Postpartum thrombotic microangiopathic syndrome

Transfusion and Apheresis Science 48 (2013) 51–57

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Postpartum thrombotic microangiopathic syndrome Michelle Y. Owens ⇑, James N. Martin Jr., Kedra Wallace, Sharon D. Keiser, Marc R. Parrish, Kiran B. Tam Tam, Rick W. Martin Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Winfred L. Wiser Hospital for Women and Infants, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, United States

a r t i c l e

i n f o

Article history: Received 12 December 2011 Accepted 12 May 2012

Keywords: Postpartum plasma exchange Thrombotic microangiopathy HELLP syndrome

a b s t r a c t Objective: Characterization of syndromes for patients with life-threatening, progressively worsening hemolysis-elevated-liver-enzymes-and-platelet (HELLP) syndrome-like diseases and with thrombotic microangiopathies. Retrospective study design: Patients who underwent postpartum plasma-exchange (PPEX) for preeclampsia-related, and microangiopathy/coagulopathy illnesses unresponsive to medical therapy between 1994 and 2008 in our center and elsewhere. Results: Nine patients were treated with PPEX in our center with 78% maternal survival. Treatment with PPEX increased platelet levels (p = 0.048), decreased serum lactic dehydrogenase (p = 0.0012) and aspartate aminotransferase (p = 0.0001). Conclusion: Nineteen patients from publications combined with our patients suggest five categories of postpartum thrombotic microangiopathy syndrome that exhibit HELLP syndrome criteria and respond to PPEX. Ó 2012 Elsevier Ltd. All rights reserved.

1. Background Very rarely, usually following delivery, a patient will develop a hemolysis elevated liver enzymes and low platelet count (HELLP) syndrome-like, progressively worsening clinical and laboratory picture with features of complex thrombotic microangiopathy or consumptive coagulopathy with multiorgan injury that defies specific disease assignment and resists response to traditional supportive medical therapy and/or corticosteroids. Since the 1995 report from our center describing a decade of experience with postpartum plasma exchange (PPEX) for patients considered to have HELLP syndrome [1], we have continued to encounter rare puerperal patients with very complex presentations whose primary disease etiology became apparent and recovery was accomplished only after PPEX was initiated. Simultaneously there have appeared case reports from around the world that described similar patients [2–21]. Often these

patients presented to their obstetricians and maternal–fetal medicine subspecialists with probable HELLP syndrome that failed to improve following delivery, oftentimes failing to respond also to aggressive therapy such as high-dose dexamethasone administered [22]. 1.1. Aim The aim of this study was to compare nine HELLP patients who had PPEX in our center to 19 others reported worldwide during the 15 year period of 1994–2008. We suggest that these 28 patients represent a pregnancy-related entity that fits the acronym of PTMS for postpartum thrombotic microangiopathy syndrome. 2. Materials and methods 2.1. Study population

⇑ Corresponding author. Tel.: +1 601 984 5327; fax: +1 601 984 6773. E-mail address: [email protected] (M.Y. Owens). 1473-0502/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2012.05.016

This was a retrospective trial that involved women admitted to the University of Mississippi Medical Center,

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Jackson, MS, between 1995 and 2008. Inclusion criteria were patients presenting in the immediate postpartum period up to 7 days postpartum with a primary indication of a HELLPsyndrome like presentation, with or without multiple organ injury (vasculature, liver, kidney, heart, and lung) that was progressive and unresponsive to traditional medical therapy and/or high dose glucocorticoids. Patients are described as having met complete or incomplete HELLP syndrome criteria using a combination of the Mississippi and Tennessee classification systems (Table 1) [22,23]. Incomplete HELLP was defined as absence of hemolysis, elevated liver enzymes or a low platelet count. This included a platelet Nadir x < 50,000 lL, total lactic dehydrogenase (LDH) >600 IU/L, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) x > 70 IU/L and the presence of red blood cell hemolysis and/or high indirect bilirubin. If the diagnostic criteria of thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or immune thrombocytopenic purpura (ITP) had not been met and there was a team consensus (maternal– fetal medicine, hematology, nephrology, cardiology, GI and pulmonary medicine) that the composite disease status of a given patient warranted a trial of PPEX, informed consent was obtained. Further diagnostic studies were undertaken to ascertain the specific underlying disease(s) and dysfunction responsible for the patient’s deteriorating condition. Exclusion criteria included prior treatment with PPEX, currently pregnant or a current diagnosis of TTP, HUS or ITP.

