You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


INTRODUCTION {#sec1-1}
============

Pulmonary hypertension (PH) is a relatively frequent and severe complication of sickle cell disease (SCD). The exact pathogenesis of PH in SCD in not known, but a number of factors have been implicated. These factors include endothelial injury due to recurrent sickling and associated vascular intimal hyperplasia, acute and chronic inflammation, and altered bioavailability of nitric oxide (NO). The vascular intimal hyperplasia can occur with or without a superimposed thrombus and can lead to chronic thromboembolism. Patients with PH secondary to SCD are classified as Group 5 PH as per the WHO guidelines.\[[@ref1]\] Patients who suffer from chronic thromboembolism secondary to SCD can also have associated chronic thromboembolic pulmonary hypertension (CTEPH), thus being classified as Group 4 PH as per the WHO classification.\[[@ref1]\] We present such a case of a patient with SCD diagnosed with severe PH who was found to have CTEPH and successfully underwent a thromboendarterectomy with resolution of symptoms.

CASE REPORT {#sec1-2}
===========

A 37-year-old male with SCD (hemoglobin (Hb) SS-disease) (treated with blood transfusion every 3 months) was diagnosed with pulmonary embolism (PE) and was being treated with enoxaparin. Apart from the SCD, the patient had a history of chronic venous stasis ulcer, which was being managed on an outpatient basis \[[Figure 1](#F1){ref-type="fig"}\]. Eighteen months after the diagnosis of PE, the patient presented to the emergency department with worsening dyspnea on exertion. A ventilation/perfusion (VQ) scan was performed at the time that showed a right middle lobe perfusion defect consistent with PE. Ultrasound of both lower extremities revealed chronic deep vein thrombosis. The patient was also noted to have nocturnal hypoxemia and hypoxemia with exertion and was thus started on home oxygen therapy.

![Patient with leg ulcer with sickle cell disease and pulmonary hypertension](LI-35-73-g001){#F1}

For further evaluation, the patient had a computed tomography pulmonary angiogram (CTPA), which demonstrated diffuse mosaic attenuation of lung parenchyma as seen in diseases such as chronic thromboembolic (CTE) disease \[Figure [2a](#F2){ref-type="fig"} and [b](#F2){ref-type="fig"}\]. A mildly dilated pulmonary artery was also noted \[[Figure 2a](#F2){ref-type="fig"}\]. A transthoracic echocardiogram showed right ventricular dilatation with estimated right ventricular systolic pressure (RVSP) of 103 mmHg. His most recent previous echocardiogram was performed 18 months ago and demonstrated a normal right ventricle with normal RVSP. A cardiac catheterization was performed which showed elevated pulmonary artery pressures with normal left-sided pressures \[[Table 1](#T1){ref-type="table"}\]. He was thus diagnosed with PH and started on sildenafil. Pulmonary function tests showed a restrictive pattern with decreased diffusion capacity (DLCO) \[[Table 2](#T2){ref-type="table"}\]. The 6-min walk distance (6MWD) was 416 M with supplemental oxygen at 5 L/min to keep the saturation above 90%. The patient required 2 L/m of supplemental oxygen at baseline. He was thus referred to the cardiothoracic surgery team for evaluation of CTEPH.

![(a and b) Computed tomography of the chest showing a diffuse mosaic attenuation of the lung parenchyma](LI-35-73-g002){#F2}

###### 

Right heart catheterization

![](LI-35-73-g003)

###### 

Pulmonary function tests (restrictive pattern with reduced diffusing capacity of the lungs for carbon monoxide)

![](LI-35-73-g004)

The pulmonary angiogram demonstrated filling defects in the right lower and middle lobes and left lower lobe, consistent with CTE disease \[Figure [3a](#F3){ref-type="fig"} and [b](#F3){ref-type="fig"}\]. Severely elevated pulmonary pressures were again noted \[[Table 3](#T3){ref-type="table"}\]. Two months later, the patient underwent a successful pulmonary endarterectomy (PEA) with removal of the thrombus \[[Figure 4](#F4){ref-type="fig"}\]. He was also started on riociguat for residual PH and enrolled in the cardiopulmonary rehabilitation program. His repeat 6MWD increased to 432 M without any supplemental oxygen. Interestingly, on follow-up, it was also noted that the patient\'s chronic venous stasis ulcer showed remarkable improvement with improvement in his oxygen saturation and improvement in his functional status \[[Figure 5](#F5){ref-type="fig"}\]. The patient continues to have a stable follow-up course.

