Pediatrics

Thromboembolism

OVERVIEW: What every practitioner needs to know

Thrombosis is a common problem among adults, and management of many of the diverse clinical presentations has been subjected to randomized clinical trials. In pediatrics, most treatment is based on that used in adults (with adjustment of drug doses, of course). However, there is universal agreement about the key elements of management:

· Prompt diagnosis and evaluation of extent of thrombosis and risk for life-threatening sequelae (clinical examination, diagnostic imaging)

· Assessment of bleeding risk (clinical history, PT, aPTT, hemoglobin, platelet count)

· Immediate anticoagulation with a parenteral anticoagulant (heparin, low molecular weight heparin or fondaparinux)

· Determination of the necessary duration of therapy based on risk of recurrence and morbidity that an occurrence could impose (e.g., cerebral thrombosis may warrant a longer duration of therapy than distal deep venous thrombosis of a leg, since recurrence in cerebral veins could have disastrous consequences)

· Anticoagulation for the recommended duration using an oral anticoagulant in most patients or a parenteral one in patients with cancer, in whom the risk of recurrent thrombosis is lower when treated with low molecular weight heparin, or who may become pregnant, since warfarin is teratogenic and not safe during pregnancy.

·Careful monitoring for adherence to therapy, adequacy of anticoagulation, bleeding, or changes in the clinical situation that would warrant adjustments in the duration or type of anticoagulation

Are you sure your patient has thromboembolism? What are the typical findings for this disease?

Symptoms of thrombosis depend on the location of the clot, but in general include:

  1. No symptoms (detection by screening)

  2. Swelling

  3. Erythema

  4. Pain

  5. Fever

Pulmonary embolism can present with the following symptoms:

  1. Anxiety

  2. achypnea, tachycardia

  3. Shortness of breath

  4. Chest pain

  5. Cough

Central nervous system thrombosis usually presents with:

  1. Headache

  2. Vomiting

  3. Lethargy

  4. Seizure

  5. Blurred vision

  6. Neurologic deficits

What is the definition of thromboembolism?

Thrombosis refers to abnormal clot formation. Thromboembolism is defined as a thrombosis in which part, or all, of the clot embolizes. Most emboli go to the lungs since thrombosis occurs more frequently in the venous circulation. However, clots in the left atrium or ventricle of the heart and those in the arterial circulation can embolize to the brain, limbs, or other end organs. Further, venous emboli can cross to the arterial circulation in patients with cardiac abnormalities, such as septal defects or patent ductus arteriosus.

Pulmonary embolism is the most frequent type; it will be discussed in more detail later in this chapter.

What other disease/condition shares some of these symptoms?

Symptoms similar to those that occur in patients with thrombosis can occur in the following conditions:

  1. Cellulitis

  2. Lymphedema

  3. Congestive heart failure

Diseases whose symptoms may mimic those of pulmonary embolism include:

  1. Pneumonia or pneumonitis - chest pain, shortness of breath, and radiographic infiltrates may mimic pulmonary embolism

  2. Congestive heart failure - shortness of breath and cardiomegaly may mimic pulmonary embolism

What caused this disease to develop at this time?

  • Genetic predisposition – see Table I for inherited prothrombotic conditions. In addition to those listed in Table I, hyperhomocysteinemia, methylenetetrahydrofolate reductase (MTHFR) mutation, elevated lipoprotein(a) levels, and elevated Factor VIII and IX levels have also been associated with increased thrombosis risk.

  • Acquired pro-thrombotic risk factors – trauma, inflammation, or infection. These risk factors can include acquired protein C deficiency, protein S deficiency, antithrombin deficiency, and Factor VIII elevation.

  • Chronic conditions that increase thrombosis risk – congestive heart failure, inflammatory conditions (e.g., autoimmune diseases, inflammatory bowel disease)

  • Medications that promote thrombosis – oral contraceptives, asparaginase, thalidomide/lenalidomide

  • Behaviors that increase thrombosis risk – smoking

    • History, family history, physical exam, and laboratory studies are necessary to identify all thrombotic risk factors and to determine the proper course of treatment.

Table I.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • PT, aPTT, fibrinogen, complete blood count, and D-dimers are evaluated in patients with suspected thrombosis, but thrombosis must be confirmed by diagnostic imaging evaluation. An elevated PT and aPTT with low fibrinogen and a low platelet count can be associated with disseminated intravascular coagulation. An elevated D-dimer increases the probability that thrombosis is present in patients with clinically suspected thrombosis. However, an elevated D-dimer can also be associated with other conditions, including disseminated intravascular coagulation.

