Critical Care Medicine
- 1. Description of the problem
2. Emergency Management
- 3. Diagnosis
What's the evidence?
Thrombosis in critically ill children
Also known as: Hypercoagulability, venous thrombosis
Venous thromboembolism (VTE)
Deep venous thrombosis (DVT)
Cerebral sinus venous thrombosis (CSVT), venous sinus thrombosis, cerebral venous thrombosis, sinovenous thrombosis, sinus thrombosis, sagittal sinus thrombosis, dural sinus thrombosis, intracranial venous thrombosis, cavernous sinus thrombosis
Renal vein thrombosis
Renal artery thrombosis
Portal vein thrombosis
1. Description of the problem
Thrombosis occurs because of an imbalance between coagulation (the formation of the insoluble blood protein fibrin) and fibrinolysis. Attributed to observations by Virchow in 1856, the three major mechanisms contributing to development of thromboses include hypercoagulability, hemodynamic alterations such as stasis or turbulence, and endothelial injury or dysfunction. This forms the so-called Virchow's triad.
Thrombotic etiology can be categorized as acquired, or genetic or a combination of both; thrombosis may be arterial, venous, or both.
Protein C deficiency—usually heterozygotes; homozygotes typically present as neonates Protein S deficiency
Factor V Leiden
Systemic lupus erythematosus (SLE)
Anti-phospholipid antibody syndrome (APAS)
Sickle cell disease (HgbSS)
Prothrombin variant G20210A
Increased plasma lipoprotein (a)
Methylene tetrahydrofolate reductase (MTHFR) genotype
Indwelling central venous line (CVL), including umbilical venous and arterial catheters
Heparin-induced thrombocytopenia, type 2 (HIT-2)
Chemotherapy: L-asparaginase use is associated with thromboembolic events, especially in the first 30 days of chemotherapy.
Infection, especially methicillin resistant Staphylococcus aureus (MRSA)
VTE is increasingly recognized as a complication of progressively complex tertiary care in infants and children. VTE may result in mortality or cause serious long-term morbidity, including the postthrombotic syndrome. As such, children may be faced with unpleasant prolonged, or life-long, effects (eg, leg size discrepancy). Thus, diagnosis and treatment strategies for VTE in children are extremely important to avoid such sequelae.
Thrombotic events in children will present with symptoms related to location of the occlusion and the extent of the thrombus.
Signs and symptoms
CSVT: headache, seizures, altered mental status, cranial nerve palsies, papilledema, visual disturbances (one or both eyes), double vision, lethargy, sleepiness, dizziness, ataxia, weakness, coma
DVT: swelling of the leg, extremity pain, reddish or purplish discoloration of the affected extremity (
Deep venous thrombosis - note the change in extremity circumference and coloration.
Renal vein thrombosis: hematuria, anuria, proteinuria, emesis, thrombocytopenia, rapid decline in renal function, flank pain
Portal vein thrombosis: May have acute (acute abdominal pain) or subacute presentation with signs or portal hypertension
Heparin-induced thrombocytopenia: In patients who have not had heparin previously, heparin-induced thrombocytopenia (HIT), an immune response, may occur 5 to 14 days after beginning exposure. Generally, the immune complex triggers platelet activation, and though the platelet count is reduced, the aggregated platelets can lead to thrombosis and arterial or venous clot formation. This can occasionally happen in patients who have not had heparin before.
CSVT: Anticoagulation is the treatment of choice. Rarely is thrombolysis indicated because of the high rate of hemorrhagic complications. Given that there is usually an underlying cause for the disease, tests may be performed to look for these. The disease may be complicated by elevated intracranial pressure. Neonates are most commonly affected. In one study (deVeber 2001), 58% of the children had seizures, 76% had diffuse neurologic signs, and 42% had focal neurologic signs. Poor outcome is more likely if a child with CSVT has seizures or evidence of infarction on imaging.
Children with protein C or S deficiency will require life-long oral anticoagulant therapy with target international normalized ratio (INR) of 3.0 to 4.5 (Monagle 2008).
