Perioperative Managment OF Thromboembolism

Thromboembolism (TE) in adults is a leading cause of morbidity and mortality. Although incidence of TE in children is much lower than in adults, morbidity and mortality are still significant. Diagnosis and treatment of thrombosis in children was based initially on adult standards of care. However, over the past 10 years pediatric data have emerged, stressing some of the differences in etiology, pathophysiology, and drug pharmacokinetics in children with TE.

History:

• Symptoms potentially caused by DVT include the pain and swelling of acute onset. These symptoms obviously are nonspecific. Swelling and pain in the lower extremities can have multiple etiologies, including trauma, sports injuries, congestive heart failure, or nephrotic syndrome. Swelling and pain in an upper extremity is more suspicious for thrombosis.

• Symptoms potentially due to PE include the acute onset of chest pain or shortness of breath. The chest pain from PE usually is not constant. Keep in mind that chest pain in children usually is benign. In adults, the first presentation of PE may be cardiovascular collapse, cardiac arrest, or sudden death.

• Symptoms of CNS thrombosis include vomiting, lethargy, seizures, or extremity weakness. Most strokes that occur in utero present with pathological early hand preference late in the first year of life. Neonates often present with seizures and lethargy. Older children usually present with headaches and extremity weakness of acute onset. Infection and dehydration also have been found to be common in infants and young children with CNS thrombosis.

• Renal vein thrombosis may present with flank pain and hematuria.

• Recent surgery, trauma, immobilization, or prolonged bedrest are factors that can contribute to TE. These factors have been documented most thoroughly in adults but can contribute to thrombosis in children as well.

• Look for a history or symptoms suggestive of heart disease or congestive heart failure, including dizziness, bilateral extremity swelling, and poor weight gain. Congenital heart disease and/or recent cardiac catheterization are the most common causes of arterial thrombosis in children.

• Also look for a history or symptoms suggestive of malignancy. This includes fevers, bone pain, weight loss, bruising, or fatigue. If a history of malignancy is present, inquire about central venous catheters (CVCs) and recent chemotherapy with L-asparaginase.

• Elicit a history of previous thrombosis. Similarly, obtain a thorough family history, documenting age at thrombosis as well as type of thrombosis (DVT, PE, myocardial infarction [MI], stroke).

• Estrogen-containing medications, such as oral contraceptive pills (OCPs), have been shown to increase the risk of thrombosis in adult women, including adolescents. This risk is even higher in women who are heterozygous for the factor V Leiden mutation.

Physical:

• Signs of DVT include leg or arm edema, erythema, increased warmth, a palpable cord, tenderness, and positive Homans sign (pain on dorsiflexing the foot). Other important features include predisposing conditions such as CHF or heart disease, malignancy, and the presence of a CVC.

• Thrombosis of the inferior vena cava and/or renal vein(s) can cause nephromegaly and flank tenderness.

• Signs of PE also are nonspecific. They include apprehension, diaphoresis, tachycardia, and/or tachypnea. Hemoptysis seldom is present in children but can be a sign in adolescents or adults.

• Signs of arterial thrombosis include absent or diminished peripheral pulses and a cool extremity with or without mottling of the skin.

Causes:

• Acquired conditions

• Arterial catheters: Central venous or arterial catheters are the most common risk factor found in children with TE. Cardiac catheterization via the femoral artery for congenital heart disease is the most common risk factor for arterial thrombosis in children. Prophylaxis with heparin (100-150 U/kg) during the procedure lowers the incidence of thrombosis from 40% to 8% in children younger than 10 years. In neonates, umbilical artery catheterization carries similar risks, although the absolute incidence of thrombosis ranges from 10-90% based on angiographic diagnosis.

• CVC-associated thrombosis has been reported in 29% of children in one report from Denver (in Nuss et al, Childhood thrombosis from Pediatrics) and 33% of children in the Canadian series. Several other studies of children with central lines for malignancy, sickle cell anemia, total parenteral nutrition, and critical care support reported thrombosis in 8-67%, depending on how the diagnosis was made (clinical vs radiographic evidence). Approximately 80% of newborns and 60% of children with upper extremity thrombosis also had CVCs in place.

