plt: platelets.
R. Kato et al. 2506-g baby was delivered 6 min after skin incision. Apgar scores at 1 and 5 min were 8 and 9 respectively. Surgery was uneventful and lasted 52 min. Estimated blood loss was 400 mL. A total of 1900 mL of crystalloid was infused during the procedure. Ephedrine 12 mg and phenylephrine 0.25 mg were given i.v. to treat hypotension. Platelets and Hb were 84 · 109/L and 9.8 g/dL at the end of surgery. The spinal block resolved approximately 5 h after the intrathecal injection. Neither backache nor neurological deficit was observed afterwards. The post-partum course was uneventful. A further unit of FFP was given following surgery with five more units transfused over the next 48 h. On the third postoperative day her platelet count was 170 · 109/L.
Discussion Thrombotic thrombocytopenic purpura is often overlooked and misdiagnosed. This is because the disease is rare and a definitive method for diagnosis has not been established.2,4 The five classic symptoms of TTP are thrombocytopenia, hemolytic anemia, fluctuating neurological abnormalities, renal failure and fever. However, these symptoms are not specific to TTP. According to a TTP-HUS (hemolytic uremic syndrome) registry, fever was observed in only 20% of patients, and about half had normal renal function.4 Similarly, laboratory findings are not always definitive.2,4 When it was reported in the late 1990s that patients with a clinical diagnosis of TTP were severely deficient in the VWF-cleaving protease ADAMTS13, the deficiency was proposed as a highly specific and sensitive marker for TTP. However, this paradigm was challenged by the discovery that some patients with TTP had normal or only slightly reduced ADAMTS13 levels.2 Further complexity arises because ADAMTS13 deficiency may be found in other clinical syndromes and is not confined to patients with TTP-HUS: sepsis and DIC may be associated with a marked deficiency of the protease.4 Finally, ADAMTS13 and its antibody tests are not generally available in a hospital laboratory and results can be delayed. Therefore, the diagnosis of TTP should be considered in any patient with otherwise unexplained microangiopathic hemolytic anemia and thrombocytopenia in order to enable timely life-saving treatment. The hematologist must diagnose TTP by simple laboratory tests: complete blood counts (anemia, thrombocytopenia, and normal white blood cell count) and LDH (markedly elevated), and promptly start plasma infusion followed by plasma exchange.2,4 It is well established that prompt plasma therapy reduces the mortality rate of TTP from 80–90% to 10–20%.2 Pregnancy may precipitate TTP. George found 13% of women diagnosed with TTP- HUS to be pregnant.5 Congenital ADAMTS13 deficiency may initially appear in
75 infancy or childhood and then recur as relapsing TTP. However, many other women have their first episode of TTP during pregnancy or the postpartum period, presumably triggered by physiological changes of pregnancy, such as increased procoagulant factors and VWF, and decreased fibrinolytic activity, endothelial thrombomodulin and ADAMTS13.5–7 The treatment of congenital ADAMTS13 deficiency is to provide ADAMTS13 by FFP transfusion.4,8 According to a review of the literature, 100% of pregnant women diagnosed with congenital ADAMTS13 deficiency developed recurrent TTP in the subsequent pregnancy.9 Acquired TTP may initially be manifest during pregnancy. Acquired TTP is classified according to the trigger and each subtype shows different clinical features and requires different treatment. In addition to pregnancy, triggers include drug toxicity, autoimmune diseases, infection and cancer. The pathogenesis of each subtype has not been fully elucidated. Pregnancyinduced acquired TTP is usually developed near term or post partum and deficiency of ADAMTS13 may be severe. Plasma exchange may be required and immunosuppressive agents may not be beneficial.2,4,10,11 About a quarter of women previously diagnosed with one of the acquired TTP subtypes had one or more episodes of TTP in subsequent pregnancies.9 TTP can be misdiagnosed as another pregnancyrelated disease such as HELLP syndrome, disseminated intravascular coagulation (DIC) and ITP.8 ITP and TTP have thrombocytopenia in common, but ITP is not accompanied by either hemolytic anemia or signs of end-organ ischemia. Coagulopathy is marked in DIC, but not in TTP. In contrast, it can be extremely challenging to distinguish TTP from HELLP syndrome.4 Both diagnoses present microangiopathic hemolytic anemia and end-organ ischemic damage.5,7 In addition, hypertension and gastrointestinal abnormalities are often present in TTP.5 Women with HELLP syndrome have been shown to have lower ADAMSTS activity (31%) than that of healthy pregnant (71%) and nonpregnant (101%) women.7 Indeed, Rehberg et al. reported a case of TTP masquerading as HELLP syndrome.12 The patient had a headache, epigastric pain, hypertension and proteinuria. Laboratory data showed severe thrombocytopenia and mild anemia, markedly elevated LDH and mildly increased liver transaminases. HELLP syndrome was diagnosed and treated with high-dose dexamethasone, magnesium and an antihypertensive drug. Platelets were transfused before cesarean section. On the first day after surgery, her condition rapidly deteriorated and she died. Autopsy findings included petechial hemorrhages in some organs and tissues. ADAMTS13 level was 4% of normal. Dexamethasone produced little improvement, and both thrombocytopenia and LDH increase were disproportionately severe compared to the increase in liver en-
