Catastrophic antiphospholipid syndrome after pregnancy complicated by hemolysis,elevated liver enzymes and low platelets syndrome

Introduction

Antiphospholipid syndrome (APLS) is an autoimmune thrombophilic condition marked by the presence of antibodies that target phospholipid-binding proteins, resulting in vascular thrombosis. Pregnancy complications in the setting of APLS include recurrent spontaneous miscarriage, maternal thrombosis, and early onset placental insufficiency. Catastrophic antiphospholipid syndrome (CAPS) is a rare condition that represents the most severe disease, often presenting with acute onset multiorgan failure secondary to factors that activate the immune system.^1,2 Pregnancy, particularly in the first trimester and early second trimester, is thought to be a pro-inflammatory state, which can trigger APLS and CAPS. ³ However, most cases of pregnancy-related CAPS are reported in the third trimester and peripartum period. ⁴ Only 6% of all cases of CAPS have been reported during pregnancy. ⁵ This case report highlights the important consideration of CAPS in pregnant women with multiorgan disease.

The mortality of CAPS was once as high as 79%, but after the introduction of triple therapy (anticoagulation, corticosteroids, and plasma exchange therapy), this mortality rate has decreased to approximately 30%. ⁶ Given the high degree of morbidity and mortality, as well as its similarities with alternative obstetric diagnoses including preeclampsia and Hemolysis Elevated Liver Low Platelet (HELLP) syndrome, it is imperative to recognize and diagnose CAPS for expeditious treatment and improved outcomes. In this case report, we describe a woman with known APLS at 22 weeks, gestation presenting with epigastric pain found to have HELLP syndrome complicated by CAPS.

Case

The patient is a 27-year-old nulliparous woman with a history of primary APLS diagnosed in 2011 after an unprovoked lower extremity deep vein thrombosis (DVT) with laboratory confirmation of persistent positive lupus anticoagulant and beta-2 glycoprotein I (IgG > 150, IgM 125). During her pregnancy, she was on therapeutic enoxaparin (1 mg/kg twice daily) and aspirin 81mg daily. She was monitored with monthly anti-Xa laboratory tests, confirming therapeutic levels and medication adherence. At 22 weeks and 3 days of gestation, she presented to the emergency department (ED) with epigastric pain and vomiting. On examination, she was normotensive with mild epigastric tenderness. Serum laboratory evaluation was notable for lipase 34 U/L (Reference Interval < 50 U/L), elevated liver function tests (AST 45 U/L (10–40 U/L), ALT 71 U/L (10–40 U/L)) and low platelets (108 × 10³/µL (140–440 × 10³/µL)) (Figure 1(a)). A right upper quadrant ultrasound revealed cholelithiasis without evidence of cholecystitis. The liver parenchyma was unremarkable, and hepatic vessels were patent by color Doppler. She was discharged home with medication for gastritis and outpatient follow-up.

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Figure 1.

Laboratory result of our patient during her admission. (a) AST, aspartate aminotransferase (units/liter (U/L)); ALT, alanine aminotransferase (Units/Liter). Platelets (Plt; 10³/µL). (b) Serum creatinine (µmol/L).

She represented to the ED one day later afebrile (36.9°C) and clinically stable, though with worsening symptoms and hypertension (159/87 mmHg). Laboratory evaluation revealed AST 75 U/L, ALT 134 U/L, platelets 95 × 10³/µL, hemoglobin 12.5 g/dL (11.7–15.5 g/dL), serum creatinine 68.95 µmol/L (52.2–91.9 µmol/L), urine protein 34 mg/dL (0–14 mg/dL), lactate dehydrogenase (LDH) 287 U/L (110–240 U/L), haptoglobin 9 mg/dL (43–212 mg/dL), fibrinogen 450 mg/dL (150–440 mg/dL), prothrombin time 11.3 s (9.6–12.4 s), INR 1.0 (2.0–3.5), and PTT 42.5 s (23–32 s) (Figure 1(a)). The patient was admitted for blood pressure monitoring, serial laboratory evaluation, and maternal–fetal medicine consultation due to possible HELLP syndrome and need for periviable delivery.

An obstetric ultrasound revealed an estimated fetal weight of 386 g (<2.5th percentile by WHO growth standard, 2nd percentile by Hadlock) with normal umbilical artery Dopplers. Laboratory evaluation within 12 h of admission was notable for worsening hepatic function and thrombocytopenia (Figure 1(a)), raising concern for worsening HELLP syndrome. She had a multidisciplinary discussion with Maternal–Fetal Medicine and Neonatology. Given the overall poor neonatal prognosis, she elected for termination of pregnancy by dilation and evacuation. The patient was transitioned to an intravenous heparin infusion, laminaria were placed, and she was initiated on magnesium for seizure prophylaxis. Due to persistent abdominal pain preoperatively, patient underwent CT imaging that revealed an infarction of the left lobe of the liver (Figure 2(a)). Gastroenterology was consulted and recommended continuing anticoagulation with repeat imaging in 48 h.

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Figure 2.

