Diagnostic dilemma: Severe thrombotic microangiopathy in pregnancy

Abstract

A diagnostic dilemma occurred when thrombotic microangiopathy developed during pregnancy. The diagnostic criteria of thrombotic microangiopathy include thrombocytopenia (platelets <100) and microangiopathic haemolytic anaemia (including thrombotic thrombocytopenic purpura and haemolytic-uraemic syndrome). An urgent interdisciplinary approach is required to treat thrombotic microangiopathy in pregnancy to differentiate between thrombotic microangiopathy and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).¹ This case presented with the pentad of thrombotic thrombocytopenic purpura: severe thrombocytopenia (platelets 9 × 10⁹/L), microangiopathic haemolytic anaemia (reticular count 245 × 10⁹/L (20–110)), LDH >5000 U/L (<425)), neurological abnormalities (Glasgow Coma Scale 10/15), renal failure (creatinine 140 µmol/L (<97)), fever (37.7℃). A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 (ADAMTS13) activity of less than 5% and anti-ADAMTS13 antibodies retrospectively confirmed the diagnosis of acquired idiopathic thrombotic thrombocytopenic purpura in pregnancy. The immediate management in the Emergency Department with an interdisciplinary team of Consultant Nephrologists, Intensivists, Haematologists and Obstetricians facilitated prompt diagnosis resulting in immediate plasma exchange (PEX) and coordination of semi-elective delivery of the foetus.

Introduction

Thrombotic microangiopathy (TMA) syndromes are characterized by microangiopathic haemolytic anaemia (MAHA), platelet clumping and organ failure of variable severity, for example thrombotic thrombocytopenic purpura (TTP), haemolytic-uraemic syndrome (HUS), haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, acute fatty liver of pregnancy (AFLP), antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE).

In this case, there was a high suspicion of TTP due to severe thrombocytopenia (platelets < 30 × 10⁹/L), mildly raised creatinine < 200 µmol/L, normal coagulation screen and liver function test. Cardiolipin antibodies and complement (C3/C4) levels were normal.

TTP is characterised by a severe deficiency (<5%) of A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 (ADAMTS13), which is required to break down ultra large von Willebrand factor multimers (ULVWFM), which increase platelet adhesion and capillary occlusion. Acquired TTP is caused by ADAMTS13 antibodies (anti-ADAMTS13 immunglobulin G). Congenital TTP is confirmed by mutation analysis of ADAMTS13 resulting in persisting ULVWFM. Variable ADAMTS13 activity and antibody levels can be found in secondary causes of TTP such as human immunodeficiency virus infection, hepatitis B and C virus, drugs or pregnancy.

In acute TTP, plasma exchange (PEX) should be initiated within 4–8 h with 1.5 plasma volume (PV) ¹ changes and should be intensified in life-threatening cases. This allows delivery of sufficient volumes of plasma to replace ADMATS13 enzyme and to remove potential antibodies. Daily PEX should continue for a minimum of two days after platelet count has been >150 × 109/L. ²

TMA presenting in the first trimester are more likely TTP than HUS (90% of HUS occurs post-partum). HUS is caused by uncontrolled activation of complement system resulting in platelet activation, endothelial cell damage, TMA and potentially severe renal failure. It is treated with the complement inhibitor eculizumab. In the majority of cases proteinuria, growth retardation and hypertension are present which makes the initial diagnosis of TTP, HUS and HELLP difficult. Less severe manifestation of microangiopathy and thrombocytopenia can be due to AFLD, APS and SLE.

Case report

A 21-year-old primigravida (22/40) suffered severe back pain. Paramedics attending her identified hypertension (BP 140/90 mmHg) and proteinuria. She was advised to see her General Practitioner who treated a presumed urinary tract infection with Nitrofurantoin.

