Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management

ARTICLE IN PRESS Transfusion and Apheresis Science ■■ (2015) ■■–■■

Contents lists available at ScienceDirect

Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i

Review

Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management Chiara Savignano *, Cristina Rinaldi, Vincenzo De Angelis Therapeutic Apheresis Unit and Stem Cell Manipulation Laboratory, Department of Transfusion Medicine, Azienda Ospedaliero Universitaria, Udine, Italy

A B S T R A C T

Thrombotic thrombocytopenic purpura (TTP) is a severe, life-threatening disease that needs urgent diagnosis and prompt therapeutic intervention. In pregnant women TTP may complicate the course of gestation putting mother and child at vital risk. Differential diagnosis with other obstetric and medical disorders may be difficult due to the overlap of several clinical and laboratory findings. Our understanding of the pathophysiology of TTP has allowed ADAMTS13 testing to have a central role in confirming the clinical diagnosis but the main limitation is that an ADAMTS13 assay is not available in “real time”. Here we report the clinical course and treatment outcome of two young women with clinical manifestations of pregnancy associated TTP and briefly discuss the main topics of disease diagnosis and management. © 2015 Published by Elsevier Ltd.

Contents 1. 2.

3.

4.

Introduction .............................................................................................................................................................................................................................. Case reports .............................................................................................................................................................................................................................. 2.1. Patient 1 ........................................................................................................................................................................................................................ 2.2. Patient 2 ....................................................................................................................................................................................................................... Discussion .................................................................................................................................................................................................................................. 3.1. Differential diagnosis with TMAs ......................................................................................................................................................................... 3.2. Multidisciplinary clinical management ............................................................................................................................................................. 3.3. Therapeutic options .................................................................................................................................................................................................. 3.3.1. Therapeutic plasma exchange .............................................................................................................................................................. 3.3.2. Plasma infusion ......................................................................................................................................................................................... 3.3.3. Adjunctive therapies ............................................................................................................................................................................... 3.4. Pregnancy outcome and risk of recurrence in subsequent pregnancies ................................................................................................ 3.5. Counseling ................................................................................................................................................................................................................... Conclusions ............................................................................................................................................................................................................................... References ..................................................................................................................................................................................................................................

1. Introduction Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, potentially fatal disorder presenting with

* Corresponding author. Therapeutic Apheresis Unit and Stem Cell Manipulation Laboratory, Department of Transfusion Medicine, Azienda Ospedaliero Universitaria, Pz.le S. Maria della Misericordia 1, 33100 Udine, Italy. Tel.: +39 0432 552350; fax: +39 0432 554018. E-mail address: [email protected] (C. Savignano).

1 2 2 2 3 3 4 5 5 5 5 6 6 6 7

microangiopatic hemolytic anemia (MAHA), thrombocytopenia and disseminated microvascular thrombosis that lead to organ dysfunction [1]. In recent years the pathophysiology of the disease has been elucidated and now a severe deficiency (<10%) of plasma ADAMTS13 activity is recognized as the main confirmatory finding for diagnosis [2]. The acquired form of TTP (aTTP) represents about 95% of all cases. The disease is commonly associated with anti-ADAMTS13 IgG antibodies [3,4] and generally affects women with a peak incidence in the third to fourth decade of life [5]. In

http://dx.doi.org/10.1016/j.transci.2015.11.005 1473-0502/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

2

congenital TTP (cTTP) or Upshaw–Shulman syndrome, several mutations of the ADAMTS13 gene – homozygous or compound heterozygous mutations – have been identified leading to different clinical phenotypes [6]. Some patients exhibit their first episode in the neonatal period with repeated exacerbations, whereas about one half of them are asymptomatic until adulthood. Both acquired and congenital forms, may complicate the course of pregnancy presenting as the first manifestation of the disease or a recurrence of a previously diagnosed TTP [7,8]. A pregnancyassociated onset of aTTP is described in 7–11.5% of women in childbearing age but recent published studies showed that the recurrence in subsequent pregnancies may be uncommon [9]. In cTTP, the role of pregnancy as a trigger for an acute disease manifestation is well recognized. Affected women can display the initial, delayed presentation of cTTP during their first pregnancy and, in the absence of prophylactic plasma infusion, in almost all pregnancies [10]. Pregnancy associated TTP shares many clinical and laboratory features with other conditions that can occur during gestation or in the immediate postpartum period with a picture of thrombotic microangiopathy (TMA) and organ damage: hemolytic uremic syndrome (HUS), secondary TTP (mainly in the context of connective tissue diseases, drug adverse reactions, HIV infection), preeclampsia (PE), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, acute fatty liver (AFL) of pregnancy, obstetric antiphospholipid antibody syndrome (APL), and sepsis with disseminated intravascular coagulation (DIC) [11]. The differential diagnosis among these disorders is difficult and often impossible at presentation requiring a strict cooperation between different clinicians (obstetrician, hematologist, anesthesiologist and apheresis expert) to assure proper management and optimal maternal and fetal outcomes. We describe herein the cases of two young women with clinical manifestations of pregnancy associated TTP and briefly discuss the main topics of diagnosis and management of the disease. 2. Case reports 2.1. Patient 1 A 29-year-old woman was referred to our Apheresis Unit during her second pregnancy. The patient was at the 20th week of gestational age (GA) and in good general condition. Past medical history was negative except for diagnosis of thrombocytopenia/HELLP Syndrome developed at the 38th week of her first gestation. Obstetrical ultrasound examination demonstrated a fetus appropriate for the GA and a normal umbilical artery flow. Clinical examination and routine laboratory tests showed no abnormalities. Additional laboratory parameters revealed: normal haptoglobin, lactate dehydrogenase (LDH), alanine and aspartate aminotransferase (AST-ALT), negative direct antiglobulin test, normal levels of complement C3, C4, undetectable levels of antinuclear (ANA) and antiphospholipid-antibodies (aPL). No schistocytes were seen on the blood smear. Blood samples sent to a reference laboratory revealed a moderately reduced ADAMTS13 activity (18%) without anti-ADAMTS 13 antibodies. In the hypothesis of previous pregnancy associated

