12 April 2023: Articles
A 25-Year-Old Woman with a High-Risk Large and Occlusive Pulmonary Embolism, Later Diagnosed with Primary Antiphospholipid Syndrome and Hyperhomocysteinemia: A Case Report
Challenging differential diagnosis
Juan-Manuel Muñoz-Moreno 1ABCDEF*, Anthony Ramos-Yataco2CDEF, Emanuel Salcedo-Davila3DEF, Carlos Alcalde-Loyola4DEF, Carina Halanoca-Quispe1BDEF, Carlos Requena-Armas5DEFDOI: 10.12659/AJCR.939078
Am J Case Rep 2023; 24:e939078
Abstract
BACKGROUND: High-risk pulmonary embolism (PE) occurs when the pulmonary circulation is suddenly occluded by a thrombus and is a life-threatening medical emergency. In young and otherwise healthy individuals, there may be undiagnosed underlying risk factors for PE that require investigation. This report presents the case of a 25-year-old woman admitted as an emergency with a high-risk large and occlusive PE, later diagnosed with primary antiphospholipid syndrome (APS) and hyperhomocysteinemia.
CASE REPORT: A 25-year-old woman presented with sudden-onset dyspnea after elective cholecystectomy. One year earlier, the patient had lower limb deep vein thrombosis without an identified predisposing cause, and she received anticoagulation for 6 months. On physical examination, she had right leg edema. Laboratory tests revealed elevated levels of troponin, pro-B-type natriuretic peptide, and D-dimer. Computed tomography pulmonary angiography (CTPA) demonstrated a large and occlusive PE, and an echocardiogram showed right ventricular dysfunction. Successful thrombolysis was performed with alteplase. On repeat CTPA, a significant reduction in filling defects in the pulmonary vasculature was observed. The patient evolved uneventfully and was discharged home on a vitamin K antagonist. Due to unprovoked recurrent thrombotic events, suspicion of underlying thrombophilia was raised, and hypercoagulability studies confirmed primary APS and hyperhomocysteinemia.
CONCLUSIONS: This report presents the case of a life-threatening high-risk PE in a previously healthy young woman and highlights the importance of emergency management followed by investigation and treatment of underlying risk factors for venous thromboembolism, including APS and hyperhomocysteinemia.
Keywords: Antiphospholipid Syndrome, Hyperhomocysteinemia, Pulmonary Embolism, Thrombophilia, venous thromboembolism, Female, Humans, Adult, Venous Thrombosis, Tissue Plasminogen Activator
Background
High-risk pulmonary embolism (PE) is defined by the presence of hemodynamic instability and evidence of right ventricle (RV) dysfunction in transthoracic echocardiogram (TTE) [1]. RV dys-function occurs due to an increase in pulmonary artery pressure, which occurs if >30–50% of the cross-sectional area of the pulmonary bed is occluded by thrombus [1].
Venous thromboembolism (VTE) can occur in approximately 14% of patients with antiphospholipid syndrome (APS) [2,3]. APS is a systemic autoimmune disease with an incidence of 5 per 100 000, characterized by vascular thrombosis, obstetric complications, and the presence of antiphospholipid antibodies (aPL) [3]. It is classified as primary if there is no evidence of an autoimmune disease or secondary usually in the setting of systemic lupus erythematosus (SLE) [3,4]. Hyperhomocysteinemia is associated with an increased risk of VTE and can aggravate the thrombotic tendency in APS [5]. In addition, it has been reported that high levels of homocysteine are a marker of high risk of vascular thrombosis in patients with SLE and no APS history [6].