Two days later, this patient attended the Emergency Department with worsening confusion. She was irritable with a Glasgow Coma Scale (GCS) of 10/15, no evidence of seizure activity. She was hypertensive (135/90 mmHg), with a temperature of 37.7℃. Rapidly expanding facial and peripheral oedema was noted. Blood tests demonstrated severe thrombocytopenia (platelets 9 × 10⁹/L), MAHA (red cell fragments, red cell anisocytosis and polychromasia on blood film, elevated lactate dehydrogenase (LDH) > 5000 U/L (<425), haemoglobin 61 g/L) and acute kidney injury (creatinine 140 µmol/L (<97). Urgent multidisciplinary team (MDT) review was initiated with senior support from Haematology, Nephrology, Intensive Care and the obstetric team. The following differential diagnoses were considered: TTP, early onset HELLP syndrome, pregnancy induced HUS and Urosepsis. Cefuroxime, Metronidazole and Gentamicin for sepsis of unknown origin with Penicillin sensitivity were commenced with Methylprednisolone. An abdominal ultrasounds scan identified foetal demise. Urgent transfer to intensive care unit (ICU) was agreed by the MDT to facilitate urgent PEX.

The patient was prepared for rapid sequence induction of anaesthesia to support the care of the patient. Airway management of the pregnant patients is a common challenge for Anaesthetist and Intensivist but is largely practised in the context of emergency caesarean section. The understanding of anatomic and physiological changes in pregnancy paired with adequate preparation for airway management was particularly important in this case as the patient was very agitated with GCS 10/15 which made appropriate positioning for intubation, considering physiological changes in pregnancy more difficult. Severe thrombocytopenia and haemolysis leading to anaemia put her at increased risk of bleeding in her airway and cardiovascular compromise both during airway manipulation as well as with line insertion to facilitate PEX.

Due to the instability of the patient and the time critical initiation of PEX, the patient was transferred to ICU immediately after intubation, without diverting to radiology for computed tomography (CT) brain.

Within 48 h of twice daily PEX (5 L Octaplas) thrombocytopenia improved from initial platelets 8 × 10⁹/L to 76 × 10⁹/L. Once platelets had stabilised above 50 × 10⁹/L, PEX was changed to once daily and continued for 11 days when platelets had stabilised above 150 × 10⁹/L.

In close cooperation with experts at University College of London Hospitals, the presence of ADAMTS13 antibodies was confirmed and the diagnosis of acquired TTP in pregnancy was made. Treatment with Prednisolone, Rituximab and N-Acetylcholine infusion was recommended.

After initial stabilisation at day four a hysterotomy was performed to deliver the dead fetus and placenta. A CT brain scan demonstrated multifocal cerebral infarcts. The MDT made the decision to initiate anticoagulation with Aspirin for stroke prophylaxis, and thromboprophylaxis with Heparin once platelets stabilised above 50 × 10⁹/L. At day eight, the patient developed hypertension which was initially treated with Labetalol infusion and later changed to Amlodipine, ACE-Inhibitor and Atenolol. Significant polyuria was treated with Desmopressin.

The initial Troponin was 2.09 µg/L (<0.04) which peaked at 2.87 µg/L within the first 24 h which represents a very high risk of morbidity and mortality due to evidence of cardiac involvement.

After 13 days in ICU and 12 days of intubation, she was discharge from ICU to a ward. Significant cognitive problems including poor safety awareness requiring constant one-to-one supervision, severe dysphagia requiring feeding via nasogastric tube. ADAMTS13 activity recovered from initial <5% on admission to 65% two weeks later. She was able to be discharged to community rehabilitation after a hospital stay of 40 days.

One year after this incident, she still has difficulties with normal daily activities but has support of her family and her partner. She has pain syndrome, low mood and reduced mobility. She continues physio- and occupational therapy.

Discussion

We reviewed 64 articles on PubMed which were related to TTP in pregnancy. Moschcowitz ³ was the first person to publish a case of idiopathic TTP. On further review, the majority of literature was related to either pregnancy complicated by congenital TTP or reports of pregnancies after a diagnosis of acquired TTP. Up until the publication of TTP cases recruited to the United Kingdom TTP Registry, ⁴ only one case report was found which describes a new diagnosis of acquired TTP during pregnancy of a patient with a known diagnosis of Acquired Immune Deficiency Syndrome. ⁵ Since then 12 cases of new presentation of acute acquired TTP pregnancy have been described in the UK. ⁴ Two patients presented with TTP before 20-week gestation, four between 21 and 29 weeks and six after 30-week gestation. In seven pregnancies, the fetus survived. There has been no description of maternal mortality or morbidity.