TTP cases we planned a close observation with monthly access to our unit. On the 28th GA, the laboratory tests showed a mild thrombocytopenia (PLT 113.0 × 109 L) but not anemia or schistocytes on the blood smear. One week later a blood count showed a further decrease in platelet count to 85.0 × 109/L (hemoglobin, LDH, creatinine, AST, ALT, haptoglobin levels were normal) and the patient was admitted to the hospital. A new assay for ADAMTS 13 revealed a severely reduced activity (<10%) in the blood smear. One week later a blood count showed a further decrease in platelet counts to absence of antibodies. An ultrasound examination upon admission showed a fetus in a transverse position, with adequate biometric parameters and normal placenta and amniotic fluid. Plasma infusion was started but due to the rapid drop in platelet count (PLT 40.0 × 109/L), mild anemia (Hb 104.0 g/L) and elevated LDH (780 U/L) a shift to therapeutic plasma exchange (TPE) was established. Plasmapheresis therapy was planned on a daily basis with continuous cardiotocography recording and with the cooperation of an intensive care specialist. During the first TPE, the patient showed a moderate allergic reaction to fresh frozen plasma (FFP) with urticaria and laryngeal edema and was treated with 100 mg of methylprednisolone. Moreover, 500–1000 mL of albumin 5% was used along with FFP (20 mL/kg) as replacement fluid. A total of six procedures was performed with prompt response of hematological parameters but despite premedication (methylprednisolone 40–80 mg iv and chlorpheniraminemaleate 10 mg) the patient developed more severe allergic reactions. The last TPE was interrupted for generalized urticaria, respiratory distress and evidence of cardiographic abnormalities. An urgent caesarean section was performed (at 31 + 1 GA). The female neonate had a weight of 1580 grams and an APGAR score of 6/8, no hematologic abnormalities and was admitted to the neonatology intensive care unit (NICU). After delivery the patient’s clinical condition and laboratory tests rapidly normalize without any treatment and six days later she was discharged with close follow up. Mutational analysis of the ADAMTS13 gene (obtained 6 months later) showed two heterozygous novel mutations on exon 6 and exon 11 and the diagnosis of congenital TTP was made. No recurrences were seen in the three years of follow up although the residual plasma ADAMTS 13 activity remain lower than 20%. 2.2. Patient 2 A 32-year-old woman at 23th weeks of GA was admitted to our tertiary care hospital with epigastric pain and emesis. She had a history of systemic lupus erythematosus (SLE) diagnosed at the age of 26, with predominant joint involvement and the presence of antiphospholipid antibodies (aPL), lupus anticoagulant (LAC) and anticardiolipin (ACL) IgM. No previous thrombotic complications were reported, but she had had a spontaneous abortion at the 8th week of GA. From the beginning of pregnancy she was treated with plaquenil, low dose aspirin and LMWH at a prophylactic dosage. On admission the patient had normal blood pressure values and in a few days the abdominal pain and emesis resolved. The laboratory tests showed severe anemia and thrombocytopenia (Hb 78 g/L, platelet 114.0 × 109/L), increased ALT and AST (respectively 148 U/L and 57 U/L), C3

