Thrombotic microangiopathy in pregnancy: it's more than just a "classic triad"

Written by: Priya Yenebere, DO MS (@PriRenalAKI)

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Thrombotic microangiopathy (TMA) is a pathological process of thrombotic occlusion of systemic microvasculature, resulting in end-organ ischemia and infarction. Classically, we know this by a familiar triad: consumptive thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and acute kidney injury. TMA is characterized by the formation of fibrin-rich platelet clots in glomerular capillaries and arterioles. TMA can present either during pregnancy or in the postpartum period whereby early recognition is necessary as it impacts the health of both mother and newborn. While the differential for TMA is long in pregnancy, there are select diagnoses that must be considered, which we will discuss below.

1. Preeclampsia

2. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome

3. Acute fatty liver of pregnancy (AFLP)

4. Complement-mediated HUS (also known as atypical HUS [aHUS])

5. Thrombotic thrombocytopenic purpura (TTP)

(Adapted from Scully and Goel)

Preeclampsia

We discuss preeclampsia in a separate review, please visit here for more information.

HELLP

Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious, pregnancy-specific disorder characterized by the classic triad of increased transaminases, reduced platelet counts, and hemolysis. There have been accounts of partial or incomplete forms, where only one of two parts of the triad are present. Overall, this syndrome occurs in approximately 0.5 to 0.9% of all pregnancies but is seen in up to 10 to 20% of severe preeclampsia cases which can result in increased maternal and perinatal morbidity and mortality. While cardiopulmonary complications are already high in severe preeclampsia, they double to 12% in patients with HELLP syndrome.

Classically, this is seen during the third trimester with peak frequency between gestational weeks 27 through 37 but can also occur in the postpartum period, coupled with other morbidities. A large prospective cohort study of 442 pregnancies found that 30% of HELLP syndrome cases occurred postpartum, which were associated with an increased risk of serious maternal morbidity including disseminated intravascular coagulation (DIC), placental abruption, and acute renal failure. Overall maternal mortality was 1.1% in this study.

HELLP should be considered in the setting of epigastric or right upper quadrant pain and elevated AST or ALT levels (alkaline phosphatase levels are usually increased in normal pregnancy physiology). Hemolysis usually presents in the form of microangiopathic hemolytic anemia with red cell fragmentation (schistocytes) or contracted red cells with spicules (burr cells) on peripheral smear. Red cell destruction leads to increased serum lactate dehydrogenase (LDH) levels and decreased haptoglobin levels. Thrombocytopenia is a consumptive process, as activated platelets adhere to damaged vascular endothelial cells.

While there are different HELLP severity classifications (Table 1), these predict the risk for hemorrhagic complications rather than drive treatment plans. Hemorrhagic complications are higher in platelet counts less than 40 x 109/L. Similar to pre-eclampsia, the definitive treatment of HELLP is the delivery of the fetus. However, gestational age is very important when making this decision. Prompt delivery is most acceptable for gestational age greater than 37 weeks in the setting of HELLP syndrome. Management may also include immediate hospitalization, seizure prophylaxis with magnesium sulfate, and corticosteroids for gestational weeks 25 through 34 to minimize the risk of infant respiratory distress syndrome.

(from Haram et al.)

Acute fatty liver of pregnancy (AFLP)

There is noticeable overlap between HELLP syndrome and AFLP. AFLP is a rare but life-threatening cause of liver failure, multiorgan involvement, and coagulopathy affecting about 2 to 3 thousand patients annually. Although rare, it is considered the most common cause of acute liver failure in pregnancy - more common than hepatitis and drug-induced etiologies. AFLP occurs during the third trimester with nonspecific symptoms of malaise, anorexia, nausea and vomiting. More worrisome symptoms such as right upper quadrant pain and jaundice can be observed. Usually, there is no associated hypertension or proteinuria, but metabolic acidosis, acute liver failure, and low-grade DIC identified laboratory studies can be observed (see below for evaluation of AFLP). It is thought that AFLP is caused by mitochondrial dysfunction during the oxidation process of fatty acids. Delivery is the definitive treatment for AFLP. Interestingly, as the patient is severely coagulopathic, vaginal delivery is preferred over cesarean. AFLP improves within weeks of delivery, but may recur in subsequent pregnancies, although very rare.