The mortality rate was 20% in children with heritable conditions, with cumulative recurrence-free survivals at 1 and 7 years of 92% and 82%, respectively (van Ommen 2003).
2. Emergency Management
Treat any underlying or predisposing condition.
- Elevation of head of the bed
- Anticoagulation, but rarely thrombolysis
- May need to monitor intracranial pressure (ICP) or provide external ventricular drainage
General venous thrombosis: Anticoagulation therapy should begin immediately. According to the guidelines published by the American College of Chest Physicians, children experiencing a first episode of VTE should either be treated with unfractionated heparin (UFH) (goal anti-Xa 0.35–0.7 U/mL) or low molecular-weight heparin (LMWH) (goal anti-Xa 0.5–1.0 U/mL).
Thrombosis due to hyperleukocytosis: Apheresis is indicated. Exchange transfusion may be utilized if apheresis is not available. Cytotoxic therapy should be initiated as soon as feasible given appropriate diagnostics. Avoid transfusion of packed red cells as this may exacerbate hyperviscosity.
HIT-2: Immediately stop all heparin exposure, whether IV, SQ, or via impregnated catheters. This includes heparin flushes.
If known or suspected homocysteinuria (developmental delay, lens dislocation, skeletal involvement, arterial and venous thromboses), give B12 and B6.
In a Cochrane Review by Shah in 2008, there were no statistically significant differences in the risk of thrombosis (typical RR 0.93, 95% CI 0.58, 1.51) for peripherally inserted central catheters (PICC) in neonates.
In a survey of pediatric intensive care unit (PICU) physicians (Faustino 2011), for mechanically ventilated children, 42.3% of the respondents would usually or always prescribe thromboprophylaxis for the adolescent but only 1.0% would prescribe it for the child and 1.1% for the infant.
An abnormal D-dimer level at the end of treatment (3-6 months) might signal the need for continued treatment for patients with a first unprovoked DVT.
UFH has activity against thrombin and factor Xa. In adults, a goal of an activated partial thromboplastin time (aPTT) of 1.5x mean control, with maintenance of 1.5 to 2.5 times the patient's baseline, which is roughly equivalent to an anti-Xa assay of 0.3 to 0.7 units/mL. In children, it is recommended that aPTT not be used in isolation but in conjunction with heparin levels, as under-dosing may otherwise occur.
Loading dose is 75 to 100U/kg IV over 10 minutes. In one study, the average heparin dose needed to maintain therapeutic levels was 22U/kg/h for children and 28 U/kg/h for infants under 1 year of age, as they have a higher clearance (Andrew 1994).
LMWH catalyzes antithrombin with a high specific activity against Factor Xa; therefore anti-Xa levels and not aPTT should be monitored. Goal is anti-Xa level between 0.5 to 1.0U/mL, with levels being drawn 4 to 6 hours after the SQ injection. Levels only need to be followed for therapeutic, not prophylactic, therapy. Two doses should be withheld prior to lumbar puncture.
Vitamin K antagonists inhibit the synthesis of vitamin K-dependent coagulant proteins, which are factors II, VII, IX, and X. prothrombin time (PT) and INR need to be monitored morefrequently than in adults. Desired INR is 2.0-3.0. Initial dose 0.2mg/kg PO.
Children with protein C or S deficiency will require life-long oral anticoagulant therapy with target INR of 3.0 to 4.5 (Monagle 2008).
Thrombolytic therapies: Catalyze conversion of plasminogen to plasmin.
Recombinant tPA (r-tPA) may be instilled into the thrombus via a catheter-directed method or in low-dose continuous infusions, though the latter have a higher incidence of bleeding complications. Infusions: 0.1 to 0.6mg/kg/h. Catheter-directed infusion of 0.01 to 0.2 mg/kg/h for 24 hours. After 24 hours, there is considered to be no additional benefit of infusion as plasminogen will be depleted.
