**3.3.2.3 Thrombosis and antiphospholipid syndrome (APS)**

APS is an antibody-mediated thrombophilic state characterized by specific clinical manifestations of venous, arterial or small vessel TE at any site as well as the presence of antiphospholipid antibodies (APA) in the blood. In addition to DVT, acute ischemic stroke or transient ischemic attack are characteristic. APS is often associated with a number of autoimmune disorders.(Miyakis et al, 2006) APS in women causes adverse pregnancy outcome including unexplained still birth or prematurity because of severe placental insufficiency (multiple infarction) or severe (pre)eclampsia. APS is classified as primary and secondary; the clinical picture, however, is the same. Patients with no underlying disease are diagnosed as primary APS. Secondary APS refers to patients with underlying autoimmune (mainly rheumatologic) disorders as well as viral and bacterial infections or cancer.

All proposed pathophysiological mechanisms share the binding of the APA to anionic protein-phospholipid-complexes, leading to activation of endothelial cells, platelets and prothrombin, interference with natural inhibitory pathways and fibrinolysis, and disruption of the binding of annexin V to phospholipids coating the vascular system.(Levine et al, 2002; Rand, 2003) There are clinical/laboratory diagnostic and therapeutic criteria for adults (Miyakis et al, 2006) that do not apply equally for children. There have been recent reports on gene expression profiles to identify subtle distinctions in order to define the clinical relevance of different APA.(Ortel, 2006; Ortel, 2006) Apart from DVT as the most frequent clinical symptom in children along with the presence of LAC and high risk of recurrence without adequate long-term anticoagulation, there is a subgroup of children presenting with perinatal stroke and no risk of recurrence independent of secondary antithrombotic prophylaxis.(Kenet, 2006)This underlines the discordance to adults and the need for diagnostic and therapeutic guidelines to be defined for pediatric patients.

APA along with decreased activity of various coagulation factors, mainly F XII, are found in about 50% of otherwise healthy children with multiple viral infections, screened for prolonged a PTT preceding tonsillectomy or adenotomy.42, 44 APA in this context are in association to the repeated infections and do not appear to be clinically relevant, carry no risk for bleeding or TE, and hence do not influence perioperative management. They usually disappear after tonsillectomy and/or with decreasing frequency of infectious episodes. In contrast, life-threatening TE including purpura fulminans may occur with varicella, which have been shown to have a increased prevalence of APA and associated PS deficiency.(Manco - Johnson, 1998) Bleeding is rare and responds to corticosteroids.

#### **3.3.2.4 Heparin – induced thrombocytopenia type 2 (HIT)**

The overall incidence of HIT type 2 is estimated around 1% of patients hospitalized in pediatric intensive care units.(Klenner et al, 2004; Newall et a, 2003)Most often it is observed in neonates and infants after cardiac surgery and in adolescents treated with unfractionated heparin (UFH) for venous thrombosis. HIT-associated TE is mainly venous but arterial events may occur.

### **3.3.2.5 Other acquired prothrombotic conditions**

Perinatal asphyxia, systemic infections/sepsis/DIC, congenital heart disease (CHD) and hypovolemia are the main risk factors in neonates, the latter particularly prone to arterial events in association with CHD and/or arterial catheters frequentlyused in an intensive care setting.47 There are additional factors in older children: trauma, major surgery, immobilization, estrogen containing contraceptives in adolescent girls, corticosteroid therapy, nephrotic syndrome, hemolytic uremic syndrome, inflammatory bowel disease, and rheumatic and other chronic disorders. To date, it remains an individual decision if and which antithrombotic prophylaxis should be offered considering additional and individual risk factors.

#### **3.4 Therapy and prophylaxis**

Pathophysiology and Clinical Aspects of 56 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

TE in cancer is the result of complex interactions of a variety of factors such as the malignancy itself, chemotherapy and its side effects including infections or dehydration, CVCs, the unbalanced hemostatic system with predominant hypercoagulability as well as possible hereditary thrombophilia. The impact of the different types of childhood malignancy on the hemostatic system is still not well understood. Most reports are regarding ALL and show the highest risk for TE under ALL/non-Hodgkin lymphoma (NHL) treatment is during induction and re-induction therapy that contains L-asparaginase,

APS is an antibody-mediated thrombophilic state characterized by specific clinical manifestations of venous, arterial or small vessel TE at any site as well as the presence of antiphospholipid antibodies (APA) in the blood. In addition to DVT, acute ischemic stroke or transient ischemic attack are characteristic. APS is often associated with a number of autoimmune disorders.(Miyakis et al, 2006) APS in women causes adverse pregnancy outcome including unexplained still birth or prematurity because of severe placental insufficiency (multiple infarction) or severe (pre)eclampsia. APS is classified as primary and secondary; the clinical picture, however, is the same. Patients with no underlying disease are diagnosed as primary APS. Secondary APS refers to patients with underlying autoimmune

the most common site being the upper deep venous system and the cerebral veins.

