Rare disease
CASE REPORT
Phlegmasia cerulea dolens in a teenage boy found to have Factor V Leiden Emily Junck, Sachita Shah Division of Emergency Medicine, University of Washington, Seattle, Washington, USA Correspondence to Dr Emily Junck, [email protected] Accepted 9 March 2015
SUMMARY A 16-year-old boy with morbid obesity and asthma presented with 1 week of progressive right leg pain, swelling and discolouration that started 1 week after a minor fall. Ultrasound and then CT with contrast revealed a large occlusive deep venous thrombosis (DVT) extending from the calf through the inferior vena cava bifurcation. Heparin was initiated and catheter-directed thrombolysis with tissue plasminogen activator and balloon angioplasty were performed with good flow postprocedure, however, the clot reaccumulated after several days and the procedure had to be repeated. After this occurred twice more, finally a right common iliac and femoral vein stent was placed to prevent clot reaccumulation and vein stenosis. Hypercoagability testing revealed activated protein C resistance and genetic testing confirmed homozygous Factor V Leiden (FVL). Family history was significant for maternal lower extremity DVT at age 21 and possible DVT in the patient’s maternal grandmother.
maternal grandmother. He denied use of tobacco and hormonal supplements. He had no personal history of malignancy, and denied constitutional and autoimmune symptoms. Examination showed a dusky bluish right lower extremity distal to the groin with moderate tense swelling (figure 1). Compartments were compressible though the entire leg was tender, and there were several areas of potential skin compromise on his lateral thigh. Posterior tibial, dorsalis pedis and popliteal artery pulses were detectable by Doppler and distal capillary refill was delayed to 5 s. Full strength and range of motion were intact at the ankle, knee and hip. Sensation was objectively intact but subjectively diminished through the right lower extremity.
INVESTIGATIONS Ultrasound revealed a large occlusive femoral DVT from the external iliac vein to the calf. CT with
BACKGROUND Acute ischaemia to an extremity is a medical emergency, however, it is usually due to arterial causes. Phlegmasia cerulea dolens (PCD) is a rare condition in which massive venous thrombosis obstructs venous drainage and causes arterial insufficiency in an extremity and can cause systemic circulatory collapse. Emergency physicians should know the potential for systemic decompensation and how to treat this condition. While PCD is highly associated with systemic disease and inherited coagulopathies in adults, its relation to inherited coagulopathies in children is not well understood.1–4 Hospitalists and primary care providers should understand implications and management of PCD. This case report will review the presentation, pathophysiology, diagnosis and treatment of PCD.
CASE PRESENTATION
To cite: Junck E, Shah S. BMJ Case Rep Published online: [ please include Day Month Year] doi:10.1136/ bcr-2014-207959
A 16-year-old morbidly obese boy with a history of asthma presented with progressive right leg pain and discolouration. He had fallen down a flight of stairs and landed on his right leg 2 weeks prior to presentation, but was ambulatory and asymptomatic at that time. He began having an ache in his right leg 1 week after the fall, which progressed to buttock and groin pain and then swelling, erythaema and transient numbness 1 day prior to emergency department (ED) presentation. He had a family history of a lower extremity deep venous thrombosis (DVT) in his mother at age 21 that was surgically removed, and possible DVT in his
Figure 1 Visible swelling and discolouration in the right leg of a teenage boy with phlegmasia cerulea dolens.
Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
1
Rare disease contrast showed the clot extending from the internal vena cava (IVC) bifurcation through the popliteal vein (visualisation of clot distal to this point was limited by technique), with a new clot in the common iliac vein within the 12 h since the ultrasound. Platelets, partial thromboplastin time, prothrombin time and international normalised ratio were normal. Hypercoagulability panel was sent and later returned with normal antithrombin III, protein S free antigen, lipoprotein A and fasting homocysteine levels, and negative lupus inhibitor assay. Protein C activity was low at 62% inhibition (though confounded by the patient’s acute clot; normal reference range 60– 150% inhibition), factor VII activity assay was elevated at 443% (normal reference range 50–200%) and activated protein C (APC) resistance was positive.5–6 Genetic testing returned negative for prothrombin G20210A mutation and positive for homozygous Factor V Leiden (FVL) mutation.
