Protein C deficiency in Neonate - rare presentation

20 day old new born presenting with loose motions and blackish discoloration of the distal phalanxes.
extensive work up done for sepsis and bleeding diathesis, finally the diagnosis of purpura fulminans was made and the baby was managed on these lines and treated to be discharged successfully.

1. PROBLEM CASE PRESENTATION DR. NOUREEN MUSHTAQ FCPS TRAINEE NICU/NICH

2. BIO DATA : B/O TAHIRA GENDER: FEMALE D.O.B: 26TH TH FEB 2023 D.O.A: 25 TH MARCH 2023 WEIGHT: 2.7KG BIRTH WEIGHT WAS 2.6KG RESIDENT OF: GARDEN KARACHI

3. PRESENTING COMPLAIN: PRESENTED IN ER WITH C/O: LOOSE STOOL FOR 6 DAYS BLACK DISCOLORATION OF RIGHT 4 th DISTAL PHALANX AND LEFT 4 th AND 5 TH DISTAL PHALANX OF HAND FOR 5 DAYS RELUCTANT TO FEED FOR 2 DAYS

4. HOPC : According to mother baby was alright till 20 th day of life then developed complain of loose stool that was 8 to 10 episodes per day, yellow in color watery consistency, not containing blood, associated history of reluctant to feed for 2 days. During this period mother noticed blackish discoloration of distal end of baby’s right 4 th distal phalanx and left 3 rd and 4 th distal phalanx which was progressing gradually.

5. For these complains first they visited to local clinic where baby had been prescribed antibiotics but no improvement occur, at 26th th day of life they took the baby to NICH ER, where baby was admitted, and retained in ER for one day then shifted to NICU on 27 th DOL. There was no history of bleeding from other sites, fever, rash, vomiting, trauma, no hx of previous blood transfusion.

6. BIRTH HISTORY: ANTENATAL HISTORY: BOOKED CASE AT 7 TH MONTH OF GESTATION, NO REGULAR ANTENATAL VISITS DONE 2 ULTRASOUND SCANS DONE THAT WERE ALL NORMAL MULTIVITAMIN AND FOLIC ACID SUPPLEMENTS WERE TAKEN TETNUS TOXOID WAS GIVEN NO HISTORY OF DIABETES, HYPERTENSION OR ANY OTHER CHRONIC ILLNESS DURING PREGNANCY NO HISTORY OF DRUG USE DURING PREGNANCY NO HISTORY OF FEVER RASH BURNING MICTURITION DURING PREGNANCY

7. NATAL HISTORY: BORN AT 38 TH WEEK OF GESTATION VIA SVD AT FATMIYAH HOSPITAL DUE TO PREVIOUS TWO CESAREAN DELIVERIES. NO HISTORY OF EXCESSIVE BLOOD LOSS, PROM, CPD, OBSTRUCTED LABOUR, MATERNAL FEVER, AT THE TIME OF DELIVERY.

8. POST NATAL HISTORY: CRIED IMMEDIATELY AFTER BIRTH. NO HISTORY OF CYANOSIS, MECONIUM ASPIRATION, OR JAUNDICE DURING FIRST DAY OF LIFE. PASSED URINE AFTER 1 HOUR OF BIRTH, AND STOOL AFTER 6 HRS OF BIRTh . FEEDING STARTED AFTER 4 HOURS OF BIRTH, TOP FEED STARTED.

9. FEEDING HISTORY: BABY WAS ON TOP FEED FROM FIRST DAY OF LIFE BECAUSE OF NO LACTATION FROM MOTHER. SIMILAC FORMULA FEED WAS GIVEN TO BABY, WITH DILUTION OF 1:1 IN BOILED WATER. 1.5 Oz MILK GIVEN EVERY 2 TO 3 HOURLY TO BABY. FEED WAS GIVEN THROUGH BOTTLE FEEDER, WHICH THEY USED TO WASHED AFTER EVERY FEED WITH SOAP AND BOIL THAT FEEDER TWICE A DAY.

