History:
The patient is a preterm infant born at 29 3/7 weeks of gestational age to a 28-year-old G1P0 with negative prenatal labs. The mother had antenatal complications of pre-eclampsia. The baby was in bubble CPAP in the NICU and the initial cord blood culture was positive for Streptococcus anginosus for which he was treated with antibiotics for 7 days. PICC line was placed for total parenteral nutrition and antibiotics, and the line was later removed. Screening Head Ultrasound at one week of life was normal.
Around three weeks of life, the patient had an acute decompensation of significant bradycardia with desaturation to 30s. He was started with face mask positive pressure ventilation on 100%FiO2 initially with no response and then had to be intubated. The blood gas showed significant hypoxemia with hypercarbia and was switched to oscillator from conventional mechanical ventilation. The patient was started on dopamine and hydrocortisone for hypotension. Initial echocardiogram showed increased right ventricular systolic pressure with moderate RV dilatation; started on nitric oxide. With persistent low MAPs and decreased ventricular function, he was started on Milrinone.
Physical examination:
Vitals: Temp 36.9, HR 162, Saturation was 65% on 100% FiO2 post-intubation (on nitric oxide), BP 37/23 (MAP: 28). Physical exam showed dusky extremities with capillary refill 4 seconds; otherwise, the rest of the exam is benign.
Investigation:
With no improvement in clinical status after 24 hours, a repeat echo was performed which showed large pulmonary thromboembolism obstructing the right pulmonary artery, with extension into the left pulmonary artery (Figure 1). Head ultrasound showed dural venous sinus thrombosis; the abdominal US showed the right renal vein thrombosis with extension into Inferior vena cava. Sepsis workup at the time of decompensation came back positive for Staphylococcus hominins.
Final Diagnosis:
Pulmonary thromboembolism
Management:
A multidisciplinary team meeting was held between NICU, Cardiology, Neurology, and Hematology. Per the interventional cardiology team, the options of mechanical thrombolysis such as Angiojet vs catheter-directed tPA (tissue plasminogen activator) are of high risk for two reasons – relative contraindication in the setting of sepsis, and introducing a catheter through the right ventricle to the pulmonary arteries in the setting of right ventricular dysfunction and pulmonary hypertension can induce sudden cardiac arrest and death.
Systemic thrombolysis started with tPA after explaining the risks and benefits to the parents. Prophylactic heparin infusion started; FFP is given and coagulation profile was closely monitored. Repeat echocardiogram at 60 hours life showed complete resolution of pulmonary thromboembolism with good flow in both pulmonary arteries (Figure 2), and tPA infusion was stopped. Switched to therapeutic unfractionated heparin (UFH) infusion which was later changed to low molecular weight heparin (LMWH). Repeat renal US was normal; MRA/MRV showed non-occlusive thrombus in superior sagittal sinus and right transverse sinus but there was no white matter injury in MRI Brain. He was weaned off the respiratory support slowly and the patient was discharged home on LMWH.
Post-discharge Follow up:
The hematology clinic tested for factor II/V mutation which came back negative; also protein C/S clot activity was normal. LMWH discontinued after 3 months of treatment. Repeat echocardiogram at cardiologic clinic visit was normal. His developmental milestones were appropriate at 1 year of age.
Discussion:
The incidence of neonatal thrombosis is 5.1 per 100,000 live births; 2.4 per 1000 NICU admissions of which 45 to 55% of them are premature neonates. Venous thrombosis is more common than arterial thrombosis.
Etiopathogenesis: Two factors that contribute to the hypercoagulable state in newborns are:
- Anti-thrombin, protein C, and protein S level are reduced in the newborn period (30 % compared to adults)
- The reduced activity of the fibrinolytic system (decreased plasminogen and increased plasma levels of plasminogen activator inhibitor).
The intravascular catheter is one of the most common acquired cause of thromboembolism. Other risk factors include sepsis, hypotension, dehydration, congenital heart disease, post-cardiac surgery, and perinatal asphyxia. The incidence of prothrombotic disorders is rare and the most common inherited conditions are antithrombin deficiency, protein C/S deficiency, factor 5 Leiden mutation.
Pulmonary thromboembolism: It is a rare event in the neonatal period. Patients can present with massive V/Q mismatch, difficulty in oxygenation, and signs of right heart failure. An echocardiogram can miss the diagnosis but a CT angiogram is more sensitive. Cardiac catheterization with angiography is the gold standard. Management options include the following:
- Anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin(LMWH)
- Potentiates the inhibitory effect of antithrombin on thrombin and Factor Xa
- UFH: Initial bolus dose of 75 U/kg - -> Followed by continuous infusion of 28 U/kg/hr - -> Titrated to a target aPTT or anti Xa level. Goal: aPTT of 1.5 to 2.5 times the control value; anti X a level of 0.35 – 0.7. Adverse effect: Includes bleeding (Management: Stop heparin infusion and give Protamine sulfate) and can also cause heparin-induced thrombocytopenia (more common in adults; but if it happens, use other anticoagulants like factor Xa inhibitors such as fondaparinux, rivaroxaban or direct thrombin inhibitors such as argatroban).
- LMWH: More predictable pharmacokinetics but longer half-life. Therapeutic dose: 1.5 mg/kg/dose q12; prophylactic dose: 0.75 mg/kg/dose q12. Target anti Xa level: 0.5 to 1 U/ml for therapeutic dosing; 0.1 to 0.3 U/ml for prophylactic anticoagulation. Bleeding is of lower incidence compared to UFH
2. Thrombolytic therapy with t-PA
- Alteplase is the most commonly used. Indicated only in case of life-threatening embolism with clinical instability because of adverse effects; intracranial hemorrhage is seen in one-fourth of the neonates receiving thrombolysis.
- Plasminogen supplementation considered before tPA administration. tPA recommended dose is 0.5 mg/kg/hr. Lower dose can also be used: 0.06- 0.1 mg/kg/hr. Prophylactic UFH (10 U/kg/hr) administered concurrently for therapeutic heparinization post lysis. Goal is to maintain fibrinogen > 100, platelets >100. If there is intracranial bleeding, stop tPA and anticoagulation; start cryoprecipitate and add antifibrinolytic agents
3. Surgery and catheter-based embolectomy
- Used in case of unstable pulmonary embolism
- Interventional therapy:
A. Rheolytic thrombectomy: Angiojet uses high pressures at the tip to disrupt the thrombus and allow for aspiration in the low pressures zone. Catheters can spray saline or thrombolytic agents
B. Catheter-directed fibrinolysis: Infusion of the thrombolytic agent intravascularly adjacent to the clot burden through percutaneous transcatheter
- Surgery: Median sternotomy access with cardiopulmonary bypass. This is very rarely used as there is a high mortality rate. Also, there is the high rate of re-occlusion of the affected vessels.
Message to the clinician:
Our patient had risk factors for prothrombotic conditions which include prematurity, central catheter, sepsis, hypoxemia, and metabolic acidosis. Prothrombotic conditions during pregnancy in mothers can also lead to increased coagulation potential in babies. The benefit of identifying thrombophilia in the sick preterm newborns with risk factors may facilitate thromboprophylaxis. Further research regarding the assessment of risk factors, diagnostics, and treatment strategy is required
