C) Modelos y formularios*
I. Maternidad
DVT and PE most but unusual thromboses are seen 햲
Medical and family history 햳
Catheters and other risk factors for thrombosis 햲 Signs of underlying medical conditions or old thrombosis
Perform level I evaluation (at time of thrombosis) 햵 CBC, blood smear, liver and renal function, PT, PTT, ESR, C-reactive protein, FVIII:C
Lupus anticoagulant and anticardiolipin antibody 햶 Antithrombin (functional assay) 햷
Protein C (functional assay) 햸 Protein S (free antigen)
Factor V Leiden PCR or functional APCR 햹 Prothrombin G20210A (PCR)
Homocysteine level 햺 Sickle cell screen
If positive family history, family studies may be very helpful 1–2 defects
Treat 1–2 years after thrombotic event and observe with prophylactic heparin around high-risk events햻 Positive level I evaluation
Factors under investigation as potential etiologies of thrombophilia햾
Factor VIII Factor XII Factor XI
von Willebrand factor level and multimers Spontaneous platelet aggregation Platelet receptor polymorphisms TPA (tissue plasminogen activator) TFPI (tissue factor pathway inhibitor) Thrombomodulin
Consider further testing depending on strength of patient and family history >2 defects
Consider long-term (indefinite) anticoagulation
Routine screening may not be indicated with localized thrombosis at site of CVL or femoral catheter햴
Normal studies and underlying predisposing medical condition or provoking factor:
Anticoagulation for 3 months or until the predisposing condition resolves Negative level I evaluation
Recurrent or
progressive thrombosis Positive family history
Recurrent or
progressive thrombosis
Perform level II evaluation햽
Fibrinolytic evaluation: euglobulin clot lysis time, plasminogen, plasminogen activator inhibitor Dysfibrinogenemia evaluation: fibrinogen activity and antigen, thrombin time, reptilase time, fibrin degradation products, consider crossed immunoelectrophoresis
Heparin cofactor II
Paroxysmal nocturnal hemoglobinuria (flow cytometry for CD 55 and 59) Lipoprotein(a)
If not previously performed
Functional activated protein C resistance (modified functional assay) Hemoglobin electrophoresis
No abnormality identified
with level I or II testing 1–2 defects: treat 1–2 years after thrombotic event and observe with prophylactic heparin around high-risk events
>2 defects: consider long-term (indefinite) anticoagulation Routine screening of well children without thrombosis is not recommended given their very low risk of thrombosis
M.J. Manco-Johnson
Thrombophilia evaluation in a child with thrombosis Coagulation Disorders73
쏹햲–– Childhood thrombotic events, although rare, are in- creasingly being recognized in tertiary care. The rarity of thromboses in children requires some extrapolation from adult data, but there are important differences. Pediatric thromboses are most common in the first months of life or in adolescence. They are most often related to CVLs but there are many other risk factors. Several inherited pro- thrombotic defects are associated with thrombosis, but usually with multiple thrombophilic genes or acquired risk factors (e.g. indwelling catheter, malignancy [most often leukemias], congenital heart disease, trauma/surgery/im- mobilization, total parenteral nutrition, pregnancy and puer- perium, medications [most importantly oral contracep- tives], infection, nephrotic syndrome, SLE, sickle cell dis- ease, polycythemia and liver failure). Most children already have an apparent underlying disease. Thromboses are of- ten unusual: ischemic strokes, peripheral arterial disease (most often related to catheterization), and sagittal sinus, mesenteric, renal, or hepatic venous thrombosis. 20% of children have recurrent thromboses. A spontaneous throm- bosis or stroke in an otherwise healthy child suggests a hereditary deficiency or an APLA. However, most children with inherited prothrombotic defects do not develop throm- bosis so routine screening is not indicated. Also note that many of the factors decreased by congenital defects may also be decreased by some acquired conditions.
쏹
햳–– In addition to risk factor assessment, consider possi- ble past thromboses (which are often clinically silent in chil- dren), other medical problems and medications and family history (particularly if _> 1 first-degree relative had thrombo- sis). Examination should evaluate signs of old thrombosis including limb swelling, dilated veins and skin changes.
쏹
햴–– Approximately one-third of children with CVLs devel- op thrombosis; this is so common that routine screening for prothrombotic defects is not necessary.
