Pediatric emergency medicine trisk 563

mutation, family history is often positive for bleeding symptoms; however, even within
a family, the degree of symptomatology can be variable. Type 3 VWD is rare and
inherited in an autosomal recessive fashion; clinical symptoms resemble severe
hemophilia.
Diagnostic Testing
Patients with VWD will typically have a normal PT/aPTT, except for those with more
severe disease who have a prolonged aPTT. The diagnosis of VWD requires a special
coagulation study which examines VWF antigen level (VWF:Ag), its function, often
ristocetin-induced platelet agglutination (VWF:RCo), and factor VIII activity (FVIII:C),
the protein that it carries in plasma. The normal level for each of these components is
greater than 50%. The lower limit of normal and how to define VWD has been
controversial, but it is presently generally accepted that levels <30% constitute VWD
and levels between 30% and 50% are designated as “low von Willebrand.” Part of the
challenge arises because VWF level is influenced by blood type (e.g., lower with blood
type O) and disease states such as acute illness and hypothyroidism. It can be elevated
by estrogen levels, stress, and exercise. Some patients with low von Willebrand will
manifest a bleeding phenotype and may require treatment for menorrhagia or
prophylaxis prior to dental procedures while others will be asymptomatic despite
hemostatic challenges. A diagnosis of a type 2 subtype is often suggested by a ristocetin
cofactor to antigen ratio of less than 0.6. Additional testing to evaluate von Willebrand
multimers and ristocetin-induced platelet aggregation (RIPA) may be necessary to make
a diagnosis but is outside of the scope of testing typically sent from the emergency
department.
Management
Most patients with VWD only require episodic management at the time of a bleeding
episode or planned procedure. For most mild bleeding events including epistaxis,
gingival bleeding, or menorrhagia, antifibrinolytic therapy with aminocaproic acid or
TXA is adequate (see Table 93.2 ). Patients with menorrhagia may benefit from
hormonal (e.g., estrogen) therapy. DDAVP (desmopressin) is another staple of therapy
for patients with type 1 VWD who respond. DDAVP stimulates the secretion of VWF
from endothelial cells and can transiently result in a sufficient increase to facilitate

hemostasis and may be used for bleeding symptoms or prior to a procedure. Common
side effects include facial flushing, tachycardia, and headache. Careful attention to fluid
management is necessary to avoid severe hyponatremia. For children with VWD who do
not respond to DDAVP, treatment with plasma-derived concentrates containing VWF is
indicated. Dosing is based on the ristocetin cofactor activity. A recombinant VWF
product has been approved for use in adults. For minor bleeding episodes, raising the
VWF:RCo level above 50% should provide adequate hemostasis. For more serious


bleeding or for the prevention of surgical bleeding, an initial dose calculated to raise the
VWF:RCo to 100%, followed by repeat dosing every 12 hours is clinically indicated.

HYPERCOAGULABILITY
Goals of Treatment
The primary goal of anticoagulation is to halt progression of abnormal thrombus
formation and to prevent or minimize morbidity due to restricted perfusion. Evaluation
of an underlying thrombophilia (i.e., predisposition to abnormal clot formation) may be
warranted for some patients; however, this investigation should not delay initial
management and need not be sent from the emergency room. Except for rare
deficiencies of anticoagulant factor proteins (generally noted in infancy), the underlying
genetic risk factors do not alter the initial approach to anticoagulation.
CLINICAL PEARLS AND PITFALLS
The most frequent risk factor for thrombosis in children is the presence of a
central venous catheter.
If levels of anticoagulant factors are sent, they must be interpreted with care
(and in consultation with hematology) as normal levels are age dependent
and can be affected by acute thrombosis or use of warfarin.

Current Evidence
Recognition of venous thromboembolism (VTE) in pediatric patients has increased over

recent years due to increased awareness and expanded critical care capabilities. The
majority of thrombotic events in children occur in the setting of identifiable, acquired
risk factors: presence of a central venous catheter, medications (e.g., L-asparaginase,
corticosteroids, estrogen-containing oral contraceptive pills), tumors, inflammatory
conditions (e.g., inflammatory bowel disease, vasculitis, antiphospholipid antibody
syndrome [APS], autoimmune disorders), prolonged immobilization, obesity, and
anatomic variants (e.g., Paget–Schroetter syndrome, May–Thurner syndrome).
Inherited variants impact the risk of VTE in pediatric thrombosis. In decreasing order
of frequency, the following laboratory findings have been associated with an increased
risk of thrombophilia: factor V Leiden, prothrombin gene mutation G20210A, protein C
deficiency, protein S deficiency, and antithrombin deficiency. By potentially disrupting
the normal balance of procoagulant and anticoagulant proteins in favor of thrombus
formation, these variants confer an increased risk of thrombosis in the heterozygous
state and even more significantly in the homozygous state. Factor V Leiden results from
a point mutation of the factor V gene that renders it resistant to activated protein C, and
thus factor V remains active and drives thrombin formation. Likewise, insufficient
amounts of the natural anticoagulant factors (e.g., protein C, protein S, antithrombin) or


excess prothrombin permit unchecked propagation of the coagulation cascade.
Heterozygosity for factor V Leiden is found in about 5% of the Caucasian population in
the United States, but it is rare in those of African or Asian descent. It carries a two- to
sevenfold increased relative risk of VTE compared with normal individuals, whereas the
relative risk for homozygotes is 80-fold. Homozygous protein C deficiency may cause
widespread thrombosis in the neonatal period leading to purpura fulminans
(hemorrhagic skin necrosis) and cerebral thrombosis.

