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Differentiation between severe HELLP syndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators

European Journal of Obstetrics & Gynecology and Reproductive Biology

Abstract

Pre-eclampsia complicated by severe HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome is a multi-organ disease, and can be difficult to differentiate from thrombotic microangiopathy (appearing as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome), acute fatty liver, systemic erythematous lupus, antiphospholipid syndrome and severe sepsis. Many papers have highlighted the risks of misdiagnosis resulting in severe consequences for maternal health, and this can be fatal when thrombotic thrombocytopenic purpura is misdiagnosed as severe HELLP syndrome. The aim of this paper is to propose relevant markers to differentiate pre-eclampsia complicated by severe HELLP syndrome from its imitators, even in the worrying situation of apparently indistinguishable conditions, and thereby assist clinical decision-making regarding whether or not to commence plasma exchange. Relevant identifiers to establish the most accurate diagnosis include the frequency of each disease and anamnestic data. Frank hemolysis, need for dialysis, neurological involvement and absence of disseminated intravascular coagulation are indicative of thrombotic microangiopathy. The definitive marker for thrombotic thrombocytopenic purpura is undetectable ADAMTS 13 activity.

Keywords: HELLP syndrome, Pre-eclampsia, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura, Hemolytic uremic syndrome.

Background and objectives

The description of HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome by Weinstein, over 30 years ago, offered clear evidence that pre-eclampsia is a really complex syndrome involving placenta, kidney and other organs and systems [1]. In some cases, HELLP syndrome can present as multi-organ failure, severe enough to require admission to an intensive care unit, and can be difficult to differentiate from other diseases. Several diseases that can occur during pregnancy or post partum have to be considered, including thrombotic microangiopathy (TMA) [appearing as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)], acute fatty liver during pregnancy (AFLP), systemic lupus erythematous (SLE), antiphospholipid syndrome (APS) and severe sepsis. It is of paramount importance to develop a clear and practical method to help differentiate pre-eclampsia complicated by severe HELLP syndrome from its imitators, which have been described for more than 20 years by several authors [2], [3], and [4]. These papers emphasized the risks of misdiagnosis resulting in severe consequences for maternal health, including fatalities when TTP is misdiagnosed as pre-eclampsia complicated by HELLP syndrome [5] and [6]. The aim of this paper is to propose relevant clues to establish the most accurate diagnosis in this very peculiar circumstance of clinical practice, even in the worrying situation of apparently indistinguishable conditions, and thereby assist clinical decision-making regarding whether or not to commence plasma exchange. The definitive marker for TTP is undetectable blood ADAMTS 13 (thrombospondin type-1 motif A disintegrin and metalloproteinase with a thrombospondin type1 motif, member 1) activity [7]. ADAMTS 13 activity can be determined in blood and can help to establish a final diagnosis, as activity is normal or slightly diminished in HELLP syndrome but undetectable in TTP [7] and [8].

What is the matter with imitators of HELLP syndrome?

Generally speaking, when faced with onset of arterial hypertension associated with proteinuria, renal failure, hemolysis, elevated liver enzymes and thrombocytopenia – and, in some cases, with signs of neurological, retinal, pancreatic or pulmonary disorders – there are difficulties in establishing a diagnosis (Table 1). When dealing with differential diagnoses of pre-eclampsia complicated by severe HELLP syndrome, it is relatively easy to decide rapidly for AFLP, SLE and APS, but sometimes it can be difficult, almost impossible, to differentiate it from multi-organ failure linked with severe sepsis or TTP/HUS due to TMA. Other imitators of pre-eclampsia also occur, but far more rarely, such as viral disseminated infection [9], severe folate deficiency [10] or, exceptionally, paroxysmal nocturnal hemoglobinuria [11]. Rapid diagnosis is vital to ensure that all appropriate symptomatic treatments of pre-eclampsia (antihypertensives, magnesium sulphate) and other treatments can be commenced without delay. If a diagnosis of severe HELLP syndrome is made, a cesarean section should be performed rapidly; in this case, steroids are not recommended for treating HELLP syndrome, in accordance with evidence-based medicine [12], [13], and [14], although they are often prescribed [15] and [16]. If a diagnosis of AFLP is made, a cesarean section should be performed immediately, as a rule, together with blood product infusion [17]. In the case of SLE flare-up, high-dose steroids are needed [18]. If APS is diagnosed, heparin therapy should be commenced, sometimes in conjunction with other drugs in the case of catastrophic APS [19]. If severe multi-organ failure is thought to be due to severe sepsis, broad-spectrum antibiotics should be infused. If the diagnosis of TTP or HUS is certain or highly probable, plasma exchange should be commenced immediately, often in conjuction with steroids [7] and [20]. Platelet transfusion should be avoided, even in cases of profound thrombocytopenia, as platelet infusion can be followed by severe cardiovascular events in TTP [21].