76 zymes, which, as Rehberg, et al. noted, was expected in TTP but not in HELLP syndrome.12 Our patient was diagnosed during her first pregnancy with HELLP syndrome and placental abruption. Further information about this pregnancy could not be obtained. In retrospect, this may have been her first episode of TTP. All women with congenital ADAMTS13 deficiency will again develop TTP during a subsequent pregnancy,9 HELLP syndrome can be very difficult to distinguish from TTP, and her clinical state deteriorated rapidly. During the second pregnancy she was diagnosed with ITP and treated as such. In retrospect, TTP could have been suspected because she had markedly high LDH and did not respond to treatment with corticosteroid and immunoglobulin. Luckily, she did not develop thrombosis despite receiving a platelet transfusion before cesarean section. TTP is difficult to diagnose, can be triggered by pregnancy, and has clinical features similar to those of other pregnancy-associated diseases. We believe that the obstetric anesthesiologist should be aware that both congenital and acquired types of TTP cause thrombocytopenia, are related to pregnancy, and may mimic HELLP syndrome. The opinion of a senior hematologist should be sought when TTP is suspected, before giving a platelet transfusion. One week after our patient initially presented to hospital, we held a multidisciplinary conference with representation from obstetrics, hematology, anesthesiology and neonatology. Our plan was as follows: (1) serial platelet counts and assessment for symptoms of TTP would be performed as an outpatient; (2) aspirin would be stopped when platelets were <100 · 109/L; (3) hospitalization and plasma transfusion would begin when platelets reached <50 · 109/L; (4) timing of cesarean section would be determined by signs and symptoms of TTP, response to treatments, fetal condition and gestational age; and (5) the platelet count should be >50 · 109/L for cesarean section. We treated the patient as planned. At 36+6 weeks she was hospitalized when the platelet count was 15 · 109/L and treated with FFP, with an excellent response. At 37+2 weeks, she was asymptomatic and her platelet count was 71 · 109/L, when the obstetricians and hematologists decided to proceed to cesarean section. There may be disagreement as to the best timing for cesarean section: Some would have carried out surgery on the day of admission to avoid further maternal deterioration, while others would prefer to wait 2–3 days to permit a higher platelet count. With a definitive diagnosis of congenital ADAMTS13, we thought that improvement after FFP infusion was more likely than further deterioration. However, as mother and fetus were both well, there was no indication mandating a cesarean section at 37+2 weeks. We chose to perform surgery when the platelet count was 71 · 109/L, rather than give more FFP and wait for a
ADAMTS13 deficiency (TTP) in pregnancy further increase in platelet count. The timing of delivery would have been more controversial had our patient developed TTP earlier in her pregnancy when fetal outcome could be compromised by prematurity. We chose spinal anesthesia for this patient. Her airway was reassuring and lumbar spines were easily palpable. There were no factors, apart from congenital ADAMTS13 deficiency, that indicated a particular anesthetic technique. At the multidisciplinary conference we planned to finalize the anesthetic approach at the time of surgery, taking into account her platelet count, TTP symptoms, response to treatment and fetal condition. After FFP infusion for 3 days, the platelet count had increased to 71 · 109/L. Both hematuria and bleeding tendency disappeared, her condition was improving and fetal monitoring was reassuring. There is no specific platelet count below which we consider spinal anesthesia contraindicated, but between 50 and 80 · 109/L it is controversial. Our decision on the day of surgery was to provide spinal anesthesia administered by an experienced anesthesiologist using a 27-gauge needle. If multiple punctures were required, general anesthesia would have been used instead. However, we recognize that some anesthesiologists would have been reluctant to perform spinal anesthesia in this situation due to fear of epidural or subdural hematoma. In summary, we describe successful anesthetic management for cesarean section in a woman with congenital ADAMTS13 deficiency. Though this metalloprotease deficiency is well described in the hematology journals, we found no reports of management of congenital ADAMTS13 deficiency in the anesthesia literature. However, not only acquired but also congenital ADAMTS13 deficiencies are related to pregnancy. We believe that the anesthesiologist should be aware of both congenital and acquired types of ADAMTS13 deficiency as causes of thrombocytopenia during pregnancy, and should promptly consult a hematologist when TTP is suspected. The ideal management of pregnancy and delivery is yet to be established in women with TTP or ADAMTS13 deficiency.