Hyperhomocysteinemia is known to coexist in patients with primary APS, with a reported rate of 30.8% [5], with smaller studies reporting high levels of homocysteine in 22% to 34.4% in patients with primary APS [7,8]. Additionally, high homocysteine levels can be related to the positivity of multiple antiphospholipid antibodies and simultaneous vascular events [8]. One prospective study showed that moderate hyperhomocysteinemia was more common in patients with APS who also had high lupus anticoagulant; therefore, it is proposed that both factors can promote thrombotic events [9]. However, the high-risk PE secondary to the association between primary APS and hyperhomocysteinemia is unusual [10–13], and has not been previously reported in the English literature.
This report presents the case of a 25-year-old woman admitted as an emergency with a high-risk large and occlusive PE, later diagnosed with primary APS and hyperhomocysteinemia.
Case Report
A 25-year-old woman was admitted to the Emergency Department with sudden-onset dyspnea after elective cholecystectomy. One year earlier, she was diagnosed with lower extremity deep venous thrombosis (DVT) without an identified predisposing cause and was treated with a vitamin K antagonist (VKA) for 6 months. She had no history of hypertension, diabetes, hypercholesterolemia, obesity, or use of combined oral contraceptives. There was no family history of hemato-logic or autoimmune conditions. Her initial blood pressure was 95/60 mmHg, pulse rate was 94 beats/min, respiratory rate was 24 breaths/min, and oxygen saturation was 95% on oxygen 3 L/min. On physical examination, she had right lower extremity edema. The 12-lead electrocardiogram (ECG) showed sinus rhythm, and incomplete right bundle branch block (RBBB) and S1Q3T3 pattern (prominent S wave in I, Q wave in III, and negative T wave in III; also called McGinn-White sign) (Figure 1). Laboratory tests revealed elevated levels of troponin T 0.3 ng/ml (reference: <0.1 ng/mL), pro-B-type natriuretic peptide 938 pg/ml (reference: <125 pg/ml), and D-dimer 5.4 mg/L (reference: <0.5 mg/L). Chest X-rays ruled out other acute pulmonary conditions. Due to the high pre-test probability of PE, she was started on empiric anticoagulation with low molecular weight heparin (LMWH) (subcutaneous injection, 60 mg/12h). Computed tomography pulmonary angiography (CTPA) demonstrated a large and occlusive PE (Figure 2A, 2B).
The TTE revealed normal left ventricle (LV) ejection fraction of 60%, reduced RV systolic function parameters [tricuspid annular plane systolic excursion (TAPSE) of 13 mm, peak systolic velocity of tricuspid annulus (S’) of 8 cm/s, and RV fractional area change (RVFAC) of 28%], dilated RV with paradoxical septal motion, and positive 60-60 sign (coexistence of a pulmonary ejection acceleration time <60 ms and a midsystolic “notch” with a tricuspid regurgitant peak gradient <60 mmHg) consistent with right sided pressure overload (Figure 3A, 3B). There was also distended inferior vena cava with diminished inspiratory collapsibility. After confirmation of high-risk PE with RV dysfunction, LMWH was switched to unfractionated heparin (UFH). The patient then became hypotensive, requiring vasopressor support with norepinephrine. The decision was made to proceed with thrombolysis, and alteplase was given by peripheral infusion of 100 mg over 2 hours per institutional protocol, with gradual resolution of hypotension and hypoxia. On repeat CTPA, a significant reduction in filling defects in the pulmonary vasculature was observed (Figure 2C, 2D). Venous ultrasound of the lower extremity revealed right leg DVT.
The patient evolved uneventfully and was discharged on a VKA with goal international normalized ratio (INR) of 2 to 3. Due to her age and the unprovoked nature of her VTE, hypercoagulability studies were performed and showed high titers for anti-cardiolipin autoantibodies IgG >160 (reference: <12 GPLU/ml), anti-beta-2 glycoprotein-I IgG 140 (reference: <15 U/ml), and positive lupus anticoagulant, corresponding to a triple-positive aPL profile. In addition, elevated homocysteine levels were 24.7 umol/L (reference: 5–15 umol/L). The antinuclear antibodies, anti-double–stranded deoxyribonucleic antibodies, and anti-smith markers were negative. These results suggested primary APS and hyperhomocysteinemia. At the same time, other tests were within normal ranges, such as protein C, protein S, antithrombin III, factor V Leiden, prothrombin G20210A mutation, complete blood count, vitamin B levels, and kidney function.