2.3. World literature search A systematic world literature search for clinical reports and reviews published between 1994 and 2008 was undertaken using Pub Med and the OBGLine Knowledge Finder databases (Aries Systems Corporation, USA). Search words were ‘‘HELLP syndrome’’, ‘‘postpartum HELLP syndrome’’, ‘‘postpartum plasma exchange’’, ‘‘postpartum plasmapheresis’’, ‘‘postpartum hemotherapy’’, ‘‘postpartum renal failure’’, ‘‘complicated postpartum preeclampsia/eclampsia’’, ‘‘postpartum hemodialysis’’ and ‘‘postpartum microangiopathy’’. Publications were selected for review based on original research, detailed case reports, and comprehensive reviews. Publication inclusion criteria included articles published in English (1) which contained individual patient data and (2) plasma exchange treatment. Publications were excluded if the authors of the publications presented cases of adult plasma exchange in which the conclusion or initial diagnosis was TTP, HUS or ITP. 2.4. Statistical analysis Data were collected and analyzed by appropriate tests. The percent change between laboratory values before PPEX treatment and after PPEX treatment for each patient were determined and analyzed using paired student’s t test.

Percent change calculated per case as

2.2. Plasma exchange

: Bedside PPEX was initiated using an automated IBM/ Cobe Model 2997 Cell Separator or (more recently) a Cobe Spectra Cell Separator to accomplish a 3.5–4.0 L plasma exchange using fresh frozen plasma as the primary replacement fluid [1]. Serial PPEX was undertaken every 24–48 h on an individual patient basis until there was clear clinical and laboratory evidence of sustained recovery. Baseline and follow-up laboratory studies included platelet count, total LDH, AST, and serum creatinine measurements every 12–24 h.

After PPEX Before PPEX  100 Before PPEX

Before PPEX lab values correspond to serum collected 24 h before the first PPEX administration and after PPEX lab values correspond to serum collected 24 h after the last PPEX administration. Two-sided Fisher’s Exact test was used to compare the percent of cases positive cases between the UMMC population and the cases from the world literature search. Pearson correlation (two-tailed) was used to determine if there was a relationship between the postpartum day of PPEX initiation and the number of PPEX

Table 1 Complete HELLP and postpartum thrombotic microangiopathy syndrome (PTMS) characteristics. Complete HELLP classifications HELLP category

Platelet Nadir (lL)

LDH (IU/L)

AST or ALT (IU/L)

RBC hemolysis and/or high indirect bilirubin

I II III

x < 50000 100000 < x < 50000 150000 < x < 100000

x > 600 x > 600 x > 600

x P 70 x P 70 x > 40

Yes Yes Yes

PTMS classifications PTMS category

Final diagnoses

Characteristics

I II

HELLP class 1–3 Probable TTP

III IV V

Probable HUS SLE-APS Misc. Disseminated Vascular injury with AFLP/HgbSS/Shock injury

Steroid-unresponsive HELLP; possibility of renal injury, Possibility of HELLP; possibility of renal injury; pre-eclampsia or eclampsia clinical picture HELLP syndrome vs. HUS picture; dominate renal injury Lupus; APS; possibility of HELLP; Possibility of renal injury Hypotensive; hypovolemic; possibility of HELLP; Pre-eclampsia or eclampsia clinical picture; possibility of renal injury

Total lactate dehydrogenase (LDH), aspartate amniotransferase (AST) or alanine aminotransferase (ALT); red blood cells (RBC); thrombotic thrombocytopenic purpura (TTP); hemolytic urine syndrome (HUS); preeclampsia (PE); systemic lupus erythematosus (SLE); antiphospholipid syndrome (APS); acute fatty liver of pregnancy (AFLP); sickle cell vasoocclusive crisis (HgbSS).

