1. An interesting presentation in an infant of a diabetic mother

2. History Baby SB, male infant
Born 3 December 2009 at Bedford Gardens Hospital, JHB
Caesarean section – difficult delivery anticipated
Mother 41 years old, first pregnancy
Gestational diabetes, treated with Glucophage.
Not optimally controlled – HbA1c levels after delivery 7.9%. Estimated average glucose – 10.0mmol/l
Excessive weight gain in past week – oedema. Reportedly not hypertensive. Mother’s weight 143kg. Blood pressure at delivery 220/140mmHg
Gestational age 36 weeks. Mother received 2 doses steroids
Delivery not particularly difficult – no obvious trauma to baby
Apgar score 9/10 at 1 minute, 9/10 at 5 minutes

3. Initial Clinical Findings
Large-for-gestational-age baby
Weight 5.3kg, head circumference 38cm, length 54cm
Not dysmorphic
Not obviously plethoric
Mild-moderate respiratory distress
Admitted to neonatal ICU for oxygen and blood-glucose monitoring
Initial blood glucose 1.7mmol/l

4. NB: no procedures (arterial) had been performed on this arm
While admitting and examining baby, noted to have bluish right arm, with poor perfusion and capillary refill
NB: no procedures (arterial) had been performed on this arm
Clear line of demarcation became evident, high up on right arm. Arm/hand not atrophic
Chest – clear
Cardiovascular system
normal heart sounds, no murmurs audible
Pulses present in lower limbs and left arm, but no right brachial/radial pulses felt
Blood pressure recorded in lower limbs and left arm, but not recordable in right arm. BP similar in 3 limbs, high-normal(systolic 70-80mmHg, diastolic 40-50mmHg)

5. Abdomen
no exomphalos
large/thick umbilical cord, normal 3 vessels present
firm, large mass felt in left flank. Most likely renal mass. No bruit heard. No overlying bruising suggestive of trauma to abdomen
Normal male genitalia
Central Nervous System – active baby. Moving limbs, but right arm less - ?painful

6. Assessment: Large-for gestational-age male infant of diabetic
Hypoglycaemia
Mild respiratory distress - transient tachypnoea of newborn/ hyaline membrane disease
Left flank mass – most likely renal origin. Possibly nephroblastoma/neuroblastoma
Evidence of spontaneous acute vascular (arterial) occlusion in right arm

7. Management Intravenous fluids commenced (potassium-free Neonatalyte)
Nasal prong oxygen applied. Transcutaneous oxygen saturation 95%
Called for help! (acutely threatened limb)
Surgical opinion sought
Came to see infant within an hour
Suggested local massage over area of suspected arterial occlusion to try to disperse clot
Advised initiating anticoagulation with Heparin – loading dose followed by maintenance, intravenously

8. Reluctant to start thrombolytic therapy as risks (intracranial haemorrhage) outweigh possible benefits
Predicted probable tissue loss
Counselled mother regarding baby’s condition
Angiogram not indicated at that stage

9. Investigations and Specialist Consults
Full Blood Count
Haemoglobin – 13.7g/dl
Haematocrit
Platelets – 127
Urea and electrolytes
Normal
INR and PTT (following day, on Heparin)
normal

10. Cardiology consult
Cardiology opinion sought (day 2 of life) to exclude intracardiac lesion predisposing to embolic events (hypertrophic cardiomyopathy, intracardiac thrombus)
Echocardiogram normal
Advised angiogram if arm not improving, or if new evidence of vascular occlusions
Advised thrombophilic workup

11. Haematology consult
Haematologist advised thrombotic screen, not immediately. Generally after 6 weeks as some factors may be abnormal because of therapy, or the acute thrombosis
Advised Antiphospholipid screen on mother – maternal antibodies may predispose to thrombosis in infant
Screen negative
Suggested anticoagulation with Low Molecular Weight Heparin (Clexane – Enoxaparin) rather than Unfractionated Heparin
Easier administration – subcutaneous vs intravenous
More predictable dose-response
Easier to monitor with Anti Factor Xa levels. Aim for (therapeutic range)
Dose 1mg/kg subcutaneously 12 hourly

12. Radiology Abdominal ultrasound performed day after delivery
Showed an enlarged adrenal gland (2cm) on the left, with inhomogeneous hypoechoic area within
?haemorrhage
?neuroblastoma
?adrenal cyst
Both kidneys reported as normal
(Difficult to correlate with clinical impression of a large, hard renal mass. ?Actually feeling kidney pushed down by adrenal)

13. Cranial sonar requested to exclude any evidence of intracerebral thromboses, although clinically no concerns
Normal
Arterial doppler of right arm demonstrated flow within the subclavian artery, axillary artery, brachial artery and radial artery => confirmed arterial flow down to the hand.
Reported as unable to demonstrate any strictures along arterial path but arterial flow confirmed
(clinically no pulses however)

