Journal of Thrombosis and Thrombolysis

A left main coronary artery thrombosis is a life-threatening condition demanding immediate therapeutic management. Traditional treatment options include thrombolysis, percutaneous coronary intervention (PCI) with stenting or cardiac bypass surgery. The number of reported cases in which aspiration thrombectomy has been used is limited. Indications for this therapeutic approach are determined by coronary anatomy, clinical stability, and hemodynamic condition of the patient. We present the case of an acute left main coronary artery thrombosis leading to progressive deterioration of left ventricle function that was successfully treated with aspiration thrombectomy.

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84–1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77–2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77–1.27) and 1.23 (0.74–2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.

As patients with COVID-19 pneumonia admitted to intensive care unit (ICU) have high rates of thrombosis, high doses of thromboprophylaxis have been proposed. The associated bleeding risk remains unknown. We investigated major bleeding complications in ICU COVID-19 patients and we examined their relationship with inflammation and thromboprophylaxis. Retrospective monocentric study of consecutive adult patients admitted in ICU for COVID-19 pneumonia requiring mechanical ventilation. Data collected included demographics, anticoagulation status, coagulation tests and outcomes including major bleeding and thrombotic events. Among 56 ICU COVID-19 patients, 10 (18%) patients had major bleeding and 16 (29%) thrombotic events. Major bleeding occurred later than thrombosis after ICU admission [17(14–23) days versus 9(3–11) days respectively (p = 0.005)]. Fibrinogen concentration always decreased several days [4(3–5) days] before bleeding; D-dimers followed the same trend. All bleeding patients were treated with anticoagulants and anticoagulation was overdosed for 6 (60%) patients on the day of bleeding or the day before. In the whole cohort, overdose was measured in 22 and 78% of patients receiving therapeutic anticoagulation during fibrinogen increase and decrease respectively (p < 0.05). Coagulation disorders had biphasic evolution during COVID-19: first thrombotic events during initial hyperinflammation, then bleeding events once inflammation reduced, as confirmed by fibrinogen and d-dimers decrease. Most bleeding events complicated heparin overdose, promoted by inflammation decrease, suggesting to carefully monitor heparin during COVID-19. Thromboprophylaxis may be adapted to this biphasic evolution, with initial high doses reduced to standard doses once the high thrombotic risk period ends and fibrinogen decreases, to prevent bleeding events.

Stents are intravascular prostheses which provide endoluminal scaffolding, effectively reducing elastic recoil and sealing local dissections. Stents have become the treatment of choice for acute vessel closure following percutaneous coronary intervention. In addition, by providing a large, smooth lumen, stenting increases procedural success and decreases late restenosis compared with conventional balloon angioplasty. All stents evaluated clinically are constructed of non-corrosive metallic alloys which are inherently thrombogenic. The incidence of stent thrombosis ranges from 0.4-18%. While acute thrombosis is uncommon, subacute thrombosis may occur from 5 to 21 days (mean 7 days) after placement. Predictors of stent thrombosis include stenting for bailout indication, angiographically visible thrombus after implantation, stenting of smaller vessels, presence of residual dissection after stenting, poor distal runoff, incomplete stent expansion and stenting in the setting of acute myocardial infarction. Stent thrombosis is associated with high incidence of Q-wave myocardial infarction (70–90%) and mortality (7–20%), and is best treated with emergency catheterization and balloon angioplasty. To prevent stent thrombosis, aggressive procedural and postprocedural pharmacological regimens employing antiplatelet agents (aspirin, dipyridamole and dextran) and anticoagulation (heparin followed by warfarin) have been used. While these regimens have reduced the incidence of stent thrombosis to <5%, they are associated with a high incidence of vascular and hemorrhagic complications, increased length of hospitalization and total cost. To decrease the incidence of stent thrombosis and obviate the need for anticoagulation, strategies such as intravascular ultrasound guided “optimal stenting” and addition of the antiplatelet agent ticlopidine, are being evaluated. In the future coating of stents with agents such as heparin, may further reduce the risk of thrombosis and the requirement for long-term anticoagulation.

While the risk for arterial vascular disease has been shown to be influenced by socioeconomic status (SES), there is limited information whether SES also influences the risk for venous thromboembolism (VTE). To evaluate whether there is an association between SES and VTE incidence. In 1990, all 730,050 inhabitants (379,465 women and 350,585 men) above 25 years of age in the County of Skåne in Sweden were evaluated with regard to age, household income, marital status, country of birth, number of years of residence in Sweden, educational level, and concomitant diseases. The cohort was hereafter prospectively investigated regarding diagnosis of, or death from VTE (deep venous thrombosis or pulmonary embolism ), during 1991–2003. The association between socioeconomic data and concomitant diseases at the baseline investigation 1990 and incidence of VTE during follow-up was examined by Cox proportional hazard models. During the 13 years prospective follow-up, 10,212 women and 7,922 men were diagnosed with VTE. In both genders, age above 40 years at baseline, low income, single status, and a lower level of education were associated with an increased risk of VTE. However, both men and women born outside of Sweden have a lower risk for VTE during follow-up, however. Age above 40 years, low income, single marital status, and lower level of education were independently related to an increased risk of VTE diagnosis during 13 years of prospective follow-up.