DIFFERENTIAL DIAGNOSIS Initially, there was concern for arterial or venous thrombus related to possible vascular trauma from the patient’s fall. However, this aetiology was less likely given that the fall was minor by description, there was no immobilisation thereafter and symptoms were delayed in onset. Compartment syndrome due to trauma or burns, though unlikely in this patient’s case, can also cause arterial insufficiency. The most likely diagnosis given the patient’s history was venous thrombosis due to acquired or genetic causes. Possible acquired causes in our patient included acute lymphoblastic leukaemia (ALL), nephrotic syndrome, systemic infection, HIV, severe liver disease or vitamin deficiency. Common genetic coagulopathies include FVL, prothrombin mutation, antithrombin deficiency, protein S and C deficiencies and increased lipoprotein A.1 2 7 The patient’s APC resistance assay returned positive, which narrowed the differential of FVL mutation to some degree; though not applicable for our patient, women can develop APC resistance with use of oral contraceptive pills and pregnancy-related hormonal changes.
TREATMENT Heparin infusion was started in the ED and the patient was admitted to the intensive care unit with vascular surgery and paediatrics. Symptoms did not significantly improve, and after 2 days he underwent catheter-directed thrombolysis with 24 h infusion of tissue plasminogen activator (tPA) through his right popliteal vein. A venogram was performed the next day and given a large residual clot burden, balloon angioplasty of the ileofemoral segment was performed with restoration of flow in the iliac vein. The patient worked with physical therapy and his subjective symptoms and his examination both improved. However, routine follow-up ultrasound to assess flow on postoperative day 3 showed reaccumulation of occlusive DVT from the common femoral through the gastrocnemius veins, and the patient was transferred to Seattle Children’s Hospital for paediatric haematology consult and further intervention. Catheter-directed tPA thrombolysis and angioplasty was repeated, this time showing a mild right common and external iliac vein stricture but good postprocedure flow. However, follow-up ultrasound after 3 days again showed recurrent iliofemoropopliteal thrombosis, and the patient was taken for repeat thrombolysis, angioplasty and stent placement across the right common and external iliac vein stricture. The venogram during this procedure revealed that the patient had severe left common iliac vein stenosis from right common iliac artery compression (May-Thurner syndrome). The patient was asymptomatic in his 2
left leg, so no immediate intervention was performed, but stent placement was recommended electively within 6 months.
OUTCOME AND FOLLOW-UP The patient was bridged to warfarin and discharged on hospital day 18. After genetic testing confirmed homozygous FVL mutation, haematology recommended lifelong anticoagulation. Follow-up ultrasound after 6 weeks showed continued patency. The patient had gradual improvement in pain and swelling, and barring one area with persistent paresthesias, he had full symptomatic recovery by 8 weeks.
DISCUSSION PCD is a rare condition of massive proximal venous thrombosis obstructing superficial and deep venous drainage in the lower extremities with high morbidity and mortality. Patients may present with sudden and severe leg pain, swelling, cyanosis, compartment syndrome, venous gangrene and/or arterial compromise. Release of inflammatory mediators can cause a vasodilatory state, and patients may develop circulatory collapse and hypovolaemic shock due to third spacing. Progressive swelling preceding arterial insufficiency, and associated with pain and cyanosis, is highly suggestive of PCD. Cancer is the most common cause in obese adults, with advanced age and immobilisation as other contributing factors. Diagnosis is performed clinically with ultrasound and venography adjunctively. Treatment involves heparinisation, catheter-directed thrombolysis and thrombectomy.8 9 Non-gangrenous forms of PCD respond well to anticoagulation.10 Phlegmasia alba dolens is differentiated from PCD by the lack of tissue ischaemia due to preservation of some venous drainage through collateral vasculature.8 The majority of DVTs in children is related to central line placement, though between 10 and 59% have genetic coagulopathies.2–4 7 One study showed venous thromboemboli (VTEs) in children were related to a genetic coagulopathy in 13% of their participants, an underlying medical condition in 91%, and central line placement in 77%, however, many