Protein C Deficiency

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ESPR146
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History:

A three-day-old full term male infant was transfered from an outside hospital with left lower leg bruising and concerns of ischemia. He was born to a 37 year old G3P1011 mother via vacuum-assisted repeat Cesarean delivery with APGAR scores 9 and 9. The mother had poor prenatal care, severe preeclampsia, and gestational diabetes mellitus controlled with diet. Family history was non-contributory. Maternal blood type was O+. All prenatal labs were negative, including HIV, SARS-CoV-2 PCR, and COVID-19 antibodies, but her GBS was unknown at the time of delivery. Infant received prophylactic vitamin K was given intramuscularly shortly after birth.Within a few minutes of life, patient developed respiratory distress and failure requiring intubation and mechanical ventilatory support. Chest X-ray was consistent with severe respiratory distress syndrome (RDS)/congenital pneumonia. He was started on empiric antibiotics (Ampicillin and Gentamicin) for presumed sepsis and also received one dose of surfactant for severe RDS. Patient also developed severe hypotension requiring normal saline boluses, dopamine, and hydrocortisone. Inhaled nitric oxide (iNO) was started for possible persistent pulmonary hypertension but echocardiogram at the outside hospital showed a small patent ductus arteriosis and patent foramen ovale and no significant pulmonary hypertension. Baby remained unstable and critical. On day three of life, the patient was noticed to have bluish discoloration and undetectable pulses in the left lower extremity with no spontaneous movement in left foot. He was transferred to our hospital for further management and evaluation.


Physical Exam:

Upon admission, infant was placed on high frequency oscillator ventilator with iNO. Echocardiogram at our hospital was suggestive of pulmonary hypertension. Infant was appropriate for gestational age for weight, head circumference, and height (25th, 20th, 54th). 

Pertinent physical examination findings included bluish discoloration of the left lower extremity extending from the mid-thigh to the foot with undetectable left femoral, popliteal, and dorsalis pedis pulses. Right femoral pulses were palpable. He had no other rashes or skin changes. He had a systolic murmur on auscultation of the heart. He was sedated due to intubation with minimal movements.


Laboratory testing and/or diagnostic imaging:

Screening blood work was performed including CBC, electrolytes, and clotting factors. Patient's CBC was significant for thrombocytopenia (42 K/uL). CMP was largely unremarkable. Blood culture remained negative. He had elevated clotting times with PT of 16.0 seconds, aPTT of 50.0 seconds, and an INR of 1.43. Protein C functional assay with reflex was <10% (normal range 74-150%) and protein C antigen assay was 23.8% (normal range 59-155%). 

Echocardiogram was significant for moderately dilated right ventricle, moderate global hypokinesia of the right ventricle, significant systolic flattening of the interventricular septum and subtle bowing of the septum in the systole towards LV, and severely elevated right ventricular and pulmonary arterial pressure, predicted systemic. 

Bilateral lower extremity arterial doppler showed no flow detected within the right superficial femoral and popliteal arteries, and within the left common femoral, superficial femoral, and popliteal arteries. Hypoechoic material were present bilaterally, suggesting bilateral acute arterial thromboses.

The patient's parents were tested for protein C deficiency and have normal protein C levels.


Final Diagnosis:

Acquired protein C deficiency, likely secondary to sepsis/hypoxia.

Infant was aggressively managed by multidisciplinary teams and was started initially on heparin. Anticoagulant was subsequently changed to tissue plasminogen activator (tPA) after doppler was suggestive of arterial thrombosis. Baby received multiple transfusion of platelets and fresh frozen plasma. Wound care was done by nitropaste initially, followed by plurogel on viable tissue and collagenase on dying tissue. As patient started improving and repeat doppler was negative for any arterial or venous clots, patient's anticoagulation therapy was transitioned to Lovenox subcutaneous injections. Baby was subsequently weaned off iNO and successfully extubated on day of life seventeen.

As foot started demarcating at mid dorsal level, patient was followed closely and amputation of the left foot was performed at the trans-metatarsals of all digits with stravix graft on day forty-four of life. Postoperatively baby remained stable and discharged home on day of life fifty-five. Follow up in neonatal high risk clinic on day of life eighty showed well healing left mid-foot with pink well-perfused tissue.


Discussion:

Neonatal thromboembolic phenomenon is an uncommon and scary event that can be associated with devastating outcomes and death. Incidence of thromboembolism is significantly low in children as compare to adults, but neonates are at the highest risk for developing thromboembolic event among children. The transition from intrauterine to extrauterine life is associated with circulatory changes and triggers such as genetic factors, infections, and asphyxia which predispose newborns to arterial and venous thrombi.

Protein C is an anticoagulant protein and play a complex and important role in maintaining hemostasis and microcirculation. Protein C deficiency increases the risk for thromboembolic event. Protein C deficiency is a rare disease and can cause by congenital (hereditary) or acquired form. Our patient had severe multiple arterial thrombi and purpura fulminans, likely secondary to the acquired form of protein C deficiency. Acquired protein C deficiency can occur in several conditions, including severe infections and hypoxia.

Our patient was a term baby who did not have significant risks for infection. However, the baby developed severe respiratory distress/hypoxia at birth which may have precipitated the cascade of reaction leading to purpura fulminans and arterial thrombi. Anticoagulation therapy was started upon arrival in our tertiary center. Baby responded to the anticoagulant therapy and we were able to savage his left foot just proximal to the mid-tarsal level. 

It is important to recognize the ischemia/necrosis leading to purpura fulminans early in the course as it can compromise the organ function in the affected neonate. Physician should be aware of the possibility of protein C deficiency (congenital and acquired) in newborns presenting with skin necrosis and its rapid progression. Neonates should be appropriately screened and treated aggressively to improve neonatal outcome. Multidisciplinary team approach is the key for successful patient care and outcome.

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Northwell Health - Cohen Children's Medical Center
Northwell Health - Cohen Children's Medical Center
Cohen Children Medical Center ,Northwell Health

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