At the 5-month outpatient follow-up after discharge, the patient remained in New York Heart Association class II, on oral anticoagulation with VKA. TTE showed improvement in RVFAC to 32%, and repeated immunological studies again revealed a triple-positive aPL profile and slightly elevated levels of homocysteinemia, thus confirming the diagnosis of APS and hyperhomocysteinemia.
Discussion
VTE is the third most frequent cause of acute cardiovascular syndrome worldwide and includes DVT and PE [1,14]. VTE events are classified into “provoked” and “unprovoked” [14], with “unprovoked” VTE in up to 50% of cases [14,15]. It is recommended to investigate an unprovoked VTE in young individuals to rule out underlying thrombophilia [16]. Thrombophilia is defined as an inherited, acquired, or mixed (both congenital and acquired) coagulation disorders predisposing to a prothrombotic state [17,18]. There are different risk factors associated with DVT, which is the most common mechanism of PE [19]. Major risk factors for DVT (odds ratio (OR) ≥10) include APS, major surgery (orthopedic or neurologic)/major trauma, recent hospitalization (<3 months) for acute cardiac disease, prior VTE, and active cancer; and among the intermediate risk factors (OR 2–9) are oral contraception, pregnancy, and hereditary thrombophilia, which can cause hyperhomocysteinemia [17,20]. In people under 45 years of age, a higher incidence of PE has been reported in women, probably secondary to use of oral contraceptive containing estrogens, high estrogen endogen levels, and pregnancy [19]. In our case, the patient was not using oral contraceptives, so we attributed her recurrent VTE events to APS and hyperhomocysteinemia, which can coexist [5]. Some case reports have described the association between APS and hyperhomocysteinemia with thrombotic complications but in other vascular territories [10–13]. To the best of our knowledge, no such case of high-risk PE secondary to the association of primary APS and hyperhomocysteinemia has been reported in the English literature.
The clinical presentation in acute PE usually involves sudden-onset dyspnea, chest pain, syncope, or hemoptysis [1]. The approach to suspected PE involves determination of the pre-test probability into low, intermediate, and high, using the rules of Geneva and Wells [1,19]. The 2019 European Society of Cardiology (ESC) guidelines recommend CTPA as the diagnostic imaging technique of choice for PE, with a high positive predictive value (92–96%) in patients with intermediate or high pre-test probability [1]. A positive CTPA distinguishes thrombi from intraluminal contrast, showing them as filling defects, with a sensitivity of 83% and a specificity of 96% [21]. Twelve-lead ECG can reveal right ventricular overload suspicious for high-risk PE, such as inversion of T waves in leads V1–V4, S1Q3T3 pattern, RBBB, QR pattern in V1 [1], ST-segment elevation in aVR, and atrial fibrillation [22]. Our patient presented all the previously described findings except for QR pattern, ST-segment elevation, and atrial fibrillation.
TTE plays a fundamental role in the initial approach to high-risk PE patients, showing signs of RV overload and dysfunction, which frequently include RV dilation (≥25% of cases), baseline RV/LV ratio >1, flattening of the interventricular septum, distended inferior vena cava with reduced inspiratory collapsibility (<50%), and reduced TAPSE and S’ (less than 16 mm and 9.5 cm/s, respectively) [1]. Among the more specific findings, the McConnell sign (depressed contractility of the RV compared to the RV apex), the 60/60 sign, and the presence of mobile thrombi visualized in the right heart chambers stand out, with a reported frequency of approximately 20%, 12%, and <4% of patients, respectively [1,21]. In our case, the 60/60 sign was found together with all the signs of RV overload and dysfunction described.