(mainly rheumatologic) disorders as well as viral and bacterial infections or cancer.

diagnostic and therapeutic guidelines to be defined for pediatric patients.

prolonged a PTT preceding tonsillectomy or adenotomy.42,

**3.3.2.4 Heparin – induced thrombocytopenia type 2 (HIT)** 

All proposed pathophysiological mechanisms share the binding of the APA to anionic protein-phospholipid-complexes, leading to activation of endothelial cells, platelets and prothrombin, interference with natural inhibitory pathways and fibrinolysis, and disruption of the binding of annexin V to phospholipids coating the vascular system.(Levine et al, 2002; Rand, 2003) There are clinical/laboratory diagnostic and therapeutic criteria for adults (Miyakis et al, 2006) that do not apply equally for children. There have been recent reports on gene expression profiles to identify subtle distinctions in order to define the clinical relevance of different APA.(Ortel, 2006; Ortel, 2006) Apart from DVT as the most frequent clinical symptom in children along with the presence of LAC and high risk of recurrence without adequate long-term anticoagulation, there is a subgroup of children presenting with perinatal stroke and no risk of recurrence independent of secondary antithrombotic prophylaxis.(Kenet, 2006)This underlines the discordance to adults and the need for

APA along with decreased activity of various coagulation factors, mainly F XII, are found in about 50% of otherwise healthy children with multiple viral infections, screened for

association to the repeated infections and do not appear to be clinically relevant, carry no risk for bleeding or TE, and hence do not influence perioperative management. They usually disappear after tonsillectomy and/or with decreasing frequency of infectious episodes. In contrast, life-threatening TE including purpura fulminans may occur with varicella, which have been shown to have a increased prevalence of APA and associated PS

The overall incidence of HIT type 2 is estimated around 1% of patients hospitalized in pediatric intensive care units.(Klenner et al, 2004; Newall et a, 2003)Most often it is observed in neonates and infants after cardiac surgery and in adolescents treated with unfractionated

deficiency.(Manco - Johnson, 1998) Bleeding is rare and responds to corticosteroids.

44 APA in this context are in

**3.3.2.3 Thrombosis and antiphospholipid syndrome (APS)** 

Irrespective of an underlying disease, every thromboembolic manifestation should be treated, aiming at the complete recanalization of the occluded vessel and stopping the thrombotic process. In the vast majority of cases thrombosis will resolve under heparin given for 5–14 days. Other therapy options with a higher risk such as thrombolytic therapy or surgical embolectomy should be limited for patients with extensive thrombosis and/or threatened organ function. As LMWH show considerable advantages over UFH for therapeutic as well as prophylactic purposes, the following recommendations are in favor of LMWH. Yet evidence shows no difference in the antithrombotic efficacy. For detailed recommendations refer to **Table 4** and reference (Monagle et al, 2004).


\* 1 mg Enoxaparin = 110 anti-FXa units

For UFH: aPTT 4 hours after loading dose and 4 hours after each dosage adjustment, at least once daily; keep AT level within normal range; daily blood count (platelets!). For LMWH: anti-FX activity 4 hours after injection

Table 4. Recommended dosing of UFH and LMWH in neonates and children.

#### **Recommendations**

In children with VTE (CVL and non-CVL related): first TE for children:

In children with thrombosis, we recommend anticoagulant therapy with either UFH or LMWH (Grade 1B).

Venous Thromboembolism in Neonates, Children and

thrombus reaccumulation (Grade 2C).

Pediatric Cancer Patients With DVT

Use of Anticoagulants as Therapeutic Agents

consider these factors on an individual basis. Use of Anticoagulant as Thromboprophylaxis

recommendations for management of DVT in children.

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

**Recommendations** 

**Recommendations** 

**Recommendations** 

to LMWH.

and central VADs (Grade 2C).