(Nelson et al.)

Complement-mediated HUS (CM-HUS or C-HUS) or atypical HUS (aHUS)

CM-HUS (also known as atypical HUS) is a dysregulation disorder of the alternative complement pathway whereby complement protein mutations lead to an overactive complement cascade and eventual endothelial cell injury. Major complement gene mutations include factor H, factor I, membrane cofactor protein, factor B, complement component 3 (C3), and thrombomodulin. Similar complement gene mutations are seen in patients with preeclampsia and HELLP syndrome, demonstrating overlap between TMA conditions in pregnancy. CM-HUS triggers include medications, infections, or systemic illness, and pregnancy is considered a frequent trigger for CM-HUS, where 20% of cases occur prior to delivery and 80% of cases occur in the postpartum setting.

Clinical features usually reveal the classic triad of anemia, thrombocytopenia, and decreased renal function, in addition to schistocytes on blood smear, low haptoglobin levels, and high lactate dehydrogenase levels. ADAMTS-13 levels may be decreased, but not to the degree seen in TTP. Initial treatment for CM-HUS is similar to TTP with plasma exchange, but eculizumab can also be part of the treatment strategy in severe cases. Eculizumab is a recombinant, humanized, monoclonal antibody that binds to C5 which prevents its cleavage to C5a and C5b, necessary players in the overstimulated complement cascade. Eculizumab is safe to give during pregnancy, and prompt initiation of the medication is encouraged while the workup is pending. The risk of relapse in subsequent pregnancies is about 25%, with the greatest risk occurring in patients with complement factor H and I mutations. There is no data on starting treatment for high-risk cases once pregnancy is confirmed, but it may be considered in certain cases.

Thrombotic thrombocytopenic purpura (TTP)

TTP is a systemic disorder of microvascular thrombosis that is due to an inherited or acquired severe deficiency of von Willebrand factor (vWF)-cleaving protease called ADAMTS-13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13). During pregnancy, there are increased levels of Von Willebrand factor which may remain elevated in the postpartum period. There is also a relative decrease in ADAMTS-13 levels, but they are still within the usual normal range. In pregnancy-associated TTP, an ADAMTS-13 level of < 10% supports this clinical diagnosis. The classic pentad of TTP is as follows: 1) thrombocytopenia 2) MAHA 3) acute renal failure 4) fever 5) neurological changes, but this pentad is neither sensitive nor specific. A clinical prediction tool, called the PLASMIC score, has been developed to determine the risk of a patient developing severe ADAMTS-13 deficiency, as it is rare to present with the complete pentad of symptoms. The scoring tool takes into account the platelet count, evidence of hemolysis, active cancer diagnosis, history of transplant (solid-organ or stem-cell), mean corpuscular volume (MCV), INR, and creatinine level - the higher the score, the higher the risk of severe ADAMTS-13 deficiency. This score is helpful as timely results of ADAMTS-13 activity testing may be unavailable.

There are many TTP triggers (ie malignancy, infection, or medication), pregnancy is a well-recognized trigger of TTP and is referred to as pregnancy-associated TTP or pregnancy-related TTP. While congenital and acquired TTP are associated with pregnancy-onset TTP, congenital TTP is often triggered by the first pregnancy and carries a maternal mortality rate of more than 90% if left untreated. Pregnancy-associated TTP accounts for approximately 5 to 10% of all TTP cases and can happen at any stage of pregnancy but is most frequently observed in the third trimester and postpartum period.

TTP treatment relies on prompt plasma exchange therapy at the time of diagnosis (Figure 1 below). This differs from previously discussed pregnancy-related TMAs where delivery is the definitive treatment.

(Scully, Thomas, et al.)

Although HELLP, AFLP, aHUS, and TTP share pathological features of TMA, they carry distinct clinical courses and triggering events. While many of them are rare, they remain life-threatening, with high maternal and fetal morbidity and mortality, and should always be on the differential for maternal hypertension.

(Adapted from Vijayan, Critical Care 2019)

Reviewed by: Amy Yau MD, Sophia Ambruso DO, and Silvi Shah MD, MS

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.