Treatment and Clinical Management of Chronic Thromboembolic Pulmonary Hypertension:An Update of Literature Review

Chronic thromboembolic pulmonary hypertension(CTEPH)is a chronic,progressive,debilitating,and life-threa-tening complication of pulmonary embolism(PE).Recent technological advances have permitted various treat-ment options for the treatment of CTEPH,including surgery,angioplasty,and medical treatment,depending on the location and characteristics of lesions.Pulmonary endarterectomy(PEA)is the treatment of choice for CTEPH,as it offers excellent long-term outcomes and a high probability of recovery.Moreover,various medical and interventional therapies are currently being developed for patients with inoperable CTEPH.This review mainly summarizes the current treatment approaches of CTEPH,offering more options for specialist physicians to,thus,better manage chronic thromboembolic syndromes.

THROMBOENDARTERECTOMY FOR CHRONIC PULMONARY THROMBOEMBOLISM

Objective To evaluate the improving reliability and safety of thromboendarterectomy and perioperative management for chronic pulmonary thromboembolism. Methods The clinical data of 12 cases with chronic pulmonary thromboembolism, who underwent thromboendarterec- tomy assisted by low flow or circulation arrest with deep hypothermia, were reviewed retrospectively. Results Pulmonary artery pressure decreased 20 to 40 mmHg immediately after surgical procedures in 9 cases. The postoperative pulmonary edema at various degrees happened in 12 cases, among them, 1 died of severe lung infection and pulmonary re-embolism at 19 days postoperation. Computed tomography pulmonary angiography and angiography of 11 cases indicated that the original obstruction of pulmonary artery disappeared. During the follow-up period of 2 months to 5 years, the clinical symptoms and activity was improved. Conclusion Thromboendarterectomy is an effective treatment for chronic pulmonary thromboembolism. The outcome of the surgical procedure needs to be further investigated and followed up regularly according to an evaluative system, because it might be influenced by multiple factors.

Choriocarcinoma-associated pulmonary thromboembolism and pulmonary hypertension： a case report

Cases of pulmonary embolism and pulmonary artery hypertension caused by choriocarcinoma represent a rare clinical emergency. We report a case of a 25-year-old woman who presented with pulmonary embolism and hyper- tension and died soon after complete pulmonary embolectomy. A related literature review revealed that almost all of these patients had previously experienced a spontaneous abortion （average, 6 months） and were not pregnant.

Influence of L-arginine on the Expression of eNOS and COX2 in Experimental Pulmonary Thromboembolism

The influence of L-arginine on endothelial nitric oxide synthase （eNOS） and cyclooxygenase 2 （COX2） was observed in experimental pulmonary thromboembolism and the action mechanism on pulmonary thromboembolism was explored. Wistar rats were randomly divided into control group, model group and treatment group. Pulmonary thromboembolism models were established by auto-blood back transfusion, and L-Arg 100 mg/kg was intraperitoneally injected after successful model preparation. The animals were sacrificed at 3 h, 1 day, 3 days and 7 days after embolism. Plasma NO, TXB2 and 6-Keto-PGF1 α were detected. The expression of eNOS and COX2 protein and mRNA in pulmonary tissues was detected by immunohistochemistry and RT-PCR respectively. The results showed that pulmonary thrombosis could be seen post pulmonary embolism and inflammatory reaction was significant. Plasma NO was decreased （P〈0.01）, and the levels of TXB2, 6-Keto-PGF1α and T/P ratio were all elevated. The expression of eNOS protein and mRNA in the pulmonary tissue was down-regulated （P〈0.05）, while that of COX2 protein and mRNA was upregulated （P〈0.01）. In treatment group, the level of NO was increased, the levels of TXB2 and T/P ratio were decreased, but the level of 6-Keto-PGF1 α was increased. The expression of eNOS protein and mRNA in pulmonary tissue was upregulated （P〈0.05）, while that of COX2 protein and mRNA was down-regulated （P〈0.05）. In conclusion, L-arginine can educe the role of pulmonary tissue protection through up-regulating the expression of intra-pulmonary NOS and down -regulating COX2 in pulmonary thromboembolism.