more were related to genetic coagulopathies in older children (60%).1 FVL is the most common genetic coagulopathy, followed by prothrombin mutation, antithrombin deficiency, protein S and C deficiencies and increased lipoprotein A. Other non-inherited conditions associated with VTEs in children include infection, HIV, severe liver disease or vitamin deficiency, congenital heart disease, trauma, nephrotic syndrome, SLE, malignancy and, specifically, ALL.1 2 7 Factor V is a clotting factor that amplifies thrombin production when activated, which contributes to clot formation by converting fibrinogen to fibrin. APC is an inhibitory regulator of the clotting cascade through cleavage and inactivation of factor V. In FVL, mutation occurs in the gene on factor V at the APC cleavage site. Inheritance is incomplete autosomal dominant and patients have somewhat increased risk with heterozygous mutation and higher risk with homozygous mutation.11 FVL has a general population prevalence of 3–7% and is more common in Caucasians. One study found FVL in 15–20% of first time DVTs in adults and another found FVL in 18.8% of all-comers with VTE. Relative risk for VTE is increased to 3–8 times the general population in heterozygous patients and 8–80 times in homozygous FVL.11 12 Diagnosis is performed with a positive APC resistance assay, confirmed with genetic testing. Anticoagulation is recommended during higher risk circumstances (ie, surgery, pregnancy, etc) and long-term is advised after spontaneous VTE has occurred in heterozygous and homozygous FVL.11 13 Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
Rare disease REFERENCES Learning points
1
▸ Phlegmasia cerulea dolens (PCD) is a rare condition of massive proximal venous thrombosis obstructing superficial and deep venous drainage in the lower extremities. It can cause arterial insufficiency, venous gangrene, systemic shock and circulatory collapse, and has high morbidity and mortality. ▸ Treatment of PCD involves early anticoagulation and can involve invasive measures including chemical catheter-directed thrombolysis, mechanical thrombectomy and angioplasty, and stenting by vascular surgery or interventional radiology. ▸ Venous thromboemboli in children and young adults are most commonly associated with central line placement, genetic coagulopathies, malignancy and specifically acute lymphoblastic leukaemia, nephrotic syndrome and systemic infection. ▸ Factor V Leiden is the most common genetic coagulopathy and has been found in 15–20% of adults with deep venous thrombosis. Relative risk for venous thromboembolism is increased to 3–8% with heterozygous mutation and 8–80% with homozygous mutation.
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Contributors EJ was the resident physician overseeing this patient’s care in our emergency department, and was the primary author of this case report. SS was the attending physician for this patient’s care and assisted with writing and editing the case report. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
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Revel-Vilk S, Chan A, Bauman M, et al. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost 2003;1:915–21. van Ommen CH, Heijboer H, Büller HR, et al. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands. J Pediatr 2001;139:676–81. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251–7. Kuhle S, Massicotte P, Chan A, et al. Systemic thromboembolism in children: data from the 1-800-NO-CLOTS Consultation Service. Thromb Haemost 2004;92:722–8. U.S. National Library of Medicine, National Institutes of Health. Protein C. Medline Plus 2013 Mar. http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm (accessed 10 Jan 2015). U.S. National Library of Medicine, National Institutes of Health. Factor VII assay. Medline Plus 2013 Mar. http://www.nlm.nih.gov/medlineplus/ency/article/003676. htm (accessed 10 Jan 2015). van Ommen CH, Heijboer H, van den Dool EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003;1:2516–22. Gibson CJ, Britton KA, Miller AL, et al. Out of the blue. N Engl J Med 2014;370:1742–8. Kalagher SD, Kane DD. Phlegmasia cerulea dolens: before and after lysis. Intern Emerg Med 2015;10:103–4. http://www.ncbi.nlm.nih.gov/pubmed/24858817 (accessed Dec 2014). Lugo-Vicente H, ed. Phlegmasia cerulea dolens. Pediatr Surg Update 2006;27:1. Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia screening. Vasa 2008;37:19–30. Juul K, Tybjaerg-Hansen A, Schnohr P, et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140:330–7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl):e195S–226S.