Confirming the diagnosis

of thrombosis is the key first step, and depends on diagnostic imaging studies (see next section). Once confirmed, a search for pro-thrombotic conditions must be undertaken, especially in patients with no thrombotic risk factors. Work-up includes a detailed family history of thrombosis, stroke, myocardial infarction (at a young age), or multiple miscarriages, and laboratory testing for inherited or acquired thrombophilic states (Table I). Hyperhomocysteinemia, methylenetetrahydrofolate reductase (MTHFR) mutation, elevated lipoprotein(a) levels, and elevated Factor VIII and IX levels have also been associated with increased thrombosis risk. Testing for these conditions may be appropriate in some situations.

Would imaging studies be helpful? If so, which ones?

  • The most useful imaging study to diagnose thrombosis depends on the site of suspected thrombosis:

  • Extremities – Doppler ultrasound

  • Central venous circulation (especially in patients with a central venous catheter), portal vein – magnetic resonance venogram, computed tomography angiogram, venogram

  • Cardiac – echocardiogram (sometimes transesophageal echocardiogram is needed to visualize the thrombus)

  • Central nervous system – magnetic resonance venogram, angiogram

    • Superficial veins – imaging of the deep veins proximal to the superficial venous thrombosis determines the extent of the thrombosis

Confirming the diagnosis

  • The diagnosis of thrombosis is suspected in patients who present with extremity swelling, erythema, and pain or with shortness of breath, chest pain, and hypoxemia.

  • EVERY patient with suspected thrombosis should have a complete evaluation, including the laboratory and imaging studies above. A patient with a new thrombosis is at high risk for progressive thrombosis and pulmonary embolism, both of which can cause significant morbidity and mortality.

  • Evaluation and treatment of newly diagnosed thrombosis is a medical emergency. If thrombosis is strongly suspected but definitive diagnosis will be delayed, antithrombotic therapy may be initiated prior to definitive diagnosis to reduce the risk of clot progression and embolism while awaiting confirmation of the diagnosis.

A note about asymptomatic thrombosis: In studies that use thrombosis screening methods, such as ultrasound of the iliac and femoral veins, about 80% of cases of thrombosis identified are asymptomatic. However, since the management of asymptomatic thrombosis is controversial (most clinicians would favor a watch-and-wait approach), screening of asymptomatic patients is not warranted in most situations.

If you are able to confirm that the patient has a thromboembolism, what treatment should be initiated?

  • Anticoagulation should be initiated immediately in patients with newly diagnosed thrombosis unless an absolute contraindication is present (e.g., active bleeding, disseminated intravascular coagulation).

  • Detailed recommendations for anti-thrombotic therapy are available in the guidelines published by the American Academy of Chest Physicians ( Chest 2012;141:e737S-e801S). Information about specific anticoagulants, antiplatelet agents, and antithrombotics is listed in Table IIa, Table IIb, Table IIc, and Table IId. The use of thrombolytic therapy to rapidly dissolve a new thrombus is controversial. Site-directed thrombolysis is usually recommended for cerebral vein thrombosis, particularly when the thrombus is rapidly progressive or the patient is symptomatic. For other sites, the benefits of more rapid thrombus resolution (decreased acute symptoms and decreased risk of post-thrombotic syndrome) must be weighed against the risks (hemorrhage). See Chest 2012;141:e737S-e801S for detailed guidance.

  • Initial therapy - Most pediatric patients in the United States are treated initially with enoxaparin 1 mg/kg/12 hours (or 1.5 mg/kg/24 hours), dalteparin 200 units/kg/24 hours, or fondaparinux 0.1 mg/kg/24 hours. There are no clinical trials that document the superiority of one anticoagulant over another for initial therapy, but enoxaparin has been most commonly used in North America.

  • Subsequent therapy – Once the clot and patient have stabilized, oral anticoagulation with warfarin (or perhaps in the near future an oral direct thrombin inhibitor) may be initiated in those for whom it is suitable. Patients with cancer or who may become pregnant must continue therapy with a parenteral anticoagulant. In cancer patients, the risk of recurrent thrombosis is higher with warfarin than with low molecular weight heparin. Furthermore, anticoagulation must be held (and its effects reversed) prior to lumbar puncture, so the procedure for cancer patients who require lumbar puncture is simplified when using low molecular weight heparin, which can be held and resumed and does not require time to achieve a therapeutic dose once resumed.