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treatments received or the length of stay in the hospital following PPEX administration. A p < 0.05 was considered significant. 3. Results Nine patients with PTMS fit the inclusion criteria for PPEX and were treated with PPEX in our center between 1994 and 2008 (Table 2), with 78% classifying with complete HELLP syndrome. At presentation, no patient in this series had known prior hematologic disease except for the patient with hemoglobin SS disease (Case #5). Organ system involvement was renal (44%), evidence of liver hematoma(s) via ultrasound (11%), pulmonary (44%), central nervous system (11%), or predominantly vascular with disseminated intravascular coagulation (22%) among these patients. The mean maternal age was 26.1 ± 8.98 (range 15–42 years), and mean gestational age delivery was 31.4 ± 3.41 (range 22.2–39.6 weeks). 67% of the patients delivered via caesarean section with the remainder delivering vaginally (Table 2). One delivery occurred prior to 23 weeks gestation when newborn survival is unlikely enough to eliminate the option of cesarean delivery (Case #9). Treatment with PPEX resulted in a significant increase in platelet levels (p = 0.0048; Fig. 1A). PPEX treatment also significantly decreased serum concentrations of total LDH (p = 0.0012; Fig. 1B) and AST (p = 0.0001; Fig. 1C). PPEX treatment did not lead to a statistically significant decrease in serum creatinine levels (p = 0.627; Fig. 1D). There were two maternal and two fetal deaths among the group of nine

patients. The maternal deaths were in the following cases: Case 2 – cardiac, renal and pulmonary systems continued to worsen despite PPEX treatment and continued to do so until death. Case 9 – was recommended for suspected scleroderma/renal crisis when pulmonary function deteriorated with impending hypoxic respiratory failure followed by progressive multiple organ failure and eventual death. A negative correlation was seen between the number of PPEX treatments administered and when the initial PPEX administration began less than three post-partum days (r = 0.3456; Table 2). Also when the initial PPEX administration was less than three post-partum days a negative association was seen compared to the postpartum day of hospital discharge (r = 0.1751; data not shown). Since 1994 to the present there have been case reports of 19 patients from 13 countries that were published in the English literature as listed in Table 3 [2–21] with 68% of these patients meeting complete HELLP criteria (class 1 or 2). When the final outcomes from our population of PPEX patients were compared to the final outcomes of the 19 patients reported from the world literature search (Table 3), there were no significant differences in gestational age at delivery (31.2 + 1.67 weeks vs. 31.4 + 1.4 weeks, respectively, p = 0.956) or the incidence of cesarean delivery (67% vs. 68%, respectively, p = 1). Likewise there were no significant differences in the involvement of the renal (p = .689), liver (p = 0.317), pulmonary (p = 0.372), CNS (p = 0.630) or coagulation (p = 0.234) systems among the nine patients in this study and the 19 reported in the world literature search (Table 4, Fig. 2).

Table 2 Tabulation of nine University of MS Medical Center patients with PTMS receiving PPEX (1995–2008). Case No.

Maternal age

G/P

GA at delivery

Mode of delivery

PPD of 1st PPEX admin.

Number of PPEX TX

Dialysis admin.

Steroid TX

Class HELLP 1 met

PTMS category

1 2a 3 4 5 6 7 8 9a

20 42 30 15 21 35 24 31 17

1/0 1/0 4/2 1/1 2/2 7/6 2/1 5/7 3/0

29.4 31.4 28 39.6 29 33.5 32 36.1 22.2

C C V C C C V C V

1 4 5 6 1 1 1 14 3

3 10 1 2 13 6 4 3 14

Y Y N N N Y N N Y

Y Y Y N Y Y Y N Y

Y Y N N N Y Y Y Y

I II IV II V I I V I

Case No.

