**Recommendations**

In children with cancer, we suggest management of VTE follow the general recommendations for management of DVT in children.

We suggest the use of LMWH in the treatment of VTE for a minimum of 3 months until the precipitating factor has resolved (*eg*, use of asparaginase) [Grade 2C].

Remark: The presence of cancer, and the need for surgery, chemotherapy or other treatments may modify the risk/benefit ratio for treatment of DVT, and clinicians should consider these factors on an individual basis.

#### **3.4.3.3 Prophylaxis of TE in children with cancer**

Since a high percentage of TE seems to be directly CVC-related, it is of primary importance to maintain its patency. Though there is a lack of clear evidence based indications the following situations for primary prophylaxis may be individually considered: 1) children with hereditary thrombophilia under intensive chemotherapy, 2) adolescents in the presence of additional risk factors such as major surgery or immobilization, 3) patients with prior TE in their history and 4) children with tumors compressing large vessels. Because ALL carries the highest risk for TE an efficient prophylaxis would be of major importance. To date there are no controlled trials that allow the extrapolation of prophylactic strategies. The German BFM-Study Group is conducting the first randomized interventional trial comparing three different antithrombotic strategies during ALL-induction therapy (Thrombotect). This ongoing trial is expected to provide the basis for risk adapted prophylaxis guidelines.

#### **3.4.3.4 Antithrombotic therapy for APS**

Long-term prognosis depends on the risk of recurrent TE, which seems to be the highest within 6 months of discontinuation of anticoagulation.64 Duration and intensity of therapy are still controversial, at least for subgroups. After the first DVT, secondary prophylaxis for 12 months is indicated. Lifelong anticoagulation is to be considered after a very serious first event and recurrent TE with persistence of APA. After arterial TE the optimal secondary prophylaxis remains controversial.64, 65 In children consideration should be given to performing and/or extending first/second line antithrombotic treatment on an individual basis, depending on the presence of underlying disorders.

#### **Recommendations**

For children with VTE, in the setting of APLA (*Antiphospholipid Antibodies)*, we suggest management as per general recommendations for VTE management in children.

Pathophysiology and Clinical Aspects of 62 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

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

The main challenge is to keep the balance of benefit and risk of an antithrombotic treatment, as most children are being treated with chemotherapy with intermittent thrombocytopenia and an unbalanced hemostatic system, both of which lead to potential bleeding complications. It is therefore strongly recommended not to use antithrombotic agents with potentially serious side effects such as thrombolytic agents, UFH or vitamin K antagonists.

In children with cancer, we suggest management of VTE follow the general

We suggest the use of LMWH in the treatment of VTE for a minimum of 3 months until the

Remark: The presence of cancer, and the need for surgery, chemotherapy or other treatments may modify the risk/benefit ratio for treatment of DVT, and clinicians should

Since a high percentage of TE seems to be directly CVC-related, it is of primary importance to maintain its patency. Though there is a lack of clear evidence based indications the following situations for primary prophylaxis may be individually considered: 1) children with hereditary thrombophilia under intensive chemotherapy, 2) adolescents in the presence of additional risk factors such as major surgery or immobilization, 3) patients with prior TE in their history and 4) children with tumors compressing large vessels. Because ALL carries the highest risk for TE an efficient prophylaxis would be of major importance. To date there are no controlled trials that allow the extrapolation of prophylactic strategies. The German BFM-Study Group is conducting the first randomized interventional trial comparing three different antithrombotic strategies during ALL-induction therapy (Thrombotect). This ongoing trial is expected to provide the basis for risk adapted prophylaxis guidelines.

Long-term prognosis depends on the risk of recurrent TE, which seems to be the highest within 6 months of discontinuation of anticoagulation.64 Duration and intensity of therapy are still controversial, at least for subgroups. After the first DVT, secondary prophylaxis for 12 months is indicated. Lifelong anticoagulation is to be considered after a very serious first event and recurrent TE with persistence of APA. After arterial TE the optimal secondary

performing and/or extending first/second line antithrombotic treatment on an individual

For children with VTE, in the setting of APLA (*Antiphospholipid Antibodies)*, we suggest

management as per general recommendations for VTE management in children.

65 In children consideration should be given to

decision on a strictly individual base.

**Recommendations** 

**3.4.3.2 Management of Thrombosis in children with cancer** 

recommendations for management of DVT in children.

consider these factors on an individual basis.

**3.4.3.4 Antithrombotic therapy for APS** 

prophylaxis remains controversial.64,

**Recommendations** 

basis, depending on the presence of underlying disorders.

**3.4.3.3 Prophylaxis of TE in children with cancer** 

precipitating factor has resolved (*eg*, use of asparaginase) [Grade 2C].

Remark: Depending on the age of the patient, it may be more appropriate to follow adult guidelines for management of VTE in the setting of APLA.

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

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)


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 suggest their involvement (see text).

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

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As some studies have suggested, combined thrombophilic factors may enhance the risk of thrombosis. However, the risk of a second event in unselected patients does not seem to be high enough to justify more intense and prolonged anticoagulation, compared to patients without these risk factors. Deviations from this "minimalistic" diagnostic approach may be indicated with respect to the individual case and to the particular institutional management guidelines. Many other factors are part of diagnostic programs, although their contribution to the thrombotic risk seems to be very low or even absent.
