Researchers at the University Heart Center Freiburg-Bad Krozingen in Germany combed through fifteen years of hospital records, from January 2008 to December 2022, screening nearly twenty thousand patients admitted with acute myocardial infarction. Out of 19,964 patients, they confirmed left ventricular thrombus in 166 individuals, a hospital-based detection rate of just 0.83 percent. That figure is strikingly lower than the 5 to 12 percent incidence reported in older literature, and the authors attribute much of the decline to the modern era of rapid coronary reperfusion. In their center, patients were whisked to coronary angiography on the day of admission, with a median delay of zero days, restoring blood flow to starving heart muscle before extensive tissue death could create the stagnant, aneurysmal conditions in which clots flourish. The message is clear: the faster the artery is opened, the less likely the ventricle is to harbor a thrombus.

The typical patient profile in the study will be familiar to any cardiologist. Of the 160 patients included in the final analysis, 78 percent were men, the median age was 64 years, and 74 percent had presented with an ST-segment elevation myocardial infarction, the most severe form of heart attack. Two-thirds had anterior infarctions, the variety most notorious for damaging the heart’s apex and creating the wall-motion abnormalities that promote clot formation. Echocardiography revealed that the median left ventricular ejection fraction at diagnosis was a markedly reduced 35 percent, and 89 percent of the thrombi were located at the apex, the anatomical dead zone where blood tends to pool when the muscle beneath it stops contracting. Most clots were described as organized rather than fresh, with a median diameter of 20 millimeters, and nearly nine in ten patients had a single thrombus rather than multiple deposits.

Diagnosing these clots remains a technical challenge. Transthoracic echocardiography is the workhorse screening tool, but the cardiac apex can be notoriously difficult to visualize, and guidelines increasingly recommend contrast agents to sharpen the image. Cardiac magnetic resonance imaging with gadolinium remains the gold standard, boasting sensitivity up to 88 percent and perfect specificity. In this cohort, contrast-enhanced echocardiography was used in only 7 percent of cases, something the authors acknowledge may have limited detection, particularly since much of the study period predates the latest guideline recommendations. The researchers suggest that clinicians should aim not merely to detect a thrombus but to measure it precisely, because their regression analysis revealed that initial thrombus size was the only significant predictor of whether the clot would dissolve: each larger clot carried roughly half the odds of complete resolution, with an odds ratio of 0.55.

Treatment of left ventricular thrombus has long rested on oral anticoagulation, with guidelines recommending at least three to six months of therapy followed by repeat imaging to assess regression. For decades, the only option was a vitamin-K antagonist such as warfarin, a drug that is effective but notoriously fickle, demanding regular blood monitoring and interacting with countless medications and foods. The arrival of direct oral anticoagulants, or DOACs, beginning with dabigatran’s European approval in 2008, transformed anticoagulation across many fields of cardiology, but their role in ventricular thrombus remained uncertain because randomized evidence was scarce and trial sizes were small. The Freiburg-Bad Krozingen dataset captures this therapeutic transition in real time, and the prescribing patterns it documents tell a story of rapid cultural change within a single institution.

Between 2008 and 2016, vitamin-K antagonists dominated, accounting for between 73 and 100 percent of prescriptions at discharge. After 2016, the tide turned decisively: DOAC prescriptions climbed to 47 percent between 2017 and 2019 and reached 75 percent between 2020 and 2022, a shift the authors report as statistically significant. In the overall cohort, 85 patients were discharged on a vitamin-K antagonist, 49 on a DOAC, and 26 on other forms of anticoagulation such as heparin. Many patients also continued antiplatelet therapy, with roughly half receiving a single antiplatelet agent, usually clopidogrel, alongside their anticoagulant, and the other half on dual antiplatelet therapy, reflecting the delicate balancing act clinicians face when a patient needs protection against both clot formation in stents and clot dissolution in the ventricle.

The central question, of course, is whether the newer drugs actually work as well as the old ones in this specific setting. Among the 120 patients who returned for follow-up echocardiography within a year, 79 percent showed complete thrombus resolution. In the DOAC group, 87 percent of clots fully dissolved, compared with 79 percent under vitamin-K antagonists, a difference that did not reach statistical significance. Even among patients whose clots persisted, the majority, 70 percent, showed a measurable shrinkage, with a median reduction of nearly 6 millimeters. The analysis of antithrombotic intensity told a similar story: patients on dual antithrombotic therapy and those on triple therapy achieved nearly identical resolution rates, at 81.8 and 82.3 percent respectively. These real-world results align closely with the small randomized trials that have compared rivaroxaban or apixaban against warfarin, which consistently found comparable regression and safety between the drug classes.