- Urokinase -
- Factor Xa inhibitors
- Direct thrombin inhibitors
- lupus anticoagulant
- anticardiolipin antibodies
- anti-beta2 glycoprotein 1 antibodies
- Factor V Leiden mutation
- G20210A mutation
- antithrombin level
- protein C level
- protein S level
- serum homocysteine level
- Doppler ultrasound - lack of flow (
Ultrasound of DVT showing flow void.
- Ultrasound - inability to compress vessel (
Clot seen nearly filling vessel on ultrasound
- Computed tomography (CT) scan (
Sagittal sinus thrombosis
- Findings without contrast - hyperattenuation of material in vein
- Findings after contrast injection - absence of luminal enhancement
- Magnetic resonance imaging (MRI)
- Magnetic resonance venography (MRV)
- Magnetic resonance arteriography (MRA)
The diagnosis is made by MRI/MRV with contrast to demonstrate obstruction of the venous system. CT with contrast is an alternative method (
Unenhanced CT scans may detect DVT as linear densities in the expected locations of the deep and cortical veins (Huisman 2001). As the thrombus becomes less dense, contrast may demonstrate the “empty delta” sign, a filling defect, in the posterior part of the sagittal sinus. CT scan with contrast misses the diagnosis of CSVT in up to 40% of patients.
Elevated D-dimer supports the diagnosis, but a normal D-dimer does not exclude a CSVT. D-dimer is not definitive as some patients with confirmed venous sinus thrombosis will have a normal D-dimer (Crassard 2005).
Establish underlying etiology: bun, creatinine - dehydration? Fever—meningitis, sinusitis, otitis, mastoiditis
- Palpation of the venous cord, which is generally tender or painful.
- Homan's sign: dorsiflexion of the foot elicits pain in the posterior calf.
- Pratt's sign: pain upon squeezing the posterior calf.
- Measure circumference of extremity and compare with contralateral extremity.
- Venography, via injection of contrast in the affected limb, is the gold standard. Not widely done owing to invasiveness and availability of noninvasive diagnostics.
- Ultrasound with Doppler.
Other tests, depending upon clinical situation
- Heparin antibody assay
- D-dimer: A low D-dimer in a setting of low clinical suspicion is helpful. If clinical suspicion is high, then the D-dimer is not reliable or helpful.
- White blood cell count with differential: Acute leukemia or less frequently chronic myelogenous leukemia (CML) can present with thrombotic events. Patients with acute myelogenous leukemia (AML) can have symptoms of microvascular complications at lower white blood cell counts than CML patients.
- Protein C
- Protein S
- Factor V Leiden
- SLE work-up
- Antiphospholipid antibodies
- Anticardiolipin antibodies
- Prothrombin mutation
- Methylene tetrahydrofolate reductase
- Hemoglobin electropheresis—HgbSS, thalassemia
- Complete blood count (CBC)
- Renal functions tests
- Bone marrow aspirate and biopsy
The clinican first needs to establish that a thrombus exists and the extent of thrombus. Once established, then the search for etilogies must be undertaken.
Development of thrombus depends upon the interaction of the coagulation state, the vascular endothelium and the flow of blood through the vessel. Stasis and turbulence predispose to clot formation.
The predominant risk factor for thrombosis in children is the presence of an indwelling central venous catheter (Andrew 1994, Kuhle 2004). As in adults, use of oral contraceptives and prolonged immobilization are also known risk factors. Dehydration plays an important role in children for cerebral thrombosis.
The predominant risk factors for acquired thrombosis include a central venous catheter in situ.
Renal vein thrombosis is usually due to reduced portal blood flow or periportal fibrosis.
Cerebral venous drainage is achieved via two systems: the superficial and the deep. The superficial drainage system is composed of the superficial cortical veins, superior sagittal sinus, torcula or confluence of veins, right transverse sinus (dominant in the majority of individuals), sigmoid sinus, and internal jugular vein.