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

and C4 at low levels. Other parameters (among which LDH, total bilirubin, creatinine, haptoglobin) were within the normal range. No proteinuria was recorded in the urine analysis. The direct antiglobulin test was negative. The blood film didn’t show schistocytes. Antibodies to platelets and to platelet factor 4-heparin complex were negative. The obstetric evaluation failed to demonstrate signs of fetal growth impairment, fetal distress or other complications. Corticosteroid therapy (methylprednisolone 1 mg/kg/day) was started. No definite diagnosis was made but different options have been evaluated: HELPP (pros: anemia, elevated liver enzymes, thrombocytopenia, abdominal symptoms; cons: normal blood pressure, no proteinuria), SLE flare (pros: hematological manifestations, low C3 and C4 levels), SLE associated thrombotic thrombocytopenic purpura and, less probably, primitive TTP. Ten days later the patient developed hypertension (BP 160/105) and proteinuria (2.5 g/day), LDH increases (527 U/L) and haptoglobin reduction (3 mg/dL) but no schistocytes were seen on blood smear. A diagnosis of PE/HELPP syndrome in SLE and obstetric antiphospholipid syndrome (APS) was made. Therapeutic plasma exchange was urgently planned in the delivery room with the assistance of an obstetrician and an anesthesiologist. During TPE fetal monitoring and maternal vital signs were constantly recorded. At the end of the first procedure the patient complained of a vision decrease and an acute swelling of the retina was diagnosed. After a proper assessment of benefit/ risk ratio for the fetus and the mother a cesarean section was performed at the 25th GA. The vital baby with a birth weight of 570 g was immediately transferred to NICU. Placental histology showed several areas of ischemic necrosis. Few days later the patient developed severe thrombocytopenia (platelet nadir 40 × 109/L) and hemolytic anemia (Hb 84 g/L) with increased LDH (780 U/L), haptoglobin consumption (3 mg/dL) and the presence of schistocytes on blood smear. The clinical worsening was consistent with a secondary TTP in obstetric APS. TPE was restarted on a daily basis, using an albumin solution as a replacement fluid; after two sessions of treatment the platelets increased to 142 × 109/L, and the LDH and haptoglobin normalized. The patient has been subsequently treated with intravenous immunoglobulin (0.4 g/kg/day for 5 days) and was discharged one month later. Unfortunately no blood samples for ADAMTS13 assays were obtained in this patient. 3. Discussion These two cases offer a basis for briefly reviewing major criticisms of pregnancy associated PTT. For both patients the main concerns have been the confirmation of the diagnosis and the decision of considering TPE as an appropriate treatment. Patient 1 had a history of previous, probably misdiagnosed, HELLP syndrome. The first determination of ADAMTS13 activity (whose result was however made available only one month after blood withdrawal), showed a moderately reduced level of metalloprotease. Results of subsequent testing – ADAMTS13 activity lower than 10% – were available only at TTP clinical onset, too later for a prophylactic treatment with plasma infusion. Plasmapheresis procedures should be urgently started, with prompt response of hematological parameters but with severe side

3

effects. Patient 2 had a more complicated and dramatic course. Early GA (23th week) led clinicians to apply any effort to prolong pregnancy and fetal growth; Hence, TPE was started although no definitive diagnosis had been made but treatment was interrupted for rapid deterioration of clinical conditions. After caesarean section signs of microangiopathic involvement worsened and PEX again became necessary. These two cases prompt us to revise the following topics with the aim of improving the approach to diagnosis and treatment of pregnancy associated PPT: (1) (2) (3) (4) (5)

Differential diagnosis with TMAs Multidisciplinary clinical management Apheretic treatment and adjuvant therapy Pregnancy outcome and risk of recurrence Counseling

3.1. Differential diagnosis with TMAs When a picture of microangiopathic hemolytic anemia and thrombocytopenia occurs during pregnancy, a differential diagnosis between TMAs (TTP, PE, HELLP syndrome, HUS, AFL of pregnancy, SLE flare, obstetric APL syndrome) is crucial to ensure appropriate treatment and to avoid lifethreatening maternal and fetal consequences. Current Guidelines agree that urgent TPE is mandatory for TTP patients whereas supportive care or immediate delivery are recommended for severe PE/HELLP or AFL patients [12]. TTP is often confused with more common obstetric disorders such as severe preeclampsia or HELLP syndrome. This might be related to many factors. First of all, TTP is a rare and unexpected disease in otherwise healthy women. Furthermore, the presenting clinical features are often nonspecific including nausea, vomiting, abdominal pain, weakness and flulike symptoms. Finally, preeclampsia and HELLP syndrome may overlap TTP further confounding an already difficult diagnosis. Therefore, an effort should be made to achieve rapid and accurate diagnosis. In recent years, many reports have highlighted this topic assuming that the ADAMTS13 assay doesn’t contribute to early diagnosis even though a severe deficiency (<10%) of ADAMTS 13 activity is now sufficient to define TTP [13–15]. This is not related to the unreliability of the test but to the fact that the ADAMTS13 assay is not routinely performed in the majority of medical hospitals and the result is rarely available in a few days [16]. Therefore, in the presence of suspected TMAs, only a careful and comparative assessment of clinical parameters – time of onset, symptoms and laboratory tests – can offer the proper diagnosis (Table 1). Even today the decision to initiate TPE remains a clinical choice based on the suspicion of the treating physician. Pregnancy associated TTP, whether initial or recurrent, can occur at any time in gestation or in the puerperium but appears to be more frequent in the second and early third trimester. The classical pentad of signs with MAHA, thrombocytopenia, fever, neurological and renal involvement, is present only in a minority of cases [17]. As previously outlined, symptoms can be nonspecific at onset but the sudden occurrence of neurological impairment (headache, migraine, visual loss, transient or ischemic stroke, coma), in the absence of hypertension, proteinuria or aPL antibodies,