Table 1 Selective intensity of the main parameters in HELLP syndrome and its main imitators.

HELLP AFLP TTP HUS
Hemolysis + to +++ 0 to + +++ ++ to +++
Schistocytosis + to ++ 0 to + +++ ++ to +++
Elevated LDH ++ to +++ + to ++ +++ ++ to +++
Elevated liver enzymes ++ to +++ ++ to +++ 0 to + 0 to +
Low platelet count ++ to +++ + to ++ +++ ++ to +++
Factor V N or ↓ ↓↓ N N
Total bilirubin + ++ to +++ + to ++ + to ++
Proteinuria +++ + + to ++ + to +++
Renal failure 0 to ++ + 0 to ++ ++ to +++
DIC + to ++ + to +++ 0 0
Hypoglycemia 0 to + + to +++ 0 0
ADAMTS 13 activity Detectable NA Undetectable Detectable
Fever 0 + ++ 0

HELLP, hemolysis, elevated liver enzymes and low platelet count; AFLP, acute fatty liver of pregnancy; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic and uremic syndrome; LDH, lactate dehydrogenase; DIC, disseminated intravascular coagulation; ADAMTS 13, a disintegrin and metalloproteinase domain with thrombospondin type-1 motif A disintegrin and metalloproteinase with a thrombospondin type1 motif, member 1; NA, not assessed.

Thrombotic microangiopathy

The first and most crucial problem of differential diagnosis facing severe HELLP syndrome is represented by TMA, witnessed through clinical signs suggesting TTP or HUS (Table 1). Is severe HELLP syndrome, particularly in the postpartum period, really a form of TTP? Many papers have dealt with this topic [2], [3], [4], [5], [6], [22], [23], and [24]. However, this question is only relevant if HELLP syndrome is really a clinical manifestation of TMA, when it is necessary to modify the therapeutic approach when a diagnosis of TMA is considered. Indeed, it is well known that a prognosis of TTP has a mortality rate as high as approximately 10%, and large-volume plasma exchange (60 ml/kg) should be commenced in the first weeks of the disease, as soon as the diagnosis is highly probable, and every day until complete remission [7] and [20]. It is therefore essential not to misdiagnose a patient with TTP as HELLP syndrome, which is likely to improve within a few days of delivery [2], [3], and [4], just as it is important not to commence plasma exchange without strong evidence of TTP/HUS [22]. The risks of infusion of plasma in large quantities should not be discarded, as is the case for any blood product of human origin. Moreover, the human cost should not be neglected either, as plasma exchange requires numerous blood donations. Last but not least, the financial cost of plasma exchange should also be taken into account.

It is clear that severe HELLP syndrome closely mimics TMA as HELLP syndrome, TTP and HUS all display hemolysis, elevated liver enzymes, thrombocytopenia and renal damage [2], [3], [4], [5], [6], [22], and [23]. However, some signs may be sufficiently predominant to suggest one diagnosis: neurological signs suggest TTP, and HUS should be considered when renal failure is severe enough to indicate hemodialysis. In fact, underlying pathogenic mechanisms involved in TMA are very complex and have led to reclassification of this disease into three subtypes: TTP, due to a deficit in ADAMTS 13 activity during pregnancy, most often linked with inhibitory antibodies; typical HUS, with infectious diarrhoea and evidence of a verotoxin; and atypical HUS, with abnormalities in complement regulators and gene mutations [7], [20], and [23]. However, as the results of these crucial tests are not immediately available in everyday clinical practice, careful assessment of each clinical and biological sign, as well as precise analysis of recent anamnestic data, needs to be performed [4]. First, when dealing with blood parameters, slight differences in observed signs have to be taken into account. Hemolysis is at the foreground in TTP/HUS; it is sometimes so marked that it can be seen as red-colored urine (like port wine), and can be severe enough to require red cell transfusion. Conversely, in HELLP syndrome, the intensity of hemolysis is subtle, as emphasised by Weinstein himself who indicated that hemolysis was absent in up to 30% of cases [1]. Second, thrombocytopenia is very marked, being as low as 10–20 × 109 l−1, in TTP/HUS. It is rarely as intense in HELLP syndrome, at least on admission to hospital, with platelet counts ≤50 × 109 l−1 only found in 15% of all cases [3].

