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Case Report

The Application of ROTEM in a Parturient With Antiphospholipid Syndrome in the Setting of Anticoagulation for Cesarean Delivery: A Case Report

Fiol, Antonio Gonzalez MD*; Fardelmann, Kristen L. MD*; McGuire, Patsy J. MD*; Merriam, Audrey A. MD, MS; Miller, Alex MD; Alian, Aymen MD*

Author Information
A & A Practice: April 2020 - Volume 14 - Issue 6 - p e01182
doi: 10.1213/XAA.0000000000001182
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Abstract

Obstetric hemorrhage and thromboembolic events during pregnancy are significant contributors to preventable maternal morbidity and mortality.1 The use of point-of-care viscoelastic testing (POCVT) has gained acceptance at some institutions to guide peripartum transfusion therapy.2 Although clinically beneficial in most at risk obstetric patients, the presence of antibodies associated with antiphospholipid syndrome (APS) may limit its application.3 APS is an acquired autoimmune disorder associated with arterial and venous thromboses and adverse pregnancy outcomes.4 In addition to clinical manifestations, diagnostic guidelines require laboratory detection of antiphospholipid antibodies (aPL; ie, lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies). Triple positivity is a strong predictor of frequent APS-related events despite the use of anticoagulants.5 Although the exact mechanism for thromboembolism is unknown, it has been proposed that the antibodies associated with APS suppresses the function of protein C and S.6 In vitro, the aPL disrupts the phospholipid membranes necessary to elicit a coagulation reaction in most POCVT including prothrombin time (PT), activated clotting time (ACT), and rotational thromboelastometry (ROTEM).3,6

The management of APS consists of a combination of low dose aspirin (81 mg) and therapeutic or prophylactic unfractionated or low-molecular-weight-heparin depending on the patient’s venous thromboembolism history.4 On rare occasions, patients with aPL present with multiorgan failure as a result of small vessel thrombosis.5 Known as catastrophic antiphospholipid syndrome (CAPS), this is a potentially life-threatening complication requiring a high degree of clinical suspicion to avert morbidity and mortality.7 The diagnosis of CAPS can be challenging in pregnancy given the many potential mimics including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, heparin-induced thrombocytopenia, and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.7

We present the challenges and limitations associated with ROTEM (ROTEM delta; Finggal link Co Ltd, Tokyo Japan) when utilized in the management of a parturient with APS in the setting of thrombocytopenia, recent heparin administration, and intraoperative hemorrhage. Written informed (Health Insurance Portability and Accountability Act [HIPAA]) consent was obtained from the patient.

A 36-year-old gravida 6, para 1 at 27 weeks gestation with a known history of APS maintained on heparin 10,000 units twice a day presented to an outside hospital with chest pain. Initial workup revealed unremarkable chest x-ray, electrocardiogram (EKG), echocardiogram, and ventilation and perfusion scan. Troponins, liver function tests, creatinine, hemoglobin, and hematocrit were within normal limits. However, her platelet count was down-trending from 152 × 1000 µL to 80 × 1000 µL. The patient was transferred to our institution, shortly after receiving her last heparin dose.

On arrival, blood work revealed mildly elevated transaminases (aspartate aminotransferase [AST] 63 U/L and alanine aminotransferase [ALT] 57 U/L), normal creatinine 0.43 mg/dL, lactate dehydrogenase (LDH) 271 U/L, and a further decreasing platelet count to 57 × 1000 µL. Her coagulation profile revealed PT 12.8 seconds, activated partial thromboplastin time (aPTT) 120 seconds, international normalized ratio (INR) 1.2, and prolonged clotting time (CT) in intrinsic pathway (INTEM)-1870 seconds and extrinsic pathway (EXTEM)-567 seconds on ROTEM (Figure 1A). Heparinase assay (HEPTEM) CT of 901 seconds confirmed a contributing heparin effect. We determined her presentation to be most consistent with HELLP and attributed the chest pain to an epigastric origin. Hence, magnesium sulfate was initiated with a loading dose of 4 g over 15 minutes, and an infusion at 2 g/h for fetal neuroprotection and maternal seizure prophylaxis.