Safety data from the first year after diagnosis underscore both the danger of the condition and the rough equivalence of the two strategies. The researchers documented 14 embolic events, 8 bleeding events of at least moderate severity, and 16 deaths among 25 patients who experienced clinical events. Embolic events clustered strikingly early, occurring a median of just 2.5 days after the thrombus was diagnosed, a finding that emphasizes how quickly these clots can declare themselves and how critical early anticoagulation is. Deaths also occurred early, at a median of 6 days after diagnosis, while bleeding events tended to appear later, at a median of 51 days. Comparing the drug classes, patients on vitamin-K antagonists experienced 7 clinical events, including 3 deaths, while DOAC patients experienced 3 events, with no statistically significant difference in survival between the groups. The authors are careful to note that the small event numbers limit the statistical power of these comparisons.

The study’s strengths lie in its scale and its longitudinal sweep. Screening nearly twenty thousand patients over fifteen years dwarfs most previous cohorts, and the availability of digital echocardiographic images and reports allowed independent review by two staff members, with missing measurements completed by a board-certified echocardiographer. Yet the retrospective design imposes real constraints. The specific diagnostic code for thrombus complicating acute myocardial infarction was applied in only a minority of cases, raising the possibility that the true incidence was underestimated due to coding inconsistencies. Clinical outcomes relied on hospital documentation rather than direct patient contact, and follow-up echocardiograms performed at outside centers could have been missed. The differing timing of follow-up examinations between groups, with DOAC patients re-examined after a median of 103 days versus 65 days for vitamin-K antagonist patients, may also have influenced the observed resolution rates.

For clinicians, the practical takeaways are nonetheless concrete. Left ventricular thrombus remains a serious complication of myocardial infarction even as its incidence falls, and the embolic events observed within days of diagnosis argue for vigilant early imaging in high-risk patients, particularly those with anterior infarcts and severely reduced ejection fractions. The data support the growing use of direct oral anticoagulants as a reasonable alternative to vitamin-K antagonists, offering comparable thrombus resolution and event rates without the burden of monitoring. The authors call for larger randomized controlled trials to confirm these findings definitively, and for standardized follow-up protocols so that patients with these hidden clots are tracked consistently. In the meantime, the study adds a substantial piece of real-world evidence to a field long starved of it, suggesting that the newer blood thinners have earned their place at the bedside of heart attack survivors facing this rare but formidable complication.

Subject of Research: Left ventricular thrombus after myocardial infarction: incidence, echocardiographic features, and anticoagulation outcomes

Article Title: Echocardiographic features, antithrombotic therapy, and association with outcomes in patients with left ventricular thrombus after myocardial infarction: a single-center retrospective study

Article References: Maslarska-Martens, M., Blank, C., Li, T., Wessinger, M., Hesselbarth, D., Gjermeni, D., Franke, K., Valina, C., Jander, N., Grundmann, S., Wolf, D., Westermann, D., & Olivier, C. B. (2026). Echocardiographic features, antithrombotic therapy, and association with outcomes in patients with left ventricular thrombus after myocardial infarction: a single-center retrospective study. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03020-3

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03020-3

Keywords: left ventricular thrombus, myocardial infarction, anticoagulation, direct oral anticoagulants, vitamin K antagonists, echocardiography, thrombus resolution, STEMI, embolism, cardiology, retrospective cohort study, bleeding events

The study, led by Ju Hee Kim and Jungbin Song with colleagues at CHA University, Kyung Hee University, and Korea University Guro Hospital, examined three herbal formulations: Bojungikgitang, Ijintang, and Cheongsanggyeontongtang. All three have long histories of symptomatic use in East Asian traditional medicine for cardiovascular and cerebrovascular conditions—precisely the patient populations most likely to be taking anticoagulants. The research team designed a fixed-sequence, two-period clinical trial in which healthy volunteers received a single 60-milligram dose of edoxaban alone, and then received the same dose after repeated dosing with one of the three herbal formulations. The design allowed each participant to serve in part as their own control, isolating the effect of the herbal co-administration from natural interindividual variability in drug handling.