14. Discussed findings with radiologists, colleagues
What next?
Discussed findings with radiologists, colleagues
?any danger in anticoagulating if adrenal haemorrhage present
Decided unlikely to spread/worsen therefore not major concern
Would watch for signs of haemorrhage – haemoglobin dropping
Discussed with oncologist concerning possibility of this being a non-benign mass
Could afford to wait and watch
Even if congenital neuroblastoma, these tend to regress spontaneously
Therefore decision was to wait, whilst treating with Clexane, and follow up radiologically in about 1 week

15. Course and progress Baby remained in NICU – as high care patient
Weaned off oxygen over next 3 days
Treated with Penicillin and Amikacin for 3 days, but no signs of sepsis
Blood glucose levels not problematic. No need for intravenous fluids by day 3, fed very well
NB. No umbilical arterial or venous catheters ever inserted
Blood pressure remained stable
Urine dipstix showed microscopic haematuria, which resolved
Normal urine output, repeat urea and electrolyte results were normal
No evidence of bleeding

16. Anti Xa levels monitored (level taken 3 hours after Clexane dose)
Anti Xa levels monitored (level taken 3 hours after Clexane dose). In therapeutic range
Right arm developed superficial areas of discoloration, due to ischaemia (Day 2). However digits did NOT become gangrenous, nor did any skin ulceration ensue
Still unable to feel pulses distal to right axillary artery, but arm became pinker, warmer, and seemingly less painful
No new evidence of thromboses detected during stay

17. CT abdomen performed the following week (superior to ultrasound, MRI probably not necessary)
Left adrenal mass most likely an adrenal haemorrhage
Radiologist suspected renal vein thrombosis - left kidney also looked abnormal
Doppler ultrasound performed – confirmed left renal vein thrombosis
Renal vein thrombosis could explain ipsilateral adrenal haemorrhage
Now evidence of both arterial and venous thromboses
Renal vein thrombosis not too unusual in Infant of Diabetic, but NOT polycythaemic, and why the arterial occlusion?

18. Contacted haematologist again with new findings
Recommended thrombotic screen at this stage
Clexane not expected to alter most of results
If thrombophilic tendency detected, would
Explain findings in this patient
Determine duration of treatment
Results:
Fibrinogen – 3.10g/l (N)
Antithrombin III function – 59% (N)
Protein C function – 31% (N)
Protein S - 52% (N)
APC resistance ratio normal – no APC resistance demonstrated
Factor V Leiden mutation not detected
Prothrombin G20210A mutation not detected

19. To add to the confusion…
Day 9 – felt a firm mass just proximal to right antecubital fossa (affected arm)
3cm X 2.5cm
Not pulsatile, not fluctuant, no overlying skin discoloration
?related to thrombus in arm, but distal to original occlusion
??related to massaging the arm on Day 1 – possibly fat necrosis
Ultrasound suggested a lipoma, (clinically did not feel like one), less likely a haematoma

20. Left adrenal gland and kidney enlarged
Further discussions with colleagues and cardiologist led to decision to perform a CT angiogram
In light of thrombi in arterial and venous systems
To ensure no underlying vascular abnormalities (?aneurysms/stenoses) predisposing to further thrombotic events
Performed under general anaesthetic by a team experienced in neonatal CT angiography
Findings (17 Dec 2009)
Dystrophic calcifications in relation to left renal vein, adrenal gland and kidney
Left adrenal gland and kidney enlarged
No flow demonstrated in left renal vein
No arterial flow bilaterally from level of trifurcation (legs)

21. Deep venous system both lower legs poorly visualised (. thrombosed)
Deep venous system both lower legs poorly visualised (?thrombosed). Collateral flow demonstrated
Upper limb arteries and veins patent
Further evaluation with Doppler ultrasound recommended
Doppler ultrasound repeated following day
Flow present in left renal vein
No evidence of thrombosis
Good flow noted in arteries of lower limbs

22. Final outcome
Baby discharged 18 December 2009, Day 16 of life
Lump on right arm diminishing in size
Discharge weight 5.36kg
Plan: to come in twice daily for Clexane injections until mother confident to continue with administration herself

23. Follow up
Seen one week later – all going well. Mother started giving Clexane herself
Seen in January for follow up. Pulses now felt in right arm, renal mass much smaller, no complications of heparin therapy, anti Xa level 0.44
Plan is to remain on Clexane for 3-6 months
Should follow up closely for renal damage secondary to renal vein thrombosis
NB – omit Clexane day before vaccines due

24. Thromboembolic disorders in neonates
Concentrations of various components of coagulation system differ greatly between neonates and adults
Age-appropriate reference ranges must always be used when interpreting results
Despite striking differences in levels of individual components, neonatal coagulation somewhat more rapid or robust than an adult’s