• Antiphospholipid antibody syndrome (APLA): Antiphospholipid antibodies (diagnosed by either positive lupus anticoagulant [LA] or anticardiolipin antibodies) are associated with thrombosis in both adults and children. In children with systemic lupus erythematosus (SLE), the incidence of TE was 9.2% and 17% in 2 studies. However, most children with APLA have the condition incidentally and do not have SLE. In one recent study, the cases of 95 children with LA were followed for a median of 5.3 years. Ten percent had bleeding symptoms, while 5% had a thrombotic event.

• Disseminated intravascular coagulation (DIC): Sepsis and DIC have been associated with TE both in children and adults. Microvascular thrombosis consumes clotting factors, predisposing the patient to both hemorrhage and TE. Treatment of the underlying cause is essential.

• Surgery/immobilization/prolonged bedrest: These risk factors have been studied most extensively in adults and have generated recommendations regarding prophylaxis against TE. Children have a much lower risk of thrombosis with surgery, so prophylactic heparin or low molecular weight heparin is not recommended.

• Malignancy: TE has been studied most extensively in children with acute lymphoblastic leukemia (ALL). Mechanisms are complex and include the effect of leukemia itself and the use of chemotherapy, especially L-asparaginase. Many of these children also are managed with CVCs.

• Estrogen-containing medications: OCPs alone are associated with a 4-fold increased risk of venous thrombosis and a 22-fold increased risk of cerebral thrombosis. This risk may be explained by development of acquired resistance to activated protein C. Administration of OCPs to patients who are heterozygous for the factor V Leiden mutation and have a protein C and/or protein S deficiency increases the risk of VTE 35- to 50-fold.

• Nephrotic syndrome: In children with proteinuria greater than 0.5 g/d, loss of anticoagulant proteins, such as antithrombin, has been documented, leading to an increased risk of TE. Most TEs develop within several months of diagnosis. Both arterial and venous TE can occur, with renal vein thrombosis being the most common site.

• Heparin-induced thrombocytopenia: This is characterized by a greater than 50% drop in platelet count after 5 or more days of unfractionated heparin (UHF). Risk for venous TE is present mainly in adults, but a high index of suspicion is needed to recognize this in children (even if only receiving heparin flushes for intravenous or central lines).

• Inherited prothrombotic disorders: Several dominantly inherited deficiencies or abnormalities of proteins in the coagulation and fibrinolytic pathways now are recognized. On occasion, more than one such abnormality may coexist in a single patient. Furthermore, the expression of these abnormalities (ie, the development of a clot) frequently reflects the additive effects of acquired risk factors: orthopedic surgery or trauma, immobility, pregnancy, OCPs, dehydration, etc.

• Factor V Leiden: Resistance to activated protein C is the most common genetic risk factor associated with venous thrombosis in adults and children. The majority of cases are due to a point mutation in the factor V gene (factor V Leiden [FVL]), which prevents the cleavage of activated factor V by activated protein C, thus promoting ongoing clot development. Approximately 3-8% of white adults are heterozygous for the mutation, but many of these individuals have no history of thrombosis. Several pediatric studies have demonstrated that, as in adults, 10-50% of children with thrombosis are heterozygous for the FVL mutation. Double heterozygotes with FVL and protein C, protein S, or antithrombin deficiency have been reported with further increased risk of thrombosis. Women heterozygous for FVL who also are taking OCPs increase their risk of thrombosis 35-fold.

• Antithrombin (AT) deficiency: Produced in the liver, antithrombin is the most important inhibitor of activated clotting factors. Most patients with AT deficiency are heterozygous (levels <50%), and thrombosis usually is venous. Thrombosis can occur in children as young as 10 years. Homozygous deficiency of AT is rare but devastating. Presentation usually is within hours of birth, and patients have extensive thrombosis. Most infants die soon after birth.