  • Duration of therapy: Depends on the causes, extent and location of the thrombosis, whether the thrombophilic risk factors have resolved, whether residual thrombus persists after initial therapy, and risk factors for major hemorrhage while anticoagulated (which affect the risk-benefit ratio for individual patients). Duration can range from 3 months to lifelong at the maximum. See Chest 2012;141:e737S-e801S.

Table IIa

Table IIb

Table IIc

Table IId

Some comments regarding the attached tables:

Note that Table I only addresses inherited thrombophilic conditions. Many thrombophilic states can be acquired, and are beyond the scope of this chapter.

Trade names are shown in parentheses, since many have become synonymous with the drug and clinicians may be unaware of the generic drug name in some cases.

Abbreviations:

U, units

IU, international units

aPTT, activated partial thromboplastin time

PT, prothrombin time

INR, international normalized ratio

What are the adverse effects associated with each treatment option?

Anticoagulation is necessary in patients with thrombosis, but has unavoidable risks. The rate of clinically important bleeding in children receiving therapeutic doses of anticoagulation is 1% to 4% per year, and 5% to 20% of children experience minor bleeding each year. In patients with cancer and thrombosis, bleeding risk is exacerbated by thrombocytopenia after chemotherapy, so platelets must be transfused to keep the platelet count above 20,000/mm3, or anticoagulation reduced or withheld during periods of profound thrombocytopenia. In patients with new thrombosis, continuing anticoagulation is mandatory, so it is preferable to maintain full-dose anticoagulation and transfuse platelets as needed to reduce the risk of major hemorrhage.

What are the possible outcomes of thromboembolism?

Thrombosis carries significant risks for subsequent adverse events, including death (usually from pulmonary embolism), recurrent thrombosis (in about 1/3 of patients), post-thrombotic syndrome (1/3 of patients), and thromboembolism (1/3 of patients).

Risks of anticoagulation include hemorrhage, possibly altered bone metabolism with risk for low bone mineral density, and the cost and inconvenience of daily injections and regular monitoring. However, the risks of not treating thrombosis are much greater, since almost all untreated thrombosis will progress and cause additional morbidity and increased mortality.

What causes this disease and how frequent is it?

  • Thromboembolism is caused by abnormalities in blood flow (stasis), vascular injury, and/or blood hypercoagulability.

  • Abnormal blood flow is uncommon in children, but can occur with extrinsic compression of blood vessels by a mediastinal mass (superior vena cava syndrome), anatomic vascular anomalies that compresses veins (e.g., May-Thurner syndrome), and the presence of a central venous catheter.

  • Vascular injury is also uncommon in children; it may result from vasculitis due to autoimmune disease (e.g., systemic lupus erythematosus), antiphospholipid antibody syndrome, and heparin-induced thrombocytopenia, in which anti-heparin antibodies damage vascular endothelium.

  • Detailed epidemiology:

    • Thrombosis is rare in children who have no known risk factors, but when it does occur, it is more common in neonates and adolescents. After adolescence, the risk increases progressively with age, with no known plateau. The incidence in neonates is about 5 per 100,000 live births, and the annual incidence in children is about 5 per 100,000.

    • Inherited thrombophilic states, most commonly Factor V Leiden (in Caucasians), are present in 3% to 8% of children, but in the absence of other risk factors rarely cause thrombosis.

    • Predisposing exposures include smoking, oral contraceptives, trauma, immobility, infection, or other types of inflammation.

Genetics plays a role in thrombotic risk in some cases of symptomatic thrombosis in children, but the annual risk for patients with inherited thrombophilic states is quite low (0% to 1% in one cohort study). Usually additional risk factors are needed for thrombosis to develop. Genetic screening of asymptomatic people with no personal or family history of thrombosis is not warranted, but screening of family members with multiple non-genetic risk factors may be useful once a genetic prothrombotic predisposition is diagnosed. Although the benefits of primary prophylaxis in people with a genetic prothrombotic predisposition rarely exceed the risks, knowledge of the genetic finding may help promote reduction of other risk factors (e.g., smoking cessation) or use of short periods of prophylaxis during periods of increased risk (e.g., hospitalization, trauma, pregnancy).

How to these pathogens/genes/exposures cause the disease?

How do these risk factors cause thrombosis?

  • Inherited thrombotic risk factors induce a permanent mild hypercoagulable state by increasing thrombin formation via removal of inhibiting factors (protein C, protein S, antithrombin) or the addition of promoting factors (Factor V Leiden, prothrombin 20210). Use of oral contraceptives (especially those that contain estrogens) and some chemotherapy agents (asparaginase, glucocorticoids, lenalidomide, bevacizumab) also induces a hypercoagulable state.

