A 17-year-old male subject with a history of deep venous thrombosis presented with acute unilateral severe chest pain. His examination was nonspecific, and vital signs were normal. His initial laboratory evaluation revealed mild thrombocytopenia, elevated troponin levels, and critically elevated activated partial thromboplastin time. A computed tomography angiogram of the chest revealed a pulmonary embolus, and anticoagulation therapy was initiated. His course was complicated by the development of multiple thrombi and respiratory failure. Extensive evaluation revealed a rare, underlying diagnosis in time for life-saving treatment to be initiated.
- ACR —
- American College of Rheumatology
- aPTT —
- activated partial thromboplastin time
- CAPS —
- catastrophic antiphospholipid syndrome
- CT —
- computed tomography
- DVT —
- deep vein thrombosis
- ECG —
- PE —
- pulmonary embolism
- SLE —
- systemic lupus erythematosus
- SLICC —
- Systemic Lupus International Collaborating Clinics
Case History With Subspecialty Input
Ankoor Y. Shah, MD, MPH (Pediatrics, Chief Resident)
A 17-year-old male subject with a history of 2 previous deep vein thromboses (DVTs) presented to a community hospital with right-sided pleuritic chest pain. His initial left lower extremity DVT had been diagnosed 7 months earlier and was treated with rivaroxaban. After discontinuation of anticoagulation therapy, 2 weeks before admission he was diagnosed with a new left lower extremity DVT, and rivaroxaban was restarted. At the community hospital, a right-sided pulmonary embolism (PE) was diagnosed by using a computed tomography (CT) angiogram. Upon transfer to Children’s National Health System, the patient’s respiratory rate was increased, and his heart rate was at the upper limit of normal. His vital signs were otherwise stable (temperature, 37.5°C; blood pressure, 114/79 mm Hg; heart rate, 97 beats per min; respiratory rate, 22 breaths/min; oxygen saturation, 98% on room air). On physical examination, he had diffuse right-sided chest and nonspecific back pain. His cardiac examination consisted of a regular rhythm, normal S1 and S2, no murmurs or gallops, as well as distal pulses equal in all 4 extremities with no pulsus paradoxus. His lungs were clear to auscultation, with no wheezes or crackles. He had good aeration with minimally increased work of breathing. Chest pain worsened during inspiration, representing a pleuritic pain. The remainder of the patient’s examination was within normal limits as well.
The initial evaluation from the community hospital revealed mild thrombocytopenia with a normal white blood cell count and hemoglobin (Table 1). Hematologic testing revealed elevated prothrombin time and highly elevated activated partial thromboplastin time (aPTT), which are nonspecific in the setting of ongoing rivaroxaban therapy. His D-dimer level was normal at 448 ng/mL.
Dr Frank, the troponin I value was 0.34 ng/mL; is that concerning to you?
Lowell Frank, MD (Pediatric Cardiology)
I am glad you brought this finding up because at the most literal level, an elevated troponin I value simply means there is damage to cardiac muscle. An elevated troponin I level is not specific to pulmonary emboli in general or to the right ventricle specifically. Troponin elevation in acute PE can result from microinfarctions due to alterations in oxygen supply and demand of the right ventricle.1 In addition, troponin I elevation has been associated with increased segmental defects in ventilation/perfusion lung scans and may thus be sensitive to minor myocardial damage.2 Lastly, the value of 0.34 ng/mL, although flagged as abnormal, is not significantly high and not particularly concerning.
In the context of an adolescent patient with chest pain, troponin I can be a confounding test. Recent studies have found little diagnostic value of troponin measurements in pediatric patients presenting with chest pain, as well as little prognostic value for patients with additional symptoms of fever and electrocardiogram (ECG) changes who are subsequently diagnosed with myopericarditis.3,4 There are no data available in children regarding the correlation between elevated troponin levels and prognosis, but it has been found to correlate in adults.5
What should a cardiac evaluation consist of for this patient?
In this case, in which a PE was already confirmed, the cardiac evaluation should first focus on addressing the hemodynamic stability of the patient and secondarily on assessing right ventricular function. Additional consideration could be given to ordering diagnostic testing that might inform prognosis. The clinical presentation of this patient, with normal vital signs and an overall stable appearance, is the first critical element of the cardiac evaluation. For right ventricular function, a relatively quick and often readily available method of assessment would be an echocardiogram. Although echocardiography has its pitfalls when assessing the right ventricle (compared with the left ventricle), it can provide a good qualitative assessment of right ventricular size and function, as well as usually providing a quantitative assessment of the right ventricular pressure.