Edoxaban is a direct factor Xa inhibitor, a member of the direct oral anticoagulant family that has largely displaced warfarin in many markets because it requires no routine monitoring and has fewer dietary interactions. Its disposition in the body, however, depends heavily on the efflux transporter P-glycoprotein and, to a lesser extent, on cytochrome P450 3A4 (CYP3A4) metabolism, which produces an active metabolite known as M4. This pharmacological profile makes edoxaban particularly vulnerable to interactions with drugs—and potentially herbal phytochemicals—that inhibit or induce P-glycoprotein or CYP3A4. Strong P-glycoprotein inhibitors such as quinidine and cyclosporine are already known to raise edoxaban levels, while inducers such as rifampin can slash them, and the edoxaban label reflects those established interactions.

To measure what the herbal formulations did to edoxaban, the researchers quantified plasma concentrations of both the parent drug and its active M4 metabolite using liquid chromatography coupled with tandem mass spectrometry, a gold-standard bioanalytical technique aligned with international ICH M10 validation guidance. Pharmacokinetic parameters—the area under the concentration-time curve, peak concentrations, and clearance measures—were compared between treatment periods using linear mixed-effects models, a statistical framework well suited to repeated-measures crossover designs. In parallel, the team assessed pharmacodynamic effects using prothrombin time and activated partial thromboplastin time, the two coagulation assays most commonly used to gauge anticoagulant intensity at the bedside. Finally, in laboratory experiments, the formulations were tested for their capacity to inhibit CYP3A4 activity in vitro.

The pharmacokinetic results were striking in their divergence. Bojungikgitang approximately doubled systemic exposure to edoxaban, effectively reproducing the magnitude of interaction seen with known strong P-glycoprotein inhibitors. At the other extreme, Cheongsanggyeontongtang reduced edoxaban exposure by roughly 40 percent—a reduction in the range that regulators associate with inducers of the drug’s clearance pathways and one that could, in theory, erode the anticoagulant’s protective effect against stroke. Ijintang, by contrast, exerted only minimal effects on the drug’s pharmacokinetic profile. The active metabolite M4 followed the same directional pattern as the parent compound in each case, indicating that the herbal formulations were shifting edoxaban’s overall systemic disposition rather than selectively rerouting its metabolism.

Perhaps the most provocative—and most cautionary—finding came from the pharmacodynamic measurements. Despite the substantial pharmacokinetic shifts, the researchers detected no significant changes in prothrombin time or activated partial thromboplastin time in any of the herbal co-administration groups. In other words, a patient’s exposure to edoxaban could double, or fall by 40 percent, while the standard laboratory coagulation tests remained essentially silent. This dissociation matters because clinicians sometimes lean on coagulation assays when concerns arise about anticoagulant intensity, and the results suggest those assays are poor sentinels for herb-driven changes in edoxaban levels. The therapeutic window of a drug, not the laboratory value alone, ultimately determines whether exposure changes translate into bleeding or thrombotic risk.

The mechanistic work offered clues about how the divergent effects arise. In vitro testing showed negligible inhibition of CYP3A4 by Bojungikgitang and Ijintang and only weak inhibition by Cheongsanggyeontongtang, indicating that direct CYP3A4 blockade is unlikely to explain the doubling of edoxaban exposure seen with Bojungikgitang. The more plausible culprit is interference with P-glycoprotein, the efflux pump that governs edoxaban’s intestinal absorption and biliary excretion. Many phytochemicals common in traditional formulas—including compounds found in ginseng, licorice, and astragalus, herbs represented in some of these formulations—have been shown in laboratory studies to modulate P-glycoprotein and CYP enzymes. The precise constituent responsible for the Bojungikgitang effect, however, remains to be pinned down, and the authors’ data do not permit attribution to a single botanical ingredient.