Is HELLP syndrome really a form of TMA? This question is the main concern in clinical practice. If one accepts the consensus view of the vast majority of authors, it is necessary to remember the accepted definition of TMA [7] and [20]. Initially, TMA was defined as the association of five groups of signs. The first sign, intravascular hemolysis, includes negative Coombs’ test, which rules out autoimmune hemolytic anemia and microangiopathic hemolysis as shown by significant schistocytosis on several occasions [20]. The second sign is marked thrombocytopenia as, as a rule, platelet count is always very low in TMA, without signs in favor of disseminated intravascular coagulation (DIC). The three other classical signs are far less common: renal failure, central nervous system disorders and fever [20]. Therefore, a diagnosis of TMA is generally considered when hemolysis is associated with severe thrombocytopenia [7], [20], and [21]. Very recently, a lactate dehydrogenase (LDH)/aspartate aminotransferase (AST) ratio above 22.12 has been proposed to suggest TTP [24]. However, other studies are needed to confirm the value of this ratio for diagnosing TTP. This diagnosis cannot be confirmed without evidence. Initially, pathological criteria were mandatory to define the disease, consisting of widespread arterial thrombosis; subendothelial clear deposits in glomerular capillaries; and microvascular thrombi of platelets, von Willebrand factor and fibrin (as opposed to fibrin thrombi alone as documented in HELLP syndrome) in kidneys, skin or bone marrow [7], [23], [25], and [26]. Over the last 20 years, it has become possible to define TTP without histopathological evidence with a biological parameter, i.e. undetectable activity of ADAMTS 13 [7], [20], [25], and [26]. ADAMTS 13 activity below 10% is now sufficient to define TTP (the clinical form of TMA that most closely mimics HELLP syndrome) regardless of whether or not autoantibodies directed against ADAMTS 13 are found [7] and [20].

If these precise signs for defining TMA are taken in account, there is no doubt that HELLP syndrome is truly a microangiopathy, as it includes a microangiopathic disease, small vessel disease, deformed erythrocytes, and glomerular disease with proteinuria and elevated blood pressure. Conversely, there is no evidence to suggest that HELLP syndrome is a microangiopathy identical to TMA, as this assertion would require real histological evidence of thromboses, as they appear in TMA, in cases of HELLP syndrome. In a short series of four cases of severe HELLP syndrome associated with acute renal failure, kidney biopsy was performed in the immediate postpartum period. No lesions suggestive of TMA, and no thromboses, were found; on the contrary, in three of the four cases, lesions responsible for renal insufficiency were acute tubular necrosis, due to tubular ischemia, without any thromboses [22]. In a review of 21 HELLP patients whose renal biopsy results have been published, only two cases of biopsy-proven TMA were found [27]. In the vast majority of cases, histological proof is not obtained because thrombocytopenia prohibits renal biopsy. ADAMTS 13 activity is decreased in HELLP syndrome, but not to the same extent as in TTP (<10%); mean ADAMTS 13 activity in HELLP syndrome has been reported to be 31% (range 12–43%), compared with 71% at the end of a normal pregnancy [8] and [28]. A recent series of cases of severe HELLP syndrome in the postpartum period illustrated the difficulty of differentiating HELLP syndrome from TTP, and how ADAMTS 13 activity may help in therapeutic decision-making [29]. However, results of ADAMTS 13 activity are not usually available immediately. Therefore, the clinician has to use other clues to reach a diagnosis, such as the severity of liver involvement compared with the intensity of hemolysis: very high levels of transaminases suggest HELLP syndrome rather than TTP; conversely, mild liver injury, high LDH level, elevated LDH/AST ratio and gross hemoglobinuria are suggestive of TTP [24]. ADAMTS 13 activity within the range usually seen at the end of pregnancy [30] and [31] (i.e. diminished but not very low) allows the exclusion of TTP, in which case postpartum severe HELLP syndrome can be diagnosed; this usually resolves rapidly without the need for plasma exchange.