The described case of acute life-threatening TTP is unique due to the severity of the clinical presentation and the maternal morbidity despite intensive treatment. The patient was left with neurological impairment even after a year of extensive rehabilitation. The case demonstrates the diagnostic dilemma and difficulties in treatment of pregnant patients presenting with thrombocytopenia and haemolysis. TMA in pregnancy is extremely rare but must be considered as a differential diagnosis to Pre-Eclampsia with severe thrombocytopenia and neurological impairment. Pregnancy itself is associated with increase thrombotic risk due to increase of pro-coagulant activity and a decrease of fibrinolytic activity. Thrombocytopenia is commonly found at the end of pregnancy which indicates pregnancy itself is a triggering event for the onset of TTP. ⁶

In cases of life-threatening thrombocytopenia in pregnancy treatment, options are contradictory and potentially harmful. Establishing the correct diagnosis will determine if platelet transfusion versus PEX as well as anticoagulation versus thromboprophylaxis need to be administered.

The diagnosis was unclear at presentation and treatment needed to be initiated prior to confirmation of diagnosis. In Pre-eclampsia versus TTP in pregnancy, the treatment can be contradictory. Pre-eclampsia is triggered by the pregnancy itself and removal of it will limit the pathological immune response. This case however presented with severe thrombocytopenia which would have made a safe delivery hazardous. Platelet transfusion is absolutely contraindicated in TTP due to potential presence of antibodies causing severe clot formation. This could have potentially caused further cerebral infarcts. Thrombocytopenia improved within 48 h of initiation of PEX to remove ADAMTS13 antibodies. ADAMTS13 activity of <10% is in keeping with TTP which can be congenital or acquired. Late-onset congenital TTP requires regular plasma therapy. Acquired TTP requires immunosuppressive treatment. ⁷ Both treatments were combined in the described case. PEX leads to elevation of platelet counts which facilitated safe removal of pregnancy and placenta which may have been the original or additional trigger for a pathological immune response.

A CT brain scan was performed after stabilisation of clinical picture which demonstrated multiple cerebral infarcts. Clinical correlation was not possible as the patient was deeply sedated to facilitate treatment with PEX. It remains difficult to judge what impact an earlier CT brain scan would have had on the care of the patient and ultimate outcome. A second CT brain to exclude increased intracranial pressure was necessary to facilitate antihypertensive treatment.

This case report highlights the importance of getting the basics right. To get the basics right you have to succeed in two areas: (1) robust processes and systems and (2) the right people doing the right thing. A primigravida at 22/40 with severe pain and hypertension should have been treated for pre-eclampsia at first presentation to health care professionals. The initiation of early investigation and treatment may have reduced the degree of morbidity.

A prompt and multidisciplinary approach is important in the management of pregnant patients with thrombocytopenia and haemolysis which facilitates early treatment with PEX. The decision about immediate and lifesaving PEX versus immediate delivery needs to be made prior to confirmation of diagnosis when results of ADAMTS13 deficiency and complement levels were still awaited. In this case, an ADAMTS13 activity was <10% which is in keeping with TTP. The presence of ADMATS13 antibodies confirmed the diagnosis of acquired TTP in pregnancy. Acquired TTP is treated with immunosuppression. ⁷ Whereas congenital TTP, which can present late, for example in pregnancy, is caused by mutation of ADAMTS13. This leads to ULVWFM. The treatment for congenital TTP is regular plasma therapy. ⁷

Despite daily multidisciplinary discussion between Consultant Nephrologist, Haematologist, Obstetrician and Intensivist and correct and prompt diagnosis, the patient only survived with significant morbidity.

Conclusion

Basic screening methods in pregnancy like blood pressure monitoring and testing for proteinuria can identify and prevent potentially life-threatening complication for mother and baby. Pregnant patients presenting with life-threatening condition require prompt MDT review to facilitate optimal treatment. The presence of thrombocytopenia in pregnancy is common and differential diagnosis especially with presence of haemolysis is wide. As demonstrated in this case treatment may need to be initiated prior to full diagnosis. Despite early recognition and optimal treatment of a rare acquired TTP in pregnancy, morbidity remains high and long-term outcomes of larger cohorts are still to be awaited. TTP in particularly when it occurs in pregnancy remains a challenge for the MDT and requires further studies to improve optimal treatment.