The clinical context amplifies the significance of the findings. Surveys of Korean medical hospital practice have documented frequent combination therapy between herbal extracts and antiplatelet or anticoagulant drugs in ischemic stroke patients, and Korean medicine clinical practice guidelines for stroke, developed under the National Institute for Korean Medicine Development, formalize herbal care pathways for the same patients who often need anticoagulation. Case reports from around the world have described increased bleeding in patients combining oral anticoagulants with herbal products ranging from saffron to Salvia miltiorrhiza, and St John’s wort has been shown to lower rivaroxaban exposure in controlled human studies. Meanwhile, cohort data have suggested that some concurrent Chinese herbal medicine use may even be associated with fewer major bleeding events, underscoring that the herb-drug interaction landscape is neither uniformly dangerous nor uniformly benign—it is formulation-specific, and largely unmapped.

That is precisely the gap this trial helps to fill. By testing three named, commercially supplied formulations under controlled conditions in healthy volunteers, and by measuring both drug levels and clotting outcomes with validated methods, the Korean team has converted a vague anxiety—herbs might interact with blood thinners—into concrete, quantifiable risk statements: Bojungikgitang approximately doubles edoxaban exposure, Cheongsanggyeontongtang cuts it by about 40 percent, Ijintang is relatively benign, and conventional coagulation tests will not warn you about any of it. The authors conclude that clinical consideration is warranted when edoxaban is combined with Bojungikgitang or Cheongsanggyeontongtang, and the magnitude of the observed changes supports that caution, situating both interactions on par with labeled drug-drug interactions of edoxaban.

Important caveats temper the translation to patient care. The study enrolled healthy volunteers, not the older, multimorbid patients with atrial fibrillation or venous thromboembolism who actually take edoxaban, and it could not assess hard clinical endpoints such as bleeding or stroke. Fixed-sequence designs and modest sample sizes, typical of exploratory interaction studies, also limit generalizability, and the duration of herbal pre-dosing may not capture longer-term induction or adaptation effects. Even so, the work delivers a clear, actionable message for prescribers, pharmacists, and practitioners of traditional medicine alike: herbal formulations are not pharmacologically inert companions to modern anticoagulants. Until larger outcome studies are done, patients taking edoxaban who also use Bojungikgitang or Cheongsanggyeontongtang deserve explicit attention, honest conversations about herbal supplement use, and a healthy skepticism toward coagulation tests that may not reveal what the body is actually doing.

Subject of Research: Herb-drug interactions between traditional Korean herbal formulations and the anticoagulant edoxaban

Article Title: Effects of Bojungikgitang, Ijintang, and Cheongsanggyeontongtang on the pharmacokinetics and pharmacodynamics of edoxaban

Article References: Kim, J. H., Song, J., Kim, M., Kim, H., Cho, H.-Y., & Chung, H. (2026). Effects of Bojungikgitang, Ijintang, and Cheongsanggyeontongtang on the pharmacokinetics and pharmacodynamics of edoxaban. Journal of Pharmaceutical Investigation. https://doi.org/10.1007/s40005-026-00828-z

Image Credits: AI Generated

DOI: 10.1007/s40005-026-00828-z

Keywords: edoxaban, herb-drug interaction, Bojungikgitang, Ijintang, Cheongsanggyeontongtang, pharmacokinetics, pharmacodynamics, direct oral anticoagulants, P-glycoprotein, CYP3A4, traditional Korean medicine, clinical trial

The epidemiological data assembled in the review are striking. Active cancer is present in roughly 5 to 10 percent of patients presenting with ischemic stroke, a proportion that rises among those with embolic stroke of undetermined source, the cryptogenic category in which no conventional mechanism can be identified. In 3 to 5 percent of such patients, the stroke actually precedes the cancer diagnosis by up to two years, making it the first clinical manifestation of an occult malignancy. Occult cancer is detected in about 5.3 percent of patients with embolic stroke of undetermined source, with the highest detection rate occurring in the early period after the stroke, at 14.3 per 1,000 person-months. Among cancer patients who do stroke, cancer-associated coagulopathy is the most frequent cause, accounting for 39.8 percent of cases, while traditional mechanisms such as large-artery atherosclerosis and cardioembolism from atrial fibrillation are comparatively less common.

