**3.4.3 Special conditions**

#### **3.4.3.1 Prophylaxis of CVC occlusion**

#### 3.4.3.1.1 UFH

Pathophysiology and Clinical Aspects of 60 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

we recommend LMWH with therapeutic anti-Xa levels for 4–6 weeks, followed by prophylactic dosage up to 6 months. For the treatment duration of different sites, types

The agent of choice is rt-PA. Streptokinase should not be used because of its allergic reactions. The use of urokinase at least in the USA is restricted for safety concerns. rt-PA may be indicated if thrombosis is extensive or organ/life threatening. The established contraindications in adults apply for children as well but should be considered relative.53

and age groups refer to references (Monagle et al, 2004; Andrew et al, 2000).

**3.4.1.3 Thrombolytic agents** 

**Contraindications** 

sepsis

**3.4.1.4 Vitamin K antagonists** 

no bleeding, rapid

life threatening

threatening

significant bleeding, not

significant bleeding, life

multiple drug interactions

reversal

**Reversal of oral anticoagulant therapy** 

Therapeutic recommendations are listed in **Table 5.** 

Soft within 48 hours after cerebral convulsion prematurity < 32 weeks of gestation

active minor hemorrhage

Strong within 10 days after hemorrhage or major surgery within 7 days after severe asphyxia within 3 days after invasive procedure

refractory thrombcytopenia and hypofibrinogenemia

UFH none 5–10 U/kg/h Apt

**Therapy Loading Dose Maintenance Monitoring**

Table 5. Recommendations for systemic thrombolysis in neonates and children

no bleeding, slow reversal vitamin K 0.5–2.0 (–5.0) mg orally (s.c., i.v.)

rt-PA 0.1–0.2 mg/kg/10 min. 0.8–2.4 mg/kg/24 h FI, platelets, D-dimers

**OAC Day 1 Day 2 From Day 3 Target INR**  Phenprocoumon 6 mg/m2 3 mg/m2 1–2 mg/m2 2.0–3.0 Warfarin 0.2 mg/kg 0.2 mg/kg 0.1–0.3 mg/kg 2.0–3.0

vitamin K 0.5–2.0 (–5.0) mg s.c. or i.v.

Coumarin therapy always to begin with concomitant heparin therapy (UFH or LMWH); to stop heparin, INR within therapeutic range for 2 days, concomitant medication at least 5 days; attention to

Table 6. Recommended dosing of oral anticoagulants (OAC) in neonates and children.

vitamin K 0.5–2.0 (–5.0) mg s.c. or i.v. + FFP 20 mL/kg

prothrombin concentrate (Prothomplex) 50 U/kg i.v.

vitamin K 5 mg i.v. over 20 min. (risk of anaphylactic shock) +

Indications: extensive and/or life/organ-threatening thrombosis. Contraindications: on an individual basis to be considered relative, not absolute; keep fibrinogen > 0.5 g/L and platelets > 50 g/L; increasing D-dimers indicate effective fibrinolysis; dose reduction or cessation of rt-PA if major bleeding occurs; minor bleeding (oozing from catheter puncture site or wound) treat with local pressure; optimal duration of rt-PA therapy uncertain, mostly up to 7 days, shorter/longer courses

> Prophylactic UFH seems to significantly decrease CVC-related DVT as well as bacterial colonization of the catheter.(Hentschen & Sutor, 2002) Heparin-bonded catheters do not reduce clot formation and bacterial colonization beyond 24 hours after CVC insertion.

#### 3.4.3.1.2 Thrombolytic agents (urokinase, rt - PA)

Thrombolytic therapy is widely and safely used for the management of occluded catheters. There are only a few studies using thrombolytic agents prophylactically in order to reduce catheter infections and occlusions. Some studies show a substantial benefit of thrombolytic agents over UFH or no prophylaxis.(Hentschen & Sutor, 2002) whereas others get contradictory results.(Aquino et al, 2002; Solomon et al, 2000)

#### 3.4.3.1.3 LMWH

Prophylactic use of LMWH has been efficient and safe in the treatment and prevention of DVT in children with cancer.(Elhasid et al, 2001; Massicotte et al, 2003; Tabori et al, 2006) However, LMWH to maintain CVC-patency and prevent CVC-related DVT has to remain an individual decision. For the recommended dosage see **Table 4**.