25. Neonate’s haemostatic system delicately balanced
Neither bleeding nor thrombosis common in healthy, term neonates
However - number of perinatal conditions can disrupt the balance, increase risk for haemorrhage or thrombus formation

26. Developing haemostatic system has decreased concentrations of
procoagulant proteins
naturally occurring anticoagulants
haemostatic control proteins
Overall – tendency to a prothrombotic state
Co-existence of inherited risk factors with acquired risk factors (sepsis, perinatal asphyxia, polycythaemia) => thrombo-embolic states
Virchow’s triad – vessel wall damage, stasis/turbulent flow of blood, hypercoagulability of blood

27. Incidence – varies depending on type of thromboses reported, and methods of screening
Relatively rare, obviously more common in an ICU setting (5.1 per live births, 2.4 per 1000 NICU admissions)
Term and preterm infants
Male = female, except renal vein thrombosis males > females
Approximately 90% of neonatal venous thromboses associated with central venous catheters (iatrogenic)

28. Neonatal thromboembolism
Arterial thromboses
Venous thromboses
Ischaemic Perinatal Stroke
Iatrogenic arterial thromboses
Spontaneous arterial thromboses
Catheter-related thrombosis (non-cardiac)
Intracardiac thrombosis, thrombosis associated with congenital heart disease
Renal vein thrombosis
Portal vein thrombosis
Cerebral sinovenous thrombosis

29. Risk Factors Maternal Neonatal Diabetes Thrombotic states in pregnancy
Preeclampsia
Chorioamnionitis
Prolonged rupture of membranes
Autoimmune disorders
Oligohydramnios
Central catheters
Congenital heart disease
Sepsis, necrotising enterocolitis
Perinatal asphyxia
Respiratory distress
Dehydration, shock
Polycythaemia
Surgery
Medications
Prothrombotic disorders

30. Ischaemic Perinatal Stroke
Constitutes majority of arterial thromboses
Occurs within 2 days after birth, up to 28 days postnatally
Signs – seizures, lethargy, hypotonia, poor feeding, apnoea
20-63 per live births
Most in left hemisphere, distribution of middle cerebral artery
Numerous potential risk factors
Prothrombotic disorders (hereditary) with/without other risk factors contributing factors

31. Iatrogenic arterial thromboses
Mainly related to complications from umbilical arterial catheters (UAC’s), peripheral arterial catheters, and femoral arterial catheters
Been shown to occur in up to 1 in 5 babies who have had an UAC placed
Complications – mesenteric ischaemia, hypertension, renal dysfunction/failure, limb loss
High positioning fewer complications
Suggestive signs – line dysfunction, extremity blanching/cyanosis, persistent thrombocytopenia, sepsis

32. Spontaneous arterial thromboses
Extremely rare
Usually involve aorta
Mimic congenital heart disease
Signs – decreased pulses, cool, mottled extremity
Treatment of arterial thrombosis
depends on clinical symptoms, location
Observation, supportive care
Anticoagulation
Fibrinolytic therapy
Surgery
Goal – to restore blood flow if there is limb/organ ischaemia

33. Catheter-related thrombosis (venous)
Central venous catheters improve neonatal care, but increase risk for thrombosis
Umbilical venous catheters (first week of life)
Peripheral venous catheters – parenteral nutrition, prolonged antibiotics
Study shown 1 in 5 patients with UVC’s had thrombus formation
Up to 65% in autopsy studies, with microscopic evidence of thrombi

34. Signs – persistent infection, thrombocytopenia, line dysfunction
CDC recommends use no longer than 14 days
Suspicion of venous thrombosis warrants prompt removal (some advise starting anticoagulant therapy first)

35. Intracardiac thrombosis
Central venous catheter placement into right atrium poses risk of damage to endocardium => thrombus formation
+ line infections = intracardiac vegetations, dissemination of septic emboli
Can embolise to lungs or obstruct pulmonary artery
Thrombosis of superior vena cava also a complication of surgery for complex congenital cardiac disease

36. Renal Vein Thrombosis
Incidence been reported as 0.5 per 1000 NICU admissions
70% unilateral (64% involving left kidney)
Males more frequently affected
Signs – macroscopic haematuria, palpable abdominal mass, thrombocytopenia, hypertension
Risk factors – perinatal asphyxia, dehydration, maternal diabetes
Acute complications – serious – adrenal haemorrhage, extension of clot into inferior vena cava, renal failure, hypertension, death
Chronic complications – most suffer complete, cortical, or segmental infarction of affected kidney/s and/or hypertension

