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Current Pediatric Reviews, 2014, 10, 169-176 169

Thrombotic Complications of Neonates and Children with Congenital

Nephrotic Syndrome
Keith K. Lau*,1, Howard H. Chan2,3, Patti Massicotte4 and Anthony K. Chan1

1
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 2 Thrombosis and Atherosclerosis Re-
search Institute, 3 Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 4Department of Pediat-
rics, University of Alberta, Edmonton, Alberta, Canada

Abstract: Congenital nephrotic syndrome (CNS) refers to a disease presenting with massive proteinuria in association
with hypoalbuminemia, hyperlipidemia, and edema at birth or within the first three months of life. In the past, most chil-
dren with CNS had extremely poor prognosis and succumbed to various complications, usually within the first 6 months.
Recent advancements in protein supplementation and nutritional support, renal replacement therapy and renal transplanta-
tion in infancy, render these patients to have much better outcomes [1-5]. However, there are still many hurdles in the
management of this disease. Thromboembolism is an uncommon, yet important complication which the healthcare givers
must be aware of. This article reviews the challenges in the management of the thrombotic complications with special
emphasis on the unique characteristics of the newborn hemostasis system and anti-thrombin (AT) depletion in nephrotic
syndrome. Due to the relatively low incidence of CNS in children and scarce information in the literature on the optimal
management of the thromboembolic complications, most of the recommendations are based on the authors’ experience.
Keywords: Congenital nephrotic syndrome, warfarin, thrombosis. neonates, children, management.

CONGENITAL NEPHROTIC SYNDROME Table 1. Causes of congenital nephrotic syndrome [6-9].

Nephrotic syndrome during early infancy is rare. CNS is
defined as nephrotic syndrome presenting in infants before Primary
three months of age. The underlying causes are heterogen- Minimal change disease
eous and detailed classification is beyond the scope of this
review. The key etiology identified in infants with CNS has Diffuse mesangial proliferation
been summarised in Table 1 [6-9]. The prognosis is largely Focal segmental glomerulosclerosis
dependent on the cause. For example, CNS associated with
Secondary
infections often resolves when the infectious agent is eradi-
cated by treatment. However, most of the patients with CNS Genetic
are unresponsive to conservative medical treatments [9]. In Finnish type congenital nephrotic syndrome
these patients, the strategy of current management is to
Pierson syndrome
maintain the growth and provide supportive care until renal
transplantation is performed. Denys-Drash syndrome

In a recent review of pediatric nephrotic syndrome pre- Perinatal Infection

senting in the first year of life, at least two-thirds of cases are Cytomegalovirus
associated with genetic mutations [10]. NPHS1 and NPHS2
were the most commonly identified mutations that encode Toxoplasmosis
nephrin and podocin respectively [11-13]. Both nephrin and Syphilis
podocin play pivotal roles in maintaining the integrity of the
HIV
slit diaphragm, disruption of which leads to leakage of pro-
tein in urine [10]. Although there are only a few reports Hepatitis B
available in the literature, the incidence of CNS in Finland Rubella
was estimated to be 1.2 per 10,000 births. Most of the pa-
tients with CNS in Finland have mutations of the NPHS1 Epstein-Barr virus
gene in chromosome 19q, and are commonly referred as the Malaria
CNS of Finnish type (CNF) [11, 14, 15]. CNF is inherited Miscellaneous
via the autosomal recessive pattern without any sex predilec-
tion. It has also been reported in patients with other ethnicity Mercury intoxication
background in other parts of the world [16-21]. At
least 119 different mutations in the NPHS1 gene have been
*Address correspondence to this author at the 1280 Main Street West, identified so far [19]. Children with CNS, with or without
HSC3A50, Hamilton, Ontario, Canada L8S 4K1; Tel: 1-905-521-2100; Ext genetic mutations, are usually steroid resistant and have
75635; Fax: 1-905-308-7548; E-mail: kelau@mcmaster.ca poorer clinical outcomes. In 2011, the North American Pedi-