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

4

Table 1 Clinical manifestations and laboratory profiles of thrombotic microangiopathies (TMAs).

Time of onset Fever Abdominal symptoms Neurological symptoms Renal failure Hypertension MAHA Thrombocytopenia Elevated LDH Elevated troponin Elevated liver enzymes Hypoglycemia Proteinuria Coagulopathy ADAMTS13 activity

TTP

HUS

HELLP

PE

AFLP

Ob-ALP

Any time −/+ −/++ +/+++ −/++ −/+ +++ +++ +++ +/++ −/+ − With ematuria − Severely deficient (<10%)

Post-partum −/+ −/++ −/+ +/+++ −/++ ++/+++ ++ ++/+++ NA −/+ − ++ − Normal to moderately reduced

>20 w − −/++ −/+ −/+ ++ +/+++ ++ ++/+++ NA ++/+++ − ++ −/+ Normal to moderately reduced

>20 w − −/+ −/+ −/+ +++ −/+ −/+ +/++ NA + − +++ −/+ Normal to moderately reduced

27–40 w −/+ +/++ −/++ −/+ −/+ −/+ −/+ +/++ NA +++ −/+++ −/+ ++ Normal

Any time −/+ −/+ −/++ −/+ +/++ + ++ + NA + − −/++ −/++ Normal to moderately reduced

TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; HELLP, Hemolysis, Elevated Liver Enzymes, Low Platelets syndrome; PE, preeclampsia; AFL, acute fatty liver of pregnancy; ob-APL, obstetric antiphospholipid antibody syndrome; NA, not assessed.

represent a characteristic clinical feature of the disease. Acute collapse requiring intubation and ventilation or cardiac chest pain are described but are less frequent at onset. No symptoms can differentiate congenital from acquired TTP. In TTP patients, laboratory investigations show more pronounced microangiopath anemia with significant schistocytosis, severe thrombocytopenia without signs of DIC, haptoglobin consumption, and elevated LDH with normal AST/ALT. An elevated LDH/AST ratio has recently been proposed as a possible distinctive criterion from HELLP but this needs to be confirmed [18]. Renal impairment is revealed by a mild increase of serum creatinine, hematuria and, in rare cases, proteinuria. Generally, it is less pronounced in TTP than in HUS and rarely requires dialysis [19]. In many patients elevated troponin levels represent the only sign of cardiac involvement. As recently reported by the French Registry of TMAs, cardiac complications (acute myocardial infarction or acute conduction defects affecting the SA and AV node) are a remarkable cause of death in TTP patients and a cardiac troponin I level of > 0.25 μg L(−1) is a strong independent factor in predicting death (odds ratio [OR] 2.87; P = 0.024) [20]. Systematic determination of this parameter highlighted that 42–59% of TTP patients showed this finding but its use in the differential diagnosis is not yet explored. While generally not available for an early diagnosis of acute TTP, the measurement of a pre-treatment severely deficient ADAMTS13 activity (<10%) confirms the initial suspicion [21]. The documentation of inhibitor autoantibodies demonstrates that the metalloprotease deficiency is acquired and provides support of adding or increasing the intensity of immunosuppressive therapy. Noteworthy, only 80–90% of acquired TTP patients have a detectable inhibitor at presentation but, over 90% will manifest an inhibitor at some time during the course of the disease [22]. In the absence of detectable autoantibodies, sequencing analysis of the ADAMTS13 gene may be performed to confirm the presence of causative mutations that lead to the diagnosis of congenital TTP. To date, more than 150 different mutations (~60% missense, ~ 20% small deletions and insertions, and a small percentage of nonsense and splice site mutations) have been reported [23].