Acknowledgements The authors would like to thank Drs. Paula Craigo and Hidehiko Miyake for their kind and excellent support.
References 1. Moake J L. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589–600. 2. Mannucci P M. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome: much progress and many remaining issues. Haematologica 2007; 92: 878–80. 3. Peyvandi F, Lavoretano S, Palla R et al. ADAMTS13 and antiADAMTS13 antibodies as markers for recurrence of acquired
R. Kato et al.
4.
5.
6.
7.
8.
thrombotic thrombocytopenic purpura during remission. Haematologica 2008; 93: 232–9. George J N. Evaluation and management of patients with thrombotic thrombocytopenic purpura. J Intensive Care Med 2007; 22: 82–91. George J N. The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2003; 10: 339–44. Sanchez-Luceros A, Farias C E, Amaral M M et al. von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost 2004; 92: 1320–6. Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci P M. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003; 88: 1029–34. Mannucci P M, Peyvandi F. TTP and ADAMTS13: When is testing appropriate? Hematology Am Soc Hematol Educ Program 2007; 2007: 121–6.
77 9. Vesely S K, Li X, McMinn J R, Terrell D R, George J N. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion 2004; 44: 1149–58. 10. Franchini M, Montagnana M, Targher G, Lippi G. Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic microangiopathies and other diseases. Semin Thromb Hemost 2007; 33: 787–97. 11. George J N. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354: 1927–35. 12. Rehberg J F, Briery C M, Hudson W T, Bofill J A, Martin J N, Jr. Thrombotic thrombocytopenic purpura masquerading as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in late pregnancy. Obstet Gynecol 2006; 108: 817–20.
CASE REPORT
www.obstetanesthesia.com
ADAMTS13 deficiency, an important cause of thrombocytopenia during pregnancy R. Kato, A. Shinohara, J. Sato Department of Anesthesiology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan
ABSTRACT We present the case of a woman with congenital ADAMTS13 deficiency and discuss peripartum management of her fourth pregnancy. All four pregnancies were complicated by significant thrombocytopenia. Her first pregnancy ended with fetal demise ascribed to HELLP syndrome and placental abruption. During her second pregnancy, she was diagnosed with idiopathic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura and congenital ADAMTS13 deficiency were diagnosed during the third pregnancy. She had recurrent thrombotic thrombocytopenic purpura during the fourth pregnancy and responded to treatment with fresh frozen plasma, with a successful outcome. The need for accurate diagnosis to ensure appropriate treatment is emphasized. c 2008 Elsevier Ltd. All rights reserved.