Figure 1.
Figure 1.:
Rotational thromboelastometry at baseline (before heparin reversal), during and after blood product management. A, Baseline ROTEM (INTEM, EXTEM, FIBTEM, and HEPTEM). The CT of INTEM, EXTEM, and HEPTEM were prolonged at 1870 s (normal range, 122–208 s), 567 s (normal range, 43–82 s), and 901 s, respectively. B, The CT of INTEM, EXTEM, and HEPTEM were prolonged at 624, 274, and 574 s, respectively. The INTEM/HEPTEM ratio was 1.08 (heparin neutralized). C, The CT of INTEM and EXTEM were prolonged at 347 and 230 s, respectively. α indicates degree of amplitude; A10, amplitude 10 min; CFT, clotting formation time; CT, clotting time; EXTEM, extrinsic pathway; FFP, fresh frozen plasma; FIBTEM, fibrin polymerization test; HEPTEM, heparinase assay; INTEM, intrinsic pathway; MCF, maximum clot firmness; ROTEM, rotational thromboelastometry.

Given the rapid decline in platelets, the decision was made to proceed with cesarean delivery (CD) 9 hours after the last heparin dose. After 4 units of fresh frozen plasma (FFP) and 1 unit of platelets, the patient was brought to the operating room and general anesthesia was induced. An arterial line was placed for frequent blood draws. Before incision, ROTEM revealed a prolonged CT in the INTEM-624 seconds, EXTEM-274 seconds, and HEPTEM-574 seconds (Figure 1B). A baby girl weighing 890 g was delivered via classical CD with APGAR (appearance, pulse, grimace, activity, respiration) score 2 and 9 at 1 and 5 minutes, respectively. The infant required intubation and transfer to the neonatal intensive care unit. After placental delivery, an oxytocin infusion was started at 18 units/h. Given the presence of surgical bleeding and suspected coagulopathy, 1 unit of platelets, 1 unit of packed red blood cells (PRBC), and 3 units of FFP were transfused in addition to intramuscular carboprost 250 µg, methylergonovine 0.2 mg, and intravenous tranexamic acid (1 g).

At procedure completion, hemostasis was excellent and blood loss was 1500 mL. The patient was extubated and transferred to our maternal special care unit. The postoperative laboratory evaluation revealed a hemoglobin of 9.5 g/dL, platelet count of 43 × 1000 µL, and prolonged CT in the INTEM-347 seconds and EXTEM-230 seconds (Figure 1C). Her platelet over the next 48 hours fluctuated between 43 × 1000 µL and 62 × 1000 µL. Prophylactic enoxaparin (40 mg twice a day) was started 12 hours after surgery, as per institutional thromboprophylaxis guidelines. On postoperative day 2, she experienced right lower extremity edema and pain prompting Doppler evaluation that demonstrated an acute on chronic nonocclusive thrombus in the right lower extremity. Transition to therapeutic enoxaparin (60 mg twice a day) ensued per obstetric institutional protocol. On postoperative day 3, her platelets were 38 × 1000 µL (Figure 2). Heparin-induced thrombocytopenia antibodies were negative.

Figure 2.
Figure 2.:
Platelet count throughout patient admission time. OP indicates operative.

Her postoperative course was complicated by worsening epigastric pain and hematuria on postoperative days 3–7. A computed axial tomography (CAT) scan demonstrated hypodensities scattered throughout the liver parenchyma, and a computed tomography angiography was negative for pulmonary embolism. On postoperative day 6, her platelet count was 9 × 1000 µL (Figure 2). Repeat abdomen and pelvis CAT showed hepatic hypodensities concerning for multifocal hemorrhage and a small left adrenal and right urothelial hemorrhage. Throughout her admission, 14 units of platelets were transfused aiming at maintaining a platelet count >20 × 1000 µL. Between postoperative days 6–12, her pain gradually improved, and hematuria resolved.

Given the development of multiorgan involvement, the differential diagnosis was broadened to immune thrombocytopenic purpura (ITP) and CAPS. Solumedrol 1 g/d, intravenous immunoglobulin (IVIG) 45 g, and a 1-time dose of rituximab 1400 mg were initiated. ITP was diagnosed based on normal blood smear and clinical improvement following steroids and IVIG. She was discharged on postoperative day 19.

APS can mask or imitate conditions such as HELLP, ITP, hemolytic uremic syndrome (HUS), TTP, and CAPS.8,9 This patient’s diagnosis was challenging given concerns for CAPS and HELLP. Despite a broad deferential, it was essential to balance the therapeutic management of the patient while a definitive diagnosis was reached, as these vary based on cause.