Copyright 2015 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit http://group.bmj.com/group/rights-licensing/permissions. BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. Become a Fellow of BMJ Case Reports today and you can: ▸ Submit as many cases as you like ▸ Enjoy fast sympathetic peer review and rapid publication of accepted articles ▸ Access all the published articles ▸ Re-use any of the published material for personal use and teaching without further permission For information on Institutional Fellowships contact [email protected] Visit casereports.bmj.com for more articles like this and to become a Fellow
Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
3
CASE REPORT
Phlegmasia cerulea dolens in a teenage boy found to have Factor V Leiden Emily Junck, Sachita Shah Division of Emergency Medicine, University of Washington, Seattle, Washington, USA Correspondence to Dr Emily Junck, [email protected] Accepted 9 March 2015
SUMMARY A 16-year-old boy with morbid obesity and asthma presented with 1 week of progressive right leg pain, swelling and discolouration that started 1 week after a minor fall. Ultrasound and then CT with contrast revealed a large occlusive deep venous thrombosis (DVT) extending from the calf through the inferior vena cava bifurcation. Heparin was initiated and catheter-directed thrombolysis with tissue plasminogen activator and balloon angioplasty were performed with good flow postprocedure, however, the clot reaccumulated after several days and the procedure had to be repeated. After this occurred twice more, finally a right common iliac and femoral vein stent was placed to prevent clot reaccumulation and vein stenosis. Hypercoagability testing revealed activated protein C resistance and genetic testing confirmed homozygous Factor V Leiden (FVL). Family history was significant for maternal lower extremity DVT at age 21 and possible DVT in the patient’s maternal grandmother.
maternal grandmother. He denied use of tobacco and hormonal supplements. He had no personal history of malignancy, and denied constitutional and autoimmune symptoms. Examination showed a dusky bluish right lower extremity distal to the groin with moderate tense swelling (figure 1). Compartments were compressible though the entire leg was tender, and there were several areas of potential skin compromise on his lateral thigh. Posterior tibial, dorsalis pedis and popliteal artery pulses were detectable by Doppler and distal capillary refill was delayed to 5 s. Full strength and range of motion were intact at the ankle, knee and hip. Sensation was objectively intact but subjectively diminished through the right lower extremity.
INVESTIGATIONS Ultrasound revealed a large occlusive femoral DVT from the external iliac vein to the calf. CT with
BACKGROUND Acute ischaemia to an extremity is a medical emergency, however, it is usually due to arterial causes. Phlegmasia cerulea dolens (PCD) is a rare condition in which massive venous thrombosis obstructs venous drainage and causes arterial insufficiency in an extremity and can cause systemic circulatory collapse. Emergency physicians should know the potential for systemic decompensation and how to treat this condition. While PCD is highly associated with systemic disease and inherited coagulopathies in adults, its relation to inherited coagulopathies in children is not well understood.1–4 Hospitalists and primary care providers should understand implications and management of PCD. This case report will review the presentation, pathophysiology, diagnosis and treatment of PCD.
CASE PRESENTATION
To cite: Junck E, Shah S. BMJ Case Rep Published online: [ please include Day Month Year] doi:10.1136/ bcr-2014-207959
A 16-year-old morbidly obese boy with a history of asthma presented with progressive right leg pain and discolouration. He had fallen down a flight of stairs and landed on his right leg 2 weeks prior to presentation, but was ambulatory and asymptomatic at that time. He began having an ache in his right leg 1 week after the fall, which progressed to buttock and groin pain and then swelling, erythaema and transient numbness 1 day prior to emergency department (ED) presentation. He had a family history of a lower extremity deep venous thrombosis (DVT) in his mother at age 21 that was surgically removed, and possible DVT in his
Figure 1 Visible swelling and discolouration in the right leg of a teenage boy with phlegmasia cerulea dolens.
Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
1
Rare disease contrast showed the clot extending from the internal vena cava (IVC) bifurcation through the popliteal vein (visualisation of clot distal to this point was limited by technique), with a new clot in the common iliac vein within the 12 h since the ultrasound. Platelets, partial thromboplastin time, prothrombin time and international normalised ratio were normal. Hypercoagulability panel was sent and later returned with normal antithrombin III, protein S free antigen, lipoprotein A and fasting homocysteine levels, and negative lupus inhibitor assay. Protein C activity was low at 62% inhibition (though confounded by the patient’s acute clot; normal reference range 60– 150% inhibition), factor VII activity assay was elevated at 443% (normal reference range 50–200%) and activated protein C (APC) resistance was positive.5–6 Genetic testing returned negative for prothrombin G20210A mutation and positive for homozygous Factor V Leiden (FVL) mutation.
