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- Management of acute ischemic stroke. [Journal Article]
- Hosp Pract (1995) 2013 Apr; 41(2):108-22.
Stroke is one of the most common causes of morbidity and mortality in hospitalized patients in the United States. A proper understanding of stroke mechanisms helps to guide specific case management. The only therapy approved by the US Food and Drug Administration for the management of acute ischemic stroke is initiation of intravenous recombinant tissue plasminogen activator within 3 hours of symptom onset. Other treatment options include intra-arterial recombinant tissue plasminogen activator, mechanical thrombectomy, clot retrieval, or a combination of these approaches. In this article, we provide an evidence-based review of the diagnostic approach for acute ischemic stroke, including recognizing common stroke mimics. We detail the initial medical management of acute stroke and the medical and surgical therapeutic interventions for patients who have sustained acute ischemic stroke.
- Receptors to interleukin-6 and adhesion molecules on circulating monocyte subsets in acute myocardial infarction. [JOURNAL ARTICLE]
- Thromb Haemost 2013 May 16; 110(2)
The role of individual monocyte subsets in inflammation and recovery post-myocardial infarction (MI) is insufficiently understood. It was the objective of this study to evaluate the dynamics of monocyte expression of receptors to vascular cell adhesion molecule (VCAM-1r), intercellular adhesion molecule (ICAM-1r), and interleukin-6 (IL-6r) following MI and their relation to inflammatory cytokines, fibrinolytic factors and annexin V-binding microparticles. Expression of VCAM-1r, ICAM-1r, IL-6r on CD14++CD16-(Mon1), CD14++CD16+(Mon2), CD14+CD16++(Mon3) monocyte subsets were quantified by flow cytometry in patients with ST-elevation MI (STEMI, n=50), non-STEMI (n=48) and stable coronary artery disease (n=40). In STEMI, parameters were measured on days 1, 3, 7, 30. On admission with STEMI, VCAM-1r expression was reduced on Mon1 (p=0.007), Mon2 (p=0.036), Mon3 (p=0.005), whilst in NSTEMI there was significant up-regulation of expression by Mon2 (p=0.024) and Mon3 (p=0.049). VCAM-1r on Mon1 correlated positively with plasma IL-1β levels (p=0.001). IL-6r was reduced on Mon2 in acute STEMI, with upregulation of the receptor on Mon1 and Mon2 during follow-up. IL-6r density correlated negatively with plasma levels of tissue-type plasminogen activator (p=0.0005 for Mon1, p=0.001 for Mon2 and Mon3), and positively with annexin V-binding microparticles (p=0.03 for Mon1, p=0.005 for Mon2 and p=0.005 for Mon3). There was no change in monocyte ICAM-1r expression. In conclusion, expression of IL-6r and VCAM-1r is reduced on circulating monocyte subsets involved in inflammatory responses in STEMI. This may represent a regulatory feed-back mechanism aiming to re-balance the marked inflammation which is typically present following acute MI or selective homing of monocytes with high receptor expression to damaged myocardium.
- Haemarthrosis stimulates the synovial fibrinolytic system in haemophilic mice. [JOURNAL ARTICLE]
- Thromb Haemost 2013 May 16; 110(1)
Recurrent joint bleeding is the most common manifestation of haemophilia resulting in haemophilic arthropathy (HA). The exact pathophysiology is unknown, but it is suggested that arthropathy is stimulated by liberation of fibrinolytic activators from the synovium during haemarthrosis. The aim of this study was to test the hypothesis that haemarthrosis activates the local synovial fibrinolytic system in a murine haemophilia model. The right knees of haemophilic and control mice were punctured to induce haemarthrosis. The left knees served as internal control joints. Synovial levels of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), plasmin, and alpha-2-antiplasmin (A2AP) were compared between the punctured and control knees. In haemophilic mice, an increase in synovial cells expressing urokinase-type plasminogen activator (uPA) in the right punctured knee versus the left unaffected knee was observed: (47% vs 43%) (p=0.03). Additionally, in haemophilic mice, haemarthrosis induced an increase in uPA (0.016 ng/ml vs 0.01 ng/ml) (p=0.03) and plasmin (0.53 μg/ml vs 0.46 μg/ml) (p=0.01) as promoters of fibrinolysis. Synovial levels of PAI-1 (0.32 ng/ml vs 0.17 ng/ml) (p<0.01) was also increased, whereas synovial levels of A2AP were unchanged: (0.021 μg/ml vs 0.021 μg/ml) (p=0.15). Enhanced uPA production was confirmed in human stimulated synovial fibroblast cultures and elevated levels of plasmin were confirmed harmful to human cartilage tissue explants. In this study we demonstrate that haemarthrosis in haemophilic mice induces synovial uPA expression and results in an increase in synovial plasmin levels, making the joint more vulnerable to prolonged and subsequent bleedings, and adding directly to cartilage damage.