#### 3.4.3.1.4 Oral anticoagulation with vitamin K - antagomist

There are no data for children on using low-dose oral anticoagulation to prevent CVCassociated DVT and to maintain catheter patency. Considering the heterogeneous pediatric

Venous Thromboembolism in Neonates, Children and

guidelines for management of VTE in the setting of APLA.

**3.4.3.5 Treatment - related indications for Thrombophilia Screening** 

**1 2 3** 

Antiphospholipid-Ab Dysfibrinogenemia FIX Homocysteine FVIII FXI HIT Type 2 D-Dimer FXIII ADAMTS13 VWF

Table 7. List of relevant, established and potential thrombophilic factors

suggest their involvement (see text).

Antithrombin APC resistance (FV Leiden) PAI-1 polymorphism

Column 1: factors of therapeutic and/or prognostic relevance; column 2: established risk factors with possible therapeutic and prognostic relevance for the individual patient; column 3: potential thrombophilic factors. Their therapeutic and prognostic relevance for the individual patient is doubtful. Laboratory tests for HIT type 2 and ADAMTS13 are only indicated when additional data

Protein C Prothrombin G20210A Plasminogen Protein S Lipoprotein (a) Heparin-cofactor II

Patients with Chronic Renal Disease – Special Considerations 63

Remark: Depending on the age of the patient, it may be more appropriate to follow adult

It makes a difference if children are diagnosed and treated as study patients or if they are individually seen. In the latter case, laboratory work-up of thrombosis in childhood should pertain to the following basic questions: i) is there a specific therapy and ii) what are the consequences of a particular finding concerning future management and counseling of the patient and the family? (Sutor, 2003) Keeping this in mind, the necessary investigations are only a few (see **Table 7**) which is at odds with the current recommendations published by the Subcommittee on Perinatal/Pediatric Hemostasis of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Hemostasis (ISTH). (Manco - Johnson et al, 2002) However, since there is no consensus on management guidelines yet, laboratory testing may also vary between different institutions. It is well accepted that the coagulation inhibitors AT, PC and PS should be part of the diagnostic program. Though rare, their deficiencies can be compensated for by commercially available concentrates (AT, PC) and by fresh frozen plasma (PS). In cases of TE accompanied by hemolytic anemia and thrombocytopenia, Upshaw Schulman syndrome should be suspected and ADAMTS13 activity should be determined, since fresh-frozen plasma (FFP) is a life-saving replacement therapy in this condition and plasma exchange is the method of choice in the acquired form. Fasting homocysteine may be determined, since its elevation can be treated by folic acid substitution. However, two recent studies on lowering homocysteine by folate administration in patients with vascular disease did not show a reduction of re-infarction or stroke in adults.(Lonn et al, 2006; Ho et al, 2006) HIT type 2 should be ruled out in patients with thrombosis who show a drop of the platelet count under heparin administration. APA should be determined, since the respective patients require a longer lasting prophylaxis against a relapse. There is no specific treatment for patients with Factor V Leiden or PT G20210A. Although these established hereditary risk factors are the most common, therapeutic and prophylactic measures are not necessarily different for children with or without these risk factors. Indeed, many studies on adults and a few on children have shown that these factors have only minor or even no impact on re-TE in unselected patients with or without these risk factors.(Kurnik et al, 2003; Ho et al, 2006)

population requiring a CVC with respect to age, thrombogenic risk profile, underlying disease, intensity and duration of treatment, the use of vitamin K–antagonists must remain a decision on a strictly individual base.