DIFFERENTIAL DIAGNOSIS Initially, there was concern for arterial or venous thrombus related to possible vascular trauma from the patient’s fall. However, this aetiology was less likely given that the fall was minor by description, there was no immobilisation thereafter and symptoms were delayed in onset. Compartment syndrome due to trauma or burns, though unlikely in this patient’s case, can also cause arterial insufficiency. The most likely diagnosis given the patient’s history was venous thrombosis due to acquired or genetic causes. Possible acquired causes in our patient included acute lymphoblastic leukaemia (ALL), nephrotic syndrome, systemic infection, HIV, severe liver disease or vitamin deficiency. Common genetic coagulopathies include FVL, prothrombin mutation, antithrombin deficiency, protein S and C deficiencies and increased lipoprotein A.1 2 7 The patient’s APC resistance assay returned positive, which narrowed the differential of FVL mutation to some degree; though not applicable for our patient, women can develop APC resistance with use of oral contraceptive pills and pregnancy-related hormonal changes.
TREATMENT Heparin infusion was started in the ED and the patient was admitted to the intensive care unit with vascular surgery and paediatrics. Symptoms did not significantly improve, and after 2 days he underwent catheter-directed thrombolysis with 24 h infusion of tissue plasminogen activator (tPA) through his right popliteal vein. A venogram was performed the next day and given a large residual clot burden, balloon angioplasty of the ileofemoral segment was performed with restoration of flow in the iliac vein. The patient worked with physical therapy and his subjective symptoms and his examination both improved. However, routine follow-up ultrasound to assess flow on postoperative day 3 showed reaccumulation of occlusive DVT from the common femoral through the gastrocnemius veins, and the patient was transferred to Seattle Children’s Hospital for paediatric haematology consult and further intervention. Catheter-directed tPA thrombolysis and angioplasty was repeated, this time showing a mild right common and external iliac vein stricture but good postprocedure flow. However, follow-up ultrasound after 3 days again showed recurrent iliofemoropopliteal thrombosis, and the patient was taken for repeat thrombolysis, angioplasty and stent placement across the right common and external iliac vein stricture. The venogram during this procedure revealed that the patient had severe left common iliac vein stenosis from right common iliac artery compression (May-Thurner syndrome). The patient was asymptomatic in his 2
left leg, so no immediate intervention was performed, but stent placement was recommended electively within 6 months.
OUTCOME AND FOLLOW-UP The patient was bridged to warfarin and discharged on hospital day 18. After genetic testing confirmed homozygous FVL mutation, haematology recommended lifelong anticoagulation. Follow-up ultrasound after 6 weeks showed continued patency. The patient had gradual improvement in pain and swelling, and barring one area with persistent paresthesias, he had full symptomatic recovery by 8 weeks.
DISCUSSION PCD is a rare condition of massive proximal venous thrombosis obstructing superficial and deep venous drainage in the lower extremities with high morbidity and mortality. Patients may present with sudden and severe leg pain, swelling, cyanosis, compartment syndrome, venous gangrene and/or arterial compromise. Release of inflammatory mediators can cause a vasodilatory state, and patients may develop circulatory collapse and hypovolaemic shock due to third spacing. Progressive swelling preceding arterial insufficiency, and associated with pain and cyanosis, is highly suggestive of PCD. Cancer is the most common cause in obese adults, with advanced age and immobilisation as other contributing factors. Diagnosis is performed clinically with ultrasound and venography adjunctively. Treatment involves heparinisation, catheter-directed thrombolysis and thrombectomy.8 9 Non-gangrenous forms of PCD respond well to anticoagulation.10 Phlegmasia alba dolens is differentiated from PCD by the lack of tissue ischaemia due to preservation of some venous drainage through collateral vasculature.8 The majority of DVTs in children is related to central line placement, though between 10 and 59% have genetic coagulopathies.2–4 7 One study showed venous thromboemboli (VTEs) in children were related to a genetic coagulopathy in 13% of their participants, an underlying medical condition in 91%, and central line placement in 77%, however, many more were related to genetic coagulopathies in older children (60%).1 FVL is the most common genetic coagulopathy, followed by prothrombin mutation, antithrombin deficiency, protein S and C deficiencies and increased lipoprotein A. Other non-inherited conditions associated with VTEs in children include infection, HIV, severe liver disease or vitamin deficiency, congenital