Continuing Education Activity

The syndrome of hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count, is more commonly known by the acronym HELLP syndrome in pregnant and postpartum patients. It may represent a complication or progression of severe preeclampsia; however, this relationship has been challenged by the recent evidence that these pathologies may have separate etiologies. This activity reviews the etiology, clinical presentation, evaluation, differential diagnosis, and management of HELLP syndrome.

Objectives:

• Identify the risk factors for developing HELLP syndrome.
• Recognize the clinical presentation of a patient with HELLP syndrome and review the diagnostic workup.
• Outline the management for HELLP syndrome.
• Emphasize the importance of collaboration amongst different specialties to improve maternal and neonatal outcomes in patients with HELLP syndrome.

Introduction

The syndrome of hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelets in pregnant and postpartum patients is more commonly known by the acronym HELLP syndrome.[1][2] It may represent a complication or progression of severe preeclampsia; however, this relationship has been challenged by recent evidence that they may be separate disorders as preceding hypertension or proteinuria is absent in at least 15 to 20% of patients with HELLP syndrome.[3] A previous history of preeclampsia or HELLP syndrome can lead to recurrence in subsequent pregnancies.[3] 

Multiparity and age may contribute to increased risk.[3][4][5] Genetic association for increased predisposition for HELLP syndrome has been noted.[3] It has been recently reported that patients with SARS-CoV-2 infection during pregnancy have an increased risk for preeclampsia and HELLP syndrome.[6]

Etiology

The etiology of HELLP syndrome is unclear but is thought to be a systemic inflammatory disorder mediated by a complement cascade.[5][7] It is proposed that there may be an overlap with similar pathogenesis as in preeclampsia with poor placentation, but for unknown reasons, it can lead to exaggerated activation of the complement system and greater hepatic inflammation in patients with HELLP syndrome. A subset of HELLP syndrome is caused by complement dysregulation associated with thrombotic microangiopathy and can present with pregnancy-related hemolytic uremic syndrome (HUS).[8] Fetal long-chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHAD) may be contributing to the pathogenesis of HELLP syndrome, but evaluation for these genetic variants is unnecessary as there is no identified role in clinical management.[9]

Epidemiology

HELLP syndrome has a prevalence of 0.5% to 0.9%. About 70% of cases occur in the third trimester of pregnancy, and the remainder occurs within 48 hours of delivery.[10] The mortality rate of women with HELLP syndrome is 0 to 24%, with a perinatal death rate of up to 37%.[5][11]

Pathophysiology

An ischemic-reperfusion injury triggers the systemic inflammatory process in HELLP syndrome. The spiral arteries which fail to remodel because of inadequate trophoblast invasion or defective endothelial apoptosis result in ischemia of the placenta. This causes activation of endothelium, which is accompanied by an increased release of antiangiogenic factors, which leads to multiorgan microvascular injury. In addition, abnormal oxidation of fatty acids by the fetus and release of metabolic intermediates into the mother's circulation causes liver and vascular dysfunction. This occurs when the fetus has an inherited defect in mitochondrial fatty acid oxidation. The inflammatory component includes increased leukocytes and pro-inflammatory cytokines with a reduction in anti-inflammatory cytokines.[1][7][12]

The coagulation cascade is activated by the adhesion of platelets on the activated and damaged endothelium. Platelets release thromboxane A and serotonin, causing vasospasm, platelet aggregation, and further endothelial damage. This causes the usage of platelets and hence, thrombocytopenia. The red blood cells break down while passing through these platelet-fibrin-rich capillaries, causing microangiopathic hemolytic anemia. Multiorgan microvascular injury and hepatic necrosis lead to the development of HELLP syndrome. The cascade terminates with the delivery of the fetus.[1]

Histopathology

Schistocytes or helmet cells present on a peripheral blood smear are diagnostic of microangiopathic hemolytic anemia. Hepatic histology shows fatty infiltration, intravascular fibrin deposits, neutrophilic infiltrate, sinusoidal obstruction, intrahepatic vascular congestion, hepatic necrosis, and periportal hemorrhage. This may eventually result in intraparenchymal or subcapsular hemorrhage and capsular rupture.[13]

History and Physical

Patients are usually multiparous and over the age of 35 years old. Patients usually present between 28 to 37 weeks of pregnancy (third trimester)or immediate postpartum within seven days of delivery. The clinical presentation may be varied in patients with HELLP syndrome. They may present with colicky mid-epigastric and/or right upper quadrant pain associated with nausea, vomiting, and fatigue. Associated features may include jaundice, increasing abdominal girth, leg swelling, headache, and visual changes. Patients may present with severe bleeding, placental abruption, acute kidney injury, liver hematoma, or retinal detachment.