The deep venous system consists of the basal veins, which drain blood from the basal ganglia and germinal matrix in preterm neonates, the Galenic system with the two internal cerebral veins that form the vein of Galen, the straight sinus, the basal vein of Rosenthal, the torcula, and the typically nondominant left transverse sinus, which drains into the left sigmoid sinus and the left internal jugular vein.
In most infants, the cavernous sinus is not yet connected to the cerebral veins, resulting in less reserve and increased vulnerability within the venous drainage system. Thrombosis within the venous system results in outflow obstruction, venous congestion, and a consequent increase in capillary hydrostatic pressure, driving fluid into the interstitium and producing edema. A persistent increase in hydrostatic pressure may result in red blood cell diapedesis, and if in excess of arterial pressure, a reduction of arterial inflow and arterial ischemia can occur.
The thrombosis of the veins themselves causes venous infarction, resulting in both vasogenic and cytotoxic edema, and leads to small petechial hemorrhages that may merge into large hematomas. Thrombosis of the sinuses is the main mechanism behind the increase in intracranial pressure due to decreased resorption of cerebrospinal fluid.
CSVT risk factors
Risk factors for CSVT nclude head and neck disorders, 29%; acute systemic illnesses, 54%; chronic systemic diseases, 36%; and prothrombotic states, 41% (deVeber 2001). More than 40% of childhood CSVT occurs within the neonatal period. The incidence of childhood CSVT varies between 0.4 and 0.7 per 100,000 children per year (Heller 2003).
- Meningitis, mastoiditis, or sinusitis
- Direct injury to the venous sinuses
- Medical procedures in the head and neck area
- Renal vein thrombosis, most commonly seen in children with nephrotic syndrome, SLE, burns or following renal transplant
Portal vein thrombosis
Associated with liver transplant and in patients with splenectomy.
Renal vein thrombosis
Usually due to reduced portal blood flow or periportal fibrosis.
HIT-2 is caused by heparin-dependent antiplatelet antibodies.
Little data is available on the incidence of VTE in the pediatric population. One Canadian study found an incidence of 0.07 per 10,000 children aged 1 month to 18 years, with a peak incidence in infants younger than 1 year of age (Andrew 1994). Similarly, the National Hospital Discharge Survey (1979–2001) found an increased incidence in children younger than 2 years old and in those older than 15 years, compared to those between 2 and 14 years of age (10.5, 11.4, and 2.4/100,000 children per year, respectively) (Stein 2004).
In teenagers, the rate was greater in girls (14.9 versus 8.1/100,000 children per year) with pregnancy accounting for the difference. For all age groups, the rate of VTE was approximately two times higher in blacks. Approximately 1/3 to 2/3 of the VTE events are associated with an indwelling CVL (Andrew 1994, Kuhle 2004).
DVT risk factors
Risk factors for the development of DVT include:
Disorders resulting in hypercoagulable state: eg, factor V Leiden, deficiency of protein C or protein S, antithrombin 3 deficiency
Chronic inflammatory diseases, such as SLE
Pregnancy or use of estrogen-containing contraception
Prognosis depends upon the etiology of the thrombotic state and the extent of the thrombosis.
Increased frequency of inherited prothrombotic coagulation proteins was, however, found in older children with spontaneous VTE (60%) compared with older children with VTEs secondary to an underlying medical condition (10%) (P = 0.02). Prothrombotic coagulation proteins do not contribute significantly to the pathogenesis of VTEs in neonates and children, in whom the most significant etiologic factors are the presence of a CVL and/or other medical conditions (Revel-Vilk 2003).
Recurrence of thromboembolism
In a prospective study to evaluate the risk of recurrence of VTE, 301 children with an objectively confirmed first episode of spontaneous VTE were followed for a median of 7 years after therapy. Recurrent VTE occurred in 21% at a median time of 3.5 years after completion of anticoagulant treatment. When compared to children with no inherited prothrombotic defects, those with a single defect (odds ratio 4.6, 95% CI 2.3–9.0) and those with two or more defects (odds ratio 24, 95% CI 5.3–109) had significantly increased risks for VTE recurrence.