- Engineering the Cellular Protein Secretory Pathway for Enhancement of Recombinant Tissue Plasminogen Activator Expression in Chinese Hamster Ovary cells: Effects of CERT and XBP1s Genes. [JOURNAL ARTICLE]
- J Microbiol Biotechnol 2013 May 16.
Cell line development is the most critical and also the most time consuming step in the production of recombinant therapeutic proteins. In this regard a variety of vector and cell engineering strategies have been developed for generating high producing mammalian cells; however, the cell line engineering approach seems to show various results on different recombinant protein producer cells. In order to improve the secretory capacity of a recombinant tissue plasminogen activator (t-PA) producing Chinese hamster ovary (CHO) cell line, we developed cell line engineering approaches based on CERT and XBP1s genes. For this purpose, CERT S132A, a mutant form of CERT that is resistant to phosphorylation, or XBP1s were overexpressed in a recombinant t-PA producing CHO cell line. Overexpression of CERT S132A increased specific productivity of t-PA producing CHO cells up to 35%. In contrast, heterologous expression of XBP1s did not affect t-PA expression rate. Our results suggest that CERT S132A based secretion engineering could be an effective strategy for enhancing recombinant t-PA production in CHO cells.
- Haplotype Based Association Study between t-PA Gene and Essential Hypertension. [Journal Article]
- Int J Biomed Sci 2006 Jun; 2(2):166-71.
Several previous studies have shown that essential hypertension (EH) is associated with fibrinolysis. Tissue plasminogen activator (t-PA) plays a key role in fibrinolysis. Thus, it is possible that the t-PA gene is a susceptibility gene of EH. However, there have been no reported studies of association between EH and the t-PA gene using single nucleotide polymorphisms (SNPs). The aim of the present haplotype-based case-control study was to investigate whether SNPs in the human t-PA gene are associated with EH. We performed a genetic association study using 3 SNPs (rs7007329, rs8178750, rs4471024). The subjects were 276 EH patients and 283 age-matched normotensive (NT) individuals. There were no significant differences in overall distribution of genotypes or alleles between EH patients and NT subjects. Also, there were no significant differences in the haplotype-based case-control study. The present results do not indicate an association between the t-PA gene and EH.
- Tissue plasminogen activator regulates Purkinje neuron development and survival. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2013 May 14.
The cerebellar cortex is centrally involved in motor coordination and learning, and its sole output is provided by Purkinje neurons (PNs). Growth of PN dendrites and their major synaptic input from granule cell parallel fiber axons takes place almost entirely in the first several postnatal weeks. PNs are more vulnerable to cell death than most other neurons, but the mechanisms remain unclear. We find that the homozygous nervous (nr) mutant mouse's 10-fold-increased cerebellar tissue plasminogen activator (tPA), a part of the tPA/plasmin proteolytic system, influences several different molecular mechanisms, each regulating a key aspect of postnatal PN development, followed by selective PN necrosis, as follows. (i) Excess endogenous or exogenous tPA inhibits dendritic growth in vivo and in vitro by activating protein kinase Cγ and phosphorylation of microtubule-associated protein 2. (ii) tPA/plasmin proteolysis impairs parallel fiber-PN synaptogenesis by blocking brain-derived neurotrophic factor/tyrosine kinase receptor B signaling. (iii) Voltage-dependent anion channel 1 (a mitochondrial and plasma membrane protein) bound with kringle 5 (a peptide derived from the excess plasminogen) promotes pathological enlargement and rounding of PN mitochondria, reduces mitochondrial membrane potential, and damages plasma membranes. These abnormalities culminate in young nr PN necrosis that can be mimicked in wild-type PNs by exogenous tPA injection into cerebellum or prevented by endogenous tPA deletion in nr:tPA-knockout double mutants. In sum, excess tPA/plasmin, through separate downstream molecular mechanisms, regulates postnatal PN dendritogenesis, synaptogenesis, mitochondrial structure and function, and selective PN viability.