In the controversy about possible links between HELLP syndrome and TTP, there is no doubt that severe HELLP syndrome resembles TTP/HUS. However, no direct evidence exists to confirm that HELLP syndrome is strongly linked to TMA. However, this does not mean that one can discard the possibility that plasma exchange may be of some benefit in postpartum severe HELLP syndrome, as suggested by small uncontrolled series [30], [31], and [32]. The use of plasma exchange in this condition has been questioned for a long time [2] and [22] and remains unanswered. Very recently, Owens et al. published a series of nine cases defined as ‘postpartum thrombotic–angiopathic syndrome’ which were treated by plasma exchange [33]. However, it is unclear whether this is superior to symptomatic therapy used in intensive care units for treating multi-organ failure syndromes. To sum up, it is not possible to argue for the use of plasma exchange in postpartum severe HELLP syndrome, except in the following cases: if a diagnosis of TTP or HUS is very likely (a sample for ADAMTS 13 activity must be taken for documentation before the first plasma exchange), or if there is no improvement in HELLP syndrome considering LDH level and platelet count 2–3 days after delivery. Corticotherapy is not recommended in terms of evidence-based medicine [14], but some authors consider it to be of interest in selected cases [15], [16], [29], and [34]. When plasma exchange has commenced, a finding of slightly diminished ADAMTS 13 activity will lead to cessation of plasma exchange if the patient's condition has improved [29].

Acute fatty liver during pregnancy

A second imitator of pre-eclampsia is AFLP [3] and [4]. Diagnosis of AFLP is easy to establish in the presence of upper right-side abdominal pain accompanied by vomiting, hypoglycemia, severe retentional jaundice and a sharp increase in conjugated bilirubin without any clear increase in free bilirubin (as occurs in hemolytic jaundice) [17]. Echo–Doppler ultrasound of the liver will rule out a diagnosis of hepatic vessel thrombosis. The diagnosis is more certain if certain metabolic disorders are observed: recent polyuro–polydipsia (i.e. if paradoxical loss of weight occurred in the previous weeks), and acute renal failure which is unique as it is characterized by signs suggesting a functional (‘pre-renal’) origin. When considering hematological parameters, it appears that hemolysis is rare, and thrombocytopenia is moderate and secondary to DIC. Moreover, a syndrome of acute hepatic failure is present, with frequent and severe hypoglyacemia, prolonged prothrombin time, and a decrease in factor V and antithrombin blood levels (Table 1). If doubt persists, particularly if there is no improvement in hepatic insufficiency within 1–2 days, a transjugular liver biopsy has to be considered.

Another question in the field of therapeutic strategy in AFLP has been raised recently: is it necessary to commence plasma exchange? Martin et al. reported a series of six cases that were indisputably severe as four of them had encephalopathy, five had advanced hepatic failure, six had renal insufficiency and three needed mechanical ventilation; all six patients were cured [35]. Jin et al. reported a larger series of 39 patients [36]. Today, it is very difficult to assert whether or not plasma exchange is necessary, or simply useful, in AFLP. The main part of effective therapy remains symptomatic, based on usual treatments in intensive care units delivering support for failure of severe organs: renal replacement therapy (particularly with hemofiltration), substitution of coagulation factors and respiratory assistance.

Another way to differentiate HELLP syndrome from its main imitators lies in the relative frequency of each of these disorders: HELLP syndrome occurs in approximately one out of 500 pregnancies, AFLP in one out of 10,000 pregnancies and TTP/HUS in one out of 100,000 pregnancies [3] and [4].

Systemic lupus erythematosus and antiphospholipid syndrome

Other diseases imitating HELLP syndrome are autoimmune disorders, mainly SLE and APS. Diagnosis of these disorders is easy when referring to classic criteria [18]. SLE is easily diagnosed in cases meeting several criteria of the American College of Rhumatology: strong positive antinuclear factors and native anti-DNA, but also clinical evidence of recent SLE flare-up, particularly polyarthritis, inflammatory syndrome and low serum complement. Similarly, a diagnosis of APS is easy to make when referring to the revised Sapporo criteria [19]. In some cases, the diagnosis can be more difficult when APS is revealed during pregnancy as multi-organ failure, leading to the diagnosis of catastrophic APS [37].

