1. Anticoagulation in Children with Congenital Nephrotic Syndrome
Angela Lamb
Paediatric Renal Pharmacist

2. Summary Case presentation Congenital Nephrotic Syndrome CNS
Thrombotic risks in children
Anticoagulants
Monitoring

3. Case Presentation 13 month old boy
36 weeks gestation by an emergency section
Admitted to Wishaw General Hospital where he presented at 18 days old with marked ankle & facial oedema
Albumin level 12
Protein creatinin ratio of 3.29
Transferred to the Renal unit at Yorkhill for management of Congenital Nephrotic Syndrome

4. First admission: 18/08/05-8/11/05
Case Presentation
First admission: 18/08/05-8/11/05
18/08/05 Albumin & furosemide started
23/08/05 Enoxaparin started 750mcg/kg od
27/8/05 CVC inserted for long-term daily administration of albumin 6/7
Weekly iv immunoglobulins
During admission Mum was trained to administer IV albumin at home
Other medication: Dalivit, Sytron, NaCl, KCl, Co-amoxiclav, Levothyroxine Epoetin Beta
On discharge Enoxaparin dose was 1.7mg/kg bd
Genetic tests were sent

5. Case Presentation Admission History: 23/11/05 RSV bronchiolitis
27/12/05 D&V
18/01/05 Mild RSV –ve bronchiolitis
22/01/06 Viral gastroenteritis
11/02/06 Rota virus
20/03/06 Increased oedema and bronchiolitis –enalapril started
04/04/06 NPA +ve for parainfluenza
13/06/06 Dehydrated increased Cr – enalapril stopped went home on alternate day albumin

6. Anticoagulation with LMWH
Date
Enoxaparin dose
Anti Xa levels ( )
23/08/05
(0.75mg/kg od) 2mg od
01/09/05
3mg od
0.066
05/09/05
4mg od
08/09/05
0.000
09/09/05
(2.1mg/kg bd) 8mg bd
0.148
10/09/05
8mg bd
0.256
16/09/05
0.163
17/10/05
0.075
19/10/05
10mg bd
24/10/05
0.158
26/10/05
0.251
25/11/05
0.136
29/11/05
(2mg/kg bd)13mg bd
01/12/05
13mg bd
0.128
05/12/05
0.144
07/12/05
(2.1mg/kg bd) 15mg bd
19/01/06
15mg bd
20/01/06
17mg bd
25/01/06
13/02/06

7. Anticoagulation with Warfarin
Date
Warfarin dose
INR Target 2-3
07/06/06 NA
Baseline INR 0.9
11/06/06
1.5mg
12/06/06
1.2
13/06/06
0.75mg
2.1
14/06/06
2.5
15/06/06
1mg
16/06/06
1.0
17/06/06
1.75mg
1.4
19/06/06
2.4
21/06/06
1.75mg/1.5mg
1.7
23/06/06
26/06/06
1.9
28/06/06
1.75mg/1.75mg/1.5mg
1.5
03/07/06
05/07/06
07/07/06
Miss 3 days
7.0
10/07/06
0.9
12/07/06
2mg/1.75mg
0.8
14/07/06
17/07/06
19/07/06
2mg daily
1.6
24/07/06
2.2
09/08/06
23/08/06
2.3

8. Congenital Nephrotic Syndrome (CNS)
Very rare form of nephrotic syndrome that presents at birth or up to 3 months of age
1:10,000 births
The two most frequent causes of CNS are the Finnish-type (FNS) and diffuse mesangial sclerosis (DMS)
FNS is more frequent in Finland with an incidence of 1:8200 births however can affect every race and nationality
There are also other causes of CNS

9. Congenital nephrotic syndrome: classification of causes From:   Papez: Curr Opin Pediatr, Volume 16(2).April

10. Finnish Type (CNS) Inherited as an autosomal recessive trait
Mutation of the gene NPHS1
Two most common types of mutation are Fin-major and Fin-minor
50 other mutations have been detected mainly outside Finland
This mutation affects the protein nephrin which is important for the maintenance of the glomerular filtration size-selective barrier
CNS there is a fault in the structure of the glomerular filter unlike acquired forms of nephrotic syndrome where there is something wrong with the interaction of the glomerulus and the immune system