1875-6336/14 $58.00+.00 © 2014 Bentham Science Publishers

170 Current Pediatric Reviews, 2014, Vol. 10, No. 3
atric Renal Trials and Collaborative Studies (NAPRTCS)
reported 2.6% of children on dialysis as a result of CNS [22].
The long-term outcomes of neonates with CNS have been
improved dramatically due to advancements in dialysis tech-
nology and aggressive nutritional and metabolic support.
Infants with CNS are now able to be managed medically
until renal transplantation [23].
THROMBOEMBOLIC COMPLICATIONS IN CNS
Although the survival rates of infant with CNS have
improved dramatically over the past few decades, the man-
agement of these neonates still imposes a huge challenge to
the health care team. Thrombosis at various sites has been
reported in children with CNS [3, 24-30]. Infants with CNS
may present with severe proteinuria at birth and the urine
protein concentration can exceed 20 g/L [4, 24]. This de-
gree of proteinuria leads to substantial loss of AT and
plasminogen, further aggravates the prothrombotic hemo-
static system in neonates and infants, thus renders them
more susceptible to thromboembolism, albeit the risk is
still relatively low [7, 27, 31].
In an early study from Finland, seven out of 58 patients
with CNS were found to have thromboembolism at
autopsy. The anatomical sites of thrombosis include in-
ferior vena cava (IVC) (n=7), sagittal sinus (n=1), cerebral
vein (n=1) and right atrium (n=1) [15]. In this study, the
mortality rate due to thromboembolism was 5%; one of the
infants died of pulmonary embolism with the thrombus
originating from the atrium [15]. Serious thromboembolic
complications such as thrombosis of renal veins
with/without involvement of the IVC have also been re-
ported in 10% of infants with CNS [3, 28, 32]. Arterial
thrombosis involving the radial, brachial and femoral arter-
ies may occur [3]. Similarly, CNS patients may present
with stroke secondary to either arterial or venous thrombo-
sis [27, 29] and many of them may have long term neuro-
logical sequelae [24]. Severe vascular complications were
reported in 5 of 17 children with CNS between 1985 and
1989 [4]. A term neonate with CNS, who suffered from
intestinal perforation and death, was noted to have throm-
bosis of the superior mesenteric artery at autopsy [30].
During childhood, the first few weeks after birth is at the
most high risk for the development of thromboembolism. It
was estimated that about 5.1 of 100,000 live births in Ger-
many has thromboembolic disease [33, 34]. The conse-
quences of hemorrhagic and thrombotic complications are
prevented by fine balance between the anti-coagulating and
coagulating factors. Plasma levels of factors II, VII, IX, X,
XII, XI, prekallikrein and high-molecular-weight kininogen
of neonates increase rapidly during the first week of life [34-
39]. Their levels are only approximately 50% of the adults at
birth but the concentrations reach adult levels at 6 months.
The ability of newborn plasma to produce thrombin is low
(approximately 50% of that of adults) [35, 37-39]. Protein C
and protein S are low during the neonatal period, however,
the levels of active protein S are usually high due to low lev-
els of C4b-binding protein (a large glycoprotein that binds
and inactivates protein S) [35]. Protein C, when activated by
thrombomodulin, proteolyses factor Va and VIIIa in the
presence of protein S [40]. As protein S serves as the co-
Lau et al.
factor for protein C, the hypercoagulable state in nephrotic
syndrome may be related to protein S deficiency [41]. On the
other hand, plasma concentrations of plasminogen in neo-
nates are also low [35, 37-39]. However, due to the higher
concentration of tissue-type plasminogen inhibitor (PAI) in
neonates, the thrombus lysis time are prolonged in neonates
[35, 39]. Therefore, neonates are probably more prone to
thrombotic complications than their older counterparts even
in non-nephrotic state.
The functional alterations in the coagulation cascade in
adult patients with nephrotic syndrome have been well
studied in the past. There are increased levels of pro-
coagulant factors (V, VII, VIII, X and fibrinogen) due to