Depending on the resources readily available, an ECG may be a reasonable adjunct test but is unlikely to influence acute clinical management with this particular clinical presentation. ECG changes can be associated with a poor outcome in patients with PE6–8; however, recent European Society of Cardiology guidelines did not include ECG in the various tools assessed for prognostic value, perhaps suggesting that despite its availability and low cost that there are better tests available. For a pulmonary embolus, you often think of the “classic” S1Q3T3 pattern on ECG; that is, a deep S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III. However, this finding is neither sensitive nor specific for a pulmonary embolus. Furthermore, despite all the ECG patterns that can suggest right ventricular involvement, the most common finding remains sinus tachycardia, and even that is not particularly sensitive (certainly not specific), with some studies showing no significant differences in the rate of tachycardia between patients with confirmed PE and those without.9,10 Therefore, I believe an echocardiogram has more utility in this patient than an ECG.
In this case, an echocardiogram was obtained, with no concerning findings and no evidence of right ventricular dysfunction. Specifically, there was no evidence of a large saddle embolus, total or subtotal occlusion of a branch pulmonary artery, right ventricular dilation, right ventricular systolic dysfunction, or elevated right ventricular pressure.
The patient was admitted to the PICU for pain control and enoxaparin therapy. Dr Guerrera, when would you consider starting an evaluation for an underlying coagulation anomaly?
Michael F. Guerrera, MD (Pediatric Hematology)
There is debate among hematologists on whether to evaluate all patients with thrombosis or to evaluate only a select group. We believe that all pediatric patients should have a thrombophilia evaluation with their first thrombosis, especially if it was unprovoked, arterial, involved the central nervous system, or if the patient has a family history of thrombosis. For this patient, we would have recommended thrombophilia testing, with his first DVT 7 months before presentation.
Our routine thrombophilia evaluation includes assessment of protein C function, protein S function, antithrombin level, factor V Leiden, activated protein C resistance, prothrombin gene mutation, factor VIII level, homocysteine,lipoprotein(a), and antiphospholipid antibody testing (which includes lupus anticoagulants, anticardiolipin antibody panel, and β2-glycoprotein-I panel).
During this hospitalization, the patient was diagnosed with an additional occlusive thrombus in the right popliteal vein. Because he remained hemodynamically stable and his thrombus was small and distal, thrombolytic agents were not pursued, and enoxaparin was started. He was eventually discharged on enoxaparin with the plan to switch to warfarin as an outpatient. The thrombophilia evaluation Dr Guerrera recommended was pending at the time of discharge.
However, 2 days after discharge, the patient was readmitted to the PICU with severe right-sided chest pain and respiratory distress. The chest pain was caused by a new right pleural effusion, which was treated with placement of a chest tube. The pulmonary CT scan that confirmed the pleural effusion also noted a stable right-sided PE. Although the PE was stable on imaging, the presence of a pleural effusion suggested worsening of his PE, possibly due to microthrombi in the lung causing microinfarctions resulting in the pleural effusion.
During his PICU admission, the patient was started on a heparin drip that was eventually transitioned to enoxaparin, and he was transferred to the general pediatrics ward. After transfer, he continued to have an elevated aPTT. Given this persistent elevation, is there utility in a mixing study for this patient?
A mixing study is a useful first test when dealing with an abnormal coagulation screen. Baseline prothrombin time and aPTT should be obtained in all patients before initiating anticoagulation therapy to confirm that the patient does not have an existing coagulopathy and to quickly screen for a potential antiphospholipid antibody. A mixing study involves taking 1 part patient plasma and adding equal part normal pooled plasma (1:1). If the patient has a factor deficiency, the mixing study should correct because factors from the normal pooled plasma can make up for the absent factors in the patient’s plasma. If the patient has a circulating inhibitor such as an antiphospholipid antibody, the mixing study should not correct because the antiphospholipid antibody will affect both patient and normal pooled plasma.