Pulmonary thromboembolism after distal ulna and radius fractures surgery: A case report and a literature review

BACKGROUND Pulmonary thromboembolism(PTE)is a serious postoperative complication that can occur after a fracture.Generally,PTE is caused by the falling off of lower extremity deep vein thrombosis(LEDVT)after lower limb fracture surgery.LEDVT and PTE after upper extremity fracture surgery are very rare.PTE is one of the most common clinical causes of sudden death.Venous thromboembolism includes PTE and DVT.We experienced one case of LEDVT and PTE after distal ulna and radius fracture surgery.The purpose of our report is to raise awareness for orthopedic surgeons that PTE can occur after distal ulna and radius fracture surgery,and patients with high risk factors should be considered for prevention and treatment of thrombosis in a timely manner.CASE SUMMARY We report a 51-year-old Chinese male who had severe fractures of the left distal ulna,radius and little finger after a motorcycle accident.The patient underwent external fixation,open reduction and internal fixation.On the third post-operative day,computed tomographic pulmonary angiography showed PTE.Doppler ultrasonography showed thrombus formation in the bilateral posterior tibial veins.After a period of anticoagulation therapy,on the 25th d after the PTE,computed tomographic pulmonary angiography showed that thrombus in both sides of the pulmonary artery disappeared.Furthermore,about 4 mo after the PTE,thrombosis in the deep veins of the lower limbs disappeared.About 1 year after the surgery,X-rays showed good fracture healing,and the function of the wrist joint recovered well.CONCLUSION Though rare,PTE can occur after distal ulna and radius fracture surgery and patients with high risk factors should be considered for prevention and treatment of thrombosis in a timely manner.

Pulmonary artery stent thrombosis and symptomatic pulmonary hypertension following COVID-19 infection in Alagille patient:A case report

BACKGROUND Alagille syndrome is a multisystem disease that results in various vascular anomalies,commonly involving the cardiac and pulmonary systems.To the best of our knowledge,there is no literature regarding the cardiovascular outcomes of these patients in association with coronavirus disease 2019(COVID-19).CASE SUMMARY A 34-year-old woman with a history of Alagille syndrome who underwent successful atrial septal defect with partial anomalous pulmonary veins and patent ductus arteriosus repair,as well as left pulmonary artery catheterization and stenting in childhood due to pulmonary stenosis.The patient was without any respiratory symptoms and was a dancer prior to contracting COVID-19.Several weeks after her COVID-19 infection,she developed left pulmonary artery stent thrombosis and subsequent symptomatic pulmonary hypertension.A treatment strategy of anticoagulation alongside pharmacological agents for pulmonary hypertension for 3 months followed by balloon pulmonary artery angioplasty to reopen the stenosis was unsuccessful.CONCLUSION In the era of COVID-19,patients with pulmonary vascular malformations and endovascular stents are at an increased risk for chronic thromboembolic disease.Patients may benefit from prophylactic antiplatelet or anticoagulation therapy.Stent thrombosis is a devastating phenomenon and should be treated urgently and aggressively with balloon pulmonary angioplasty,and/or a thrombolytic agent.