10. VACCINATION HISTORY: NO VACCINATION DONE.

11. FAMILY HISTORY: 10 TH PRODUCT OF CONSANGINOUS MARRIAGE. HISTORY OF ONE PREVIOUS MISCARRIAGE. OTHER SIBLINGS ARE ALIVE AND HEALTHY. NO HISTORY OF ANY BLOOD DISORDER OR HERIDITARY DISEASE IN FAMILY. FAMILY HISTORY WAS UNREMARKABLE.

12. SOCIOECONOMIC HISTORY: FATHER IS RIKSHAW DRIVER, AND IS THE ONLY SOURCE OF EARNING. LIVE IN OWN HOUSE, TWO ROOMS, AND 12 MEMBERS LIVE . THEY DRINK UNBOILED WATER.

13. GENERAL PHYSICAL EXAMINATION: SICK LOOKING, LETHARGIC BABY, WITH WEAK CRY, HAVING VITALS OF: HR = 169 bpm RR = 79 breath/min TEMP = A/F SpO2 = 97% on room air on 3 lit of oxygen via nasal prong. RBS = 102mg/dl

14. SUBVITALS: THERE WAS NO ANEMIA, JAUNDICE, EDEMA and CYANOSIS. DYSNEA(marked) and DEHYDRATION(some) were present.

15. ANTHROPOMETRIC MEASUREMENTS: WEIGHT = 2.7KG (AT 25 TH CENTILE) LENGTH = 51CM (AT 75 TH CENTILE) FOC = 36.5CM (AT 50 TH CENTILE)

16. LOCAL EXAMINATION: There was obvious black gangrenous changes of distal end of right 4 th phalanx and left 3 rd and 4 th phalanx of about 0.5-1cm. Also slight discoloration of right middle finger. erythema around gangrene present.

17. HEAD TO TOE EXAMINATION: Head normal in shape with open ant fontanelle of 2*2cm No cataract formation or any other abnormal features in eye. Facial features were normal, no coarse facies or dysmorphic features present. Normal back and spine examination. Normal looking female genitalia. No any bruises, rash, or deformity noted.

18. CNS Examination: spontaneous eye opening and limb movement. Pupils were bilaterally equally reactive to light. Fontanelles were sunken, 2*2cm in diameter. Tone slightly increased in all four limbs, posturing. Power was 5/5 in all four limbs. Neonatal reflexes: Moros = incomplete Sucking = fair Rooting = fair Grasp = fair

19. RESPIRATORY SYSTEM EXAMINATION: Chest was moving bilaterally symmetrical during respiration, with marked subcoastal and intercostal recessions, with rapid deep breathing. No chest deformity were present on inspection. Trachea was centrally present. Bilateral equal air entry on auscultation, no added sound was present.

20. ABDOMINAL EXAMINATION: Normal in shape, moving symmetrically with respiration. Centrally placed umbilicus, no pus or any other discharge were there from umbilicus. Soft non tender abdomen on palpation, liver was palpable 3 cm below costal margin, spleen not palpable. Gut sounds were audible.

21. CARDIOVASCULAR EXAMINATION: Normal shape of precordium, with no visible pulsation, scar mark or bulging. Apex beat was present in 4 th ICS, medial to mid clavicular line No thrill or heave present. S1 and S2 were audible without any murmur. All peripheral pulses were palpable, were regular, weak pulses. No radio-radial or radio-femoral delay were present. CRT was less than 3 seconds.

22. PROVISIONAL DIAGNOSIS: TERM, AGA, NORMAL BIRTH WEIGHT BABY: Acute Gastroenteritis with thromboembolic phenomena secondary to dehydration Sepsis/DIC Thrombophilia secondary to : Protein C or S deficiency Factor 5 Leiden mutation Antithrombin 3 deficiency

23. INVESTIGATIONS:

24. CBC: 25/3/23 Hb 12gm/dl WBCs 2 6.7k Neutrophils 75% Lymphocytes 21.4% Eosinophils 2% Monocytes 2% Plateletes 54k CBC: 27/3/23 9.1gm/dl 13.4k 73% 25% 2% 2% 149k CBC: 31/3/23 9.6gm/dl 13.4k 57% 38% 2.8% 198k CBC: 2/4/23 10.5gm/dl 8.8k 55% 40% 2.1% 2% 178k