  • Other conditions predispose to vascular injury (antiphospholipid antibody syndrome, smoking), immobility (trauma, surgery), or act by several mechanisms to increase thrombosis risk (infection, inflammation).

Other clinical manifestations that might help with diagnosis and management

Thrombosis in particular sites not mentioned previously can cause the following symptoms:

Superior vena cava– dizziness, headache, changes in facial color, facial edema, periorbital edema, cyanosis, plethora, neck and chest vein distention, papilledema, edema of the upper extremities, and pulsus paradoxus

Among patients with leukemia and T-cell lymphoma, the superior vena cava (SVC) is susceptible to compression because it is surrounded by lymphoid tissue and has a thin, easily compressed vessel wall. Despite this, SVC syndrome occurs in fewer than 5% of children with mediastinal involvement of cancer. The severity of clinical manifestations of SVC syndrome depends on how rapidly the obstruction arises and whether there has been sufficient time for new collateral vessels to develop via the azygos and hemiazygos veins.

CT imaging should be performed to document the degree of displacement of normal anatomy, the extent of pleural or pericardial effusions (that can accompany SVC syndrome), and the magnitude of central airway compression. Doppler ultrasonography and echocardiography may be indicated to evaluate flow through the great vessels and cardiac function. Treatment of SVC syndrome includes the standard measures to treat all thromboses, plus prompt cancer therapy to reduce external compression on the vein.

What complications might you expect from the disease or treatment of the disease?

Potential complications of thrombosis include progressive or recurrent thrombosis, post-thrombotic syndrome, pulmonary embolism, and bleeding caused by anticoagulation.

Progressive thrombosis occurs when anticoagulation does not adequately inhibit formation of new thrombus. One of the most thrombogenic conditions is the presence of fresh clot, which continues to activate the coagulation cascade locally and promote further thrombosis. Ongoing vascular injury, such as the injury that occurs in heparin-induced thrombocytopenia from antibody-mediated and inflammatory damage to the vascular endothelium, can also lead to progressive thrombosis despite anticoagulation.

Recurrent thrombosis most commonly occurs at the site of the initial thrombosis because of disrupted vasculature, venous stasis, and endothelial damage, but can also occur at other sites. The incidence of recurrence depends a great deal on the ongoing thrombotic risk factors and the duration of anticoagulation. For example, in adults with cancer, recurrent thrombosis occurs at such a high frequency that long-term treatment with low molecular weight heparin is needed to reduce the risk of recurrence.

Post-thrombotic syndrome occurs when venous valves and vein anatomy are disrupted sufficiently to reduce venous blood return. The consequent venous stasis causes edema of the affected extremity; pain; and skin hyperpigmentation, induration erythema, and ulceration. The condition occurs in about a third of adults after deep vein thrombosis of the legs, but reported incidences vary widely and the risk in a particular patient depends on the extent of thrombosis, the degree of clot resolution with treatment, and, most importantly, the follow-up time.

Although post-thrombotic syndrome may be somewhat less common in children with venous thrombosis (about a fourth of patients), long-term follow-up information 10 or more years after thrombosis is not available on large cohorts of patients. Furthermore, up to 83% of cases are mild and may go undiagnosed, so the incidence may be much higher (63% in a Canadian study of 153 children), and mild cases may progress with the passage of time.

The incidence of post-thrombotic syndrome can be reduced by early use of elastic compression stockings soon after thrombosis develops. Compression stockings also decrease symptoms when post-thrombotic syndrome has already developed. Elevating the affected extremity above the level of the heart so that gravity facilitates venous blood return and reduces venous stasis also reduces the sequelae after thrombosis. Ideally, this must be done for many hours each day, but is not easy to implement when the clot was in the lower extremities. This may also explain the lower incidence of post-thrombotic syndrome in patients with upper extremity thrombosis.

Pulmonary embolism complicates thrombosis in 10%-20% of cases, and accounts for most deaths due to thrombosis. It is often asymptomatic, but when symptoms and signs are present, they can include chest pain, cough, shortness of breath, anxiety, tachycardia, tachypnea, hypoxemia, and hypotension. In rare cases, a large pulmonary embolus is immediately fatal because it obstructs both the right and left pulmonary arteries and prevents circulation of blood (the so-called “saddle embolus” because it rests at the bifurcation of the pulmonary artery).