Keywords: ADAMTS13; Thrombotic thrombocytopenic purpura; Pregnancy; Cesarean delivery; Spinal anesthesia
Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease characterized by microangiopathic hemolytic anemia and consumptive thrombocytopenia leading to disseminated microvascular thrombosis. This results in a variety of signs and symptoms from organ ischemia. The etiology of TTP had remained unclear until ADAMTS13 (a disintegrin-like and metalloproteinase domain with thrombospondin type I motifs 13) was shown to be involved in its pathogenesis in the late 1990s. ADAMTS13 is a specific von Willebrand factor (VWF)-cleaving metalloprotease found in plasma. This protease limits admission and persistence of unusually large VWF multimers in the circulation, where they form abnormally large thrombi in the microvasculature. When ADAMTS13 activity is reduced, TTP develops. ADAMTS13 deficiency can be either congenital or acquired. Congenital deficiency is caused by reduced synthesis of ADAMTS13 due to genetic defect. This type shows autosomal recessive inheritance and accounts for only 2–4% of all TTP cases. Acquired TTP is, at least in part, caused by inactivation and removal of ADAMTS13 from plasAccepted July 2008 Correspondence to: Dr. Rie Kato, Department of Anesthesiology, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan. E-mail address: [email protected]
ma due to the development of anti-ADAMTS13 autoantibodies.1–3 We present the anesthetic management of a parturient with congenital ADAMTS13 deficiency and a complex obstetric history.
Case report A 36-year-old woman (G4, P3) known to have congenital ADAMTS13 deficiency, was referred to our hospital at 26 weeks of gestation for specialized hematologic and obstetric care. She was 162 cm tall and weighed 57 kg. Her obstetric history was complex. Her first pregnancy occurred at 28 years of age and was uneventful until 28 weeks when she noted lack of fetal movement. Obstetric evaluation that same day revealed intrauterine fetal demise, and she was diagnosed with HELLP (hemolytic anemia, elevated liver enzymes, low platelets) syndrome and placental abruption. Cesarean section was performed under general anesthesia. She became pregnant again the following year. At 28 weeks of gestation, her platelet count decreased to 88 · 109/L. Her hemoglobin (Hb) was 11.8 g/dL and lactate dehydrogenase (LDH) 510 units/L. At 36+5 weeks, platelets, Hb and LDH were 15 · 109/L, 10.8 g/dL and 1021 units/L, respectively. At this time, she had 2+ proteinuria. However, her blood pressure, renal function and liver enzymes remained normal throughout
74
ADAMTS13 deficiency (TTP) in pregnancy
the pregnancy. She was diagnosed with idiopathic thrombocytopenic purpura (ITP) and treated with prednisolone and immunoglobulin until 37+3 weeks, at which time her platelet count was 23 · 109/L. Due to lack of improvement in her thrombocytopenia despite treatment, cesarean section was performed the next day following a 5-unit platelet transfusion, which increased the platelet count to 96 · 109/L. She gave birth to a healthy baby. Pathological examination of the placenta showed partial placenta abruption and chorioamnionitis. Her postoperative course was uneventful. The platelet count was 92 · 109/L the following day and recovered rapidly to 268 · 109/L on the fourth day postpartum. The patient became pregnant for the third time at 32 years of age. In the intervening months since the second pregnancy, her sister had been diagnosed with TTP. She developed purpura and proteinuria at 17 weeks of gestation, followed by multi-system organ failure and eventual intrauterine fetal demise at 20 weeks. Due to her sister’s diagnosis of TTP, our patient was put on lowdose aspirin from 9 weeks of gestation onwards. At 36 weeks the platelet count was 94 · 109/L and LDH was 489 units/L. Cesarean section was performed at 37 weeks because of worsening thrombocytopenia and previous cesarean delivery, delivering a healthy baby under spinal anesthesia. Platelets were 67 and 245 · 109/L on the 3rd and 8th postoperative days. Because of repeated thrombocytopenia during pregnancy and her sister’s history of TTP, the patient was suspected of having familial TTP. Further testing showed that both she and her sister had very low (<3% of normal) activity of ADAMTS13 and no
Plt Hb (g/dL) (109/L)
12
300
11
200
2 1