Severe sepsis

HELLP syndrome must also be differentiated from multi-organ failure due to sepsis [38]. Diagnosis of sepsis may be suggested by anamnestic data, such as symptoms having preceded hospitalization, chorioamniotitis, endometritis or urinary tract infection system, severe inflammatory syndrome, and a sharp increase in plasma haptoglobin (which is decreased in HELLP syndrome, AFLP and TTP/HUS). A diagnosis can be made with microbiological cultures (i.e. blood cultures) even in the absence of high fever, as a systemic infection can appear to be TTP [38]. Faced with HELLP syndrome with no improvement in the markers following delivery, sepsis should be suspected systematically (i.e. endometritis) and bacteriological samples should be collected.

What to do in everyday clinical practice

Useful clues to differentiate HELLP syndrome from its imitators are summarized in Table 2: frequency of disease; anamnestic data suggesting SLE, APS, AFLP or sepsis; and profound thrombocytopenia, frank hemolysis, mild or absent liver involvement, renal failure requiring dialysis, neurological involvement and absence of DIC suggesting TTP/HUS. The definitive test for TTP is undetectable ADAMTS 13 activity. If liver involvement is very intense and doubt still exists, transjugular liver biopsy must be performed to diagnose AFLP. If the diagnosis remains uncertain and there is no real improvement by 48–72 h after delivery, ADAMTS 13 activity sampling should be performed, if not done previously, and plasma exchange should be commenced without delay. After 2–3 weeks, if anuria persists beyond the usual time needed for an acute tubular necrosis to resolve, and if the platelet count allows, a kidney biopsy should be performed to obtain precise information.

Table 2 Main clues to differentiate between HELLP syndrome and its main imitators at the bedside.

HELLP Sudden weight gain, diffuse swelling in the upper part of the body, severe arterial hypertension, massive proteinuria, DIC, marked elevation of AST/ALT, high level of LDH, detectable ADAMTS 13 activity
AFLP Recent weight loss, recent polyuro–polydipsia, vomiting, hypoglycemia, severe retentional jaundice (mainly conjugated bilirubin), hypoglycemia, prolonged prothrombin time, reduced factor V and antithrombin levels, DIC, ‘pre-renal’ acute renal failure
TTP Convulsive fits, hemiplegia, red-coloured urine, severe anemia, frank schistocytosis, very high level of LDH, LDH/AST ratio above 22.12, low serum haptoglobin level, slight jaundice (mainly free bilirubin), slight elevation of liver enzymes, absence of DIC, profound thrombocytopenia (below 50 × 109 l−1), fever, undetectable ADAMTS 13 activity
HUS Advanced renal failure, need for dialysis, red-colored urine, severe anemia, frank schistocytosis, very high level of LDH, low serum haptoglobin level, slight jaundice (mainly free bilirubin), slight elevation of liver enzymes, absence of DIC, moderate to profound thrombocytopenia, detectable ADAMTS 13 activity

HELLP, hemolysis, elevated liver enzymes and low platelet count; DIC, disseminated intravascular coagulation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AFLP, acute fatty liver of pregnancy; LDH, lactate dehydrogenase; TTP, thrombotic thrombocytopenic purpura; ADAMTS 13, a disintegrin and metalloproteinase with a thrombospondin type1 motif, member 1; HUS, hemolytic and uremic syndrome.

Conclusions

In all cases of severe HELLP syndrome, all the appropriate symptomatic treatments of pre-eclampsia (antihypertensives, magnesium sulphate) should be commenced without delay, and a cesarean section should be performed rapidly. However, other diseases mimic HELLP syndrome, including TMA (TTP/HUS). This article has outlined various clues to establish the most accurate diagnosis, and the definitive test for TTP is undetectable blood ADAMTS 13.

Conflict of interest statement

None declared.

Condensation

Although severe HELLP syndrome resembles thrombotic thrombocytopenic purpura (TTP), very marked thrombocytopenia and frank hemolysissuggest TTP and the definitive marker is undetectable ADAMTS 13 activity.

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Footnotes

a Obstetric Medicine Clinic, Intensive Care and Internal Medicine Unit, University of Poitiers, Jean Bernard Hospital, Poitiers Cedex, France

b Intensive Care and Internal Medicine Unit, University of Poitiers, Jean Bernard Hospital, Poitiers Cedex, France

c Department of Gynaecology and Obstetrics, University of Poitiers, Jean Bernard Hospital, Poitiers Cedex, France

Corresponding author. Tel.: +33 5 49 44 43 61; fax: +33 5 49 44 38 62.