On physical examination, patients have hypertension with a blood pressure >140/90 mmHg and may have ascites or pedal edema. Right upper quadrant or epigastric tenderness is noted. Icterus may be present. Visual disturbances may be present. A pertinent physical exam should be conducted if any of the above complications are suspected.[14]

Evaluation

When a pregnant patient in the third trimester of pregnancy or immediate postpartum <7 days of birth presents with the above symptoms of HELLP syndrome and new-onset hypertension or proteinuria is noted, the following laboratory tests are needed to establish the diagnosis of HELLP syndrome:

• Complete blood count
• Peripheral smear
• Liver function tests:aspartate aminotransferase (AST),alanine aminotransferase (ALT),bilirubin
• Creatinine[5]

If liver function tests are elevated, obtain haptoglobin, lactate dehydrogenase (LDH), and coagulation studies to include fibrinogen, prothrombin (PT), and activated partial thromboplastin time (PTT). Tennessee classification is used to diagnose HELLP syndrome and requires the presence of all three criteria.[5]

1) Hemolysis confirmed with at least 2 of the findings:

• Peripheral smear with schistocytes and burr cells
• Serum bilirubin >1.2 mg/dl
• Low serum haptoglobin(<25mg/dl) or LDH> two times the upper level of the normal.
• Severe anemia with hemoglobin <8 to 10 g/dl depending on the pregnancy stage, unrelated to blood loss.

2) Elevated liver enzymes: AST or ALT > 2 times the upper level of normal.

3) Low platelets: <100,000 cells/microL.

Mississippi classification is sometimes used to subclassify patients with HELLP syndrome.[5] The categories are in the table that follows:

Patients meeting a few of the above criteria are considered to have partial HELLP syndrome and may progress to meet all criteria and hence should be monitored carefully.

HELLP syndrome mainly involves platelet activation without affecting clotting factors, and hence patients will have normal PT, PTT, and fibrinogen. Disseminated intravascular coagulation(DIC) may co-exist if PT and PTT are prolonged or if fibrinogen is low.[15]

Treatment / Management

Medical management is mainly supportive.[1][3][5] These patients may need ventilator support, vasopressor support, pain control, monitoring of volume status, and nutritional support. As these patients can rapidly deteriorate, they are best managed at tertiary care centers with appropriate levels of maternal and neonatal intensive care units. Consideration should be given to transferring them immediately after stabilization from the hospitals where such medical attention can not be provided.

The first step in managing these seriously ill patients is to stabilize them and assess fetal status with a nonstress test and ultrasound examination for a biophysical profile.

Intensivist, hepatologist, nephrologist, hematologist, surgical, gynecologist, and neonatologist consultations should be considered promptly to comanage them.

Patients with severe hypertension should be immediately started on intravenous labetalol, hydralazine, or nifedipine.

Patients with severe right upper quadrant or epigastric pain and elevated liver function tests should be evaluated promptly with a bedside ultrasound to rule out liver rupture, fulminant liver failure, or hepatic bleeding and may need to be confirmed with computed tomography (CT) or magnetic resonance imaging(MRI).[16] Surgical intervention, including liver transplantation, may be needed if there is evidence of liver rupture. Less invasive percutaneous embolization of the hepatic arteries may be considered in stable patients.

Management is mainly supportive in patients with DIC, pulmonary edema, acute respiratory failure, and acute kidney injury and should be stabilized according to the clinical guidelines. 

Massive transfusions may be required. Consider patients for red cell transfusion if hemoglobin is <7gm/dl or if the patient has ecchymosis, severe hematuria, or suspected placental abruption. All actively bleeding patients with any degree of thrombocytopenia should be transfused with platelets. Patients with coexisting DIC may need fresh frozen plasma and cryoprecipitate.[15]

Patients with HELLP syndrome and coexisting TTP will benefit from therapeutic plasma exchange.[17]

Patients should be referred immediately to a gynecologist to consider prompt delivery as it is the only effective treatment. Betamethasone administration is recommended for fetal lung maturity when the patient presents at <34 weeks of gestation. Magnesium sulfate should be initiated at the time of admission to prevent maternal seizures and neuroprotective effects on the fetus/neonate. In two large double-blind, randomized trials, there was no proven benefit to administering dexamethasone in patients with HELLP syndrome as it did not improve maternal or perinatal/infant outcomes.[18][19]

Differential Diagnosis

HELLP syndrome should be differentiated from other disorders of pregnancy with similar features.[1][20] The following are some of the important differentials:

1. Pre-eclampsia with DIC: Usually, patients present in the 3rd trimester similar to HELLP syndrome. Pre-eclampsia with DIC Involves clotting factors and causes increased PT and PTT, unlike HELLP syndrome. Patients will have hypertension and proteinuria similar to HELLP syndrome patients.
2. Acute fatty liver of pregnancy (AFL): This is present in the third trimester, similar to patients with HELLP syndrome. These patients mainly have an obstructive pattern of liver injury. Direct bilirubin is elevated, unlike in patients with HELLP syndrome. Ammonia is elevated in these patients. Hypoglycemia is present, unlike in HELLP syndrome.
3. Thrombotic thrombocytopenic purpura (TTP): patients mainly present in the first trimester, unlike patients with HELLP syndrome. They have a characteristic pentad: fever, altered mental status, acute kidney injury/hematuria, hemolytic anemia, and thrombocytopenia. Clotting factors are not affected(PT/PTT normal). Patients are typically normotensive without proteinuria. ADAMTS-13 is low with increased VWF multimers.
4. Pregnancy-related hemolytic-uremic syndrome (HUS) is caused secondary to congenital syndrome leading to complement activation, unlike traditional HUS related to E.coli 0157:H7. They have a TTP-like picture but without fever or AMS. ADAMTS 13 is not lowered. They have increased WVF multimers. Treatment is eculizumab in these patients.
5. Systemic Lupus erythematosus flare-up: They may have thrombocytopenia and hemolytic anemia. Liver function tests are normal, and jaundice is absent in lupus. Hypertension and proteinuria may be present similar to HELLP syndrome. They have other typical characteristics of lupus-like malar rash, pleuritis, arthritis, and pericardial effusion.
6. Antiphospholipid syndrome (APS): They may have hemolysis and thrombocytopenia. Liver function tests are normal. They may have hypertension and proteinuria like patients with HELLP syndrome. Dominant features of APS are recurrent arterial/venous thrombosis and repeated spontaneous abortions <10 weeks gestation or fetal loss. Elevated Lupus anticoagulant, anti-cardiolipin antibodies, and beta2-glycoprotein antibodies are needed for diagnosis.[21]
7. Other: Fulminant Viral hepatitis should be considered in the differential. Appropriate testing and history will lead to the diagnosis.

Prognosis

HELLP syndrome is a life-threatening condition. The mortality rate of women with HELLP syndrome is 0%-24%, with a perinatal death rate of up to 37%.[11] Maternal death occurs due to disseminated intravascular coagulation (DIC), placental abruption, postpartum hemorrhage, or acute renal failure. DIC occurs in 15% to 62.5% of the cases. Placental abruption occurs in 11% to 25% of women with HELLP syndrome. Postpartum hemorrhage occurs in 12.5% to 40% and acute renal failure in 36% to 50% of the cases. Poor perinatal prognosis is because of placental abruption, intrauterine hypoxia, asphyxia, prematurity, and low birth weight.[22]

Patients with HELLP syndrome have a 19% to 27% risk of developing HELLP syndrome in subsequent pregnancies. Recurrent cases occur in the latter part of the gestation period and are less severe after two episodes.[23]

Complications

HELLP syndrome is a life-threatening condition with high maternal and infant mortality rates. Maternal complications include:

1. Eclampsia
2. Placental abruption
3. Cesarean section
4. DIC
5. Recurrent thrombosis
6. Liver rupture/hematoma
7. Fulminant liver failure
8. Cerebral infarction
9. Cerebral hemorrhage
10. Pulmonary/cerebral edema
11. Cardiovascular instability
12. Acute kidney injury
13. Infection/sepsis
14. retinal detachment
15. severe peripartum bleeding
16. Maternal death[24][22]

Fetal complications include:

1. Perinatal death
2. Intrauterine growth restriction (IUGR)
3. Preterm birth
4. Neonatal thrombocytopenia,leukopenia,neutropenia
5. Respiratory distress syndrome[22]

Consultations

• Intensive care
• Anesthesiology
• Pediatrics/neonatology
• Maternal-fetal medicine
• Hepatology
• Surgery
• Nephrology
• Hematology
• Opthalmology

Deterrence and Patient Education

Patients with HELLP syndrome should be educated about the course of the disease. The risk of maternal and perinatal complications and mortality should be explained to the patient and their family. The risk of developing HELLP in subsequent pregnancies may be decreased by maintaining a healthy lifestyle and preventing diseases such as hypertension and diabetes. Regular exercise should be followed. Routine prenatal care and laboratory testing must be initiated early in the subsequent pregnancies.

Enhancing Healthcare Team Outcomes

The management of HELLP syndrome, a disorder of pregnancy, requires input from multiple specialties in addition to an obstetrician. Acute complications and supportive management, including blood pressure control, management of pulmonary edema, and monitoring volume status, can be managed by a hospitalist. Acute respiratory failure needing ventilator support and shock needing pressors may be comanaged by a hospitalist and an Intensivist. If the patient needs a large volume of blood products, it would be in the patient's best interest to have hematology involved in the care. A nephrologist may be involved if the patient develops acute kidney injury. Hepatology and surgical team involvement is needed if the patient develops complications like liver hematoma or rupture. Ophthalmologist input may be necessary if the patient develops any vision changes. A neonatologist may be involved early to avoid any neonatal complications.

Managing HELLP syndrome also requires interprofessional team management. In addition to the clinicians above (which includes physicians as well as mid-level practitioners, i.e., NPs, and PAs), nursing staff and pharmacists can make significant contributions to patient care. Nursing will provide support for evaluation and surgical interventions, and the pharmacist a perform medication reconciliation for medications needed as part of treatment or post-surgically. All interprofessional team members must alter the rest of the team if there are any changes in clinical status and document their findings in the patient's health record. This interprofessional team approach will help drive positive patient outcomes in managing HELLP syndrome. [Level 5]