In HELLP syndrome, the associated endothelial damage has been implicated with disseminated intravascular coagulation and severe postpartum hemorrhage.8 Similarly, ITP poses a heightened risk of postpartum hemorrhage.10 In contrast, APS and CAPS are strongly associated with complications related to thromboembolic events despite prolonged CT and low platelets.9 Hence, accurate evaluation of the recently administered heparin was required to guide blood product resuscitation. Given the initial INTEM and HEPTEM CT, we concluded that heparin was a contributing factor, but an underlying coagulopathy was likely. Hence, FFP and not protamine was used for heparin reversal and correcting any underlying factor deficiency. In addition, platelets were transfused for a platelet count of 51 × 1000 µL.

POCVT has been previously described in patients with APS and concomitant use of heparin.3,6 When utilizing ROTEM, one must recognize the limitations associated with the device in the presence of aPL. Hensch et al11 described a prolonged CT of 1.6 (1.3–1.7) and 1.7 (1.4–2.0) times the upper limit of the normal range for INTEM and EXTEM, respectively, in nonpregnant patients with aPL. Of note, the CT during pregnancy has been reported to be 7.3% lower than the manufacturer reference range.12 Additional limitations of ROTEM include inadequate ability to detect platelet functionality and low von Willebrand factor.12 This is reflected in our case by a normal maximum clot firmness (MCF) despite a persistent low platelet count (Figure 1A–C).

The use of an INTEM/HEPTEM CT ratio of 1 has been described to monitor heparin reversal in cardiac literature.3,6 In our case, the second INTEM/HEPTEM CT ratio was 1.08 (Figure 1B), confirming reversal. Other systems for heparin reversal include HepCon and Hemochron. Both systems consist of mixing heparinized blood into a series of channels or an ACT with a known concentration of protamine, respectively. In HepCon, the sample with the earliest blood clot formation is utilized to calculate heparin concentration, whereas Hemochron relies on the ACT result and the patient’s estimated blood volume to calculate the protamine dose needed.13 Fahy et al14 describe the use of HepCon to confirm heparin neutralization before an epidural placement.

In conclusion, the correct interpretation and management of the hemostatic status of a parturient with APS can be challenging. When possible, obtaining POCVT before starting anticoagulation could provide a baseline target value and improve our ability to guide blood product transfusion. For patients with APS who require heparin neutralization, protamine or FFP can be used and the INTEM/HEPTEM ratio may aid to monitor the reversal. Antifibrinolytic administration is controversial and should be reserved for patients demonstrating hyperfibrinolysis; in ROTEM, this would be reflected by a maximum lysis >15%.3,6 Patients with APS should restart their anticoagulation management as soon as possible. The use of ROTEM can help perform rapid coagulation assessments and individualize transfusion management during the intraoperative period.

DISCLOSURES

Name: Antonio Gonzalez Fiol, MD.

Contribution: This author helped write the manuscript.

Name: Kristen L. Fardelmann, MD.

Contribution: This author helped write the manuscript.

Name: Patsy J. McGuire, MD.

Contribution: This author helped write the manuscript.

Name: Audrey Merriam, MD, MS.

Contribution: This author helped write the manuscript.

Name: Alex Miller, MD.

Contribution: This author helped write the manuscript.

Name: Aymen Alian, MD.

Contribution: This author helped write the manuscript.

This manuscript was handled by: Kent H. Rehfeldt, MD.

GLOSSARY

α = = degree of amplitude;

A10 = = amplitude 10 min;

ACT = = activated clotting time;

ALT = = alanine aminotransferase;

APGAR = = appearance, pulse, grimace, activity, respiration;

aPL = = antiphospholipid antibodies;

APS = = antiphospholipid syndrome;

aPTT = = activated partial thromboplastin time;

AST = = aspartate aminotransferase;

CAPS = = catastrophic antiphospholipid syndrome;

CAT = = computed axial tomography;

CD = = cesarean delivery;

CFT = = clotting formation time;

CT = = clotting time;

EKG = = electrocardiogram;

EXTEM = = extrinsic pathway;

FFP = = fresh frozen plasma;

FIBTEM = = fibrin polymerization test;

HELLP = = hemolysis, elevated liver enzymes, and low platelets;

HEPTEM = = heparinase assay;

HIPAA = = Health Insurance Portability and Accountability Act;

HUS = = hemolytic uremic syndrome;

INR = = international normalized ratio;

INTEM = = intrinsic pathway;

ITP = = immune thrombocytopenic purpura;

IVIG = = intravenous immunoglobulin;

LDH = = lactate dehydrogenase;

MCF = = maximum clot firmness;

OP = = operative;

POCVT = = point-of-care viscoelastic testing;

PRBC = = packed red blood cells;

PT = = prothrombin time;

ROTEM = = rotational thromboelastometry;

TTP = = thrombotic thrombocytopenic purpura

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