However, it is important to take notice when patients are on anticoagulant agents when the mixing study is performed. Anticoagulant agents inhibit the function of activated factors, which are required to make a clot. A mixing study adds normal plasma to the patient’s plasma; it will correct a deficiency of a factor but cannot correct a medication that blocks coagulation. If the aPTT is prolonged due to the presence of an anticoagulant, the mixing study will not correct, giving a false-positive result suggestive of an antiphospholipid antibody. For example, heparin prolongs the aPTT. It works through antithrombin to inhibit multiple factors (primarily factors Xa and IIa) for anticoagulation therapy. It is important to remember that even in patients not being treated with heparin, a blood sample can be contaminated with heparin if drawn through a heparinized line. Enoxaparin, a fractionated low-molecular-weight heparin, and rivaroxaban, a non–vitamin K oral anticoagulant that is a direct Xa inhibitor, may or may not prolong the aPTT. This outcome is because different aPTT reagents have different sensitivity to enoxaparin and rivaroxaban. In summary, interpretation of results of the mixing study in a patient receiving anticoagulation therapy can be challenging, and confirmation of an antiphospholipid antibody with further testing is indicated.
Thus, for our patient, the aPTT was persistently elevated despite the mixing study. Although there is a potential for a false-positive result as you mentioned, Dr Guerrera, this elevation still suggests an antiphospholipid antibody. But how would you confirm it?
Although antiphospholipid antibodies can include lupus anticoagulants, anticardiolipin antibodies, and β2-glycoprotein-I, we would initially repeat the aPTT with reagents more sensitive to lupus anticoagulants. If the aPTT remains prolonged, we then proceed with a series of confirmatory steps to try to rule out a coagulation factor deficiency or heparin contamination. Although anticardiolipin antibodies are more common than lupus anticoagulants, the presence of a lupus anticoagulant puts a person at a higher risk of having a clot than anticardiolipin antibodies alone and is a reason why it is tested for initially.11
Retesting with the more sensitive reagent corroborated a positive lupus anticoagulant in our patient. A diagnosis of antiphospholipid antibody syndrome (APS) was therefore made. However, Dr Guerrera, why does the presence of an antiphospholipid antibody such as a lupus anticoagulant cause a clinical prothrombotic state despite an elevated aPTT in vitro?
In vitro testing of coagulation by the aPTT requires the addition of a finite amount of phospholipids, which are required for proper clot formation. The lupus anticoagulant partially neutralizes these added phospholipids required for clot formation, which prolongs the aPTT. In vivo, the pathophysiology of the lupus anticoagulant is multifactorial and incompletely understood. The lupus anticoagulant activates endothelial cells, monocytes, and platelets, thus leading to a prothrombotic state.
Later during this second hospitalization, the patient developed an acute-onset rash on his flanks and thighs. Dr Kirkorian, how would you evaluate these skin findings?
A. Yasmine Kirkorian, MD (Pediatric Dermatology)
The patient’s skin is an important clue to his diagnosis. It shows branching and stellate purpura with central necrosis, which were distributed on the bilateral medial thighs and on the right flank (Fig 1). This morphology is called “retiform purpura” and is an indication for skin biopsy.
Understanding the normal vascular anatomy and perfusion of the skin is necessary to understanding the clinical findings. The skin vessels consist of arterioles located in the dermis oriented perpendicularly to the epidermis. Each arteriole divides to form a capillary bed, with the arteriole at the center of the bed. This arrangement gives rise to 1– to 3–cm cones of perfusion, which manifests on the skin as a net-like pattern called livedo reticularis.12 Livedo reticularis may be physiologic and resolve upon rewarming, particularly in infants, or it may be persistent and associated with underlying systemic disease.13
Purpura is defined by visible hemorrhage into the skin. This patient presented with retiform purpura. Clinically, it is helpful to think of retiform purpura as a “broken net” or “puzzle pieces” of livedo reticularis. Retiform purpura is a unique variant of purpura that results from occlusion of cutaneous vessels. Whenever I see this morphology, I begin to search for causes of microvascular occlusion by performing a thorough medical evaluation of the patient and a skin biopsy. The skin biopsy results can help to determine the nature of the microvascular thrombus. Etiologies can include fibrin thrombi secondary to a systemic coagulopathy, microorganisms in the setting of septic emboli, calcium depots in calciphylaxis, cholesterol emboli, marantic emboli, and other abnormalities in the clotting cascade.14
This patient’s skin biopsy specimen (Fig 2) revealed fibrin thrombi in numerous cutaneous arterioles and venules. Taken in the context of the patient’s clinical presentation and laboratory abnormalities, the cutaneous microvascular thrombi were a manifestation of his underlying coagulopathy due to APS.