25. UCEs: 25/3/23 RBS 102gm/dl urea 109mg/dl s.creatinine 1.2mg/dl s.sodium 156meq/lit s.potassium 3.9meq/lit s.chloride 129meq/lit s.calcium 9.2meq/lit UCEs: 26/3/23 156gm/dl 120mg/dl 1mg/dl 154meq/lit 3.5meq/lit 128meq/lit 9meq/lit UCEs: 31/3/23 127gm/dl 130mg/dl 0.3mg/dl 151meq/lit 4meq/lit 107meq/lit 8.9meq/lit UCEs: 2/423 190gm/dl 12mg/dl 0.2mg/dl 146meq/lit 4.3meq/lit 111meq/lit 9meq/lit

26. LFT: Mg Total bili SGPT ALP Albumin PT APTT 2.2 0.4 17 110 2.7 14.4 21.6

27. ABGs: 25/3/23 pH 7.27 pCO2 39 mmHg pO2 110mmHg BEecf -19mmol/lit HCO3 10mmol/lit 2/3/23 7.27 37 mmHg 102mmHg -8mmol/lit 20mmol/lit

28. Blood C/S: Shows no bacterial growth.

29. FINAL DIAGNOSIS: TERM/AGE/Normal Birth Weight Protein S deficiency secondary to???

30. COURSE IN NICU: IV line maintained Kept on 3lit oxygen via nasal prong Kept NPO initially Vitals/RBS monitoring done IV fluids first NS bolus from 15ml/kg given twice then IV fluid 2/3 RD 0.45 % DS/5% DW from 200ml/kg/day started Antibiotic Inj. Cefotaxime and Inj. Ampicilin started Inj. Phenytoin for increased tone started Labs were sent

31. FFPs in BD was transfused for initial 1week. Topical application of GTN started on fingers Workup for diagnosis done Repeat ABGs and UCEs were sent after giving two boluses of NS which shows improved blood gases and metabolic acidosis. One other bolus of NS from 20ml/kg was given with monitoring of sign of volume overload. After that blood gases and serum creatinine started to improve, but serum sodium was still on higher side, so managed according to protocol.

32. Feed via OG started and gradually increased. Injection Enoxaparin 1.7mg/kg/dose SC twice a day was started after sending workup for thrombophilia. Condition improved after 8 days and baby was stepped down to non critical area on DMF and on Room Air. Hematologist opinion also taken, and she advices to continue enoxaparin for 6 weeks and then repeat protein S function assay after stopping enoxaparin.

33. Prescription On Discharge: Continue Inj. Enoxaparin Stop IV antibiotic after 3 days of discharge Follow up in OPD Regular eye examination from ophthalmologist Plan to continue anticoagulation therapy for 6 weeks then repeat protein S level Follow up with Hemotologist

34. DISCUSSION:

35. Purpura Fulminans : Neonatal purpura fulminans describes a clinico -pathological entity of dermal microvascular thrombosis associated with disseminated intravascular coagulation (DIC) and perivascular hemorrhage, occurring in the newborn period. The clinical presentation is that of acute DIC and hemorrhagic necrosis of the skin.

36. The clinical severity may vary depending on the underlying cause, e.g. genetic variability of severe congenital protein C and S deficiencies. The onset of symptoms is usually within 2-12 h after birth. However, infants presenting with a delayed onset of purpura fulminans , between 6 and 12 months of age, are reported.The skin lesions initially appear dark red and then become purple-black and indurated

37. Etiology:

38. Protein S deficiency: Protein S deficiency is an inherited thrombophilia associated with an increased risk of thromboembolism. It serves as a cofactor for activated protein C, which inactivates procoagulant factors Va and VIIIa , reducing thrombin generation Protein S also serves as a cofactor for activated protein C in enhancing fibrinolysis and can directly inhibit prothrombin activation via interactions with other coagulation factors