increased hepatic synthesis. As the molecular weight of
AT is 65,000 daltons and is similar to that of albumin, pa-
tient with nephrotic syndrome may lose AT in the urine
along with albumin [42-52]. In neonates and children with
active nephrotic syndrome, similar changes occur in their
coagulation pathways and have been associated with a pro-
pensity to thrombosis [53-56]. This is a particular concern
as the premorbid levels of AT are physiologically lower in
neonates, further renal loss may aggravate the prothrom-
botic tendency. As a consequence, heparin may not be ef-
fective in CNS due to extremely low level of AT. Protein C
and S are important natural anticoagulants and their
deficiencies have not been reported consistently in patients
with nephrotic syndrome, probably due to increased hepatic
production during urinary loss of these proteins [57-60]. On
the other hand, protein Z, an anti-coagulant factor that in-
hibits factor Xa, is also decreased in children with neph-
rotic syndrome [61]. In addition, as the molecular weight
of plasminogen is 89,000 daltons, thus it may also be
excreted in the urine in severe nephrotic patients [42, 43].
The predisposition of thrombosis secondary to urinary loss
of AT and plasminogen is corroborated by increased
thrombosis in other patients with hereditary AT and
plasminogen abnormalities [62, 63]. α2-macroglobulin in-
hibits plasmin and reduces fibrinolytic activity [54, 64].
The levels of α2 -macroglobulin are increased in patients
with nephrotic syndrome due to the increase in hepatic syn-
thesis [65]. Reduced fibrinolytic activity has been associ-
ated with increased levels of α2 -macroglobulin, which
functions as an inhibitor of fibrinolysis by inhibiting plas-
min and kallikrein [55, 64]. Platelet aggregation is in-
versely proportional to serum albumin concentration. Hy-
poalbuminemia increase platelet aggregation and predis-
pose neonates with CNS to thromboembolism [66, 67].
Platelet aggregation is also increased during relapse and
normalizes during remission in children with nephrotic
syndrome [67-69].
In addition to the changes of anticoagulation factors,
neonates and infants with CNS are subject to other
prothrombotic conditions (Table 2). The frequent use of cen-
tral line, both for albumin infusion and nutritional supple-
mentation, increases the risk of infection and sepsis. Deple-
tion of intravascular volume secondary to low intravascular
oncotic pressures and frequent use of diuretics, need of
erythropoietin, co-existing hereditary prothrombotic risk
factors and immobilization are all possible predisposing fac-
tors that need to be considered in the management of throm-
boembolism in patients with CNS.
Thrombotic Complications of Neonates and Children with Congenital
Table 2. Clinical and environmental factors that alter the
coagulation systems in neonates and children with
nephrotic syndrome.
Increased activities of prothrombotic pathways
Higher levels of factors: V, VII, VIII and X
Higher level of fibrinogen level
Loss of plasminogen in urine
Increase in platelet aggregation
Venous catheterization
Immobilization
Infection
Vascular volume depletion
Erythropoietin replacement therapy
Reduced activities of inhibitory pathways
Loss of AT in urine
Higher level of protein C and protein S
Lower level of protein Z
Higher level of α2-macroglobulin
MANAGEMENT OF THROMBOSIS
Neonates with CNS are usually resistant to medical
treatments and renal transplantation is the only therapeutic
alternative. The infants typically require prolonged hospital
admissions, aggressive nutritional support and frequent al-
bumin infusions. Recurrent infections, impaired growth and
development, and fluid and electrolyte disturbance are com-
mon during the course. Until transplantation is feasible, the
strategies of management focus on maintaining the kidney
functions, normalizing blood pressure, and minimizing com-
plications such as infections and thrombosis.
Health care providers should be aware of the risks and
take precautionary measures, such as avoiding volume deple-
tion and performing non-traumatic femoral arterial/venous