A dose of 0.9 mg/kg of intravenous tissue plasminogen activator (t-PA) has proven to be beneficial in the treatment of acute ischemic stroke (AIS). Dosing of t-PA based on estimated patient weight (PW) increases the likelihood of errors. Our objectives were to evaluate the accuracy of estimated PW and assess the effectiveness and safety of the actual applied dose (AAD) of t-PA. We performed a prospective single-center study of AIS patients treated with t-PA from May 2010 to December 2011. Dose was calculated according to estimated PW. Patients were weighed during the 24 h following treatment with t-PA. Estimation errors and AAD were calculated. Actual PW was measured in 97 of the 108 included patients. PW estimation errors were recorded in 22.7 % and were more frequent when weight was estimated by stroke unit staff (44 %). Only 11 % of patients misreported their own weight. Mean AAD was significantly higher in patients who had intracerebral hemorrhage (ICH) after t-PA than in patients who did not (0.96 vs. 0.92 mg/kg; p = 0.02). Multivariate analysis showed an increased risk of ICH for each 10 % increase in t-PA dose above the optimal dose of 0.90 mg/kg (OR 3.10; 95 % CI 1.14–8.39; p = 0.026). No effects of t-PA misdosing were observed on symptomatic ICH, functional outcome or mortality. Estimated PW is frequently inaccurate and leads to t-PA dosing errors. Increasing doses of t-PA above 0.90 mg/kg may increase the risk of ICH. Standardized weighing methods before t-PA is administered should be considered.

Data comparing the patient characteristics, management and outcomes for dabigatran versus warfarin major bleeding in the practice setting are limited. We performed a retrospective single health system study of atrial fibrillation patients with dabigatran or warfarin major bleeding from October 2010 through September 2012. Patient identification occurred through both an internal adverse event reporting system and a structured stepwise data filtering approach using the International Classification of Diseases diagnosis codes. Thirty-five dabigatran major bleeding patients were identified and compared to 70 warfarin major bleeding patients. Intracranial bleed occurred in 4.3 % of warfarin patients and 8.6 % of dabigatran patients. Dabigatran patients tended to be older (79.9 vs. 76 years) and were more likely to have a creatinine clearance of 15–30 mL/min (40 vs. 18.6 %, p = 0.02). Over one-third of dabigatran patients had an excessive dose based on renal function. More dabigatran patients required a procedure for bleed management (37.1 vs. 17.1 %, p = 0.03) and received a hemostatic agent for reversal (11.4 vs. 1.4 %, p = 0.04). Dabigatran patients were twice as likely to spend time in an ICU (45.7 vs. 27.1 %, p = 0.06), be placed in hospice/comfort care (14.3 vs. 7.1 %, p = 0.24), expire during hospitalization (14.3 vs. 7.1 %, p = 0.24), and expire within 30-days (22.9 vs. 11.4 %, p = 0.28). In a single hospital center practice setting, as compared to warfarin, patients with dabigatran major bleeding were more likely to be older, have renal impairment, require a procedure for bleed management and receive a hemostatic agent. Patients with dabigatran major bleeding had an excessive dose for renal function in more than one-third of cases.

In recent years a variety of metals (cadmium, chromium, copper, iron) have been demonstrated to modulate coagulation in vitro and in vivo. One group of metals, the platinoids, have not been assessed, and such investigation is justified given the thromboembolic phenomena associated with platinum-based chemotherapy. Thus, the goal of the present investigation was to assess the effects of carboplatin, cisplatin (platinum compounds), NAMI-A, and ruthenium chloride (ruthenium compounds) on human plasmatic coagulation. Human plasma was exposed to clinically relevant, equimolar concentrations of the aforementioned platinum and ruthenium compounds, with changes in plasmatic coagulation assessed via thrombelastography. The first series of experiments demonstrated no significant modulation of coagulation by the platinum compounds, while NAMI-A demonstrated mild hypercoagulability and ruthenium chloride exerted marked hypercoagulability. A second series of experiments utilizing a variety of specialized modifications of thrombelastography focused on ruthenium chloride revealed that this compound enhances prothrombin activation. While the hypercoagulability associated with platinum compounds in vivo do not appear to have a basis in plasmatic biochemistry, it appears that ruthenium compounds can exert procoagulant properties by enhancing the common pathway of human plasmatic coagulation. Future investigation of Ru based chemotherapeutic agents in development to assess procoagulant activity as part of evaluating their potential clinical safety is warranted.