ADAMTS13 inhibitor. Defects of genes responsible for ADAMTS13 were also confirmed. Consequently the patient and her sister were diagnosed with congenital ADAMTS13 deficiency. The clinical course of our patient’s fourth pregnancy is summarized in Fig. 1. At her initial visit at 26 weeks of gestation there were no remarkable findings. Her medication included aspirin 81 mg per day and her platelet count was 179 · 109/L. At 35+6 weeks, the platelet count had dropped to 78 · 109/L, though there were no associated symptoms. Aspirin was stopped. One week later the patient complained of hematuria and a tendency to bruise easily. Her blood pressure was 99/58 mmHg and her platelet count had fallen to 15 · 109/L. She had 3+ hematuria and 1+ proteinuria. Her LDH was 455 units/L. Laboratory data, including a full blood count, biochemistry and coagulation studies were otherwise normal. She was admitted to the hospital and treated with fresh frozen plasma (FFP). After transfusion of FFP 1-2 units/day for 3 days, at 37+2 weeks of gestation her platelet count was 71 · 109/L and her Hb 9.5 g/dL. Cesarean section was performed under spinal anesthesia on the same day. One unit of FFP was administered preoperatively. Standard monitoring including ECG, non-invasive blood pressure and pulse oximetry were started in the operating room. An 18-gauge intravenous line was in placed. Spinal anesthesia was administered in the right lateral position at the L3/4 interspace on the first attempt with a 27-gauge pencil-point needle. Hyperbaric bupivacaine 0.5% 2.4 mL with fentanyl 10 lg and morphine 0.15 mg was given intrathecally. Sensory block to T5 assessed by pin-prick was achieved. A healthy
2.5 units/ day
FFP
LDH un its/ L
Pl t Hb LDH
400
300
c- section
10
100
9
0
200
100 26w 31w 33w 35w 36w 37w 37w 37w 1d 2d 3d 4d 5d 33d 6d 6d 6d 0d 1d 2d post partum gestation
Fig. 1
Clinical course during pregnancy and post partum. LDH: lactate dehydrogenase; FFP: fresh frozen plasma; Plt: platelets.
R. Kato et al. 2506-g baby was delivered 6 min after skin incision. Apgar scores at 1 and 5 min were 8 and 9 respectively. Surgery was uneventful and lasted 52 min. Estimated blood loss was 400 mL. A total of 1900 mL of crystalloid was infused during the procedure. Ephedrine 12 mg and phenylephrine 0.25 mg were given i.v. to treat hypotension. Platelets and Hb were 84 · 109/L and 9.8 g/dL at the end of surgery. The spinal block resolved approximately 5 h after the intrathecal injection. Neither backache nor neurological deficit was observed afterwards. The post-partum course was uneventful. A further unit of FFP was given following surgery with five more units transfused over the next 48 h. On the third postoperative day her platelet count was 170 · 109/L.
Discussion Thrombotic thrombocytopenic purpura is often overlooked and misdiagnosed. This is because the disease is rare and a definitive method for diagnosis has not been established.2,4 The five classic symptoms of TTP are thrombocytopenia, hemolytic anemia, fluctuating neurological abnormalities, renal failure and fever. However, these symptoms are not specific to TTP. According to a TTP-HUS (hemolytic uremic syndrome) registry, fever was observed in only 20% of patients, and about half had normal renal function.4 Similarly, laboratory findings are not always definitive.2,4 When it was reported in the late 1990s that patients with a clinical diagnosis of TTP were severely deficient in the VWF-cleaving protease ADAMTS13, the deficiency was proposed as a highly specific and sensitive marker for TTP. However, this paradigm was challenged by the discovery that some patients with TTP had normal or only slightly reduced ADAMTS13 levels.2 Further complexity arises because ADAMTS13 deficiency may be found in other clinical syndromes and is not confined to patients with TTP-HUS: sepsis and DIC may be associated with a marked deficiency of the protease.4 Finally, ADAMTS13 and its antibody tests are not generally available in a hospital laboratory and results can be delayed. Therefore, the diagnosis of TTP should be considered in any patient with otherwise unexplained microangiopathic hemolytic anemia and thrombocytopenia in order to enable timely life-saving treatment. The hematologist must diagnose TTP by simple laboratory tests: complete blood counts (anemia, thrombocytopenia, and normal white blood cell count) and LDH (markedly elevated), and promptly start plasma infusion followed by plasma exchange.2,4 It is well established that prompt plasma therapy reduces the mortality rate of TTP from 80–90% to 10–20%.2 Pregnancy may precipitate TTP. George found 13% of women diagnosed with TTP- HUS to be pregnant.5 Congenital ADAMTS13 deficiency may initially appear in