puncture, are essential in managing these patients. Due to the
factors discussed above, the patients have ongoing risk of
thrombosis which results in active anticoagulation and/or
secondary prophylaxis [26, 41, 60].
ANTICOAGULATION
Antithrombotic therapy in children includes unfraction-
ated heparin (UFH), low molecular weight heparin
(LMWH), vitamin K antagonists, and thrombolytic agents.
However, as age specific clinical trials are missing in neo-
nates and infants with thromboembolic complications, treat-
ment recommendations are usually adapted from small-scale
studies and from guidelines pertaining to adult patients.
HEPARINS
The potency of AT in inhibiting factors IIa and Xa in-
creases exponentially when binding to UFH and LMWH
Current Pediatric Reviews, 2014, Vol. 10, No. 3 171
[70]. Heparins have been recommended and used to treat of
thromboembolism in children with nephrotic syndrome in
the past [61]. However, using heparins in neonates can be
problematic as resistance to treatment due to the low levels
of AT in this age group has been reported [71]. During acute
nephrotic phase, the levels of AT can be very low in these
neonates with CNS that render heparins ineffective.
Concomitant administration of fresh frozen plasma or AT
concentrate may be necessary to achieve a heparin effect [33,
42, 57, 72].
Prophylactic anticoagulation is not usually recommended
in children with idiopathic nephrotic syndrome during
remission [73, 74]. However, due to the chronicity of the
illness and severity of thrombotic complications, chronic
prophylaxis should be considered in infants with CNS [3, 24,
52]. Both UFH and LMWH have been used extensively in
older children with nephrotic syndrome, but these
anticoagulants may be less effective in neonates because of
the low level of AT. Therefore, chronic oral prophylaxis
with warfarin or low dose acetylsalicylate, with or without
dipyridamole, have instead been recommended for neonates
with evidence of hypercoagulability or clinical manifesta-
tions of thromboembolism, with the caveat that warfarin’s
effect may be compromised by frequent fluctuating levels of
serum albumin [3, 52, 75].
WARFARIN
Due to the ineffectiveness of heparin in low AT levels,
warfarin may provide better anticoagulant effect. As it per-
turbs the coagulation cascade without the involvement of
AT, it has been the anticoagulant of choice in some centers
for chronic prophylaxis in infants with CNS [52]. Warfarin
inhibits vitamin K epoxide reductase that leads to depletion
of the reduced form of vitamin K. Reduced vitamin K is
needed to activate coagulation factors by carboxylation of
the glutamic residue of Gla domain. Vitamin K-dependent
coagulation factors include factors II, VII, IX, X as well as
regulatory proteins such as protein C, protein S and protein Z
[76, 77]. Warfarin therapy may be started as early as at 3-4
weeks of age. Oral absorption of warfarin is rapid and com-
plete, but the full therapeutic effects do not occur until day 3
to day 5 when prothrombin and other coagulation factors are
significantly reduced. Due to the short half-life of protein C,
initiation of warfarin therapy without heparin coverage
causes rapid decline of protein C level while other procoagu-
lant factor levels remain unchanged. This may trigger war-
farin-induced skin necrosis. In plasma, warfarin is highly
bound to albumin, but only the free fraction is pharma-
cologically active [78]. In patients with CNS, despite severe
hypoalbuminemia leading to increased free fraction of war-
farin, INR is usually not increased due to the concomitant
increase in plasma clearance [79].
However, the enthusiasm of using warfarin in children has
been deterred by the complexity in dose adjustment. INR
values, either below or above the target ranges, increase the
risks of thromboembolic and/or bleeding complications.
Hence, it is recommended to manage these patients in facili-
ties with anticoagulation clinics [80-82]. Although the mecha-
nisms responsible for the age dependency of oral anticoagu-
lant doses are not completely clear, in a prospective study
172 Current Pediatric Reviews, 2014, Vol. 10, No. 3 Lau et al.