PLT Nadir

LDH (IU/L)

Before PPEX Platelets (lL)

AST (IU/L)

LDH (IU/L)

After PPEX Platelets (lL)

AST (IU/L)

Oliguria present

Peak Creatinine (mg/dL)

Final creatinine (mg/dL)

1 2a 3 4 5 6 7 8 9a

55 72 31 43 16 39 16 35 23

34,791 1657 1217 1179 2259 3726 13,720 16,606 7834

79,000 72,000 16,700 33,000 16,000 39,000 83,000 41,000 55,300

5346 27 182 60 66 121 204 10973 190

1483 1389 646 488 1001 2943 1258 15005 3506

89,000 103,000 189,000 150,000 100,000 126,000 145,000 8700 12,500

29 70 28 13 35 58 32 3123 105

Y N N N N N Y N N

3.1 (PPD 1) 5 (PPD 3) 1.7 (PPD 4) 0.9 (PPD 6) 1.1 (PPD 1) 9.2 (PPD 4) 3.0 (PPD 2) 2 (PPD 14) 2.3 (PPD 3)

0.9 0.9 3 0.9 0.8 0.9 1.6 0.9 1.8

Complications by case: 1 – SPreE w/acute renal compromise; 2 – SPreE, cHTN, multiorgan shock injury, sepsis, adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC); 3 – systemic lupus erythematosus flare, bacteremia, acute renal failure; 4 – postpartum eclampsia, endometritis; 5 – sickle chest syndrome, substance abuse; 6 – placental abruption, fetal demise, acute renal failure; 7 – placental abruption, fetal demise, DIC, acute renal failure; 8 – postpartum eclampsia, uterine dehiscence, hypovolemia, multiorgan shock injury; 9 – scleroderma renal crisis, sepsis. Legend: postpartum day (PPD); total lactate dehydrogenase (LDH), aspartate aminotransferase (AST); serum creatinine (Creat.). a Denotes patient death.

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Fig. 1. Platelet count (A), LDH (B), AST (C) and serum creatinine (D) levels before and after plasma exchange. Data is represented as mean + standard error mean. The percent of change in values before and after PPEX was calculated and analyzed with a paired Student’s t test. ⁄p = < 0.05 the percent change due to PPEX treatment was significantly different.

The lack of significant differences between our set of patients and the cases found from the literature search (Table 4), led us to the consideration of a universal characterization of five categories of PTMS as shown in Table 1. The five categories of PTMS in Table 1 represent clinical characteristics of patients in which PPEX may be beneficial and indeed life-saving to the patients, until further laboratory tests provide conclusive results. 4. Discussion The differential diagnosis of the disorders that can contribute to produce a HELLP syndrome-like clinical and laboratory picture in a patient can be a challenging exercise because of the overlap among conditions. The present study emphasizes that the postpartum patient with a HELLP syndrome-like clinical and laboratory picture could have one of many possibilities, ranging from a preeclampsia syndrome disorder with very advanced HELLP syndrome, to a thrombotic microangiopathies such as TTP-HUS, or a significant systemic endothelial injury due to vascular insult or sepsis [24]. The physicians caring for such rare obstetric patients are faced with a daunting dilemma of differential diagnosis and a management conundrum. The acronym of PTMS to encompass the common setting of postpartum thrombotic microangiopathy syndrome for all these patients with diverse etiologies is suggested as a conceptual framework for the study and management of these chal-

lenging puerperal patients. Therefore including not only patients with HELLP, but also those patients with thrombotic microangiopathies who might also benefit from plasma exchange. A previous study of 18 post-partum patients for whom PPEX was utilized for ‘‘unremitting HELLP syndrome’’ was conducted at the University of Mississippi Medical Center [1]. An important observation from that study was the finding that these patients appeared to fall into one of two groups: (1) those which quickly responded to one or two plasma exchanges, and (2) those patients with single or multiple system impairments (frequently associated with placental abruption) which required greater exchange and transfusion requirements [1]. Twenty-eight patients, nine from our center and 19 from worldwide publications, developed a laboratory and clinical picture we term postpartum thrombotic microangiopathic syndrome (PTMS). When the nine patients from our study were compared to the 19 patients collected from worldwide publications, there were no significant differences in organ systems involved (Table 4). This suggests that the utilization of PPEX may be universally applied as long as patients meet the criteria outlined in the current study (Table 1). Differentiating TTP from HELLP syndrome is a diagnostic challenge in the pregnant patient. As the development of HELLP syndrome could predispose a genetically susceptible or disease disabled patient to develop TTP [25], the identification of such a patient becomes critical. In the current