• Protein C deficiency: This usually is transmitted in an autosomal dominant manner with incomplete penetrance. Thrombosis also is most often venous, in the lower extremities. DVT in heterozygotes can be seen as early as the teenage years. As with AT deficiency, homozygotes with PC deficiency usually present in the newborn period with purpura fulminans. A purified Protein C concentrate is being studied in these children.

• Protein S deficiency: Similar to Protein C and AT deficiency except that patients have a greater predisposition to arterial thrombosis. Most of PS is bound to C4-binding protein so one must measure both free and total PS to rule out a deficiency. Patients with either PC or PS deficiency can develop warfarin-induced skin necrosis unless heparin is started first.

• Hyperhomocystinemia (HHC) has been shown in adults to be an independent risk factor for arterial vascular disease and venous thrombosis. Few studies have examined the role of HHC in childhood thrombosis. One recent study of 45 children with ischemic stroke found an odds ratio for moderate HHC of 4.4 (versus controls). Homozygous mutations in the gene for cystathionine beta synthetase (CBS) are rare but account for most cases of severe HHC. Mild-to-moderate HHC can be seen in heterozygotes with CBS or methylene tetrahydrofolate reductase mutations.

• Prothrombin gene 20210A mutation (PGM): A recent Turkish study of 32 children with cerebral infarcts reported that 21.8% were heterozygous for the PGM. Most case reports show fewer than a dozen children with thrombosis and PGM. Several other studies have not shown an increased prevalence of PGM in children with TE, although larger numbers need to be studied.

• Other disorders, such as dysfibrinogenemia and plasminogen deficiency, are rare but should be explored if the rest of the workup is negative. Also, recent studies in adults have implicated elevated levels of Factor VIII and XI as risk factors for thrombosis. They have not been explored in children yet.

• Congenital heart disease (CHD): This includes children with mechanical or prosthetic valves and those undergoing Blalock-Taussig shunt or Fontan procedure. As noted above, cardiac catheterization is the most common risk factor for arterial thrombosis. Cardiogenic embolism due to, for example, atrial fibrillation or cardiomyopathy, is one cause of stroke in both children and adults.

• Ventilation-perfusion scan

• For children with suspected PE this is the procedure of choice. A high-probability scan shows a peripherally based perfusion defect with normal ventilation (mismatch). In adults, a high probability scan with high clinical suspicion predicts PE correctly 96% of the time. A more difficult situation occurs when the scan is read as intermediate probability for PE. In that setting, only 33% of adults ultimately prove to have PE.

• In adults, pulmonary angiography (PA)is recommended as the reference standard. However, there are no data validating either V/Q scanning or PA in children suspected of having PE. Given that PA is very invasive and may require heavy sedation in children, V/Q scanning is recommended as the diagnostic test of choice.

• Alternatively, adult studies have suggested using the D-dimer test to help screen for significant clot. If the D-dimer is elevated and the ventilation-perfusion (V/Q) scan is intermediate probability, then spiral CT scan may be useful. However, this strategy has not been evaluated in children.

• MRI and magnetic resonance angiography (MRA) of the head probably are the modalities of choice for evaluating a child with suspected CNS thrombosis. Diffusion-weighted MRI has been shown to be very sensitive in detecting hyperacute strokes in adults.

• CT scan of the head with IV contrast is sometimes useful for detecting sinovenous thrombosis. MRI and MRA are better at picking up early arterial ischemic stroke (CT scan often normal).

Other Tests:

• Chest x-ray (CXR) actually may be more helpful in suggesting alternative diagnoses, such as pneumonia. Most often it is normal. Classic findings of PE include small pleural effusions with a wedge-shaped pleural-based density of pulmonary infarction. Again, pneumonia is by far more common in children.