A mild or moderate decrease in ADAMTS13 activity (12– 50%) has been described in patients with autoimmune disorders (SLE, APS), during pregnancy or in HELLP syndrome [24] but severe ADAMTS13 deficiency (<10%) is considered to be a specific and diagnostic feature of TTP. 3.2. Multidisciplinary clinical management Many experts should play a role in the diagnosis and therapy of thrombotic microangiopaties during pregnancy/ postpartum period. Based on our experience and the literature data a multidisciplinary team approach to these patients (a kind of “brain storming”) helps shortening the disease [22]. In the absence of detectable autoantibodies, sequencing analysis of the ADAMTS13 gene may be performed to confirm the presence of causative mutations that lead to the diagnosis of congenital TTP. To date, more than 150 different mutations (~60 diagnostic process and choice of the right therapy [25]. At presentation, the patients are usually referred to an obstetric triage or emergency department. An interesting paper by Stella and co-workers [26] on the “diagnostic dilemma” of TTP/HUS demonstrates that the initial diagnosis differs between obstetricians and emergency department physicians, the former privileging HELLP/severe preeclampsia, the latter more common diagnoses such as panic attack, domestic violence or gastroenteritis. In the same report the latency period from admission to hospital to diagnosis ranges from 1 to 7 days. We have just discussed how signs and symptoms can be indiscernible and differential diagnosis difficult; the situation is further complicated because we have two patients to attend to. The availability of complete and urgent laboratory tests, radiological studies and consultants of different disciplines is extremely important to simplify the diagnostic pathway. All the mentioned tests and consultations must be urgently carried out because a delay in diagnosis may cause life threatening maternal and fetal consequences. Only a tertiary care hospital can offer a timely available intervention of an obstetric department, an intensive care unit for mothers and infants, hematology and nephrology services, an apheresis unit and reference laboratories open 24 hours a day. If early diagnosis or a suspicion

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

is made in a hospital where this set of clinical services is not available, the patient should be promptly moved to a tertiary care structure. Once the diagnosis has been made, the team of physicians (obstetrician, neonatologist, hematologist, anesthesiologist and apheresis expert) should all discuss the best therapeutic approach for the mother and fetus; it often requires an accurate evaluation of risks and benefits for both patients and sometimes the conclusions are conflicting, mainly if the diagnosis is made during the second trimester of pregnancy when fetal outcome is worse [27]. 3.3. Therapeutic options 3.3.1. Therapeutic plasma exchange Therapeutic Plasma Exchange (TPE) is the standard of care in idiopathic TTP, and previous undiagnosed congenital TTP [12,28]. A short course of TPE can also be offered to atypical HUS patients before complement inhibitory treatment with eculizumab [29,30]. When TPE is the therapy of choice the apheresis staff (physician and nurse) have to quickly face some practical and technical problems. The urgency of treatment requires the apheresis service to be available 24 hours a day, because TTP patients can rapidly worsen and suffer from severe or even fatal complications. British Guidelines [28] on TTP recommend that TPE should be started “ASAP”, preferably within 4–8 hours from presentation. Large volume plasma infusion is indicated if there is a delay in arranging TPE. Sometimes, a clear diagnosis cannot be reached and TPE is suggested on an empirical basis, like an ex juvantibus treatment [31]. Guidelines and recommendation on pregnancy associated TMAs support this kind of approach, but it should be considered that TPE treatment can be harmful and apheresis related adverse events during pregnancy can involve both the mother and the fetus. Even if TPE needs to be performed urgently, the patient has to receive detailed information regarding the procedure and related risks and she must sign an informed consent. In many occasions plasma exchange must be performed in the intensive care unit or in the delivery room. Vital signs of mother and fetus must be monitored constantly; during TPE the obstetrician follows fetal parameters while the anesthesiologist should be promptly available to treat severe side effects (for example anaphylactic reaction to plasma infusion in TTP). Apheresis staff must attend the patient during the whole duration of the procedure [32]. Pre-treatment blood samples to evaluate ADAMTS13 activity, antigen and antibody levels should always be collected. Different replacement solutions like fresh frozen plasma (FFP), Solvent/Detergent – treated plasma (S/D plasma), cryosupernatant, have been demonstrated to be equally effective in TTP patients since ADAMTS13 activity is present in normal amounts in all of them [33]. In the last years Solvent/Detergent – inactivated plasma (S/D plasma) has been used more frequently than fresh frozen plasma because of a lesser incidence of allergic reactions, anaphylaxis, central venous catheter thrombosis and TRALI; moreover S/D plasma is associated with a reduced risk of transfusion transmitted infections [17] and this aspect is of paramount importance in pregnancy. The only concern regarding S/D