11. Signs and Symptoms of CNS
Oedema usually present at birth or appears during first few weeks of life
Proteinuria
Profound hypoalbuminaemia
Severe hypogammaglobulinaemia
Hypothyroidism due to urinary losses of thyroxine binding proteins
Increased risk of thrombosis due to urinary losses of antithrombin
ESRF usually occurs between 3-8 years of age

12. Management of CNS Daily or alternate day albumin infusions
Immunoglobulin replacement
Maximize growth with high protein diet
Antibacterial prophylaxis
Anticoagulants
Levothyroxine
ACE inhibitors
DO NOT use prednisolone or immunosuppressants
Bilateral or unilateral nephrectomy
Dialysis
Kidney transplant

13. Thrombotic Risk in Children
Idiopathic VTE in children is relatively infrequent
Almost always associated with an underlying disease or risk factor
Both congenital and acquired conditions contribute to the development of thrombosis
More than 90% of children with VTE will have >=2 predisposing factors
Prophylactic anticoagulation is useful for children with congenital thrombophilia who are in high-risk situations
such as after trauma or surgery or during identified time-limited risk periods such as severe infection or presence of a CVC

14. Figure 1
                                                                                                                                                                                                                                                                                                                                                                        
Risk factors for childhood VTE. From:   Parasuraman: Circulation, Volume 113(2).January 17, 2006.e12-e16

15. Coagulation
Coagulation is initiated within 20 seconds after injury occurs
Primary haemostasis: Platelet adhesion
Platelet activation
Secondary haemostasis: Tissue Factor pathway
Contact Activation pathway

16. The coagulation cascade
Coagulation factors are serine proteases (enzymes) except FVIII and FV which are glycoproteins
Serine proteases (enzymes) act by cleaving other proteins at specific sites
FXIII is a transglutaminase
Protein C is also a serine protease
The clotting factors circulate as inactive zymogens
The main role of the Tissue factor pathway is to create a Thrombin burst
FVIIa circulates in a higher amount than any other activated coagulation factor and following damage to the blood vessel endothelium TF is released forming a complex TF-FVIIa which activates FIX & FX
Activation of FXa by TF-FVIIA is almost imm inhibited by Tissue Factor Pathway Inhibitor (TFPI)
FXa and its co-factor FVa activates Prothrombin FII to Thrombin FIIa
Thrombins

17. Antithrombin Serine protease inhibitor (serpin)
Degrade the serine proteases : Thrombin (FIIa)
FXa
FXIIa
FXIa
Anticoagulant activity antithrombin is increased 1000 fold with Heparins

18. Anticoagulants Unfractionated Heparin LMWH
Fondaparinux – synthetic pentasaccharide
Oral anticoagulant

19. Heparins
Heparin is a naturally occurring glycosaminoglycan produced by the mast cells of most species.
The pharmaceutical drug is extracted from porcine or bovine gut mucosa
MW 5000– Daltons.
LMWH - manufactured from UFH using chemical or enzymatic methods
All anticoagulant properties of UFH and LMWH depend on the presence of a specific pentasaccharide sequence, which binds with high affinity to antithrombin and potentiates its activity
This sequence is present in about one-third of the chains in UFH but in lower proportions in LMWHs
LMWH preparations the anti-Xa activity exceeds the anti-IIa activity
However, fractions with only anti-Xa activity have antithrombotic activity in animals, including the synthetic pentasaccharide, which has now been shown to be an effective antithrombotic agent in clinical trials (Buller et al, 2003). Dosage of the various LMWHs correlates better with anti-Xa rather than anti-IIa activity (Barrowcliffe, 1995), and for practical purposes, anti-Xa activity is the only measurement that can be used for monitoring LMWHs. Overall, it seems likely that both types of action contribute to the antithrombotic effects of LMWHs, although the efficacy of fondaparinux as an antithrombotic indicates that anti-Xa activity alone is also effective.
All the products currently used in the United Kingdom are of porcine origin.
Acceleration of inhibition of factor Xa (anti-Xa activity) requires only the pentasaccharide sequence (approximate MW 1700 Da), but potentiation of thrombin inhibition [anti-IIa activity, also prolongation of activated partial thromboplastin time (APTT)] requires a minimum total chain length of 18 saccharides (MW approximately 5400 Da; Lane et al, 1984). Therefore, in all