Clinical Considerations
Clinical Recognition
Thrombosis may manifest as deep venous thrombosis (DVT), pulmonary embolus

(Chapter 99 Pulmonary Emergencies ), stroke, or sinus venous thrombosis (Chapter 118
ENT Emergencies ). History should attempt to identify underlying risk factors.
Carefully review the family history for the occurrence of venous thrombosis or
pulmonary embolus, stroke, myocardial infarction, and recurrent miscarriages. Patients
with homozygous protein C, protein S, or antithrombin typically have a severe clinical
presentation in infancy with purpura fulminans. In the heterozygous state, patients may
present later in life with VTE.
Management/Diagnostic Testing
Clinical features of purpura fulminans in an infant not explained by infection should
prompt consideration for homozygous protein C or protein S deficiency. Administer
FFP (10 to 20 mL/kg q6 to q8 hours) to patients while awaiting the evaluation of these
protein levels. As noted above, levels of these anticoagulants can be difficult to interpret
in infancy (related to developmental hemostasis) and in the setting of acute VTE
(secondary to consumption), so levels drawn from the patient’s parents may be more
informative. For other patients, initiation of treatment should be managed as described
below and a workup for underlying risk factors, including protein levels, can be pursued
at a later point. Consult hematology to tailor the evaluation based on the presentation, as
well as personal and family thrombotic history. Prior to starting anticoagulation therapy,
document the patient’s platelet count, PT, aPTT, renal function, and hepatic function
since these values may be affected by the anticoagulant, and inform bleed risk.
For non–life- or limb-threatening thrombosis, start therapeutic enoxaparin (LMWH)
at a dose of 1 mg/kg SQ q12 hours. Dosing may need to be adjusted in obese patients,
and monitoring levels is imperative. The antifactor Xa assay is used to monitor
treatment with LMWH, 4 hours after the second or third dose. In general, the therapeutic
goal is an antifactor Xa level of 0.5 to 1 unit/mL. Infants up to 2 months of age need a
higher starting dose of 1.5 to 2 mg/kg SQ q12 hours in order to reach the same goal antiXa level. For patients with complex medical issues, renal insufficiency, or increased risk
of bleeding, an individualized anticoagulation plan in consultation with hematology may
be appropriate. Alternatively, IV UFH can be used. Treatment with UFH is usually

initiated with a bolus injection of 50 to 75 units/kg followed by a constant infusion of 20
units/kg/hr for children older than 1 year and 28 units/kg/hr for neonates and infants.
Adjust the UFH dose according to readily available nomograms ( Table 93.13 ).
Anticoagulation with LMWH is equal in safety and efficacy to UFH; however, a
therapeutic level can often be more quickly achieved with LMWH. UFH has the
advantage of a short half-life, so its effects are more easily reversible in the setting of a
bleed or need for a procedure. While direct oral anticoagulants (DOACs) are now firstline anticoagulation for many adult VTE indications, they are still in pediatric clinical
trials.
When venous or arterial thrombosis is extensive or occludes blood flow, threatening a
patient’s life or the integrity of a limb or vital organ, infusion of a thrombolytic agent
can result in the dissolution of the thrombus and reestablishment of blood flow.
Thrombolytic agents such as tissue plasminogen activator (tPA), streptokinase, and
urokinase have been used extensively in adult practice for decades, but tPA is the agent
of choice in pediatric patients. For maximum effectiveness in the appropriate clinical
setting, tPA is given as soon as possible after the symptoms begin and the extent of
vascular occlusion is documented. Therapy can be administered systemically or directed
to the distal end of the thrombosis by catheter placement. Typical infusion rates range
from 0.1 to 0.5 mg/kg/hr, but total dose and infusion duration are individualized.
Unanswered questions regarding thrombolysis in children include whether concomitant
heparin infusion is safe, how long therapy can be safely administered, and how to best
evaluate the degree of thrombolysis. The thrombolytic state is monitored by
prolongation of the PT and aPTT, reduction in fibrinogen, and rise in the concentration
of fibrin degradation products or d-dimer. The major risk of thrombolytic therapy is
bleeding; therefore, thrombolysis is contraindicated in patients who have had recent
abdominal or brain surgery.
Clinical Indications for Discharge or Admission
For patients with uncomplicated DVT, outpatient management is possible if the
resources to teach the patient/family how to administer LMWH are available and shortinterval follow-up with hematology is assured. For patients requiring UFH infusion or
with PE or stroke, inpatient management is appropriate.