5

plasma is the reduced content in protein S, possibly related to an increased thrombotic risk (not demonstrated in TTP patients). Despite the rarity of TTP patients, they are the single largest consumers of plasma with an average volume of 40 L/episode [17] . Only in patients with APL syndrome has the use of albumin solution instead of FFP been suggested [34] to avoid TMA worsening. The treatment schedule is similar to that in the nonpregnant patient. The optimal TPE regimen consists of daily procedures of 15 plasma volumes (PV) exchange for the first three days, reduced to 1.0 PV daily exchange at the stabilization of patient condition. Apheretic procedures should continue for a minimum of 2 days after the platelet count has reached 150 × 109/L. The number of procedures required to achieve remission is highly variable as it is in nonpregnant patients. Usually remission is attained three times longer in antibody mediated cases compared to patients without antibodies (23 days vs 7 days) [17]. Moreover TTP onset in first/second trimester may require periodic TPE (weekly or fortnightly) throughout pregnancy and postpartum based on hematological parameters and ADAMTS13 levels [35]. 3.3.2. Plasma infusion In previously diagnosed congenital TTP patients, plasma infusion (PI) may be the only therapy for the whole pregnancy. The suggested protocol [17,36] includes PI at the dose of 10 mL/kg every two weeks starting from 8 to 10 weeks of GA. The frequency should then be increased to weekly PI from the second/early third trimester to delivery or if the platelet count drop below 150 × 109/L. A patient with severe anaphylaxis to plasma has been successfully treated until delivery with an intermediate purity factor VIII concentrate BPL Y8 (BioProducts Laboratory, Elstree, Hertfordshire, UK) which contain a relatively high concentration of ADAMTS13 [31]. Therapeutic plasma exchange is rarely necessary. 3.3.3. Adjunctive therapies Corticosteroids are usually associated with TPE in the initial treatment of TTP in pregnant patients; steroids should be reserved to acquired immune TTP given their immunosuppressive effect. The recommended schedule is high dose oral prednisolone (1 mg/kg/day) or intravenous methylprednisolone (1 g/day for three consecutive days) [12,17]. No randomized controlled trial demonstrated a real advantage in their use. However, data from the Oklahoma TTP/ HUS Registry have suggested that the number of TPE necessary to achieve remission and the incidence of TPE complications were considerably reduced since the introduction of steroids in TTP therapy [37]. Steroids are usually maintained until hematological remission and then gradually tapered. Low dose aspirin therapy (75 mg) may be used in acute TTP during platelet recovery when the count exceeds 50 × 109/L often associated with low molecular weight heparin as thromboprophylaxis. The effectiveness of both therapies has been suggested but there are still few data from prospective controlled studies on the efficacy of this approach [38].

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS 6

C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

3.4. Pregnancy outcome and risk of recurrence in subsequent pregnancies With prompt diagnosis and effective therapeutic intervention maternal survival has improved in the last 20 years from 79% to nearly 100% [39]. However, maternal outcome is worse in women experiencing their first TTP episode during pregnancy than in those with recurrent disease. The cross-sectional analysis of the French National Registry for Thrombotic Microangiopathies covering the time period from 2000 to 2010 addressed this concern [40]. Moatti-Cohen and co-workers reviewed outcome data of 42 pregnancy onset TTP patients (32 with aTTP and 10 with cTTP). All but 4 patients received curative TPE that was prolonged until delivery. The maternal survival rate without sequelae was 88%, three patients showed neurological or renal impairment and two patients died. Fetal outcome was poor, with a stillbirth rate of 70% probably related to the frequency of TTP onset before 28 weeks of gestation. Additional data have been recently published by Scully and co-workers from the United Kingdom TTP Registry [27]. None of the twelve women with acquired TTP firstly presenting during pregnancy died, but, despite TPE and immunosuppressive therapy, there were 4 intrauterine fetal deaths and one pregnancy termination. The course of twenty women with de novo pregnancy associated cTTP was also detailed: some, but not all, received plasma therapy or TPE after TTP diagnosis and none died. The global live birth rate was 75%. In both groups pregnancy loss typically occurred when TTP started in the second trimester. The authors suggested that in early and later TTP presentations there is adequate placental function to avoid the development of intrauterine grow retardation (IUGR) with is the most common cause of fetal loss. The risk of recurrence in subsequent pregnancies differs between women with congenital and acquired TTP. Pregnancy associated cTTP patients have a relapse risk of almost 100% but regular plasma infusion can prevent acute TTP flare up and fetal IUGR [10,27,31,40]. Conversely, the risk of recurrence during an ensuing next pregnancy is not well defined in patients recovered from acute aTTP although earlier studies and case reports reported a risk of about 50% [41]. The recent analysis of the TTP/HUS Oklahoma Registry [42] showed that, among 16 pregnancies (in 10 women), only two relapsed suggesting that relapses in pregnancy following recovery from acquired, severe ADAMTS13-deficient TTP may be uncommon. In this group 81% of pregnancies resulted in live births in the third trimester and there were no maternal death. Five (31%) out of 16 pregnancies were complicated by preeclampsia and the relative frequency of preeclampsia per pregnancy in TTP women was significantly greater than US population estimates (2.4–3.2%). The above mentioned report of Scully seems to confirm good maternal and fetal outcome in subsequent pregnancies [27]. Six patients with a history of pregnancy associated aTTP were actively managed with close ADAMTS13 monitoring and, if necessary, plasma therapy. The relapse occurred only in two out of eight pregnancies. In this cohort, ADAMTS13 activity at the onset of pregnancy appeared to be the best indicator of the risk of relapse. The experience of the Italian TTP registry [43] of 15 women with aTTP outlined the prognostic value of ADAMTS13 activity. Reduced

