Safety and outcomes of thrombolytic therapy in patients with pulmonary embolism and thrombocytopenia: A systematic review

Thrombolysis is an established therapeutic modality for patients with high-risk (and some selected intermediate-risk) pulmonary embolism (PE) with hemodynamic instability. Physicians sometimes experience cases where both a high-risk PE and thrombocytopenia coexist. Although thrombocytopenia of < 100 × 103/mm3 is considered a contraindication in patients with ischemic stroke, the safety and outcomes of thrombolysis in patients with acute PE and thrombocytopenia are unknown. This systemic review aimed to pool data on the safety and outcomes of thrombolysis use in patients with PE and platelet count less than 150 × 103/mm3. Patients’ demographics, clinical characteristics, management, type of thrombolytic therapy, and outcomes were extracted and analyzed. Of 283 articles identified through the systematic search, 11 case reports fulfilled the inclusion criteria. The mean age of the patients was 52.27 years, and 54.5% were women. The median platelet level before thrombolysis was 65.50 × 103/mm3. Before thrombolysis was initiated, the lowest and highest platelet levels were 29 × 103/mm3 and 105 × 103/mm3, respectively. Alteplase was used in 10 patients and urokinase in one patient. One patient who had a massive PE died of aspiration pneumonia. Interestingly, no thrombocytopenia-related complications were reported. This systematic review highlights the potential benefits and safety of thrombolysis in patients with acute PE in the context of thrombocytopenia. Nevertheless, data available in the literature concerning this topic are scarce and limited to case reports. More extensive studies on the use of thrombolysis in patients with PE and thrombocytopenia are desperately needed. Systematic review registration: The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42021286415.


INTRODUCTION
Venous thromboembolism (VTE) remains a major contributor to worldwide mortality with a rising incidence. The current incidence of VTE is 1-2 cases/1000 persons per year in Europe and the USA. 1 Pulmonary embolism (PE) is a severe emergency subset of VTE that warrants urgent diagnosis and management. The primary mechanism by which an acute PE can cause mortality lies in pulmonary vascular obstruction and constriction, which leads to right ventricular dysfunction. This may manifest as fatal arrhythmias and obstructive shock. 1 Extensive research has been conducted on the management of acute PE. Established treatment modalities are anticoagulation (AC), thrombolysis, and surgical or percutaneous thrombectomy. Whether AC alone or AC with reperfusion therapy would suffice mainly depends on the risk stratification of the PE. [2][3][4] Recent PE clinical guidelines stratify the risks and severity of acute PE based on its clinical presentation and hemodynamic effects. High-risk PE is defined by the presence of hemodynamic instability that includes one of the following clinical presentations: cardiac arrest, obstructive shock (systolic blood pressure ,90 mmHg despite an adequate filling status, in combination with end-organ hypoperfusion), or persistent hypotension (systolic blood pressure $40 mmHg for .15 min, not caused by new-onset arrhythmia, hypovolemia, or sepsis). Intermediate-risk PE is defined by the presence of right ventricular dysfunction (on echocardiography/radiologic imaging) and elevated cardiac biomarker levels in the circulation (particularly a positive cardiac troponin test). Low-risk PE is defined by the absence of highor intermediate-risk features. 3 Furthermore, the treatment modality depends on the expertise of the physician and treating center, patient presentation, and PE severity. Patients with hemodynamic instability secondary to PE usually require aggressive management with urgent thrombolysis with or without surgical management. A recent Cochrane review (which comprised randomized controlled trials comparing thrombolysis with AC versus AC alone or surgical removal) revealed that thrombolysis reduced the mortality in such patients compared with heparin alone (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37-0.87). 5 Although still controversial, thrombolysis has shown mortality benefits in patients with intermediate-risk PE (without hypotension or shock but with right ventricular dysfunction). [6][7][8] The primary concern when using thrombolytic therapy in intermediate-and high-risk PE is the risk of significant bleeding. Thrombolysis is increasingly being used because of its well-established efficacy in mortality reduction regarding intermediate-high to high-risk PE and easy availability of thrombolysis compared with other aggressive measures such as surgical removal or percutaneous thrombectomy. Methods used to perform thrombolysis in patients with PE include systemic thrombolysis, catheter-guided thrombolysis, and ultrasound-accelerated catheter-thrombolysis. 9, 10 Drugs approved for thrombolysis in patients with PE include streptokinase, urokinase, tenecteplase, reteplase, and alteplase. 10 Among these, streptokinase and urokinase require loading doses, whereas others are given as boluses. Additionally, doses of alteplase lower than the recommended have been used successfully. 11 Although thrombocytopenia of ,100 £ 10 3 /mm 3 is generally considered a contraindication in patients with ischemic stroke, some evidence suggests the safe use of thrombolysis with lower platelet levels in acute ischemic stroke. 12 Furthermore, physicians sometimes experience cases where a high-risk PE and thrombocytopenia coexist, and surgical or catheter-induced thrombolysis is not feasible in their facility. To the best of our knowledge, the safety and outcomes of thrombolysis in the setting of acute PE and thrombocytopenia have not been addressed in a previous systematic review. In this review, we searched and pooled data from the available articles describing the use of thrombolysis in patients with PE who had thrombocytopenia, focusing on patients' demographics, methods of thrombolysis used, complications, and outcomes.