37. Recurrence rare, related to underlying thrombophilia
Genetic prothrombotic risk factors been detected in 43 – 67% of patients with renal vein thrombosis
Recurrence rare, related to underlying thrombophilia
Therefore comprehensive prothrombotic evaluation recommended in these patients
Diagnosed on ultrasound with Doppler
Enlarged, echogenic kidneys, attenuation/loss of coticomedullary differentiation, absence of flow in main or arcuate renal veins
Treatment controversial
No large, randomised trials
Loss of renal tissue in most cases reported, irrespective of treatment approach

38. Treatment (contd) Unilateral – absence of uraemia/extension into IVC
=> supportive care with monitoring for extension
=>OR anticoagulation with unfractionated or low molecular weight heparin for up to 3 months
With extension into IVC
=>anticoagulation recommended for 3 months
Bilateral renal vein thrombosis with renal failure
=>thrombolytic therapy plus anticoagulation with unfractionated heparin followed by anticoagulation with unfractionated or low molecular weight heparin
Fibrinolytic therapy been found to restore renal function in patients with bilateral RVT, but no effect in those with unilateral RVT

39. Portal Vein Thrombosis
Risk factors include sepsis/ oomphalitis or UVC use
Spontaneous resolution relatively common
However once detected, need to follow up closely for development of portal hypertension (up to 10 years later)
Cerebral Sinus Thrombosis
Symptoms include fever, seizures, lethargy
Large majority have predisposing risk factors and prothrombotic traits (Protein C or S deficiency), lupus anticoagulant, SLE in mother

40. Genetic risk factors
Mutations results in prothrombotic phenotype by causing
Deficiency/dysfunction of an inhibitor of haemostasis (Protein C, S, Antithrombin III)
Overproduction of a procoagulant protein (Prothrombin)
Deficiency/dysfunction of fibrinolysis
Endothelial damage (antiphospholipid antibodies)
Homozygous or compound heterozygous disorders usually present in newborn period with SEVERE clinical manifestations
Surprisingly, even in individuals with a mutation and multiple acquired risk factors, many do not develop thromboses
High prevalence of multiple thrombophilic gene mutations in white population

41. Majority of spontaneous events (not catheter-related) either due to
Infants with multiple mutations and symptomatic thrombosis are at risk of recurrence, however usually in setting of other comorbidities
No recommendations on secondary prevention of thromboses in infants with thrombophilia
Nevertheless, many experts recommend screening in a neonate with symptomatic thromboembolism, regardless of other acquired risk factors
Majority of spontaneous events (not catheter-related) either due to
Multiple haemostatic prothrombotic defects or
Combination of prothrombotic defects and environmental or clinical conditions

42. Circulating maternal antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody) can cause postnatal thrombosis
Therefore should also be excluded, easily performed with maternal blood
Transient effects
Recommended that prothrombotic evaluation be done at least 6 weeks after the event
Proteins may be lowered by the event
Anticoagulant should be stopped 2 weeks – 1 month before performing protein-based assays
DNA-based assays not affected by treatment nor thrombosis
Amount of blood required limitation in neonates, therefore use laboratory in an experienced tertiary care centre

43. Thrombolytics
Recombinant Tissue Plasminogen Activator only considered for limb- or organ-threatening postnatal thrombosis, acute atrial clots
Limited number of studies
Does not inhibit clot propagation therefore infused WITH heparin

44. Role of surgery
Microsurgical techniques combined with thrombolytic regimens can rapidly restore blood flow, avoid tissue loss, no major bleeding complications
Indications – significant arterial thrombosis, particularly from peripheral arterial line
Only in an experienced institution

45. Possible causes in this patient
Infant of diabetic - risk of thromboembolism
Renal vein thrombosis well-described
Number of cases described with arterial thrombosis of upper limb with or without concomitant RVT
Pathogenesis of thrombotic tendency in infant of diabetic not fully understood
Polycythaemia main reason (however this patient not polycythaemic)
?deficiency of natural anticoagulants such as Antithrombin III
?abnormalities of renal capillary vasculature
?placental damage leading to leakage of placental thromboplastin or other coagulation initiators into fetal blood
?free fatty acids and phospholipids may cross placenta and affect platelet function in poorly controlled diabetics

46. No other risk factors in this infant
Prothrombotic screen normal/negative
No asphyxia, no sepsis, no umbilical catheters inserted
Suggested that sheer size of infant may have predisposed to stasis of blood flow in the affected arm, due to pressure

47. Apparently well-known fact that infants with renal vein thrombosis can have simultaneous evidence of upper limb/intracerebral arterial embolism
Thrombus dislodges => travels up IVC => right atrium => foramen ovale => circulation supplying head and upper limbs

48. Learning points Renal vein thrombosis (RVT) presents with a renal mass
Missed on initial ultrasound. ‘Luckily’ patient had another thromboembolic event which required treatment or may have missed treating RVT
RVT can embolise to arterial circulation through the foramen ovale in a neonate