levels of ADAMTS13 activity (<25%) in the first trimester were associated with a 2.9-fold increased risk for pregnancy TTP flare up and with a 1.2-fold increased risk for miscarriage. 3.5. Counseling In the past, women who recovered from pregnancy associated TTP have been discouraged to undertake a subsequent gestation. Thanks to new diagnostic and therapeutic approaches, nowadays a new pregnancy has become a feasible option if the mother is followed by a team of specialists before, during and after pregnancy. Women in childbearing age recovering from acute TTP should be counseled by a pool of experts (obstetrician, hematologist, neonatologist and apheresis physicians) on the following matters: risk of recurrence, maternal and fetal outcome, risk of pregnancy related complications (hypertension, HELLP, preeclampsia), need for regular monitoring, prophylactic and therapeutic options of TTP relapses. Counseling and management advice deriving from recent literature reviews [9,10,12,27,28,31,40–42] are briefly summarized herein. Women with a cTTP diagnosis facing a new pregnancy should be prophylactically treated with periodic infusion of plasma throughout gestation and the postpartum period as previously discussed. Delivery is recommended within 38th week of GA due to the increased risk of complications later in pregnancy. Family study is suggested to identify siblings or relatives presenting with ADAMTS13 mutations. Patients with a history of aTTP planning a subsequent gestation need to be checked for their ADAMTS13 levels and anti-ADAMTS13 antibodies before conceiving. If ADAMTS13 activity is severely deficient (<10%) rituximab therapy (375 mg/mq × 4–6 doses) has been electively suggested. Noteworthy, after rituximab treatment women should wait for serum clearance of monoclonal antibodies and normalization of their CD19 lymphocyte blood count (6–12 months). During pregnancy, regular determination of ADAMTS13 levels allows decision about starting treatment before TTP flares up. Monitoring of the ADAMTS13 activity is recommended once per trimester if the values remain normal and more frequently if they decrease. A fall of ADAMTS 13 activity to < 10% may suggest starting TPE and immunosuppressive therapy. The frequency of the apheretic sessions should be increased to daily TPE in case of overt TTP. Both in aTTP and cTTP, physical examination and monitoring of laboratory tests (full blood count, LDH, haptoglobin,) should be planned monthly. Serial fetal ultrasound examination and uterine artery doppler scan are also needed to assess adequate fetal growth and placental function. Counseling should also deal with contraception: women interested in it should be offered a non estrogen containing contraception, because of reports of aTTP associated with combined oral contraceptive pill and hormone replacement therapy. 4. Conclusions Pregnancy is a recognized trigger for acute disease manifestation both in congenital and acquired TTP. In an obstetrical context, TTP may be particularly challenging because of its difficult differential diagnosis with other TMAs,

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005

ARTICLE IN PRESS C. Savignano et al. / Transfusion and Apheresis Science ■■ (2015) ■■–■■