21. Pharmacokinetics of UFH & LMWH
Properties
UFH
LMWH
Molecular Wt
5,000 – Daltons
4000 – 6500 Daltons
Half life
1-2 hours
4 hours
Bioavailability s/c
<50%
90-100%
Clearance
Renal & non Renal
Mainly Renal
Binds to plasma proteins & vascular endothelial cells
+++ +
Binds to platelets
HIT (incidence)
2-5%
1-2%
Anti FXa:Anti FIIa
1:1
2-4:1
Low-molecular weight heparins have longer half-lives than UFH, after both intravenous and subcutaneous injection (
The subcutaneous half-life of LMWHs is about 4 h, measured as anti-Xa activity although there are some differences in pharmacokinetic profiles between LMWHs.
Unlike subcutaneous UFH, which has a bioavailability of <50%, all LMWHs have a bioavailability after subcutaneous injection of 90–100%.
These differences in pharmacokinetics and bioavailability are responsible for the successful clinical use of once daily subcutaneous injections of LMWH.
Several proteins interact strongly with heparin to antagonise its anticoagulant activity, the most important being platelet factor 4 (PF4) and protamine.
Binding affinity to these proteins is reduced with decreasing MW, so that LMWH preparations require higher concentrations of PF4 or protamine to neutralise their activity than does UFH.
Low-molecular weight heparins bind less strongly than UFH to endothelial cells, and this is partly responsible for the difference in pharmacokinetics, because endothelial binding and processing is an important mechanism of clearance for UFH. LMWHs also interact with platelets less readily than UFH, whether measured as potentiation of spontaneous aggregation or inhibition of agonist-induced aggregation
the process of manufacture of LMWHs reduces the anti-IIa activity, in relation to anti-Xa activity but this relationship varies between LMWH preparations

22. Warfarin Most commonly used oral anticoagulant in UK
First discovered 65 years ago
First introduced as a rat poison in the early 1950s
WARF Wisconsin Alumni Research Foundation + the ending -arin
Mechanism of action was not discovered until 1978
Warfarin inhibits the enzyme Vitamin K epoxide reductase in the liver
Thus reducing formation in the vitamin K dependent clotting factors available for activation

23. Warfarin affect on the coagulation cascade

24. Pharmacokinetics of warfarin
100% absorption orally & detected in the plasma within 1 hour
Racaemic mixture equal parts enantomers R(+) & S (-) warfarin
The enantomers metabolise through different pathways and have different t½
S-enantomer is 5x more potent as an anticoagulant but is eliminated more rapidly & has a shorter t½
99% protein bound, principally to albumin
Small volume of distribution
Metabolised in the liver & mainly excreted in bile
Mean t½ is 40 hours

25. Dosing and monitoring Loading dose (8 days)
Dependent on the elimination of clotting factors II, VII, IX & X
This can take up to 2-7 days
Maintenance dose in adults can range from 0.25mg to 15mg daily
Dose adjustments will depend on INR
Prothrombin time (PT)
WHO 1977 International Sensitivity index (ISI)
INR=[PT patient/ PT mean normal]isi
Drug interactions
Food interactions
Disease state
Age

26. CoaguCheck S
Capillary samples can be used instead of venipunctures, whole-blood point-of-care prothrombin time/international normalized ratio devices may be a solution
These monitors may be used at home and appear to be acceptable and reliable in the outpatient laboratory and home settings.

27. Food for thought:
Higher doses of LMWH required in children with CNS due to binding to plasma proteins and to Antithrombin III which are then lost in the urine
Warfarin binding to albumin being infused and lost in the urine
Enteral feeds
Thyroid function