• ECG usually is normal or shows only sinus tachycardia. The classic findings of T-wave inversion in the right precordial leads, right axis deviation, and incomplete or complete bundle branch block rarely can be seen in children as evidence for PE.

Medical Care:

• Initial management and evaluation should occur in a pediatric inpatient ward.

• Manage severe respiratory distress or neurologic deterioration in an intensive care setting.

Surgical Care: Occasionally, surgical thrombectomy may be necessary, especially following major cardiac surgery or when thrombolytic agents have failed or are contraindicated.

Diet: Vitamin K interferes directly with the effectiveness of warfarin, potentially increasing the risk for rethrombosis.

• Daily intake of foods high in vitamin K, such as green leafy vegetables, should be kept at a consistent level.

• Maternal intake of vitamin K also can affect levels in breast milk and cause similar problems in infants. Supplementing with a consistent amount of formula per day has been recommended.

• Formula-fed infants should receive formula with the lowest concentration of vitamin K available.

• Vitamin K should be removed from total parenteral nutrition.

• Anticoagulation is begun with heparin or LMWH, followed by institution of oral anticoagulation with warfarin-type medications. Children remain inpatient until the international normalized ratio (INR) is maintained greater than 2 for 2 successive days.

• Obtain daily CBC, PT, and aPTT while children are inpatient. If using LMWH, obtain an anti-activated factor X (anti-Xa ) or heparin level, and adjust the dose to achieve a level of 0.5-1 U/mL.

Further Outpatient Care:

• For patients on oral anticoagulation, monitor PT/INR within 3 days of discharge from the hospital. Always check an INR 5-7 days after adjusting the dose. Once the INR is 2-3 (or 2.5-3.5 for mechanical valves) on 2 successive occasions a week apart, the interval can be lengthened to every 2 weeks. Monitor the INR a minimum of once a month.

• The patient should inform the physician of any changes in diet or medications.

• Duration of therapy varies, depending on the underlying problem. Children with mechanical heart valves or recurrent TE requires anticoagulation indefinitely. Children with TE and persistent risk factors may be treated for 3 months then switched to low dose warfarin until the risk factor is no longer present. Uncomplicated DVT can be treated for 3-6 months.

• Monitor children on long-term LMWH (greater than 4 weeks) with weekly CBC (looking for heparin-induced thrombocytopenia) and twice monthly anti-Xa levels. Enoxaparin may accumulate over time necessitating dose adjustments.

In/Out Patient Meds:

• Medications include heparin or LMWH, oral anticoagulants, thrombolytic agents, and occasionally, antiplatelet agents.

• Avoid antiplatelet agents in children on anticoagulation unless absolutely necessary.

• Monitor INR more closely if changes in medications or diet occur.

Prevention:

• Avoid contact sports and weightlifting while on anticoagulation.

• Sexually active adolescent girls on oral anticoagulants should use some form of birth control, preferably not OCPs.

Complications:

• Recurrent thrombosis

• Pulmonary embolism

• Postphlebitic syndrome

• Bleeding

• Death

Prognosis:

• Many children with TE have an underlying risk factor that is persistent, such as CHD.

• Recurrent thrombosis occurs in as many as 19% of children.

• Mortality from PE or arterial ischemic stroke is 6-20%.

Patient Education:

• Review vitamin K content of various foods with the family of a child on oral anticoagulation and clearly define activity restrictions (especially with adolescents).

Medical/Legal Pitfalls:

• Since TE is uncommon and symptoms often are nonspecific in children, a high index of suspicion is required.

Special Concerns:

• Neonatal thrombosis: Neonates have multiple risk factors for TE, including prematurity, sepsis, and the frequent use of central arterial and venous lines. Also, developmental differences in the hemostatic system create difficulties in management. Neonates have lower levels of antithrombin and plasminogen, which causes a relative resistance to heparin and thrombolytic agents, respectively. Newborns need 11 times the usual concentration of urokinase and 5 times the usual concentration of tissue plasminogen activator to achieve the same rate of plasminogen activation as an adult.