Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants.

Extracellular vesicles (EV) are blebs of cellular membranes, which entrap small portions of subjacent cytosol. They are released from a variety of cells, circulate in the blood for an unknown length of time and come to rest on endothelial surfaces. They contribute to an array of physiologic pathways, the complexity of which is still being investigated. They contribute to metastatic malignant cell implants and tumor-related angiogenesis, possibly abetted by the tissue factor that they carry. It is thought that the adherence of the EV to endothelium is dependent upon a combination of their P-selectin glycoprotein ligand-1 and exposed phosphatidylserine, the latter of which is normally hidden on the inner bilayer of the intact cellular membrane. This manuscript reviews what is known about EV origins, their clearance from the circulation and how they contribute to malignant cell implants upon endothelium surfaces and subsequent tumor growth.

Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding. METHODS: Patients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0-2.5), B: 2.5 mg fondaparinux daily starting 6-18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications. RESULTS: Three hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year. CONCLUSIONS: Fixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery. TRIAL REGISTRATION: ClinicalTrials.gov identifier # NCT00767559 FDA IND: 103,716.

Failure to lyse venous thrombi because of elevated plasminogen activator Inhibitor 1 (PAI-1) and 4G polymorphism of its promotor genome (The PAI-1/4G Syndrome).

Plasminogen activator Inhibitor 1 (PAI-1) inhibits plasminogen activators leading to decreased fibrinolysis and increased risk of thromboembolic disease (TED). Shifts in PAI-1 promoter genome from normal 5G>5G to 4G>5G or 4G>4G alleles are associated with overexpression of PAI-1. In this study patients with residual venous thrombi were observed to have increased PAI-1 levels and more frequent shifts to 4G alleles. Of the 26, 20 (76.9%) patients with unresolved thrombus had elevated PAI-1 values. 4G genomic shifts were found in 92.9% patients studied. Normal PAI-1 levels were found in 5 patients with 4G polymorphisms. Thus, PAI-1 is often elevated among patients with residual thrombus, with an unexpectedly high prevalence of the 4G polymorphism of the promoter genome. Patients with persistent thrombus should be considered at risk of having constituently increased PAI-1 due to genomic changes in the PAI-1 promoter genome. Hypotheses are proposed to explain those with normal PAI-1, despite having 4G polymorphisms.

Coagulopathy, following medical therapy, for carcinoma of the prostate.

Cancer of the prostate can be associated with coagulopathy characterized as primary fibrinolysis or diffuse intravascular coagulopathy (DIC) with secondary fibrinolysis. These complications are usually associated with surgical manipulation of the prostate or with advanced metastatic disease. This report describes a patient with DIC and fibrinolysis following medical management of advanced prostate cancer with gonadotropin-releasing hormone leuprolide, while receiving the androgen receptor blocking agent flutamide. This report suggests that release of procoagulant material from prostatic carcinoma may be so rapid following hormonal management that consumptive coagulopathy with fibrinolysis can follow. Shortened Abstract: Medical management with gonadotropin releasing hormone allowed the expression of consumptive coagulopathy in patients with metastatic prostate cancer.

Very low dose warfarin as prophylaxis against ultrasound detected deep vein thrombosis following primary hip replacement.

One mg daily warfarin was compared to variable dose warfarin (PT 1.3-1.5 times the normal PT), as prophylaxis against deep vein thrombosis (DVT) following unilateral hip replacement for degenerative joint disease (DJD). Ninety-eight patients entered onto study after having had negative color Doppler ultrasounds of the legs. Patients receiving 1 mg began therapy 7 days preoperatively and continued daily until discharge. Patients receiving the variable dose took 5 mg the night preoperatively, and thereafter daily based upon the daily PT. Seventy-eight patients completed the study protocol. No patient completing the protocol had DVT or pulmonary embolus (PE). Based upon intent to treat for all registered patients, one from each group had DVT after withdrawal from study. For patients receiving 1 mg warfarin daily, PTs extended none or slightly. Therefore, 1 mg warfarin can be used to prevent postoperative DVT following elective hip surgery.