Rapid initiation of therapeutic anticoagulation in patients with thrombosis is the most effective strategy to prevent embolization, and close monitoring of all patients with new thrombosis (particularly in the first few days) is warranted.

Small and asymptomatic pulmonary emboli can lead to late-onset pulmonary hypertension, so an adequate duration of therapy for the initial thrombosis and follow-up imaging of the primary thrombus is important to document that the clot has either resolved or reached a stable size after several months. In many cases, the thrombus heals by scarring and re-endothelialization, but a partial or complete obstruction of the affected vein persists.

Once two consecutive ultrasound evaluations a few months apart show no evidence of change, follow-up imaging can be discontinued (so long as no new symptoms develop that may indicate recurrent thrombosis).

Are additional laboratory studies available; even some that are not widely available?

Mandatory laboratory studies include those used to manage the acute thrombosis and its treatment (PT, aPTT, anti-factor Xa activity, etc.) and an evaluation for acquired and inherited thrombophilic conditions that will help determine the duration of therapy (see Table I). There are many very rare inherited thrombophilic conditions, and evaluation for them may be warranted in patients with a very strong family history of severe thrombosis to determine whether long-term therapeutic (or prophylactic) anticoagulation is justified.

How can thromboembolism be prevented?

Thromboembolism can be prevented by removal of risk factors. Smoking cessation and avoidance of estrogen-containing oral contraceptives are two important interventions, since both represent long-term modifiable risk factors.

What is the evidence?

Monagle, P, Chan, AKC, Goldenberg, NA. "Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. vol. 141. 2012. pp. e737S-e801S.

Astwood, E, Vora, A. "Personal practice: how we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia". Br J Haematol. vol. 152. 2011. pp. 505-11.

Brotschi, B, Hug, M, Latal, B. "Incidence and predictors of indwelling arterial catheter-related thrombosis in children". J Thromb Haemost. vol. 9. 2011. pp. 1157-62.

Chalmers, E, Ganesen, V, Liesner, R. "Guideline on the investigation, management and prevention of venous thrombosis in children". Br J Haematol. vol. 154. 2011. pp. 196-207.

Jackson, BF, Porcher, FK, Zapton, DT, Losek, JD. "Cerebral sinovenous thrombosis in children: diagnosis and treatment". Pediatr Emerg Care. vol. 27. 2011. pp. 874-80.

Jordan, LC, Rafay, MF, Smith, SE. "Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study". J Pediatr. vol. 156. 2010. pp. 704-10.

Nowak-Göttl, U, Kenet, G, Mitchell, LG. "Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment". Best Pract Res Clin Haematol. vol. 22. 2009. pp. 103-14.

Tousovska, K, Zapletal, O, Skotakova, J. "Treatment of deep venous thrombosis with low molecular weight heparin in pediatric cancer patients: safety and efficacy". Blood Coagul Fibrinolysis. vol. 20. 2009. pp. 583-9.

Yang, J, Paredes, N, Chan, AK. "Antithrombotic therapy in children with venous thromboembolism". Hamostaseologie. vol. 29. 2009. pp. 80-7.

Hanslik, A, Thom, K, Haumer, M. "Incidence and diagnosis of thrombosis in children with short-term central venous lines of the upper venous system". Pediatrics. vol. 122. 2008. pp. 1284-91.

Ongoing controversies regarding etiology, diagnosis, treatment

Controversy surrounds almost all aspects of thrombosis management in children.

  • Etiology – the relative contribution of inherited, environmental, and stochastic factors in development of thromboembolism in a particular patient at a particular time are usually not well understood.

  • Risk factors, screening, and genetic counseling – not clear whether family members should be screened for inherited thrombophilic risk factors or what to do when positive.

  • Prophylaxis – adults admitted to the hospital with 2 or more prothrombotic risk factors routinely receive enoxaparin 40 mg daily (or similar) to prevent thromboembolism. After each type of surgery, the type and duration of prophylaxis are well defined (see www.NCCN.com for example). Among children, there are no evidence-based guidelines that define the role of thromboembolism prophylaxis in the inpatient or outpatient setting.

  • Diagnosis – the relative roles of Doppler ultrasound, CT angiogram, MR angiogram, and venogram at each site remain to be clarified and optimized.

  • Treatment – the optimal choice of initial parenteral anticoagulant is not defined, and the optimal duration of treatment and need for antithrombotic prophylaxis thereafter in many specific clinical situations is unknown.

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