- Explicit Consideration of Baseline Factors to Assess Recombinant Tissue-Type Plasminogen Activator Response With Respect to Race and Sex. [JOURNAL ARTICLE]
- Stroke 2013 May 14.
BACKGROUND AND PURPOSE:Sex and race reportedly influence outcome after recombinant tissue-type plasminogen activator (rtPA). It is, however, unclear whether baseline imbalances (eg, stroke severity) or lack of response to thrombolysis is responsible. We applied balancing methods to test the hypothesis that race and sex influence outcome after rtPA independent of baseline conditions.
METHODS:We mapped group outcomes from the National Institute of Neurological Disorders and Stroke (NINDS) dataset based on race and sex onto a surrogate-control function to assess differences from expected outcomes at their respective National Institutes of Health Stroke Scale and age. Outcomes were also compared for subjects matched individually on key baseline factors using NINDS and 2 recent datasets from southeastern United States.
RESULTS:At similar National Institutes of Health Stroke Scale and age, 90-day good outcomes (modified Rankin Score, 0-2) in NINDS were similarly improved after rtPA for white men and women. There was a strong trend for improvement in black men. Conversely, black women treated with rtPA showed response rates no different from the controls. After baseline matching, there were nonsignificant trends in outcomes except for significantly fewer good outcomes in black versus matched white women (37% versus 63%; P=0.027). Pooling the 3 datasets showed a similar trend for poorer short-term outcome for black women (P=0.054; modified Rankin Score, 0-1).
CONCLUSIONS:Matching for key baseline factors indicated that race and sex influence outcome most strikingly in black women who demonstrated poorest outcomes after rtPA. This finding supports the hypothesis that poor response to rtPA, rather than differences in baseline conditions, contributes to the worse outcome. This finding requires prospective confirmation.
- Derangement of hemostasis in rheumatoid arthritis: association with demographic, inflammatory and metabolic factors. [JOURNAL ARTICLE]
- Clin Rheumatol 2013 May 15.
Disturbance of fibrinolysis is common in rheumatoid arthritis (RA), and it may be associated with the increased cardiovascular risk observed in this population. We aimed to assess coagulation derangement and investigate whether abnormalities are influenced by demographic, inflammatory or metabolic factors in patients with RA. Levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, prothrombin fragment 1 + 2 (PF1 + 2), thrombomodulin (TM), protein C and Von Willebrand factor (vWF) were compared between 141 RA patients and 50 healthy hospital controls. Within RA, coagulation factors were assessed alongside several demographic, inflammation and metabolic indicators. RA patients had higher levels of coagulation factors than controls. After correction for age and sex, having RA predicted increased tPA (B = 0.15, P < 0.001), PAI-1 (B = 0.21, P < 0.001), fibrinogen (B = 0.86, P < 0.001), PF1 + 2 (B = 0.20, P < 0.001), and TM (B = 0.01, P = 0.03) levels. CRP correlated positively with tPA (P < 0.05), fibrinogen (P < 0.001), TM (P < 0.05), PF1 + 2 (P < 0.001) and vWF (P < 0.001). Metabolic factors linked with coagulation factors were hypertriglyceridaemia (tPA, P < 0.05; PAI-1, P < 0.05; protein C, P < 0.05) and insulin resistance (tPA, P < 0.01; PAI-1, P < 0.01; vWF, P < 0.05). Imbalance of coagulation and fibrinolytic mechanisms is common in RA and associates with age, inflammation, and metabolic factors. Further studies may determine whether these abnormalities are the consequence of acute inflammation or markers of vascular dysfunction.