The ESC guidelines stratify PE according to its risk of early mortality into low, intermediate (low and high), and high risk [1]. These terms have gradually replaced the qualifiers low-risk, submassive, and massive in the 2011 American Heart Association (AHA) guidelines [23,24]. High-risk PE includes hemodynamic instability, clinical parameters of severity and/or the presence of comorbidities (Pulmonary Embolism Severity Index (PESI) class III–V or simplified PESI ≥1), RV dysfunction on imaging, and elevated levels of cardiac troponins [1,25]. It should be noted that the presence of hemodynamic instability, along with a confirmatory CTPA and/or evidence of RV dys-function on TTE, are sufficient conditions to define high-risk PE without the need for the other criteria [1]. Our patient met criteria for high-risk PE, which represents approximately 4.5–10% of all acute PE cases and has a high reported mortality rate of 33% [21,25].
Initial anticoagulant management recommended by 2019 ESC guidelines on PE is with LMWH, while UFH should be used in high-risk cases due to possible use of thrombolytic therapy [1]. The most widely used thrombolytic agent is alteplase, with a typical dosing protocol of 100 mg infused over 2 hours, with greater benefit if started within 48 hours of onset of symptoms, but it can be helpful in symptomatic patients for up to 14 days [1,25]. When there are contraindications to thrombolysis, other reperfusion strategies can be performed, such as catheter intervention and surgical pulmonary embolectomy [25,26]. In our case, initial LMWH was changed to UFH upon suspicion of high-risk PE, which was continued during thrombolysis with alteplase.
Assessment of hypercoagulable status should be performed in patients younger than 50 years with a first event of “unprovoked” VTE, history of recurrent VTE at a young age, strong family history of thrombophilia, thrombosis in unusual vascular sites (hepatic, mesenteric, splenic, portal or cerebral veins), or unexplained late-stage or recurrent early spontaneous pregnancy loss [2,17,27]. Given the age of our patient at the first episode of VTE, the presence of thrombophilia should have been evaluated. Acquired thrombophilia is mainly APS, while the most common mixed thrombophilia studied is hyperhomocysteinemia [17].
APS is a systemic autoimmune disease with a wide variety of vascular and obstetric manifestations caused by aPL [18,28]. The revised Sapporo classification criteria require at least 1 clinical and 1 laboratory criterion to define APS [3,4,28]. It can occur in its primary form (primary APS) or be associated with other autoimmune diseases, mainly SLE [3,28]. The clinical criteria include the presence of episodes of vascular thrombosis and pregnancy stillbirth; the laboratory criteria assess the presence of aPL, which includes detection of lupus anticoagulant, moderate-high titers of anticardiolipin or anti-beta-2-glycoprotein-I IgG or IgM autoantibodies, positive on ≥2 occasions at least 12 weeks apart [3,4]. IgG antibodies correlate better with clinical manifestations than IgM [4]. A high-risk aPL profile is associated with an increased risk of thrombotic and obstetric APS [28] and includes the presence of lupus anticoagulant (subtype most closely related to thrombosis), the presence of double (2 of the 3 subtypes) or triple aPL positivity (all 3 sub-types), or the presence of persistently high aPL titers (more than 40 GPLU) [28]. Our patient met the diagnostic criteria for APS, she was positive for all 3 types of aPL measured more than 12 weeks apart and had 2 events of vascular thrombosis. It is important to highlight that 44% of patients with triple-positive APS will undergo recurrent VTE during a 10-year follow-up period, even when receiving anticoagulant therapy [18]. In general, in patients with APS, the risk of a first VTE is up to 10-fold higher than in the general population, and the risk of recurrence is from 2- to 6-fold higher [17].
