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HEMORRHAGIC AND THROMBOTIC COMPLICATIONS IN CHILDREN WITH CANCER: BLEEDING DISORDERS IN CHILDREN WITH CANCER

ETIOLOGY

DIAGNOSIS

A. Assess bleeding by laboratory tests (initial).

1.     Perform a complete blood count (CBC) including platelet

count. If platelet count is <100 x 109/L, check the smear to

ensure there is no clumping (i.e., pseudothrombocytopenia).

2.     Perform an APTT. If prolonged, consider a 1:1 mix with

normal plasma and repeat the APTT. If the APTT is now

normal, an acquired factor deficiency is likely, due to

either decreased production or increased consumption

(disseminated intravascular coagulation, DIG). Ensure that the sample for APTT was not contaminated with heparin, as contamination will cause the APTT to be prolonged. This usually occurs if the blood sample was taken from a central line (especially arterial) that had not been adequately cleared of heparin before obtaining blood. If the 1:1 mix does not have a corrected normal value APTT in the absence of heparin, an antibody to a component in the coagulation mechanism is present (inhibitor).

Perform a PT or INR. If this is prolonged, consider deficiencies of factors II, V, VII, IX, X, or fibrinogen due to decreased production of functional coagulation factor (liver disease or vitamin K deficiency).

Perform a two-unit TCT. If abnormal, consider contamination of the sample with standard heparin or hypofibrinogenemia.

Perform a fibrinogen level if the TCT is abnormal. If DIC is a possibility, determine the fibrinogen level by a clottable (Claus) assay, as the nephelometric method based on particle light scatter may result in a falsely high value due to the presence of fibrinogen/fibrin split products.

RECOMMENDATIONS FOR TREATMENT

A.     Assess the bleeding patient and institute emergency measures if necessary, including oxygen therapy (by nasal prongs, mask,

or endotracheal tube) and intravenous fluids. Cross-match the

patient for blood. If bleeding is life threatening, administer packed

red cells.

B.     Start an intravenous line. If it is a major bleeding episode, use

as large a bore as possible (21 gauge for infants and children and 19

gauge for adolescents).

C.     If the hemoglobin level is <70 g/L, consider red cell transfusion.

D.     If there is a true thrombocytopenia and the platelet count is

<20 x 109/L, consider platelet transfusion. If DIC is pre-

sent, consider

platelet transfusion, but treatment of the underlying cause (malignancy, sepsis) is the accepted method of therapy to eradicate the DIC.

E.     If the APTT is prolonged and is due to liver

damage or DIC, consider plasma transfusion. If

there is liver damage with a resultant decrease in factor production

causing the increased PT/INR, plasma transfusion is indicated (see

Section IID3). Repeat the INR after the infusion of plasma. If the INR is

prolonged (INR <4.5) but there is no bleeding, repeat the INR every

3-7 days but do not administer plasma.

E If the PT/INR is prolonged and vitamin K deficiency is present, administer vitamin K subcutaneously intravenously, or orally. If the patient is bleeding, consider a plasma transfusion. If the vitamin K deficiency is severe, the amount of plasma needed for total correction is so large that it may result in volume overload. If the bleeding is life threatening or is originating from an intracranial hemorrhage, consider using prothrombin complex (see Section IID3) as well as vitamin K. If the bleeding is not life threatening, repeat the PT/INR in 24 hours to confirm the correction of the deficiency. If the INR is still prolonged, repeat the vitamin K dose.

G.     If the TCT is prolonged (without heparin contamination of

the sample), this is most likely due to hypofibrinogenemia. Measure a

fibrinogen level (see above). If the fibrinogen level is <75 mg/dL, infusion of cryoprecipitate may be necessary, especially if major bleeding is present.

H.     Acquired von Willebrand disease is rare but has been report-

ed with Wilms tumor. If the diagnosis is confirmed, the use of desmopressin can be tried; if unsuccessful, administer cryoprecipitate, a

specific vWf concentrate, immunoglobulinG, or platelet transfusions.

SPECIFIC THERAPY

A.     Plasma transfusion:

1. Fresh-frozen plasma

a.     Plasma is frozen within 6 hours of collection.

b.     All coagulation factors are present in 1 U/mL concentration

c.     Indications are vitamin K deficiency, DIC, severe deficiencies of ATM, protein C, or protein S with acute

venous thrombosis.

d.     Dosage:10-20 mL/kg intravenous (IV) 8-12hs

e.     The risk of viral transmission per unit of properly

screened fresh-frozen plasma is: human immunodeficiency virus, 1/500,000; hepatitis C, 1/100,000; human

T-cell lymphotrophic virus 1 and 2, 1/500,000; hepatitis

B, 1/50,000.

f.     Use of virally inactivated products

These products, specifically solvent detergent inactivated fresh-frozen plasma, have been used in clinical trials. Once approved, these products may become the main products used for therapy due to the decreased risk of viral transmission.

B.     Cryoprecipitate

Cryoprecipitate is the cold-insoluble portion of plasma that remains after fresh-frozen plasma has been thawed under controlled conditions. One bag of cryoprecipitate has about 15-20 mL of fluid.

The main components are factor VIII, fibrinogen (250 mg/bag), vWf, and factor XIII.

Indications for use are fibrinogen <75 mg/dL or acquired von Willebrand disease.

Dosage: 1 bag/5 kg IV; continue until fibrinogen >75 mg/dL

The risk of viral transmission per bag of cryoprecipitate is the same as for fresh frozen plasma

C.     Prothrombin complex

Prothrombin complex concentrates contain factors II, IX, and X with variable amounts of factor VII.

Patients with a life-threatening hemorrhage or an intracranial hemorrhage due to vitamin K deficiency could benefit from prothrombin complex concentrates.

Dosage: 50 U/kg

F Vitamin K

Vitamin K preparations are usually synthetic derivatives of vitamin Kj and K2 as well as the synthetic water-soluble forms (e.g., vitamin K3).

Subcutaneous vitamin K is the preferred route of administration due to reported anaphylaxis with intravenous preparation. Hypersensitivity reactions have been reported with subcutaneous administration in the form of periinjection redness and pruritus with occasional development of skin necrosis. If this occurs, do not use the subcutaneous (sc) route.

Vitamin K can be administered orally using the intravenous preparation (vitamin Kj).

The indications for use is vitamin K deficiency.

Dosage: 2-20 mg SC

Infant formula contains an average of 83 mg/100 mL. This must be taken into consideration for infants receiving Coumadin therapy.

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Cancer