![(a) Pulmonary angiogram showing filling defects in the right middle lobe and right lower lobe. (b) Pulmonary angiogram showing filling defects on the left side](LI-35-73-g005){#F3}

###### 

Right heart catheterization/pulmonary angiography

![](LI-35-73-g006)

![Clot removed after pulmonary thromboendarterectomy](LI-35-73-g007){#F4}

![Healing lung ulcer status post pulmonary thromboendarterectomy](LI-35-73-g008){#F5}

DISCUSSION {#sec1-3}
==========

PH is a common complication of SCD. The prevalence of PH in this patient group is around 10%--20% and is a common cause of mortality.\[[@ref2]\] Although there is evidence that patients with SCD have a hypercoagulable state, CTEPH in these patients is relatively uncommon. According to a study by Anthi *et al*., 23% of the SCD patients with PH had perfusion mismatch in the V/Q scan. About 11.5% of the patients had evidence of CTE disease on CTPAs.\[[@ref3]\]

There have been multiple pathophysiologic mechanisms which have been postulated which lead to thromboembolism in SCD patients and subsequently can lead to CTEPH. In fact, every aspect of Virchow\'s triad, i.e., increased coagulability, endothelial dysfunction, and impaired blood flow, is present in patients with SCD and results in a highly thrombogenic environment.\[[@ref4]\]

The repeated cycles of sickling and unsickling in SCD patients lead to an abnormal phospholipid asymmetry as well as adherence of the sickle erythrocytes to the vascular endothelium. The alteration of the membrane structure of sickle erythrocytes results in exposure of the anionic phospholipid, phosphatidylserine (PS). This phenomenon supports coagulation by PS acting as the cofactor for proteolytic reactions.\[[@ref5]\] This phenomenon is also supported by the fact that a correlation has been found between PS-positive sickle cell erythrocytes and prothrombin fragments 1.2, D-dimers, and plasmin-antiplasmin complex.\[[@ref6]\] Antiphospholipid antibodies are known to be both procoagulant and prothrombotic. Levels of these antibodies are markedly higher in patients with SCD.\[[@ref7]\] These antibodies work by tissue factor induction leading to activation of the coagulation system.\[[@ref8]\] Multiple studies have suggested that there is increased thrombin generation in SCD patients. Increased levels of prothrombin fragments1.2, D-dimers, and thrombin-antithrombin complexes support this hypothesis.\[[@ref9]\] The level of factor V is also reduced in SCD patients suggesting ongoing thrombin generation.\[[@ref10]\] Along with that, high plasma levels of procoagulants such as von Willebrand factor and factor VIII are found in SCD patients.\[[@ref10][@ref11][@ref12]\] All these changes reflect the hypercoagulable state in SCD.

Circulating free Hb in the setting of hemolysis also causes NO depletion, which leads to chronic vasoconstriction and platelet activation.\[[@ref13]\] Moderate thrombocytosis is a common feature of patients with SCD and sickle cell anemia. These changes can be attributed to the fact that splenic autoinfarction affects the majority of children with Hb SS-disease by age 1 year and a large proportion of patients with SC disease by middle childhood.\[[@ref14]\] This could also lead to the development of secondary PH. Long-standing thrombocytosis after splenectomy has been shown in one case to be associated with elevated fibrinopeptide A, thromboxane B2, and β-thromboglobulin levels resulting in endothelial damage, local platelet activation, and thrombin generation leading to CTEPH. A similar mechanism could lead to CTEPH in SCD patients due to the functional asplenia.\[[@ref15]\] Besides thrombocytosis, increased platelet adhesion may contribute to the development of pulmonary vasculopathy. There is evidence to support transmigration of intact megakaryocytes from the bone marrow to the circulation and the release of platelets from these megakaryocytes in the pulmonary capillary bed. These large-sized platelet precursors can contribute to distal *in situ* thrombosis leading to CTEPH in asplenic SCD patients.\[[@ref16]\]

Transthoracic Doppler echocardiography on patients with SCD is a cost-effective and established screening tool for PH. Elevated pulmonary artery systolic pressure on echocardiography should be confirmed by right heart catheterization (RHC). Due to the high incidence of thromboembolism in patients with SCD, patients with PH should be screened with a VQ scan and/or a CTPA. Patient with signs suggestive of CTEPH should undergo an angiography to diagnose CTE. Pulmonary function tests should be performed in all patients with SCD presenting with dyspnea. A restrictive pulmonary functional abnormality in this setting may represent areas of prior infarction.\[[@ref17]\]