as showed by many reports and also in our limited experience. Over the last years, more rapid diagnosis and close consultation with an interdisciplinary team of experts have improved maternal and fetal outcome. Counseling, close monitoring and better therapeutic management allow successful subsequent pregnancies in women recovered from acute TTP. References [1] George JN, Al-Nouri ZL. Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes. Hematology Am Soc Hematol Educ Program 2012;2012:604–9. [2] Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 2010;91:1–19. [3] Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–94. [4] Furlan M, Robles R, Galbusera M, Remuzzi G, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578–84. [5] Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severeADAMTS-13 deficiency. J Thromb Haemost 2005;3:1432–6. [6] Lotta LA, Wu HM, Mackie IJ, Noris M, Veyradier A, et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 2012;120:440–8. [7] Fujimura Y, Matsumoto M, Kokame K, Isonishi A, et al. Pregnancyinduced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients. Br J Haematol 2009;144(5):742–54. [8] George JN. The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2003;10(5):339–44. [9] von Auer C, von Krogh AS, Kremer Hovinga JA, Lammle B. Current insights into thrombotic microangiopathies: thrombotic thrombocytopenic purpura and pregnancy. Thromb Res 2015;135(S1):530–3. [10] Von Krogh AS, Kremer Hovinga JA, Tjønnfjord GE, et al. The impact of congenital thrombotic thrombocytopenic purpura on pregnancy complications. Thromb Haemost 2014;111:1180–3. [11] D’Angelo A, Fattorini A, Crippa L. Thrombotic microangiopaty in pregnancy. Thromb Res 2009;123(S2):556–62. [12] George JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood 2010;20:4060–9. [13] Sibai BM. Imitators of severe pre-eclampsia. Semin Perinatol 2009;33:196–205. [14] Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A review. BMC Pregnancy Childbirth 2009;9:8–23. [15] Pourrat O, Coudroy R, Pierre F. Differentiation between severe HELLP syndrome and thrombotic microangiopaty, thrombotic thrombocytopenic purpura and others imitators. Eur J Obstet Gynecol Reprod Biol 2015;189:68–72. [16] Cataland SR, Wu HM. Pratical issues in ADAMTS13 testing and emerging therapies in thrombotic thrombocytopenic purpura. Semin Hematol 2011;48:242–50. [17] Scully M. Trends in the diagnosis and management of TTP: European perspective. Transfus Apher Sci 2014;51:11–4. [18] Keiser SD, Boyd KW, Rehberg JF, et al. A high LDH to AST ratio helps to differentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome. J Matern Fetal Neonatal Med 2012;25:1059–63. [19] Cataland SR. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 2014;123(16):2478–84. [20] Benhamou Y, Boelle PY, Baudin B, et al. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center A. J Thromb Haemost 2015;13(2):293–302.

7

[21] Bianchi V, Robles R, Alberio L, Furlan M, et al. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood 2002;100:710–3. [22] Peyvandi F, Lavoretano S, Palla R, et al. ADAMTS13 and antiADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica 2008;93(2):232–9. [23] Knöbl P. Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. Semin Thromb Hemost 2014;40(4):493–502. [24] 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. [25] Battinelli EM. TTP and pregnancy. Blood 2014; 123:1624–5. [26] Stella CL, Dacus J, Guzman E, et al. The diagnostic dilemma of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the obstetric triage and emergency department: lessons from 4 tertiary hospitals. Am J Obstet Gynecol 2009;200(4):381. e1–6. [27] Scully M, Thomas M, Underwood M, et al. collaborators of the UK TTP Registry. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood 2014;124:211–9. [28] Scully M, Hunt BJ, Benjamin S, et al. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012;158(3):323–35. [29] Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol 2014;164:759–66. [30] Mussoni MP, Veneziano FA, Boetti L, et al. Innovative therapeutic approach: sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolyticuremic syndrome. Transfus Apher Sci 2014;51(2):134–6. [31] Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American society for apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher 2014;29(3):148–67. [32] Russi G, Marson P. Urgent plasma exchange: how, where and when. Blood Transfus 2011;9:356–61. [33] Brunskill SJ, Tusold A, Benjamin S, Stanworth SJ, et al. A systematic review of randomized controlled trials for plasma exchange in the treatment of thrombotic thrombocytopenic purpura. Transfus Med 2007;17:17–35. [34] Bontadi A, Ruffatti A, Marson P, Tison T, et al. Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome. J Clin Apher 2012;27(4):200–4. [35] Scully M, Starke R, Lee R, et al. Successful management of pregnancy in women with a history of thrombotic thrombocytopenic purpura. Blood Coagul Fibrinolysis 2006;17(6):459–63. [36] Richter J, Strandberg K, Lindblom A, et al. Successful management of a planned pregnancy in severe congenital thrombotic thrombocytopenic purpura: the Upshaw–Schulman syndrome. Transfus Med 2011;21:211–3. [37] Som S, Deford CC, Kaiser ML, et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996–2011. Transfusion 2012;52(12):222–6. [38] Fyfe-Brown A, Clarke G, Nerenberg K, et al. Management of pregnancy-associated thrombotic thrombocytopenic purpura. AJP Rep 2013;3:45–50. [39] Martin JN Jr, Bailey AP, Rehberg JF, Owens MT, et al. Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955–2006. Am J Obstet Gynecol 2008;199(2):98–104. [40] Moatti-Cohen M, Garrec C, Wolf M, et al. Unexpected frequency of Upshaw–Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012;119:5888–97. [41] Vesely SK. Life after acquired thrombotic thrombocytopenic purpura: morbidity, mortality, and risks during pregnancy. J Thromb Haemost 2015;13(S1):S216–22. [42] Jiang Y, McIntosh JJ, Reese JA, et al. Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood 2014;123:1674–80. [43] Ferrari B, Maino A, Lotta LA, et al. Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case control study. Orphanet J Rare Dis 2014;9:193–201.

Please cite this article in press as: Chiara Savignano, Cristina Rinaldi, Vincenzo De Angelis, Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.11.005