from Canada that included 319 children who received warfarin
therapy, age was found to be the single most significant factor
that influenced the dose requirement [82]. Children less than a
year old, when compared to their older counterparts, had a
significantly more complicated clinical course during treat-
ment. They required larger doses, longer overlap with heparin
and longer time to achieve the target INR. They also required
more frequent monitoring and dose adjustments and had fewer
INR values within the target range. Reasons contributing to
the need for frequent monitoring include diet, medications,
and the underlying co-morbid medical problems. Infant for-
mula is often supplemented with vitamin K to prevent hemor-
rhagic disease of newborn. As warfarin is a competitive in-
hibitor of vitamin K, and infants with CNS often required ag-
gressive nutritional therapy, the increase in dietary intake of
vitamin K may induce warfarin resistance [82-84]. If the in-
fant is receiving total parenteral nutrition, removal of all the
vitamin K prior to or at the commencement of warfarin may
prevent resistance. Otherwise, the dose of warfarin needs to be
up-adjusted accordingly. For formula fed neonates, the brand
with the least vitamin K is recommended. Breast-fed infants
are very sensitive to oral anticoagulants due to the low concen-
trations of vitamin K in breast milk [85-88]. If the patient is
exclusively breast-fed, supplementation with one formula feed
per day (120 ml of standard commercial formula) will provide
a steady intake of vitamin K. However, any change in the
feeding schedule may impact the INR profoundly, and thus the
INR requires very close monitoring. Bleeding is the major
complication in warfarin therapy. In a cohort study with a total
of 391 warfarin years, the bleeding rate was found to be 0.5%
per patient year [82]. Medications such as antibiotics and ster-
oid will also affect the INR [89-94]. Table 3 depicts some
commonly used medications that interact with warfarin. Other
non-hemorrhagic complications, such as tracheal and vascular
calcification, hair loss and decrease in bone mineral density
have also been reported [95-100]. These findings reinforce the
complexity of warfarin therapy among young infants.
The optimal range of INR for young children is not well
defined and there is insufficient data regarding the efficacy
and safety of warfarin in infants less than 3 months old.
Whether a generic formulation of warfarin can be used in-
stead of brand-name Coumadin is controversial. In Canada,
there are three generic formulations of warfarin with stand-
ardized color coding. In our practice, if a patient starts on
Coumadin, we continue to prescribe it. However, if a patient
wants generic warfarin because it is cheaper, we make this
change but monitor the INR more frequently in the first few
weeks of the transition.
Table 3. Common Medications that Interfere the INR Dur-
ing Warfarin Treatment.
Increase INR
Decrease vitamin K production by intestinal flora
Co-trimoxazole
Metronidazole
Macrolides
Fluoroquinolones
Interfere with vitamin-K dependent carboxylase
Acetaminophen
Decrease hepatic metabolism of warfarin
Amiodarone
Metronidazole
Co-trimoxazole
Decrease INR
Increase hepatic metabolism of warfarin
Barbiturates
Phenytoin
Carbamazepine
At our center, the therapeutic INR range is 2.0 to 3.0.
However, in children receiving oral anticoagulants, the ca-
pacity of their plasmas to generate thrombin is delayed and
decreased by 25%, and the plasma concentrations of pro-
thrombin fragment 1.2 (an endogenous thrombin generation
marker) is also significantly lower, when compared adults
with similar INR [101, 102]. There have been concerns that
the optimal INR in children should be lower than for adults.
The warfarin dose is adjusted according to the weight and
the average dose is 0.33 mg/kg. We start with an oral loading
dose of 0.2 mg/kg (reduced to 0.1 mg/kg in patients with
concomitant severe liver or renal dysfunction) on day 1, with
subsequent dose adjustments made according to a nor-
mogram using INR values [103]. Table 4 and 5 (modify
from the reference [104]) outlines the protocols that we used
for subsequent doses adjustment.