At the same time of the presentation of the rash, this patient developed severe generalized abdominal pain with tenderness to palpation. An abdominal CT angiography was obtained to evaluate the cause of this pain (Fig 3). Dr Otero, how would you evaluate this image?
Hansel J. Otero, MD (Pediatric Radiology)
The CT angiography of the abdomen and pelvis shows a new 5-cm right periadrenal collection with stranding of the periadrenal fat extending into the perinephric space, which is the typical CT imaging appearance of an adrenal hemorrhage.15 The cause of nontraumatic adrenal hemorrhage varies with age; in newborns, it is associated with stress and resulting hypoxia due to prolonged labor, breech delivery, large birth weight, difficult labor, asphyxia, or sepsis.16,17 In older children and adults, adrenal hemorrhage might be the result of other causes of stress, including burns, sepsis, and surgery, as well as underlying tumors and bleeding diathesis or coagulopathy.17,18 Acute intratumoral hemorrhage is most common with pheochromocytoma but has also been described in myelolipomas, metastatic lesions, adrenocortical carcinomas, adenomas, and hemangiomas.19
In the present case, there is no suggestion of an underlying lesion in the current or previous imaging studies, and the patient has a known coagulopathy. It is therefore safe to conclude that in this patient, an adrenal vein thrombosis occurred that resulted in a hemorrhagic infarction.20
Because these new thrombi all occurred while the patient was taking enoxaparin, he was transferred back to the PICU and re-started on a heparin drip. Laboratory evaluation at this time demonstrated low complement levels and a positive anti-Sm antibody. While in the PICU, he developed respiratory failure and required intubation and ventilator support. Dr Guerrera, given the events of the most recent hospitalization, is our diagnosis still APS?
This patient has APS with the evolution of multiple thrombi over time. He has had a DVT, PE, adrenal hemorrhage due to thrombosis, and cutaneous microvascular thrombi. This presentation with multiorgan thrombi in rapid succession is concerning for probable catastrophic antiphospholipid syndrome (CAPS) (Table 2). He has evidence of thromboses of ≥3 organs, histopathologic confirmation of small vessel occlusion in the skin, and laboratory confirmation of the presence of antiphospholipid antibodies, specifically the lupus anticoagulant. CAPS is a rare and life-threatening complication of APS. Similar to the concept of a “cytokine storm” during infection, CAPS can be described as a “thrombotic storm” despite adequate anticoagulation, in which thrombi are being formed everywhere. In 2012, Dr Ricard Cervera published an analysis of >400 pediatric and adult patients from the CAPS registry.21 This analysis showed that 53% of the patients with CAPS have an identified trigger, with the most common being infection (22%) and surgery (10%). Seventy-two percent of the patients were female. Primary APS syndrome was diagnosed in 46%, systemic lupus erythematosus (SLE) in 40%, lupus-like disease in 5%, and other autoimmune diseases in 9%.
Final Diagnosis: CAPS
Because this patient has a positive lupus anticoagulant, Dr Jung, should we be considering SLE as an underlying diagnosis?
Lawrence Jung, MD (Pediatric Rheumatology)
It is plausible that an initial presentation of SLE or an SLE flare could have been the patient’s CAPS trigger. However, diagnosing SLE is a little tricky. The lupus classification criteria of the American College of Rheumatology (ACR) (Table 3), most recently revised in 1997, were designed for the purpose of identifying subjects for clinical studies.22 A subject with 4 of the 11 clinical criteria serially or simultaneously is considered to be eligible for clinical studies. Although the ACR criteria have been widely used in clinical settings, clinicians need to know that there are pitfalls which lead to diagnostic errors when using the ACR criteria.
The Systemic Lupus International Collaborating Clinics (SLICC) lupus criteria (Table 3) were published in 2012 and compared favorably with the ACR criteria in identifying individuals with lupus.23 The SLICC criteria were validated in 1 study of pediatric SLE.24 In that study, the ACR criteria had 76.6% sensitivity and 93.4% specificity, whereas the SLICC criteria had 98.7% sensitivity and 85.3% specificity. Thus, in pediatric lupus, the SLICC criteria are more sensitive (P < .001) but less specific (P < .001) than the ACR criteria.
