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HEMORRHAGIC AND THROMBOTIC COMPLICATIONS IN CHILDREN WITH CANCER: NORMAL HEMOSTASIS


I. The normal hemostatic process is a balance between maintaining blood in a fluid state under normal physiologic conditions, and the ability to react to vascular injury by forming a blood clot to stop blood loss.

A. Blood is maintained in the fluid phase by the presence of inhibitors of proteins activated in the clotting mechanism [anti-thrombin III (ATIII), protein C, and protein S]. A strong stimulus (e.g., sufficient vascular injury) will initiate the explosive clotting mechanism and override the action of the inhibitors, allowing the formation of a blood clot.

B. The formation of a thrombus occurs in three stages:

Formation of a platelet plug due to activation of platelets in response to vascular injury

Activation of the proteins of the coagulation mechanism, with the ultimate formation of a fibrin clot (with platelets mixed in)

Clot lysis (fibrinolytic system) due to a protein activated at the initiation of the clotting cascade (plasminogen activated to plasmin)

C. An abnormality in any part of the hemostatic system may cause either abnormal bleeding or thrombosis.

II. TESTS MEASURING HEMOSTASIS

A.     Platelets

Platelet count

Bleeding time

Platelet aggregation

B.     Coagulation proteins and screening tests

International normalized ratio (INR)/prothrombin time (PT)

Activated partial thromboplastin time (APTT)

Thrombin clotting time (TCT)

Fibrinogen level

Functional and immunologic levels of inhibitors (AT1II, protein C, and protein S)

III. For many coagulation proteins, infants and children have different normal ranges from adults. Tests that measure hemostasis, therefore, also have age-dependent normal values.

A.     Platelets

Neonates have hyporeactive platelets due to an intrinsic defect but have shorter bleeding times than adults due to increased red blood cell size, high hematocrit, and increased levels of von Willebrand factor (vWf).

Bleeding time has been shown to be longer in children than in healthy adults, with an unknown etiology or significance.

B.     Mechanism of coagulation

1. The vitamin K-dependent coagulation proteins (factors II or prothrombin, VII, IX, and X) are decreased in childhood compared with adult levels. Blood clots in neonates and children, therefore, have less thrombin incorporated into them due to decreased prothrombin levels. Optimal anticoagulant therapy of clots involves inactivating clot-bound thrombin and may be different in children from that in adults for this reason.

C.     Inhibitors of coagulation

Protein C levels (both functional and antigenic) are lower than adult levels throughout childhood until puberty. Neonates can have levels as low as 20%. To rule out a deficiency, measure both functional and antigenic levels.

ATIII is 50% of adult levels until 3 months of age.

a2-MacrogIobulin levels are increased compared with adult values.

Protein S exists in both free and bound forms. Under normal conditions, approximately 60% of the total protein S in plasma is complexed to C4b-binding protein (a component of complement). Only the free protein S (40%) is functionally active as a cofactor with protein C to inhibit activated factors V and VIII. To rule out a deficiency, measure the total, free, and bound protein S (antigen) and functional protein S.

D.     Fibrinolytic system

The fibrinolytic system is relatively downregulated in childhood.

Plasminogen is 50% of adult levels at birth.

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Cancer