75 infancy or childhood and then recur as relapsing TTP. However, many other women have their first episode of TTP during pregnancy or the postpartum period, presumably triggered by physiological changes of pregnancy, such as increased procoagulant factors and VWF, and decreased fibrinolytic activity, endothelial thrombomodulin and ADAMTS13.5–7 The treatment of congenital ADAMTS13 deficiency is to provide ADAMTS13 by FFP transfusion.4,8 According to a review of the literature, 100% of pregnant women diagnosed with congenital ADAMTS13 deficiency developed recurrent TTP in the subsequent pregnancy.9 Acquired TTP may initially be manifest during pregnancy. Acquired TTP is classified according to the trigger and each subtype shows different clinical features and requires different treatment. In addition to pregnancy, triggers include drug toxicity, autoimmune diseases, infection and cancer. The pathogenesis of each subtype has not been fully elucidated. Pregnancyinduced acquired TTP is usually developed near term or post partum and deficiency of ADAMTS13 may be severe. Plasma exchange may be required and immunosuppressive agents may not be beneficial.2,4,10,11 About a quarter of women previously diagnosed with one of the acquired TTP subtypes had one or more episodes of TTP in subsequent pregnancies.9 TTP can be misdiagnosed as another pregnancyrelated disease such as HELLP syndrome, disseminated intravascular coagulation (DIC) and ITP.8 ITP and TTP have thrombocytopenia in common, but ITP is not accompanied by either hemolytic anemia or signs of end-organ ischemia. Coagulopathy is marked in DIC, but not in TTP. In contrast, it can be extremely challenging to distinguish TTP from HELLP syndrome.4 Both diagnoses present microangiopathic hemolytic anemia and end-organ ischemic damage.5,7 In addition, hypertension and gastrointestinal abnormalities are often present in TTP.5 Women with HELLP syndrome have been shown to have lower ADAMSTS activity (31%) than that of healthy pregnant (71%) and nonpregnant (101%) women.7 Indeed, Rehberg et al. reported a case of TTP masquerading as HELLP syndrome.12 The patient had a headache, epigastric pain, hypertension and proteinuria. Laboratory data showed severe thrombocytopenia and mild anemia, markedly elevated LDH and mildly increased liver transaminases. HELLP syndrome was diagnosed and treated with high-dose dexamethasone, magnesium and an antihypertensive drug. Platelets were transfused before cesarean section. On the first day after surgery, her condition rapidly deteriorated and she died. Autopsy findings included petechial hemorrhages in some organs and tissues. ADAMTS13 level was 4% of normal. Dexamethasone produced little improvement, and both thrombocytopenia and LDH increase were disproportionately severe compared to the increase in liver en-
76 zymes, which, as Rehberg, et al. noted, was expected in TTP but not in HELLP syndrome.12 Our patient was diagnosed during her first pregnancy with HELLP syndrome and placental abruption. Further information about this pregnancy could not be obtained. In retrospect, this may have been her first episode of TTP. All women with congenital ADAMTS13 deficiency will again develop TTP during a subsequent pregnancy,9 HELLP syndrome can be very difficult to distinguish from TTP, and her clinical state deteriorated rapidly. During the second pregnancy she was diagnosed with ITP and treated as such. In retrospect, TTP could have been suspected because she had markedly high LDH and did not respond to treatment with corticosteroid and immunoglobulin. Luckily, she did not develop thrombosis despite receiving a platelet transfusion before cesarean section. TTP is difficult to diagnose, can be triggered by pregnancy, and has clinical features similar to those of other pregnancy-associated diseases. We believe that the obstetric anesthesiologist should be aware that both congenital and acquired types of TTP cause thrombocytopenia, are related to pregnancy, and may mimic HELLP syndrome. The opinion of a senior hematologist should be sought when TTP is suspected, before giving a platelet transfusion. One week after our patient initially presented to hospital, we held a multidisciplinary conference with representation from obstetrics, hematology, anesthesiology and neonatology. Our plan was as follows: (1) serial platelet counts and assessment for symptoms of TTP would be performed as an outpatient; (2) aspirin would be stopped when platelets were <100 · 109/L; (3) hospitalization and plasma transfusion would begin when platelets reached <50 · 109/L; (4) timing of cesarean section would be determined by signs and symptoms of TTP, response to treatments, fetal condition and gestational age; and (5) the platelet count should be >50 · 109/L for cesarean section. We treated the patient as planned. At 36+6 weeks she was hospitalized when the platelet count was 15 · 109/L and treated with FFP, with an excellent response. At 37+2 weeks, she was asymptomatic