**3.4.1.1 Unfractionated heparin** 

**3.4.1 Commonly used anticoagulants** 

**3.4.1.2 Low - molecular - weight heparin** 

Patients with Chronic Renal Disease – Special Considerations 59

We suggest, following thrombectomy, anticoagulant therapy be initiated to prevent

In children \_ 10 kg body weight with lower-extremity DVT and a contraindication to

We suggest temporary IVC filters should be removed as soon as possible if thrombosis is not present in the basket of the filter and when the risk of anticoagulation decreases (Grade 2C). In children who receive an IVC filter, we recommend appropriate anticoagulation for DVT

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

We suggest clinicians not use primary antithrombotic prophylaxis in children with cancer

The following disadvantages should be considered: the need for venous access for therapy and monitoring, age-dependent unpredictable pharmacokinetics; normal AT levels required; monitoring by a PTT prone to pre-analytic errors; risk for bleeding; risk for HIT. Intravenous UFH should only be given in the initial phase of antithrombotic therapy and then switched

Advantages are easy subcutaneous administration once daily without need of venous access, predictable pharmacokinetics, minimal monitoring, minimized bleeding complications, reduced risk of HIT. Infants < 5 kg required about 50% higher doses than older children to reach equivalent anti-FXa levels.(Sutor et al, 2004) As a general guideline

If life-threatening VTE is present, we suggest thrombectomy (Grade 2C).

anticoagulation, we suggest placement of a temporary IVC filter (Grade 2C).

(see 1.2) as soon as the contraindication to anticoagulation is resolved (Grade 1B).

Remark: Dosing of IV UFH should prolong the aPTT to a range that corresponds to an anti-FXa level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing.

We recommend initial treatment with UFH or LMWH for at least 5 to 10 days (Grade 1B). For patients in whom clinicians will subsequently prescribe VKAs, we recommend beginning oral therapy as early as day 1 and discontinuing UFH/LMWH on day 6 or later than day 6 if the INR has not exceeded 2.0 (Grade 1B). After the initial 5- to 10-day treatment period, we suggest LMWH rather than VKA therapy if therapeutic levels are difficult to maintain on VKA therapy or if VKA therapy is challenging for the child and family (Grade 2C).

We suggest children with idiopathic TE receive anticoagulant therapy for at least 6 months, using VKAs to achieve a target INR of (INR range, 2.0 to 3.0) or alternatively usingLMWH to maintain an anti-FXa level of 0.5 to 1.0 U/mL (Grade 2C).

Recurrent Idiopathic TE for Children

#### **Recommendations**

For children with recurrent idiopathic thrombosis, we recommend indefinite treatment with VKAs to achieve a target INR of 2.5 (INR range, 2.0 –3.0) [Grade 1A].

Remark: For some patients, long-term LMWH may be preferable; however, there are little or no data about the safety of long-term LMWH in children.

Recurrent Secondary TE for Children

#### **Recommendations**

For children with recurrent secondary TE with an existing reversible risk factor for thrombosis, we suggest anticoagulation until the removal of the precipitating factor but for a minimum of 3 months (Grade 2C). In addition, with specific respect to the managementof CVL-related thrombosis: 1.2.8. If a CVL is no longer required, or is nonfunctioning, we recommend it be removed (Grade 1B). We suggest at least 3 to 5 days of anticoagulation therapy prior to its removal (Grade 2C). If CVL access is required and the CVL is still functioning, we suggest that the CVL remain *in situ* and the patient be anticoagulated (Grade 2C).

For children with a first CVL-related DVT, we suggest initial management as for secondary TE as previously described. We suggest, after the initial 3 months of therapy, that prophylactic doses of VKAs (INR range, 1.5–1.9) or LMWH (anti-FXa level range, 0.1 to 0.3) be given until the CVL is removed (Grade 2C). If recurrent thrombosis occurs while the patient is receiving prophylactic therapy, we suggest continuing therapeutic doses until the CVL is removed but at least for a minimum of 3 months (Grade 2C).

Use of Thrombolysis in Pediatric Patients With DVT.

#### **Recommendations**

In children with DVT, we suggest that thrombolysis therapy not be used routinely (Grade 2C). If thrombolysis is used, in the presence of physiologic or pathologic deficiencies of plasminogen, we suggest supplementation with plasminogen (Grade 2C).

Thrombectomy and IVC Filter Use in Pediatric Patients With DVT.