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M.Y. Owens et al. / Transfusion and Apheresis Science 48 (2013) 51–57 Table 3 Worldwide published experience 1994–2008 with patients considered to have PTMS presentation. Ref No.

Author (Country) Year

Del mode

Gest age

Treatment modality

Renal injury

Other injured systems

Final outcome

PTMS category

3

Hamada (Japan) 1996

CS

35 weeks

PPEX

No

HELLP

I

4 7 8

Ulrich (Germany) 1996 Lombano (USA) 2002 Forster (Finland) 2002

CS CS CS

33 weeks 32 weeks 33 weeks

PPEX P PPEX, Hep, IgG

Yes No Yes

HELLP HELLP HELLP

I I I

12 –

CS V

32 weeks 23 weeks

PPEX PPEX

Yes No

HELLP HELLP

I I

17 18 19 9a

Pitton (Italy) 2005 Niederhauser (USA) 2006 Hara (Japan) 2006 Del Fante (Italy) 2006 Cho (Taiwan) 2007 Obeidat (UK) 2005

CNS-Eyes, PP eclampsia Pulm-ARDS Eclampsia CNS-Eyes, ascites, liver MHA MHA

unstated CS CS CS

32 weeks 36 weeks 28 weeks

PPEX PPEX, S PPEX, S, IgG PPEX, S, Hep

No No Yes No

CNS-RPLS Pulm, liver Pulm, liver MHA

I I I II

21 5

Gallwas (Germany) 2008 Kahra (Norway) 1998

CS CS

38 weeks 36 weeks

PPEX, S HD, S

Yes Yes

CNS, liver MHA

Mahalati (USA) 1999

CS

33 weeks

PPEX

Yes

MHA

Iannuzzi (Italy) 2005

CS

Unstated

PPEX, S

Yes

MHA

Roberts (UK) 2003 Koenig (France) 2005 Veres (Hungary) 2008 Whitta (UK) 1995 Anacleto (Philippines) 2003

V H H V CS

36 weeks 17 weeks 23 weeks 38 weeks 33 weeks

PPEX, S P, Hep, S, IgG PPEX, IgG, S, Hep PPEX, Hep, DIC PPEX

Yes No No Yes Yes

CNS Liver, bowel Pulm-ARDS, eyes Liver, lung VASC, DIC

HELLP HELLP HELLP HELLP vs. TTP TTP HELLP vs. HUS HELLP vs. HUS HELLP vs. HUS APS, SLE APS, CAPS APS AFLP Shock

6 13

a

10a 16 20 2a 11

II III III III IV IV IV V V

Delivery modes are CS = cesarean section, V = vaginal, H = hysterectomy; treatment modalities are PPEX = plasma exchange, P = plasma infusion only, HD = hemodialysis, Hep = heparin, IgG = immunoglobulin, S = steroids; ARF = acute renal failure; other systems are CNS = central nervous system, Pulm = pulmonary, ARDS = adult respiratory distress syndrome, MHA = widespread microangiopathic hemolytic anemia, RPLS = reversible leukoencephalopathy syndrome, CARD = cardiac, DIC = disseminated intravascular coagulation, VASC = widespread vascular injury; Final diagnoses are HELLP = HELLP syndrome, TTP = thrombotic thrombocytopenic purpura, HUS = hemolytic uremic syndrome, APS = antiphospholipid syndrome, SLE = systemic lupus erythematosus, CAPS = catastrophic APS, AFLP = acute fatty liver of pregnancy. a Denotes HELLP criteria not met