The European League Against Rheumatism (EULAR) recommendations in the management of APS include that APS patients in their first episode of unprovoked VTE should receive long-term treatment with VKA with a target INR of 2–3; rivaroxaban should not be used in patients with APS who are triple-aPL-positive due to the high risk of recurrent VTE. In patients with repeated high-risk aPL profile, longer anticoagulation may be considered, and for those patients with recurrent VTE despite VKA treatment with a target INR, consideration may be given to adding low-dose aspirin, increasing the target INR to 3–4, or switching to LMWH [28].
Hyperhomocysteinemia is defined as a blood homocysteine level above 15 micromol/L [29]. This condition is associated with a nearly 3-fold increased risk of new and recurrent VTE compared to the general population [15,17]. Hyperhomocysteinemia is related to increased VTE and has been reported in up to 30.8% of patients with primary APS [5,30]. We propose that since both diseases are independent risk factors for VTE, they could trigger a higher risk of incidence and recurrence of VTE at a younger age when they coexist. The homocysteine levels can be classified as mild (15–30 umol/L), moderate (31–100 umol/L), or severe (>100 umol/L) [31]. Factors that alter homocysteine levels are divided into non-genetic, including low vitamin B levels (vitamins B6, B9, and B12) and impaired kidney function, and genetic factors involving defects in the transsulfuration pathway (cystathionine b-synthase deficiency, represent the most common inborn error) or remethylation pathway (inadequate enzyme activity of 5,10-methylenetetrahydrofolate reductase [MTHFR] due to a mutation) [29,31]. It is important to highlight the association of mild forms of hyperhomocysteinemia with a genetic basis [31]. In our case, confirmatory genetic testing was not done due to unavailability in our country.
Initial evaluation in adults with hyperhomocysteinemia should aim to rule out signs and symptoms of homocystinuria, such as ectopic lens, osteoporosis, glaucoma, and retinal detachment, as well as a family history of homocystinuria [29]. However, the decision to measure homocysteine levels in patients who do not have homocystinuria is controversial, as treatment to lower homocysteine levels (eg, vitamin B supplements) has not been shown to improve clinical outcomes or prevent future thrombosis or cardiovascular events [29,30,32].
The long-term anticoagulant treatment according to the 2019 ESC guidelines in patients with high-risk PE and triple-positive APS consists of AVK with a target INR of 2 to 3, for at least 3 months [1,14]. The EULAR recommendations in this group of patients suggest that longer anticoagulation may be considered [28]. Non-VKA oral anticoagulants are contraindicated because of the theoretical predisposition to higher rates of thrombotic and hemorrhagic events [1,14,28]. The patient was concerned about future conception and long-term anticoagulation, and she was referred to the Departments of Obstetrics-Gynecology and Hematology for outpatient multi-disciplinary follow-up.
Conclusions
This report has presented the case of a life-threatening high-risk PE in a previously healthy young woman and highlights the importance of emergency management followed by investigation and treatment of underlying risk factors for VTE, including APS and hyperhomocysteinemia.
Figures
Figure 1.. Twelve-lead electrocardiogram showing sinus rhythm (94 beats/min); a pattern of prominent S wave in I, Q wave in III, and negative T wave in III; inverted T waves in inferior and precordial leads; diffuse ST-segment depression; right atrial enlargement; and incomplete right bundle branch block. Figure 2.. Computed tomography pulmonary angiography with axial (A) and sagittal (B) views showing large and occlusive filling defects (blue arrows) predominantly involving the MPA and LPA on admission. After thrombolysis, a significant reduction of the filling defects (blue arrows) in the MPA and LPA are shown in the axial (C) and sagittal (D) views. MPA – main pulmonary artery; LPA – left pulmonary artery. Figure 3.. Transthoracic echocardiogram with parasternal short axis view at end-systole demonstrating a D-shaped LV (red arrows) (A). Apical 4-chamber view at end-diastole showing a RV (red line) to LV (blue line) diameter ratio greater than 1, in addition to RA and RV enlargement (B). LA – left atrium; LV – left ventricle; RA – right atrium; RV – right ventricle.References:
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