Neither gender nor the presence of an acquired predisposing risk factor (eg, immobilization, surgery, trauma) influenced the risk of recurrent VTE in these children (odds ratio 0.86, 95% CI 0.45–1.6). The factor V G1691A mutation was present in the majority of patients with recurrent VTE. Including genetic defects, gender, and acquired risk factors, multivariate analysis showed that only the presence of prothrombotic defects increases the risk of recurrent VTE (Nowak-Göttl 2001).
In one follow-up study of 82 children with a radiologically confirmed acute thrombotic event, elevated plasma levels of factor VIII, D-dimer, or both at the time of diagnosis (odds ratio 6.1, 95% CI 2.1–18), and a persistent elevation of at least one of these two factors after standard-duration (3–6 months) of therapy with LMWH or warfarin (odds ratio 4.7, 95% CI 1.8–13) predicted for a poor outcome (ie, lack of thrombus resolution, recurrent thrombosis, or the postthrombotic syndrome).
The combination of a factor VIII level above 150 IU/dL and a D-dimer level above 500 ng/mL at diagnosis was 91% specific for a poor outcome (Goldenberg 2004).
CVST in childhood is a rare, and likely underrecognized, disorder, typically of multifactorial etiology, with neurologic sequelae apparent in up to 40% of survivors and mortality approaching 10% (Dlamini 2010). The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 (deVeber 2001); venous infarcts occurred in 41% of the children. Fifty-three percent of the children received antithrombotic agents. Neurologic deficits were present in 38% of the children, and 8% died; half the deaths were due to sinovenous thrombosis.
Predictors of adverse neurologic outcomes were seizures at presentation and venous infarcts. Death in the first 2 weeks occurred in 3% of affected children, usually due to transtentorial herniation related to bleeding and cerebral edema; 22% had recurrent CSVT, with 70% occurring within 6 months (Kenet 2007).
In children, evidence of increased thrombin generation is present at the time of diagnosis with acute lymphoblastic leukemia (ALL), the etiology of which is unclear. Thromboembolism in children with ALL is most commonly reported after the initiation of antileukemic therapy.
Asparaginase and steroids are shown to induce hypercoagulable state by suppression of natural anticoagulants, especially antithrombin (AT) and plasminogen, and by elevations in F VIII/vWF complex, respectively. In addition, steroid therapy causes hypofibrinolytic state by dose-dependent increase in plasminogen activator inhibitor 1 (PAI-1) levels (Athule 2003).
Postthrombotic syndrome as a reflection of chronic venous insufficiency occurs in 15% of patients with DVT. It presents with leg edema, pain, nocturnal cramping, venous claudication, skin pigmentation, dermatitis and ulceration (usually on the medial aspect of the lower leg). Diagnosis of postthrombotic syndrome is made clinically. The incidence in children ranges from 10% to 50%.
What's the evidence?
Andrew, M, David, M, Adams, M, Ali, K, Anderson, R, Barnard, D. "Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE". Blood. vol. 83. 1994. pp. 1251.
Andrew, M, Marzinotto, V, Massicotte, P, Blanchette, V, Ginsberg, J, Brill-Edwards, P. "Heparin therapy in pediatric patients: a prospective cohort study". Pediatr Res. vol. 35. 1994. pp. 78.
Athale, UH, Chan, AK. "Thrombosis in children with acute lymphoblastic leukemia. Part II. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of the disease and therapy". Thromb Res. vol. 111. 2003. pp. 199.
Bracho-Blanchet, E, Cortés-Sauza, J, Dávila-Pérez, R, Lezama-Del Valle, P, Villalobos-Alfaro, C, Nieto-Zermeño, J. "Usefulness of intravenous heparin to prevent thrombosis of central venous catheter in children". Cir Cir. vol. 78. 2010. pp. 423-9.
Crassard, I, Soria, C, Tzourio, C. "A negative D-dimer assay does not rule out cerebral venous thrombosis: a series of seventy-three patients". Stroke. vol. 36. 2005. pp. 1716.
deVeber, G, Andrew, M, Adams, C. "Cerebral sinovenous thrombosis in children". N Engl J Med. vol. 345. 2001. pp. 417-23.