Timing emerges as one of the most consistent signatures of the condition. The risk of hypercoagulability-related stroke peaks within the first six months after a cancer diagnosis, and many patients have already reached metastatic disease by the time the stroke occurs. Arterial thromboembolism more broadly shows a characteristic temporal pattern, with incidence peaking in the first year after cancer diagnosis, and stroke represents the majority of these arterial events at 71.6 percent. Although the risk declines after the first year, it remains elevated above that of the general population for as long as a decade. Histologically, adenocarcinoma dominates, with lung and pancreatic cancer most frequently implicated, followed by colorectal, breast and prostate malignancies. The interval between cancer diagnosis and stroke is particularly short in pancreatic and colorectal cancer, underscoring their especially potent thrombotic potential.

The pathophysiology described in the review is a layered interplay of tumor biology and hemostasis. Adenocarcinomas produce mucin, a heavily glycosylated molecule that, although largely cleared by the liver, can engage the adhesion molecules P-selectin and L-selectin to trigger the formation of platelet-rich microthrombi. Tumor cells also overexpress tissue factor, a transmembrane receptor that activates the coagulation cascade through the extrinsic pathway, and this expression is upregulated by oncogenic events such as inactivation of the p53 tumor suppressor and activating mutations in the K-ras oncogene. More recently, alterations in K-ras and the STK11 tumor suppressor gene have been linked to arterial thromboembolism risk, with hazard ratios of 2.22 and 3.48 respectively for stroke among individuals carrying versus lacking these alterations. A recent in vitro study in human pancreatic cancer cell lines further showed that thrombosis induced by tissue factor-expressing microvesicles depends predominantly on coagulation factors VIII and IX, with von Willebrand factor playing a lesser role.

Beyond mucins and tissue factor, the review highlights two additional mechanisms that have reshaped understanding of cancer-driven thrombosis. Circulating extracellular vesicles secreted by tumor cells have been measured by flow cytometry, and levels of cancer cell-derived vesicles are higher in patients with cancer-related stroke than in other groups, correlating with D-dimer levels but not with vesicle-associated tissue factor, which points to prothrombotic pathways beyond the canonical tissue factor route. In vitro experiments also found that vesicles from adenocarcinoma cell lines shorten clotting times more than those from squamous cell carcinoma, consistent with the clinical predominance of adenocarcinoma. Separately, neutrophil extracellular trap formation, or NETosis, has emerged as a key mediator: cancers sensitize peripheral neutrophils toward NET release via granulocyte colony-stimulating factor, and in stroke patients with cancer, NET-specific biomarkers such as plasma DNA, nucleosomes and citrullinated histone H3 are significantly elevated and correlate with D-dimer and thrombin-antithrombin complex levels. A post-mortem histopathological study even demonstrated widespread microvascular thrombosis in the brain, with H3Cit-positive cells embedded in multiple cerebral thrombi.

Clots physically retrieved from patients during thrombectomy provide direct confirmation of this biology. Thrombi from stroke patients with active cancer are platelet-rich and erythrocyte-poor, a composition most pronounced in those with non-bacterial thrombotic endocarditis, and immunohistochemical analysis shows significantly higher content of von Willebrand factor and citrullinated histone H3 in clots from patients with cancer. Proteomic studies have added further markers, identifying elevated levels of proteins associated with active cancer and immune responses, such as IGHG1 and vitronectin, in cancer-related clots. This distinctive composition has a practical radiological consequence: the absence of the susceptibility vessel sign on susceptibility-weighted imaging in patients with large-vessel occlusion is associated with active cancer, with a reported sensitivity of 27 percent and specificity of 85 percent, reflecting the fibrin- and platelet-heavy, red-cell-poor nature of the thrombus.

On brain imaging, the review identifies a pattern that should raise immediate suspicion. The hallmark of cancer-associated coagulopathy stroke is multiple ischemic lesions spanning more than two vascular territories on diffusion-weighted MRI, with microembolic dispersion seen in 78 percent of patients and prior silent infarcts in half. The most specific finding is the so-called three territories sign, defined by simultaneous bilateral lesions in three vascular territories spanning both anterior and posterior circulation. In the absence of infective endocarditis, this sign is highly specific for cancer-related stroke, and among patients with three-territory infarcts and no identifiable embolic source, approximately 75 percent of cases are malignancy-related. The number of affected territories independently predicts occult malignancy in cryptogenic stroke. Cortical and subcortical regions are most frequently affected, followed by the cerebellar hemispheres and corpus callosum, while deep structures and the brainstem are rarely involved.