Literature search
We searched systematically the databases of (from any date up to 20 October 2021) PubMed, Scopus, and Google Scholar for any English language articles

Study selection and inclusion criteria
All article types, including case reports, case series, retrospective studies, prospective studies, and randomized studies addressing our research question, were considered eligible for inclusion. Endnote was used for the screening process of the articles that were found relevant to the topic. Two reviewers independently reviewed the extracted studies by title, abstract, and keywords. This was followed by a detailed full-length screening of the included studies.
A third reviewer conducted an independent review of the disputed articles to reach an agreement. Figure 1 shows the PRISMA flow diagram that maps out the number of identified, included, and excluded records.

Exclusion criteria
Articles published in languages other than English, articles on PE without radiologic confirmation, and articles on PE without laboratory confirmation of thrombocytopenia (platelets , 150 £ 10 3 /mm 3 ) were excluded.

Bias assessment
Joanna Briggs Institute case report appraisal checklist for inclusion in systematic reviews was utilized to assess the quality of case reports and series. 13

Data collection and statistical analysis
Data on sociodemographic variables, clinical and radiological data, and provoking factors of PE were collected. We also recorded the values of platelets in these patients and thrombolysis outcomes. Data were captured and analyzed in Microsoft Excel 2020. Descriptive and summary statistics were used to describe the study cohort's sociodemographic parameters. Platelet levels were collected at three-time points: admission, lowest level during the hospital stay, and last platelet level before thrombolysis ensued. Continuous variables (means^standard deviation or median with interquartile range) and categorical variables (presented as numbers with percentages) were reported as appropriate.

RESULTS
Only 11 articles (all were case reports) that met the inclusion criteria of thrombolysis use in the context of PE and thrombocytopenia were found. One abstract that reported 17 patients with upper and lower limb deep vein thrombosis (DVT) and thrombocytopenia who underwent catheter-directed thrombolysis without thrombolysis-related complications was excluded because it did not include patients with PE and the required details about the cases. 14  hemodynamic instability with features of obstructive shock (n ¼ 1, 9.1%) were less common. Only one patient with massive PE died from aspiration pneumonia. No thrombocytopenia-related mortality was reported.
Other less common provoking factors were also reported ( Table 2).

Comorbidities
Of all 11 cases, chronic lung disease and hypertension were reported in 2 (18.2%) and 1 (9.1%) cases, respectively. A previous history of PE was reported in only 1 (9.1%) patient. A history of cardiovascular disease (including coronary artery disease and heart failure) was found in 2 (18.2%) patients. A patent foramen ovale was found in 1 (9.1%) case, and atrial fibrillation was reported in 1 (9.1%) patient.

Management
All 11 patients received thrombolysis, whereas 10 (90.9) were reported to have also received AC. The most commonly used AC method was heparin initially, followed by warfarin in 2 (18.2%) patients or heparin only in 2 (18.2%). Other patients reported the use of argatroban (n ¼ 1, 9.1%), bivalirudin, and fondaparinux (n ¼ 1, 9.1%), initial heparin then switched to argatroban (n ¼ 1, 9.1%), or phenprocoumon (n ¼ 1, 9.1%) due to HIT. The reason for the initiation of thrombolysis despite thrombocytopenia was not reported in the majority of the cases. A clear reason was reported in only two cases. The first patient was a 65-year-old woman with metastatic breast cancer who had thrombocytopenia due to chemotherapy (60 £ 10 3 /mm 3 ). She was planned for catheterguided or surgical embolectomy; however, due to the nonavailability of the former, thrombolysis was decided. 24 The second patient was a 60-year-old man with pancreatic cancer. He developed thrombocytopenia due to HIT (77 £ 10 3 /mm 3 ). He was deemed unfit for surgery because of his advanced cancer stage; thus, thrombolysis was performed. 25 Overall, the most common thrombolysis method was systemic (n ¼ 7, 63.6%), whereas catheter-guided thrombolysis was used in 4 (36.4%) patients. The most common thrombolytic agents used were alteplase in 10 (90.9%) patients and urokinase in 1 (9.1%). One patient (9.1%) reported administration of thrombolysis as a bolus, whereas others reported infusion ranging from 2 hours (n ¼ 2, 18.2%), 12 hours (n ¼ 1, 9.1%), 24 hours (n ¼ 3, 27.3%), or .48 hours (n ¼ 2, 18.2%). None of the included articles reported platelet transfusion to optimize platelet count before thrombolysis.