PULMONARY THROMBOEMBOLISM FOLLOWING THORACOTOMY FOR LUNG CANCER

Objective： To investigate the clinical features of pulmonary thromboembolism in patients with primary lung cancer in relation to thoracotomy, and to shed light on prevention, diagnosis and treatment of this fatal disease after lung resection. Methods： A total of 1245 cases with primary lung cancer received thoracotomy in the past 13 years were retrospectively reviewed. Clinical data of a total of 14 patients （1.1%） suffering from pulmonary thromboembolism and requiring cardiao-pulmonary resuscitation were collected and analyzed. Results： The diagnosis was established primarily by clinical findings in 9 cases （64.3%）, including further confirmation of one case during operation, by pulmonary ventilation-perfusion scan in 2, by spiral CT angiography in I, by pulmonary angiography in 1, and by autopsy in I case. Even using prompt resuscitation, 8 patients （57.1%） died within 48 h （mean 4 h） after the onset of the symptoms. Six cases eventually recovered. Of the 6 salvaged patients, they all received anticoagulation therapy with heparin intravenously and warfarin orally, including 3 cases of additional thrombolytic therapy with urokinase. Two cases with massive pulmonary emboli received emergency surgery, including one pulmonary embolectomy, and one bilobectomy after right upper Iobectomy, with satisfactory results. Conclusion： Massive pulmonary embolism is an infrequent but fatal early postoperative complication after lung resection. The diagnosis should be based mainly on clinical findings in order to initiate the appropriate therapy immediately. The direct diagnostic techniques including radionuclide pulmonary scan, spiral CT angiography, and pulmonary angiograpby could be based on a careful evaluation of the expected benefits and risks of the various available treatments.

Simple mechanical thrombectomy with intrapulmonary arterial thrombolysis in pulmonary thromboembolism： a small case series

Pulmonary thromboembolism （PTE） is a life-threatening condition with a high early mortality rate caused by acute right ventricular failure and cardiogenic shock. We report a series of three patients who presented with acute and subacute submassive PTE. They were suc-cessfully treated by simple catheter-based mechanical thrombectomy and intrapulmonary arterial thrombolysis. Mechanical fragmentation and aspiration of thrombus was performed by commonly used J-wire, multi-purpose and Judkin Right guiding catheters and this obviated the need of specific thrombectomy devices.

Pulmonary embolism after shoulder surgery:Is it a real threat?

Pulmonary embolism(PE)is a rare but devastating complication of shoulder surgery.Apart from increased morbidity and mortality rates,it may significantly impair postoperative recovery and functional outcome.Its frequency accounts for up to 5.7%of all shoulder surgery procedures with a higher occurrence in women and patients older than 70 years.It is most commonly associated with thrombophilia,diabetes mellitus,obesity,smoking,hypertension,and a history of malignancy.PE usually occurs secondary to upper or lower-extremity deep vein thrombosis(DVT).However,in rare cases,the source of the thrombi cannot be determined.Prophylaxis for PE following shoulder surgery remains a topic of debate,and the standard of care does not routinely require prophylactic medication for DVT prophylaxis.Early ambulation and elastic stockings are important preventative measures for DVT of the lower extremity and medical agents such as aspirin,low-molecular-weight heparin,and vitamin K antagonists are indicated for high-risk patients,long-lasting operations,or concomitant severe acute respiratory syndrome coronavirus 2 infection.The most common symptoms of PE include chest pain and shortness of breath,but PE can also be asymptomatic in patients with intrinsic tolerance of hypoxia.Patients with DVT may also present with swelling and pain of the respective extremity.The treatment of PE includes inpatient or outpatient anticoagulant therapy if the patient is hemodynamically unstable or stable,respectively.Hemodynamic instability may require transfer to the intensive care unit,and cardiovascular arrest can be implicated in fatal events.An important issue for patients with PE in the postoperative period after shoulder surgery is residual stiffness due to a delay in rehabilitation and a prolonged hospital stay.Early physiotherapy and range-of-motion exercises do not adversely affect the prognosis of PE and are highly recommended to preserve shoulder mobility and function.

Late Thrombolysis in Massive Pulmonary Thromboembolism

Pulmonary thromboembolism (PTE) remains a diagnostic and therapeutic challenge for physicians. Anticoagulation with heparin remains as the cornerstone in its management, reserving thrombolysis for cases with hemodynamic impairment. The later has been associated with haemorrhagic complications and has proved beneficial when initiated within the first 48 hours of PTE;but there is little evidence supporting its use passed this time. We present a case of an 84 year old female admitted in our unit and treated successfully with thrombolysis for massive PTE at the fifth day of diagnosis. The patient improved towards complete recovery and was discharged from the hospital 22 days after admission without complications.