Biomarker evidence converges on D-dimer as the single most useful test, despite its lack of specificity. Proposed diagnostic thresholds vary, with one study suggesting a cutoff of 5.5 micrograms per milliliter yielding 99.7 percent specificity and 92.9 percent positive predictive value, and a later study proposing 2.785 micrograms per milliliter with 50.9 percent sensitivity and 98.5 percent specificity. The authors caution, however, that different analytical platforms and reporting units, fibrinogen-equivalent versus D-dimer units, preclude a universal cutoff. D-dimer remains the only biomarker consistently associated with recurrent stroke and mortality in this population, and elevated levels after anticoagulant therapy predict early recurrence. Supporting markers include C-reactive protein above 20 milligrams per liter and fibrinogen above 600 milligrams per deciliter, both highly specific for occult malignancy in cryptogenic stroke, along with CA-125, elevated neutrophil-to-lymphocyte ratio above 15, and transcranial Doppler microembolic signals, though the latter show limited specificity. The NORSTROKE score, combining age, D-dimer, hemoglobin and smoking status, offers a probabilistic approach, estimating a 53 percent probability of active cancer in a patient under 75 with cryptogenic stroke, D-dimer above 3 milligrams per liter, hemoglobin below 12 grams per deciliter and a smoking history.

Treatment remains the weakest link in the evidence chain. Low-molecular-weight heparin and direct oral anticoagulants are the most commonly used secondary prevention strategies, with low-molecular-weight heparin generally preferred in gastrointestinal malignancies because of the higher bleeding risk of direct oral anticoagulants in that setting, while vitamin K antagonists are less effective. Comparative studies have shown broadly similar outcomes between agents: enoxaparin versus aspirin, direct oral anticoagulants versus enoxaparin, apixaban versus aspirin in a post hoc analysis of the ARCADIA trial, and oral edoxaban versus subcutaneous enoxaparin all failed to show significant differences in major bleeding, thromboembolism or survival. A recent retrospective study found no mortality or recurrence difference between anticoagulant and antiplatelet therapy, and a 2026 American Heart Association scientific statement concluded there is insufficient evidence to choose between anticoagulation and antiplatelet therapy for this indication. Current guidelines for cancer-associated thrombosis recommend at least three to six months of anticoagulation, extended when cancer remains active.

The prognosis statistics explain why the authors frame this as an urgent, underrecognized problem. Thirty-day mortality ranges from 25 to 50 percent, compared with 14 percent in stroke patients without cancer, and more than half of deaths occur within six months. The median modified Rankin Scale score at discharge is 3, and at three months 75.6 percent of patients remain at least moderately disabled. Recurrence rates reach 13.6 percent, roughly three times that of patients without cancer, with cumulative rates of 7 percent at one month and 16 percent at six months. When stroke is the first manifestation of occult malignancy, median survival is only 58 days, and median survival in cancer patients with cryptogenic stroke ranges from 62 to 365 days, versus 590 days for stroke of other causes. In patients with non-bacterial thrombotic endocarditis, up to 90 percent die or suffer recurrent stroke within six months. The review’s authors acknowledge limitations, including the predominance of retrospective observational data, the absence of prospective protocol registration, marked heterogeneity that prevented meta-analysis, and language restrictions to English and Spanish. They call for prospective multicenter cohorts, standardized D-dimer assays, external validation of the NORSTROKE score and randomized trials comparing low-molecular-weight heparin, direct oral anticoagulants and antiplatelet therapy. As cancer incidence rises and survival improves, they warn, the burden of this devastating stroke subtype will only grow, making earlier recognition and personalized antithrombotic strategies a clinical imperative.

Subject of Research: Ischemic stroke caused by cancer-associated coagulopathy, including its epidemiology, mechanisms, biomarkers, imaging features and treatment

Article Title: Stroke secondary to cancer-associated coagulopathy: a systematic review

Article References: Stroke secondary to cancer-associated coagulopathy: a systematic review. (n.d.). https://doi.org/10.1007/s00415-026-14119-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14119-y

Keywords: stroke, cancer-associated coagulopathy, Trousseau syndrome, adenocarcinoma, D-dimer, hypercoagulability, three territories sign, anticoagulation, low-molecular-weight heparin, direct oral anticoagulants, neutrophil extracellular traps, tissue factor