There are obvious differences in these 2 sets of criteria and how they apply to this patient in particular. This patient meets the SLICC criteria (thrombocytopenia, positive anti-Sm antibody, antiphospholipid antibodies, and low complement levels). However, he does not meet the ACR criteria because low complement level is not considered a classification criterion. Furthermore, his thrombocytopenia may be the result of consumption due to his CAPS and not due to the presence of autoantibodies. The only feature that is lupus-specific is the presence of anti-Sm antibody. Based on the SLICC criteria, we made a presumptive diagnosis of SLE with the understanding that further clinical observation will help to clarify the diagnosis.
Does this ambiguity change the patient’s acute management?
Actually, the diagnosis of SLE does not change the acute management in this case. However, for long-term management, he should be given hydroxychloroquine, which is a disease-modifying medication to help keep the suspected lupus activity under control.
Upon further questioning of the patient’s family, a history of a second cousin with APS and a deceased first cousin with Goodpasture syndrome were discovered. Dr Regier, is there a genetic link to APS?
Debra Regier, MD, PhD (Pediatric Genetics and Metabolism)
In general, autoimmune disorders do have an increased relative risk in family members. There are case reports that show an increase predisposition to CAPS within families.25 CAPS genetic predisposition has low penetrance and is most likely multifactorial, which makes it difficult to identify a clear genetic link. This situation is likely because although the genetic predisposition to CAPS is an inherited trait, clinical symptoms present only when there is a CAPS trigger. Thus, patients without the trigger or inadequate trigger do not have CAPS, and the pedigree seems to have incomplete penetrance.
This patient was started on high-dose steroids, plasmapheresis, and later on rituximab; he subsequently improved in the PICU. He was weaned off respiratory support and was transferred back to the general pediatrics ward. Dr Guerrera, can you explain why this specific treatment course was successful for this patient?
It is critical to make an early diagnosis of CAPS and to initiate aggressive management because CAPS has a high mortality, and early treatment may be lifesaving. Plasmapheresis has been shown to significantly decrease mortality in CAPS, most likely by removing the high-titer antiphospholipid antibodies as well as other stimulating cytokines. Corticosteroids in combination with plasmapheresis and anticoagulation therapy have been the most successful treatment of CAPS.26 Intravenous immunoglobulin has been added to many regimens to prevent recurrent thrombosis in patients refractory to conventional anticoagulant treatment.27,28 Rituximab was added to reduce the B-lymphocyte population and antibody production, which has been shown to help in autoimmune and alloimmune disorders. In some instances, cyclophosphamide is used when CAPS is associated with underlying SLE.
On the general pediatric ward, the patient’s respiratory symptoms improved to baseline. In addition to the hydroxychloroquine for SLE mentioned by Dr Jung, what other medications should the patient continue at home?
Given the patient’s history of recurrent thromboses, it is absolutely vital that he continues on warfarin at an international normalized ratio therapeutic range of 2.5 to 3.5. In addition, aspirin should be included in his antithrombotic regimen. Given the patient’s previous treatment with rituximab, he will also need to receive intravenous immunoglobulin monthly to correct his hypogammaglobulinemia.
Since discharge from the hospital, our patient has continued receiving anticoagulation therapy with warfarin and aspirin, with no further thrombosis or bleeding symptoms. At his last visit 12 months after discharge, the patient is doing well and back to normal activities. Given his improvement, he has been able to return to college. He continues to have chronic, stable occlusion of bilateral popliteal veins. He remains on a low dose of prednisone, which will be discontinued over the next few months. He will remain on hydroxychloroquine.
The survival rate for CAPS is estimated to be 50%.29 Of those who survive, two-thirds remain symptom-free with anticoagulation therapy. In those survivors who have additional thrombotic events, the mortality rate is increased, and 1 in 4 may die. Therefore, even though CAPS is a rare diagnosis, a high level of suspicion is warranted in patients with antiphospholipid syndrome, especially if there is evidence of progression to multiorgan thrombosis. Early diagnosis and aggressive management are paramount to saving the patient’s life. We believe early and aggressive treatment contributed to this patient’s survival. He remains healthy and is doing remarkably well.
We thank Dr Debra Regier for her essential input and advice on this case. We thank Dr Bernard Cohen for the photograph of physiologic livedo reticularis in Fig 1 and Gregory Kirkorian for assistance in the creation of Fig 1.
- Accepted June 21, 2016.
- Address correspondence to Ankoor Y. Shah, MD, MPH, Children’s National Health System, 1901 Mississippi Ave SE, Ste #104, Washington, DC 20020. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2017 by the American Academy of Pediatrics