쏹
햵–– This initial evaluation is performed even if there is a family history of an inherited procoagulant defect, because the risk of a second defect in a child with a thrombosis justi- fies the additional evaluation. Acute-phase reactants and other general studies help to recognize underlying acquired risk defects. Elevated factor VIII coagulant (FVIII:C) activity is now known to be a specific risk factor for thrombophilia.
쏹
햶–– Antiphospholipid antibodies (including lupus anti- coagulants and anticardiolipin antibodies) are strong acquired risk factors for thrombosis. Most children do not have SLE. Confirming the diagnosis is complex, requiring at least two abnormal phospholipid- based assays (e.g. PTT), an inhibitory effect (failure to correct upon dilution with normal plasma) and correction of the abnormality with ex- cessive phospholipid (hexagonal phospholipid assay). Anti- cardiolipin antibody and anti- GP1 antibodies are assayed. Abnormalities that persist for 2–4 months constitute an anti-phospholipid antibody syndrome. More often these findings are transient and benign in children.
쏹
햷–– Antithrombin deficiency has a higher risk of thrombo- sis than the other common congenital disorders; its odds ratio in adults (increased risk of thrombosis compared to the general population) is 10–20:1. Its population incidence is 1/250–500. Most childhood thromboses are deep venous and are postpubertal. Rare homozygotes can have arterial thrombosis.
쏹
햸–– Protein C deficiency occurs in 0.2–0.4% of the popula- tion with an odds ratio for venous thrombosis of 6.5–8 in adults; oral anticoagulant use can induce skin necrosis. Pro- tein S deficiency is less common but similar clinically ex- cept that arterial thromboses are more frequent. Normally 40% of the protein is both free and active. Both proteins C and S are vitamin K dependent and are reduced in infants and by oral anticoagulants; delay testing until the latter are stopped for 10 days. Both autosomal-dominant genes cause venous thrombosis but homozygotes have life-threat- ening purpura fulminans.
쏹
햹–– APCR, due to the factor V Leiden mutation in >95% of cases, occurs in 3–12% of Caucasians but is rare in other groups. There is a functional assay for APCR as well as DNA testing for V Leiden. The odds ratio for adult thrombo- sis is 3–7:1, but increases to 48:1 with oral contraceptive use. Thromboses usually follow puberty, but occur earlier with other risk factors. Prothrombin mutation G20210A oc- curs in 1–2% of European and Middle Eastern but is rare among Asian and African populations; the odds ratio for thrombosis in adults is 2–5:1. It is associated with an in- creased risk of both arterial and venous CNS thrombosis in children.
쏹
햺–– Hyperhomocysteinemia increases the risk of arterial stroke and venous thrombosis in children and adults, with an odds ratio of 2–5:1 and may be due to congenital or ac- quired factors. It can occur in as high as 5–10% of the popu- lation. Rare homozygotes for cystathionine -synthetase deficiency are at much higher risk. Blood samples should be obtained fasting, kept cold and centrifuged quickly. Defi- ciencies of vitamin B12, B6or folate can cause it but whether treatment decreases thrombosis is not known. Elevated lipoprotein(a), a low-density lipoprotein, is a risk factor for stroke in young adults. Sickle cell disease is a risk factor for stroke; a negative screen makes it unlikely but a positive screen is more often due only to sickle cell trait.
쏹
햻–– Treat 1–2 years with oral anticoagulants and then pro- phylactic LMWH or unfractionated heparin at time of high risk events (see 햲). Although LMWH is an attractive option to oral anticoagulants, its long-term toxicity has not yet been evaluated. Its better therapeutic/safety record in the short run will make it attractive if longer-term follow-up confirms its safety, but it is much more expensive.
쏹
햽–– The level II evaluation examines less common proco- agulant conditions, including abnormalities of fibrinolysis (as determined by a long euglobulin clot lysis time, low plasminogen, increased plasminogen activator inhibitor), dysfibrinogenemia, and low heparin cofactor II, and is used to exclude paroxysmal nocturnal hemoglobinuria and sickle cell disease.
쏹
햾–– Some of these studies may be indicated especially as experience defines their role as risk factor for thrombosis.
Selected reading
Chalmers EA: Heritable thrombophilia and childhood thrombosis. Blood Rev 2001;15:181–189.
Monteleone PM: Thromboembolism; in Johnston E (ed): Pediatric Medicine. Emedicine, 2002 (hptt://www.emedi- cine.com).
Nowak-Gottl U, Junker R, Kreuz W, von Eckardstein A, Kosch A, Nohe N, Schobess R, Ehrenforth S: Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001;97:858–862.