Dlamini, N, Billinghurst, L, Kirkham, FJ. "Cerebral venous sinus (sinovenous) thrombosis in children". Neurosurg Clin North Am. vol. 21. 2010. pp. 511-527.
Faustino, EV, Patel, S, Thiagarajan, RR, Cook, DJ, Northrup, V, Randolph, AG. "Survey of pharmacologic thromboprophylaxis in critically ill children". Crit Care Med. 2011 Mar 17.
Goldenberg, NA, Knapp-Clevenger, R, Manco-Johnson, MJ. "Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children". N Engl J Med. vol. 351. 2004. pp. 1081.
Heller, C, Heinecke, A, Junker, R. "Cerebral venous thrombosis in children: a multifactorial origin". Circulation. vol. 108. 2003. pp. 1362-7.
Huisman, T.A., Holzmann, D, Martin, E. "Cerebral venous thrombosis in childhood". Eur Radiol. vol. 11. 2001. pp. 1760-5.
Kenet, G, Kirkham, F, Niederstadt, T, Heinecke, A, Saunders, D, Stoll, M. "Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicenter cohort study". Lancet Neurol. vol. 6. 2007. pp. 595.
Kosinski, CM, Mull, M, Schwarz, M. "Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?". Stroke. vol. 35. 2004. pp. 2820.
Kuhle, S, Massicotte, P, Chan, A, Adams, M, Abdolell, M, de Veber, G. "Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service". Thromb Haemost. vol. 92. 2004. pp. 722.
Monagle, P, Chalmers, E, Chan, A, DeVeber, G, Kirkham, F, Massicotte, P. "Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. vol. 133. 2008. pp. 887S.
Nowak-Göttl, U, Junker, R, Kreuz, W, von Eckardstein, A, Kosch, A, Nohe, N. "Childhood risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Thrombophilia Study Group". Blood. vol. 97. 2001. pp. 858.
Revel-Vilk, S, Chan, A, Bauman, M, Massicotte, P. "Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease". J Thromb Haemost. vol. 1. 2003. pp. 915.
Shah, PS, Shah, VS. "Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters". Cochrane Database Syst Rev. vol. 16. 2008. pp. CD002772.
Stein, PD, Kayali, F, Olson, RE. "Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey". J Pediatr. vol. 145. 2004. pp. 563.
van Ommen, CH, Heijboer, H, van den Dool, EJ, Hutten, BA, Peters, M. "Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome". J Thromb Haemost. vol. 1. 2003. pp. 2516.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Sign Up for Free e-newsletters
Psychiatry Advisor Articles
- Etiology of Schizophrenia: Strong Association With Certain Rare Copy Number Variants
- Long-Term Lithium Use: More Evidence Needed to Associate With Cancer Risk
- FDA to Review Lumateperone for Treatment of Schizophrenia
- Revised Children's Anxiety and Depression Scales Reliable Measurement Tool for Adults
- AMA Survey Collects Advice for Physicians Approaching Retirement
- Cannabis Use, Cannabis Use Disorder Linked to Psychotic, Depressive Symptoms
- Abstinence From Regular Cannabis Use Improves Memory Among Adolescents, Young Adults
- Group Cognitive Behavioral Therapy Is Effective Treatment for Adolescent Anxiety
- Association Between Opioid and Benzodiazepine Misuse and Suicidal Ideation
- The Intersection of Eating and Alcohol Disorders: Detecting and Managing "Drunkorexia"
- Cognition, Depression, and Limited Functioning Linked in Middle Age
- Coping With Challenges When Working the Holidays
- Lithium Preferred Method of Maintenance Monotherapy in Older Adults With Bipolar Disorder
- Hypobetalipoproteinemia Associated With Aggression and Schizophrenia
- AMA Code of Medical Ethics Guides Physicians in Fighting Harmful Online Health Information