Radiologic findings of our patient (a) computed tomography at 22 weeks five days of gestation the day before delivery with large patchy hypo-attenuated area in left lobe of liver concerning for ischemia/infarction (arrow). (b and c) Repeat computed tomography axial and coronal view on postoperative day 2 revealing unchanged hepatic infarct (arrow). (d–f) Magnetic resonance cholangiopancreatography on postoperative day 4 with initial hepatic infarct seen previously (arrow, d), new infarct in segment 4 of liver (dashed arrow, e), new renal infarct in the posterior medial left kidney (solid arrowhead, e) and new splenic infarction in posterior upper spleen (open arrowhead, f).

The patient underwent uncomplicated dilation and evacuation. By postoperative day 2, serum laboratory evaluation showed improving platelets and liver function tests (Figure 1(a)). Repeat imaging revealed unchanged hepatic infarcts in the left lateral segment of the liver (Figure 2(b) and (c)) with patent hepatic vasculature. She was transitioned to therapeutic enoxaparin.

On postoperative day 4, her abdominal pain worsened, platelets decreased, and transaminase levels increased (Figure 1(a)). Due to concern for worsening hepatic infarction, magnetic resonance cholangiopancreatography (MRCP) was obtained that revealed new areas of infarction in her liver, spleen, and kidney (Figure 2(d)–(f)). Laboratory evaluation revealed acutely worsening creatinine (Figure 1(b)). Transthoracic echocardiogram was performed that was unremarkable with normal systolic and diastolic function.

However, given her history of APLS and new acute involvement of several organs, there was a high concern for CAPS. She was transferred to the intensive care unit where she received triple therapy including high-intensity heparin, high-dose corticosteroids, and plasma exchange therapy (PLEX). On day 2, PLEX was discontinued due to transfusion-related acute lung injury (TRALI) for which the patient required a high-flow nasal cannula for support. She was then transitioned to intravenous immunoglobulin therapy (IVIG).

Her renal function continued to deteriorate with a peak creatinine of 533.17 µmol/L (Figure 1(b)), so the decision was made to initiate dialysis. ADAMST13 was within normal limits. She was started on labetalol for blood pressure control. After receiving hemodialysis, her renal function recovered completely (Figure 1(b)), and therapy was discontinued. She was bridged from heparin to warfarin for long-term anticoagulation. On hospital day 20, she was discharged home in stable condition with close follow-up with Maternal–Fetal Medicine, Rheumatology, Nephrology, Hepatology, and Hematology.

Discussion

CAPS presenting in the setting of APLS in pregnancy is exceedingly rare, occurring in less than 1% of cases of patients with APLS. ⁷ CAPS carries significant associated maternal and fetal morbidity and mortality, and prompt diagnosis and aggressive treatment are imperative to reduce these associated morbidity rates.

Diagnosis may be challenging given CAPS can be easily mistaken for other conditions, including preeclampsia/HELLP, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), sepsis, heparin-induced thrombocytopenia (HIT), and acute fatty liver of pregnancy. These conditions may be characterized by microangiopathic hemolytic anemia and thrombocytopenia with renal, cardiovascular, and central nervous system involvement. As a result, precise diagnosis is imperative, as treatments vary. Although HELLP and CAPS are clinically separate syndromes, HELLP can trigger the development of CAPS. ⁵ Therefore, it is crucial to consider CAPS in patients with evidence of thrombotic microangiopathy during pregnancy, especially with features of HELLP syndrome. ⁸

This patient initially presented with symptoms of HELLP syndrome and subsequently developed CAPS. When the patient began to have worsening abdominal pain and serial tests revealed acute worsening in her liver and renal function after termination, the decision to pursue further imaging was essential given her high risk for complications.

Because of the high morbidity and mortality associated with CAPS, treatment must be initiated immediately with a multidisciplinary team approach. CAPS treatment is “triple therapy,” including therapeutic anticoagulation, immunosuppression with high-dose corticosteroids, and plasma exchange therapy to remove pathologic antibodies and other pro-inflammatory mediators. However, given its high rate of mortality, it is imperative for physicians to be aware of alternative treatment for refractory CAPS, such as rituximab and eculuzimab. Eculizumab, a monoclonal antibody targeting the complement system, has been proposed, though there are limited data on its effectiveness. Yelnik and colleagues found that though its use has been inconsistent in efficacy, eculuzimab has been found to be impactful in patients with thrombocytopenia and microangiopathic features. ⁹ Similarly, rituximab, a chimeric monoclonal antibody, has been shown to play a role in treating recurrent episodes of CAPS. ¹⁰

With regard to future fertility, given the rarity of this diagnosis, the risk of recurrence of CAPS in future pregnancies is unknown. As a result, it is essential that these patients are on therapeutic anticoagulation throughout pregnancy. However, this may not be sufficient, as seen in this case, as our patient was already on the appropriate anticoagulation upon presentation. Hydroxychloroquine has been proposed for primary prophylaxis given its reduction in rates of arterial and venous thromboses. However, this has not been studied in the context of pregnancy, and therefore, its benefits remain unclear. ¹¹ Postoperatively, our patient was counseled regarding this risk of recurrence in future pregnancies. Although she expressed interest in future fertility, she was amenable to delaying this by at least 12 months to allow for recovery and prevention of short-interval pregnancy.

Conclusion

This case provides an opportunity to review the diagnosis and management of CAPS in the peripartum period and to emphasize the importance of diagnosis of early onset HELLP in patients with APLS, as this increases a patient's risk of CAPS.