The Clinical Value of NLR, D-D and CRP/ALB Ratio in the Diagnosis of Pulmonary Thromboembolism

Objective: To evaluate the clinical diagnostic value of C-reactive protein/albumin ratio (CAR), neutrophil/lymphocyte ratio (NLR) and D-dimer (D-D) in patients with pulmonary thromboembolism (PTE). Methods: We conducted a retrospective analysis comparing hematology and coagulation in 362 PTCA-confirmed PTE patients with the control group and analyzing their relationships with CAR, NLR, and D-D. Receiver operating characteristic curve (ROC) was used to analyze the diagnostic threshold, area under the curve (AUC), diagnostic sensitivity and specificity of CAR, NLR and D-D for PTE. Results: 1) CAR, NLR and D-D levels in PTE patients were 2.13 ± 2.08, 8.96 ± 1.94 and 9.69 ± 8.61 respectively, significantly higher than those in control group (CAR = 0.03 ± 0.01, t = 20.7736, P < 0.01;NLR = 1.76 ± 0.53, t = 2.4281, P < 0.05 and PTE = 0.20 ± 0.11, t = 3.0066, P < 0.01 respectively). 2) NLR was positively correlated with CAR (r = 0.2111, t = 4.0971, P < 0.01) and D-D (r = 0.1065, t = 2.0481, P < 0.05), but CAR was not correlated with D-D (r = 0.0975, P > 0.05). 3) The levels of HB, LY, PLT and AT in PTE patients were significantly lower than those in control group, while WBC, NE and FB were significantly higher than those in control group. 4) CAR was negatively correlated with Hb and AT (P all < 0.01), but positively correlated with WBC, NE, MO and FB (P all < 0.01). NLR was negatively correlated with LY and AT (P all < 0.01), but positively correlated with WBC, NE and FB (P all < 0.01). DD was negatively correlated with Hb and PLT (P all < 0.05), but positively correlated with WBC, NE and MO (P all < 0.01). Conclusion: The levels of Hb, LY, PLT and AT were significantly decreased in PTE patients, while WBC, NE and FB were significantly increased. CAR, NLR and D-D were highly expressed in PTE patients, and were closely correlated with Hb, AT and FB. Combined detection of CAR, NLR and D-D can improve the diagnostic value of PTE.

Diagnostic value of lead corrected Vt and V6 in patients with acute pulmonary thromboembolism

Objective: To investigate the diagnostic value of lead corrected Vt and V6 in patients with acute pulmonary thromboembolism. Methods: A total of 89 patients with suspected acute PTE were examined in our hospital from January to December 2017. A baseline 12-lead ECG was recorded on admission, with a gain of 10 mm/mV and a paper velocity of 25 mm/s. Results: Of the 89 suspected PTE patients enrolled in this study, 45 patients with acute PTE and 44 patients without PTE were identified by CTA. The chief complaint of most patients in both groups was dyspnea or dyspnea, with no significant difference between the two groups. The levels of d-dimer and high-sensitivity troponin in patients with PTE were significantly higher than those without PTE. QT and QTc in the V1 lead in the PTE group were significantly greater than those in the non-PTE group, but QT and QTc in the V6 lead were not significantly different between the two groups. The QTc difference (V1-V6) in the PTE group was significantly greater than that in the non-PTE group. In the morphological analysis, T wave inversion in lead III of PTE group, T wave inversion of V1 or V1 and V2 was significantly higher than that of non-PTE group. There was no significant difference in the incidence of S1Q3T3 between the two groups. For the prediction of acute PTE, the maximum accuracy of the maximum QTc difference (V1-V6)≥20 ms, the sensitivity was 83.2%, and the specificity and positive predictive value was 100%. T-wave inversion in V1 leads is the most sensitive morphological abnormality associated with PTE with a sensitivity of 80.06% and a specificity of 62.29%. T-wave inversion in lead III is a sub-sensitive predictor with a sensitivity of 51.20%. The specificity is 70.53%. Conclusions: The QTC difference (V1-V6) is a distinct feature of acute PTE, and QTC difference (V1-V6)≥20 ms as an important indicator of acute PTE in emergency settings.