Outcome and Complications
Among the 11 included cases, 1 (9.1%) reported death as the final outcome. This patient had a massive PE and received alteplase. The cause of death was reported as aspiration pneumonia, which complicated his course of hospitalization. Nevertheless, the authors reported an initial improvement in the patient's condition after alteplase initiation. 25

DISCUSSION
Although bleeding diathesis and active bleeding are absolute contraindications for thrombolysis, there is no agreement on the level of platelet count to consider an absolute contraindication. 3 There are many situations in which thrombocytopenia and PE can coexist in clinical practice. Examples of such situations are patients with malignancies, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation, autoimmune and connective tissue disorders. Cancer is a significant risk factor for PE and can cause thrombocytopenia because of the associated bone marrow suppression and adverse effects of chemotherapy. 27 In the present review, 3 (27.2%) patients had malignancies. 17,24,25 The first patient was a women with breast cancer. 24 Her thrombocytopenia (60 £ 10 3 /mm 3 ) was attributed to chemotherapy. She received thrombolysis as PE treatment following deterioration of her condition. She received alteplase (100 mg over 2 hours) with half-dose heparin and recovered successfully without treatment complications. The second patient, a man with metastatic pancreatic cancer, developed HIT when he was diagnosed and managed for a PE. His platelet level dropped from 150 £ 10 3 /mm 3 to 77 £ 10 3 /mm 3 . However, due to worsening PE, he was re-perfused via thrombolysis (was also considered unfit for surgery because of advanced malignancy). He received alteplase at 0.5 mg/h for 20 hours. Although the patient's symptoms improved and oxygen demands decreased post thrombolysis, he ultimately died of aspiration pneumonia on day 6. 25 The third patient had gastric carcinoma complicated by PE and HIT (platelet level, 65 £ 10 3 /mm 3 ). He received 30 mg of alteplase as reperfusion therapy. The reason for thrombolysis, despite thrombocytopenia, was not mentioned in this case. 17 Other than solid malignancies, patients with hematologic cancers are also at dual risk of thrombocytopenia (bone marrow involvement and cytotoxic effects of therapy) and thrombosis (due to cancer itself, endothelial damage secondary to chemotherapy, and asparaginase induced pro-thrombotic state). 28 Very few studies have evaluated the effects of AC or thrombolysis in such patients. In one study, of 82 patients with malignancy and VTE who had anticoagulation, 31 (37.8%) developed bleeding. Nevertheless, significant bleeding was observed in 10.9%. 29 Experts recommend full-dose AC in these patients when platelet levels are more than 50 £ 10 3 /mm 3 and reduced dose AC when less than 50 £ 10 3 /mm 3 . AC is not an absolute contraindication in either case, and thrombocytopenia should be managed concomitantly if needed. 30 Thrombocytopenia in the setting of an otherwise pro-thrombotic state may not be a significant bleeding diathesis, as it would be in the absence of a pro-thrombotic state such as malignancy. In the CLOT trial (676 patients with cancer and VTE who received either dalteparin or oral AC), 31 (4.5%) patients had a major bleeding event. Of these 31 patients, only two had thrombocytopenia. 31 In the present review, we could also find situations (other than malignancy) in which patients had PE along with thrombocytopenia and an immediate thrombectomy was not feasible, or the patient was not suitable for surgical management. In these cases, authors used thrombolysis as a last resort in patients with hemodynamically deteriorating condition and massive PE. Zhu 33 The increasing prevalence of HIT during the pandemic caused by increased heparin use as a VTE prophylaxis is also an issue. 32 AC appears to be nonprotective in preventing VTE in these patients. 33 Apart from COVID-19, all the mainstream mRNA vaccines against the virus (including mRNA-1273, BNT162b2, and AZD1222 COVID-19 vaccines) have been reported to cause thrombosis at one end and thrombocytopenia at the other (called vaccine-induced immune thrombotic thrombocytopenia). 34,35 Given that the pandemic continues and mass vaccinations have been used, a considerable population is currently at risk of thrombosis and thrombocytopenia. 36 Studying the safety of thrombolysis in such a population is interesting in formulating guidelines for this patient group.
The main strength of our review lies in its novelty and a detailed literature search (involving three databases that were searched systematically) to find cases in which thrombolysis was used in patients with PE who had thrombocytopenia. Our review has some limitations inherent for systematic reviews of rare conditions. First, all the included studies are case reports. Despite the extensive search, we could not find any higher level of evidence, resulting in a small sample size. However, we did not conduct any correlation statistics to maintain data accuracy. Second, publication bias is possible, as we could only add published cases. Third, we acknowledge that case reports based on adverse effects of treatment may focus only on significant side effects and ignore minor events. In view of this, the results of this review should be taken with caution until a higher level of evidence is generated.

CONCLUSION
This systematic review highlights the potential benefits and safety of thrombolysis use in patients with acute PE in the context of thrombocytopenia, as both the initial treatment and last resort when other treatment options are not feasible. Nevertheless, data available in the literature concerning this topic are scarce and limited to case reports. More extensive studies on patients with PE and thrombocytopenia are urgently required to refine guidelines concerning thrombolysis as a preferred treatment or as a secondline option.

DECLARATIONS Ethics approval and consent to participate
Private information from individuals will not be published. This systematic review does not involve endangering participant rights. Ethical approval is not required for this systematic review as only a secondary analysis of data already available in the electronic databases was conducted.