study ADAMST13 activity was only measured in case 9, in which activity was decreased to 38%. As utilization of laboratory markers such as ADAMTS13 for diagnosis of various thrombotic microangiopathies such as TTP continue to evolve [26–30], further study of ADAMTS13 activity and inhibitors, its estimation and its implications for management, is warranted in pregnant patients with microvascular thrombotic disease. An argument for early initiation of PPEX in such patients as considered in this report is the potential that the patient may have underlying TTP [31]. In as much as ADAMST13 and other laboratory tests to establish a diagnosis of TTP usually requires several days, a delay in the initiation of life-saving PPEX therapy could be catastrophic [32]. The decision to initiate PPEX should not be made without consideration of the complications that could ensue or without taking into consideration the diagnosis of other conditions such as sepsis or placental abruption [33]. We have previously reported that up to 43% of HELLP patients have sepsis which contributes to maternal morbidity and that administration of either corticosteroids or PPEX reduces maternal morbidity to 18% [22]. Also despite the fact that patients with placental abruption can sometimes recover without PPEX, both of the cases presented in this study had early PPEX therapy due to acute renal failure (Case 6) and worsening hemolysis (Case 7). As such we do feel that the patient with sepsis and/ or placental abruption should definitely be considered for

PPEX in addition to continuation of antimicrobial treatment, but on a case by case basis. In the current study 44% of our patients underwent PPEX in the immediate post-partum period due to the severity of their conditions [Case 1 – worsening renal condition; Case 5 – severe pulmonary condition; Case 6 – acute renal failure; Case 7 – worsening hemolysis]. As a result we found a negative correlation between the onset of PPEX administration and the number of PPEX treatments administered. Additionally, there was also a negative correlation between the timing of PPEX administration and the length of hospital stay following the onset of PPEX administration. These results suggest that means to better assess optimal timing of PPEX for the individual patient are needed in addition to clarification of whether continuation or discontinuation Table 4 Comparison of organ injury between patients treated at the University of Mississippi Medical Center and the world literature search. Organ

UMC

World lit. search

p value

Renal Liver hematoma Pulmonary CNS Coagulation GA at delivery Cesarean delivery

44% 11% 44% 11% 22% 31.2 weeks 67%

42% 32% 21% 26% 5% 31.4 weeks 68%

0.689 0.317 0.372 0.630 0.234 0.956 1

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Fig. 2. Comparison of organ system involvement and evidence of liver hematoma(s) between the nine patients in the current study and the 21 patients from the world literature search.

of corticosteriods (when used) during PPEX is advisable. While efforts continue to understand the nuances of better treatment of pregnant patients with HELLP syndrome or related thrombotic microangiopathies such as TTP and coagulopathies such as acute fatty liver of pregnancy, PPEX can be an effective adjunctive therapy in its role to facilitate the elimination of noxious substances such as circulating immune complexes and protein bound toxins, while replacing needed elements for restoration of vascular health [34–38]. We believe that the current study supports the contention of Forster and colleagues as well as other investigators in that ‘‘early plasma exchange is worth considering as part of the treatment regimen if postpartum HELLP persists and progresses, and features of HUS-TTP exist’’ [10,39]. Recent studies from other investigators have shown that PPEX proves therapeutic in other systems of multiorgan failure that occur outside of pregnancy, thus giving further support to the work of Forster and colleagues [40,41]. Our current findings suggest that early plasma exchange is worth considering as part of the treatment regimen of a postpartum patient who expresses a complete or incomplete HELLP syndrome-like picture complicated by single or multiple organ injuries and fails to respond to >24 h of corticosteroid (i.v. dexamethasone) [42,43]. Due to the rarity of these patients and the complexity of their presentations, it is difficult to construct studies to answer the question(s) of exactly when and when not to undertake PPEX, and when initiated, how much and how long to exchange. Presently it appears that in the deteriorating postpartum patient with a HELLP syndrome-like clinical and laboratory picture that is unresponsive to medical therapy (as outlined in Table 1), timely initiation of PPEX should be considered.

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