Venous thromboembolism in inflammatory bowel disease

Patients with inflammatory bowel disease(IBD)are at an increased risk for venous thromboembolism(VTE).VTE events carry significant morbidity and mortality,and have been associated with worse outcomes in patients with IBD.Studies have suggested that the hypercoagulable nature of the disease stems from a complex interplay of systems that include the coagulation cascade,natural coagulation inhibitors,fibrinolytic system,endothelium,immune system,and platelets.Additionally,clinical factors that increase the likelihood of a VTE event among IBD patients include older age(though some studies suggest younger patients have a higher relative risk of VTE,the incidence in this population is much lower as compared to the older IBD patient population),pregnancy,active disease,more extensive disease,hospitalization,the use of certain medications such as corticosteroids or tofacitinb,and IBD-related surgeries.Despite the increased risk of VTE among IBD patients and the safety of pharmacologic prophylaxis,adherence rates among hospitalized IBD patients appear to be low.Furthermore,recent data suggests that there is a population of high risk IBD patients who may benefit from post-discharge prophylaxis.This review will provide an overview of patient specific factors that affect VTE risk,elucidate reasons for lack of VTE prophylaxis among hospitalized IBD patients,and focus on recent data describing those at highest risk for recurrent VTE post-hospital discharge.

Facing the challenge of venous thromboembolism prevention in patients undergoing major abdominal surgical procedures for gastrointestinal cancer

Venous thromboembolism(VTE)refers to a hypercoa-gulable state that remains an important and preven-table factor in the surgical treatment of malignancies.VTE includes two identical entities with regards to deep vein thrombosis and pulmonary embolism.The incidence of VTE after major abdominal interventions for gastro-intestinal,hepato-biliary and pancreatic neoplastic disor-ders is as high as 25%without prophylaxis.Prophylactic use of classic or low-molecular-weight heparin,anti-Xa factors,antithrombotic stocking,intermittent pneumatic compression devices and early mobilization have been described.Nevertheless,thromboprophylaxis is often dis-continued after discharge,although a serious risk may persist long after the initial triggering event,as the coagu-lation system remains active for at least 14 d post-opera-tively.The aim of this review is to evaluate the results of the current practice of VTE prevention in cancer patients undergoing major abdominal surgical operations,with special attention to adequately elucidated guidelinesand widely accepted protocols.In addition,the recent literature is presented in order to provide an update on the current concepts concerning the surgical manage-ment of the disease.

Arterial complications, venous thromboembolism and deep venous thrombosis prophylaxis after anterior cruciate ligament reconstruction: A systematic review

AIM To summarize the current knowledge on vascular complications and deep venous thrombosis(DVT) prophylaxis after anterior cruciate ligament(ACL) reconstruction.METHODS A systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. MEDLINE, EMBASE, Cochrane,Web of Science, CINAHL, PubMed publisher, and Google scholar medical literature databases were searched up to November 10, 2015. Any arthroscopic surgical method of primary or revision intra-articular ACL reconstruction of all graft types in humans was included. A risk of bias assessment was determined.RESULTS Fourty-seven studies were included in the review.Pseudaneurysms were the most frequently reported arterial complication after ACL reconstruction, irrespective of graft type or method of graft fixation with an incidence of 0.3%. The time to diagnosis of arterial complications after ACL reconstruction varied from days to mostly weeks but even years. After ACL reconstruction without thromboprophylaxis, the incidence of DVT was 9.7%, of which 2.1% was symptomatic. The incidence of pulmonary embolism was 0.1%. Tourniquet time > 2 h was related to venous thromboembolism.Thromboprophylaxis is indicated in patients with risk factors for venous thromboembolism.CONCLUSION After ACL reconstruction, the incidence of arterial complications,symptomatic DVT and pulmonary embolism was 0.3%, 2.1% and 0.1% respectively. Arterial complications may occur with all types of arthroscopic ACL reconstruction, methods of graft fixation as well as any type of graft. Patients considered to be at moderate or high risk of venous thromboembolism should routinely receive thromboprophylaxis after ACL reconstruction.