39. Total protein S levels in healthy newborns at term are 15 to 30 percent of that in adults, while C4b-binding protein is markedly reduced to less than 20 percent. Thus, free protein S predominates and functional protein S levels are only slightly reduced compared with those in adults C4b-binding protein is an acute phase reactant. Thus, several of the conditions listed previously may be associated with a shift of protein S from the free form to the bound (inactive) form, potentially leading to an erroneous diagnosis of protein S deficiency

40. Genetics of protein S deficiency: Protein S deficiency (MIM 612336) is an autosomal dominant condition due to mutations in the PROS1 gene, a large gene on chromosome 3. Subsequently, a number of additional familial mutations have been described The majority of individuals with hereditary protein S deficiency are heterozygous for a PROS1 mutation, although rare homozygous or compound heterozygous individuals with much more severe clinical features have been reported

41. Types Of Congenital/Hereditary Protein S Deficiency: Type I – Type I deficiency (reduced total protein S, free protein S, and protein S function) is the classic type of inherited protein S deficiency. Type II – Type II deficiency (normal total and free protein S; reduced protein S function) is rare (case reports only). ●Type III – Type III deficiency (selectively reduced free protein S and protein S function; normal total protein S)

42. Clinical Presentation: The age of onset of thrombosis varies by heterozygous versus homozygous state. Heterozygous protein S deficiency causes thrombosis in persons younger than 40 to 45 years of age. The rare homozygous patients have onset in early infancy.
Severe protein S deficiency resulting from congenital homozygous mutations presents in neonates soon after birth and has a characteristic presentation of purpura fulminans (PF). Affected individuals rarely survive childhood without early diagnosis and treatment

43. Laboratory Investigations: Choice and interpretation of protein S assay — Protein S deficiency is the most difficult of the hereditary thrombophilias to document with certainty. As previously noted, protein S levels in the general population vary more widely than those of protein C or antithrombin . Free protein S is our preferred approach to screening as it appears to be the best test for true deficiency [72,73]. Combining free protein S levels with other testing such as a functional assay does not appear to improve diagnostic accuracy.

44. In practice, it is preferable to investigate patients suspected of having protein S (or protein C) deficiency after a vitamin K antagonist has been discontinued for at least two weeks. If it is not possible to discontinue warfarin due to the severity of the thrombosis or thrombotic risk, it may be possible to assay protein S levels while the patient is receiving heparin, which does not alter protein S concentration. Direct oral anticoagulants (DOACs; dabigatran , apixaban , edoxaban , rivaroxaban ) can affect the functional assays for protein S Heparin and low molecular weight heparin do not interfere with testing for protein S deficiency

45. Management: The mainstay of management of severe acquired, transient deficiencies of protein C or S is aggressive treatment of the underlying cause, although replacement therapy has been used in such cases. Initial anticoagulation consists of either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) UFH should be administered at a dose of 28 U/kg/h with a Target anti- Xa level of 0.3-0.7 U/ mL. The recommended dose of LMWH is 1.0-1.5mg/kg/dose every 12h with a therapeutic target anti- Xa level of 0.5-1 U/ mL. Initiation of warfarin therapy should overlap and only commence after several days of anticoagulation with UFH/LMWH to avoid warfarin induced skin necrosis and other thrombotic complications

46. Monitoring Of Therapy: Due to the risk of bleeding or recurrent purpura fulminans , INRs often need to be monitored on a weekly basis. D-Dimer is a useful marker for activation of the coagulation cascade and has been a helpful indicator both of adequate replacement and anticoagulation therapy in neonates. A rising or elevated D-dimer may be the first sign of recurrent purpura fulminans .

47. Prognosis: Neonatal purpura fulminans , whether caused by congenital or acquired deficiencies of protein C or S, remains a life-threatening condition. Early recognition of clinical symptoms ,prompt diagnosis and judicious replacement therapy decreases both the morbidity and mortality associated with this condition. Every effort should be made to increase awareness of this rarely diagnosed condition and its treatment, so that affected infants and their families will derive maximum benefit, even if replacement therapy with protein C concentrate is not widely available.

48. THANK YOU💥