- Reversal of Acute Ischemic Stroke After THA Using Tissue Plasminogen Activator. [Journal Article]
- Orthopedics 2013 May 1; 36(5):e676-8.
Acute ischemic stroke is a potentially catastrophic medical emergency. Recently, successful reversal of the neurologic deficits associated with major ischemic strokes has been accomplished in selected patients through the use of intravenous tissue plasminogen activator (tPA), an agent that can accomplish thrombolysis of arterial clots if given within the first few hours after the onset of stroke. Because tPA works by thrombolysis of fresh clots, a potential exists for catastrophic hemorrhage if given to acute postoperative patients. Therefore, the use of tPA has never been studied in postoperative patients, and the safety of the drug in postoperative patients is unknown.The author describes a patient who had an acute ischemic stroke 2 days after total hip arthroplasty who was successfully treated with tPA without major complications. The patient was 51 years old and developed progressive facial droop, right arm paralysis, and dysarthria 2 days after elective hip arthroplasty. Imaging confirmed occlusion of the left middle cerebral artery. Neurologic recovery was believed to be unlikely without tPA. After tPA administration, the patient had full neurologic recovery within minutes but did develop a large (nondraining) hematoma and severe ecchymosis at the surgical site; a drop in hematocrit required 3 units of packed red blood cell transfusion. The wound did not develop skin necrosis, infection, or compartment syndrome, and the hematoma resolved within several weeks without the need for surgical intervention.The author describes the patient's specific circumstances, the decision-making process behind the use of tPA, and the need for contingency plans in the event that severe uncontrolled hemorrhage occurs. This information may be useful if other surgeons are faced with the dilemma of a major stroke in acute postoperative patients.
- Individual lytic efficacy of recombinant tissue plasminogen activator in an in vitro human clot model: rate of "nonresponse". [Journal Article]
- Acad Emerg Med 2013 May; 20(5):449-55.
Recombinant tissue plasminogen activator (rt-PA) is a lytic medication widely used in the emergency department to treat acute thrombotic disorders such as ischemic stroke and myocardial infarction. It is known in the clinical use of this drug that it can be less effective in approximately 25% of individuals receiving such treatment. However, there are no data on the variation of lytic efficacy of rt-PA in decreasing individuals' clot size over time. In this study, in vitro lytic efficacy was determined by measuring the decrease in clot diameter after 30 minutes of drug exposure. The authors sought to explore whether there are individuals who do not respond to this lytic therapy and to estimate the rate of nonresponse.Human whole blood clots were made from blood drawn from 22 adult volunteers. The only exclusion criterion was the use of aspirin within 72 hours of the blood draw. Blood clots were allowed to spontaneously form at room temperature and were then incubated at 37°C for 3 hours to ensure complete clot retraction. Sample clots from the same individuals were then exposed to human fresh-frozen plasma (hFFP) control or rt-PA in hFFP (rt-PA) at a concentration of 3.15 μg/mL. All clots were exposed at 37°C for 30 minutes, and clot diameter was measured as a function of time, using a microscopic imaging technique. The fractional clot loss (FCL), which is the percentage decrease in clot diameter at 30 minutes, was used as a measure of lytic efficacy.Means with standard deviation (SD) FCL values were 8.6% (±3.0%) for control and 20.6% (±9.3%) for rt-PA-treated clots. The mean (±SD) difference in FCL values was 12.0% (±8.8%) and was significant (p < 0.05, paired t-test). Five of the 22 subjects (23%) were "rt-PA nonresponders," in that their FCL (rt-PA) values fell within that of the FCL control values.Overall, rt-PA does not produce clot lysis in vitro in clots from a substantial minority of the population, likely due to individual variations in clot composition and structure.