The effects of obesity on venous thromboembolism: A review

Obesity has emerged as a global health issue that is associated with wide spectrum of disorders, including coronary artery disease, diabetes mellitus, hypertension, stroke, and venous thromboembolism (VTE). VTE is one of the most common vascular disorders in the United States and Europe and is associated with significant mortality. Although the association between obesity and VTE appears to be moderate, obesity can interact with other environmental or genetic factors and pose a significantly greater risk of VTE among individuals who are obese and who are exposed simultaneously to several other risk factors for VTE. Therefore, identification of potential interactions between obesity and certain VTE risk factors might offer some critical points for VTE interventions and thus minimize VTE morbidity and mortality among patients who are obese. However, current obesity measurements have limitations and can introduce contradictory results in the outcome of obesity. To overcome these limitations, this review proposes several future directions and suggests some avenues for prevention of VTE associated with obesity as well.

Advances in research on personalized venous thromboembolism risk assessment tools

This paper describes the de？nition of venous thromboembolism and introduces to personalized venous thromboembolism risk assessment tools overseas. Thoughts are given on the development, amendment,application and validation of these tools. The paper provides a reference for building personalized venous thromboembolism risk assessment tools in China.

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension: How can patients be better selected?

Chronic thromboembolic pulmonary hypertension (CTEPH) comprises organizing thrombotic obstructions in the pulmonary arteries by nonresolving thromboemboli, formation of fibrosis and remodeling of pulmonary blood vessels. Surgical pulmonary endarterectomy (PEA) is the therapy of choice for patients with surgically accessible CTEPH, which leads to a profound improvement in hemodynamics, functional class and survival. Select- ing the candidates that will benefit from surgery is still a challenging task. Criteria for surgical suitability have been described but the decision-making for or against surgical intervention remains still subjective. The optimal characterization of the reciprocal contribution of large vessel and small vessel disease in the elevation of pulmonary vascular resistance is crucial for the indication and outcome of PEA. Recently, Toshner et al intended to validate the partition resistance into small and large vessels compartments (upstream resistance:Rup) by the occlusion technique in the preoperative assessment of PEA. We discuss the advantages and disadvantages of Rup and compare it with other hemodynamic predictor to evaluate operative risk in CTEPH patients.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension:State of the art

Chronic thromboembolic pulmonary hypertension(CTEPH)is a complex chronic disease in which pulmonary artery stenosis or obstruction caused by organized thrombus can lead to increased pulmonary artery pressure and pulmonary vascular resistance,ultimately triggering progressive right heart failure and death.Currently,its exact mechanism is not fully understood.Pulmonary endarterectomy(PEA)has immediate effects with low perioperative mortality and satisfactory prognosis in experienced expert centers for CTEPH patients with proximal lesions.Nevertheless,37%of patients are deemed unsuitable for PEA surgery due to comorbidities and other factors,and nearly half of the operated patients have residual or recurrent pulmonary hypertension.Riociguat is the only approved drug for CTEPH,although its effect is limited.Balloon pulmonary angioplasty(BPA)is a promising alternative treatment for patients with CTEPH.After more than 30 years of development and refinements,emerging evidence has confirmed its role in patients with inoperable CTEPH or residual/recurrent pulmonary hypertension,with acceptable complications and comparable longterm prognosis to PEA.This review summarizes the pathophysiology of CTEPH,BPA history and development,therapeutic principles,indications and contraindications,interventional procedures,imaging modalities,efficacy and prognosis,complications and management,bridging and hybrid therapies,ongoing clinical trials and future prospects.