heart disease, trauma, nephrotic syndrome, SLE, malignancy and, specifically, ALL.1 2 7 Factor V is a clotting factor that amplifies thrombin production when activated, which contributes to clot formation by converting fibrinogen to fibrin. APC is an inhibitory regulator of the clotting cascade through cleavage and inactivation of factor V. In FVL, mutation occurs in the gene on factor V at the APC cleavage site. Inheritance is incomplete autosomal dominant and patients have somewhat increased risk with heterozygous mutation and higher risk with homozygous mutation.11 FVL has a general population prevalence of 3–7% and is more common in Caucasians. One study found FVL in 15–20% of first time DVTs in adults and another found FVL in 18.8% of all-comers with VTE. Relative risk for VTE is increased to 3–8 times the general population in heterozygous patients and 8–80 times in homozygous FVL.11 12 Diagnosis is performed with a positive APC resistance assay, confirmed with genetic testing. Anticoagulation is recommended during higher risk circumstances (ie, surgery, pregnancy, etc) and long-term is advised after spontaneous VTE has occurred in heterozygous and homozygous FVL.11 13 Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
Rare disease REFERENCES Learning points
1
▸ Phlegmasia cerulea dolens (PCD) is a rare condition of massive proximal venous thrombosis obstructing superficial and deep venous drainage in the lower extremities. It can cause arterial insufficiency, venous gangrene, systemic shock and circulatory collapse, and has high morbidity and mortality. ▸ Treatment of PCD involves early anticoagulation and can involve invasive measures including chemical catheter-directed thrombolysis, mechanical thrombectomy and angioplasty, and stenting by vascular surgery or interventional radiology. ▸ Venous thromboemboli in children and young adults are most commonly associated with central line placement, genetic coagulopathies, malignancy and specifically acute lymphoblastic leukaemia, nephrotic syndrome and systemic infection. ▸ Factor V Leiden is the most common genetic coagulopathy and has been found in 15–20% of adults with deep venous thrombosis. Relative risk for venous thromboembolism is increased to 3–8% with heterozygous mutation and 8–80% with homozygous mutation.
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Contributors EJ was the resident physician overseeing this patient’s care in our emergency department, and was the primary author of this case report. SS was the attending physician for this patient’s care and assisted with writing and editing the case report. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
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Revel-Vilk S, Chan A, Bauman M, et al. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost 2003;1:915–21. van Ommen CH, Heijboer H, Büller HR, et al. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands. J Pediatr 2001;139:676–81. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251–7. Kuhle S, Massicotte P, Chan A, et al. Systemic thromboembolism in children: data from the 1-800-NO-CLOTS Consultation Service. Thromb Haemost 2004;92:722–8. U.S. National Library of Medicine, National Institutes of Health. Protein C. Medline Plus 2013 Mar. http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm (accessed 10 Jan 2015). U.S. National Library of Medicine, National Institutes of Health. Factor VII assay. Medline Plus 2013 Mar. http://www.nlm.nih.gov/medlineplus/ency/article/003676. htm (accessed 10 Jan 2015). van Ommen CH, Heijboer H, van den Dool EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003;1:2516–22. Gibson CJ, Britton KA, Miller AL, et al. Out of the blue. N Engl J Med 2014;370:1742–8. Kalagher SD, Kane DD. Phlegmasia cerulea dolens: before and after lysis. Intern Emerg Med 2015;10:103–4. http://www.ncbi.nlm.nih.gov/pubmed/24858817 (accessed Dec 2014). Lugo-Vicente H, ed. Phlegmasia cerulea dolens. Pediatr Surg Update 2006;27:1. Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia screening. Vasa 2008;37:19–30. Juul K, Tybjaerg-Hansen A, Schnohr P, et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140:330–7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl):e195S–226S.
Copyright 2015 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit http://group.bmj.com/group/rights-licensing/permissions. BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. Become a Fellow of BMJ Case Reports today and you can: ▸ Submit as many cases as you like ▸ Enjoy fast sympathetic peer review and rapid publication of accepted articles ▸ Access all the published articles ▸ Re-use any of the published material for personal use and teaching without further permission For information on Institutional Fellowships contact [email protected] Visit casereports.bmj.com for more articles like this and to become a Fellow
Junck E, et al. BMJ Case Rep 2015. doi:10.1136/bcr-2014-207959
3
![[Phlegmasia cerulea dolens].](/assets/img/hold.png)