and her platelet count was 71 · 109/L, when the obstetricians and hematologists decided to proceed to cesarean section. There may be disagreement as to the best timing for cesarean section: Some would have carried out surgery on the day of admission to avoid further maternal deterioration, while others would prefer to wait 2–3 days to permit a higher platelet count. With a definitive diagnosis of congenital ADAMTS13, we thought that improvement after FFP infusion was more likely than further deterioration. However, as mother and fetus were both well, there was no indication mandating a cesarean section at 37+2 weeks. We chose to perform surgery when the platelet count was 71 · 109/L, rather than give more FFP and wait for a
ADAMTS13 deficiency (TTP) in pregnancy further increase in platelet count. The timing of delivery would have been more controversial had our patient developed TTP earlier in her pregnancy when fetal outcome could be compromised by prematurity. We chose spinal anesthesia for this patient. Her airway was reassuring and lumbar spines were easily palpable. There were no factors, apart from congenital ADAMTS13 deficiency, that indicated a particular anesthetic technique. At the multidisciplinary conference we planned to finalize the anesthetic approach at the time of surgery, taking into account her platelet count, TTP symptoms, response to treatment and fetal condition. After FFP infusion for 3 days, the platelet count had increased to 71 · 109/L. Both hematuria and bleeding tendency disappeared, her condition was improving and fetal monitoring was reassuring. There is no specific platelet count below which we consider spinal anesthesia contraindicated, but between 50 and 80 · 109/L it is controversial. Our decision on the day of surgery was to provide spinal anesthesia administered by an experienced anesthesiologist using a 27-gauge needle. If multiple punctures were required, general anesthesia would have been used instead. However, we recognize that some anesthesiologists would have been reluctant to perform spinal anesthesia in this situation due to fear of epidural or subdural hematoma. In summary, we describe successful anesthetic management for cesarean section in a woman with congenital ADAMTS13 deficiency. Though this metalloprotease deficiency is well described in the hematology journals, we found no reports of management of congenital ADAMTS13 deficiency in the anesthesia literature. However, not only acquired but also congenital ADAMTS13 deficiencies are related to pregnancy. We believe that the anesthesiologist should be aware of both congenital and acquired types of ADAMTS13 deficiency as causes of thrombocytopenia during pregnancy, and should promptly consult a hematologist when TTP is suspected. The ideal management of pregnancy and delivery is yet to be established in women with TTP or ADAMTS13 deficiency.
Acknowledgements The authors would like to thank Drs. Paula Craigo and Hidehiko Miyake for their kind and excellent support.
References 1. Moake J L. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589–600. 2. Mannucci P M. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome: much progress and many remaining issues. Haematologica 2007; 92: 878–80. 3. Peyvandi F, Lavoretano S, Palla R et al. ADAMTS13 and antiADAMTS13 antibodies as markers for recurrence of acquired
R. Kato et al.
4.
5.
6.
7.
8.
thrombotic thrombocytopenic purpura during remission. Haematologica 2008; 93: 232–9. George J N. Evaluation and management of patients with thrombotic thrombocytopenic purpura. J Intensive Care Med 2007; 22: 82–91. George J N. The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2003; 10: 339–44. Sanchez-Luceros A, Farias C E, Amaral M M et al. von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost 2004; 92: 1320–6. Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci P M. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003; 88: 1029–34. Mannucci P M, Peyvandi F. TTP and ADAMTS13: When is testing appropriate? Hematology Am Soc Hematol Educ Program 2007; 2007: 121–6.
77 9. Vesely S K, Li X, McMinn J R, Terrell D R, George J N. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion 2004; 44: 1149–58. 10. Franchini M, Montagnana M, Targher G, Lippi G. Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic microangiopathies and other diseases. Semin Thromb Hemost 2007; 33: 787–97. 11. George J N. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354: 1927–35. 12. Rehberg J F, Briery C M, Hudson W T, Bofill J A, Martin J N, Jr. Thrombotic thrombocytopenic purpura masquerading as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in late pregnancy. Obstet Gynecol 2006; 108: 817–20.