Table 4. Loading Doses of Warfarin for Day 2 to 4 After Initiating Therapy.

INR Warfarin dose Adjustment Recommended

1.1 - 1.3 repeat loading at initial dose

1.4 - 1.9 give another loading at 50% of initial dose

if INR > 2.0 after 1 or 2 days, omit dose for 1 day, then give another loading at 50% of initial dose if INR > 2.0 after 3 or 4 days,
2.0 - 3.0
proceed as per table 4

3.1 - 3.5 give 25% of loading dose

> 3.5 hold the dose until ING < 2.5, then re-initiate with 50% of the initial dose
Thrombotic Complications of Neonates and Children with Congenital
Table 5. Nomogram for Dose Adjustment of Warfarin Maintenance Therapy.
INR Warfarin Dose Adjustment Recommended
1.1 - 1.4 increase the dose by 20%
1.5 - 1.7 increase the dose by 10%
1.8 - 3.2 no change necessary
3.3 - 3.5 decrease the dose by 10%
> 3.5 hold the dose until INR < 3.5, then restart at 20% decrease of the initial dose
Monitoring oral anticoagulant therapy in children is dif-
ficult and requires close supervision with vigilant dose ad-
justments [82, 103]. In adults, the College of American
Pathologists recommends the INR be checked at least four
times during the first week of therapy and then less fre-
quently, depending on the stability of the INR [105]. We
recommend checking the INR daily or every other day until
it is in the therapeutic range for 2 consecutive days. Once
the INR is in the therapeutic range for 2 consecutive days,
it should be checked every 3 to 5 days. When the INR and
warfarin dose remain stable for 1 week, the INR should be
checked weekly. Once the INR and warfarin dose remain
stable for an additional 2 to 3 weeks, the testing interval
can be extended to every 4 weeks [106]. The INR needs to
be checked within 5 to 7 days of a dose change. In most
cases, if the dosage needs to be adjusted, then it should be
adjusted by 5% to 20% of the total weekly dose, depending
on the current INR, the previous dose, and any changes
identified that may have been the cause for the INR to be
too high or too low [106]. Warfarin should be stopped be-
fore surgical procedures, and as thrombosis prophylaxis,
AT (50 IU/kg) is administered to correct the AT deficiency
temporarily [24].
NEW ANTICOAGULANTS
There are an increasing number of available direct
thrombin (argatroban, bivalirudin, lepirudin and dabigatran)
and Factor X (apixaban, danaparinoid, fondaparinux and
rivaroxaban) inhibitors in adults and some of them have been
used in children. While most of them are only available as
parenteral formula (argatroban, bilvalirudin, danaparoid,
hirudin, fondaparinux and lepirudin), some of them can be
given orally (apixaban, dabigatran andrivaroxaban) [107-
117]. However there are only limited data on these drugs in
children and their use in patients with CNS cannot be rec-
ommended at this time.
THROMBOLYSIS
Thrombolytic agents, such as tissue plasminogen activa-
tor, streptokinase, and urokinase, lyse thrombus by activating
the endogenous plasminogen to plasmin [76]. The guidelines
on dosing, monitoring and duration of therapy are direct ex-
trapolations from adults [76, 102, 118-120]. Although anec-
dotal success have been reported in nephrotic children suf-
fered from thrombosis, studies evaluating the efficacy and
safety of thrombolytic therapies in children is still scarce
[121-123]. The effectiveness of thrombolytic agents in in-
fants may be reduced due to lower plasma levels of plasmi-
Current Pediatric Reviews, 2014, Vol. 10, No. 3 173
nogen in newborns (only 50% of adult levels), with further
decreased levels in patients with CNS due to excessive renal
loss [76, 124].
ANTI-PLATELET THERAPY
As arterial thrombi are primarily composed of primarily
platelets, inhibition of platelet aggregation with low-dose
aspirin therapy has been proposed by some clinicians for
CNS [3]. Guidelines on dosing, therapeutic monitoring, and
duration regarding the use of anti-platelet agents are avail-
able, but mainly derived from adult studies [76, 102, 118-
120]. There are also a few reports on the use of aspirin and
dipyridamole as prophylactic agents in neonates and children
with nephrotic syndrome [3, 73].
CONCLUSION
CNS is a heterogeneous group of diseases that are usually
resistant to treatment. Intensive nutritional support and
secondary prophylactic treatment of the thromboembolic
complications are essential to improve their outcomes. Due
to the unique hemostatic circumstances in neonates and ex-
cessive loss of coagulation inhibitor proteins in urine, infants
with CNS are particularly prone to thrombosis and the man-
agement of such thromboembolic complications is still chal-
lenging.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
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