The diagnosis of CTE and related CTEPH can alter management strategies and the classification of PH. PH associated with SCD is classified as Group 5 PH. A recent guideline from the American Thoracic Society proposes the screening for PH in patients with SCD every 3 years.\[[@ref18]\] A different guideline by the sickle cell expert panel did not endorse these recommendations, suggesting echocardiographic evaluation followed by RHC in symptomatic patients only.\[[@ref19]\] PH related to CTEPH is classified as Group 4 as per the WHO classification system. Although PEA is recommended for patients with PH related to CTE disease, chronic hemolysis and the associated proliferative vasculopathy in the distal vessels put patients with SCD at increased risk of residual PH after PEA. CTEPH in SCD patients has been treated surgically with success \[[Table 1](#T1){ref-type="table"}\]. Jerath *et al*.\[[@ref20]\] demonstrated normalization of pulmonary artery pressures, after a PEA in a patient with SCD and CTEPH. Deep hypothermic circulatory arrest (DHCA) during PEA exposes the SCD patient to a hypothermic, hypoxic, acidotic, and a low-flow state. These patients are thus at an increased risk of sickling during this procedure. While there is no consensus on the values of Hb S in patients with SCD, Firth and Head have proposed that the level of Hb S should be reduced to \<30% for a major surgical procedure and to \<10% for a cardiopulmonary surgical procedure.\[[@ref21]\] Five cases in literature demonstrated a successful PEA under DHCA after exchange transfusion to reduced Hb S to \<10% \[[Table 4](#T4){ref-type="table"}\].\[[@ref20][@ref23][@ref24]\] Attention should be paid to maintaining good flow states, a normal acid-base balance status, and limit the duration of circulatory arrest periods. The use of specific PAH therapies for the management of SCD-associated PH is a controversial matter. Two randomized control trials have studied the role of bosentan but have been prematurely terminated.\[[@ref25]\] Another trial addressing the role of sildenafil was discontinued due to increased hospitalization for pain crisis.\[[@ref26]\] To date, there have been no studies to inform anticoagulation practices in patients with SCD.\[[@ref27]\] Anticoagulation management of symptomatic VTE and CTEPH, therefore, currently relies on established general guidelines for VTE management.\[[@ref28]\] Further studies are necessary to determine adequate treatment approach and to determine which subgroup of patients might benefit from PAH-targeted therapies and anticoagulation.

###### 

All reported patients with sickle cell disease who underwent pulmonary endarterectomy

![](LI-35-73-g009)

Leg ulcerations have been a long-recognized complication of SCD. Minniti *et al*. in their review concluded that the epidemiological relationship between leg ulcers and PH supported an overlap of pathobiological mechanisms.\[[@ref29]\] The possible overlapping mechanisms include mechanical obstruction by dense sickled red cells, *in situ* thrombosis, anemia with decrease in oxygen carrying capacity, and decreased NO bioavailability leading to impaired endothelial function.\[[@ref30]\] One interesting case report has noted leg ulcer healing during treatment of pulmonary arterial hypertension with an endothelin receptor antagonist.\[[@ref31]\] Management of PH is currently recommended as one of the systemic interventions for managing this complication of SCD.\[[@ref22]\] Our patient demonstrated healing of the ulcer after undergoing a successful thromboendarterectomy for management of his CTEPH. We hypothesize that the possible mechanisms of improvement of the leg ulcer include increased peripheral oxygen supply as evidenced by the decrease in supplemental oxygen requirement. Another possible contributing factor is the reduction of right-sided pressures after the endarterectomy leading to decreased venous stasis and decreased peripheral edema, thus helping the healing of the ulcer.

CONCLUSION {#sec1-4}
==========

We present a case of a 37-year-old male with SCD and associated Group 4 PH due to chronic thromboembolism who underwent a successful PEA. This helped reduce his oxygen requirement, increased his 6MWD, and also helped with healing of his chronic venous stasis ulcer, all likely manifestations of his PH. Thus, the clinicians should screen and assess for CTEPH in patients with SCD with elevated pulmonary artery pressures as this would offer possible treatment options such as pulmonary thromboendarterectomy and/or riociguat in this subset of patients.

Declaration of patient consent {#sec2-1}
------------------------------

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship {#sec2-2}
---------------------------------

Nil.

Conflicts of interest {#sec2-3}
---------------------

There are no conflicts of interest.