Soluble Coagulation Factors Research Articles

Coagulation Abnormalities in Renal Pathology of Chronic Kidney Disease: The Interplay between Blood Cells and Soluble Factors.

Coagulation abnormalities in renal pathology are associated with a high thrombotic and hemorrhagic risk. This study aims to investigate the hemostatic abnormalities that are related to the interaction between soluble coagulation factors and blood cells, and the effects of hemodialysis (HD) on it, in end stage renal disease (ESRD) patients. Thirty-two ESRD patients under HD treatment and fifteen healthy controls were included in the study. Whole blood samples from the healthy and ESRD subjects were collected before and after the HD session. Evaluation of coagulation included primary and secondary hemostasis screening tests, proteins of coagulation, fibrinolytic and inhibitory system, and ADAMTS-13 activity. Phosphatidylserine (PS) exposure and intracellular reactive oxygen species (iROS) levels were also examined in red blood cells and platelets, in addition to the platelet activation marker CD62P. Platelet function analysis showed pathological values in ESRD patients despite the increased levels of activation markers (PS, CD62P, iROS). Activities of most coagulation, fibrinolytic, and inhibitory system proteins were within the normal range, but HD triggered an increase in half of them. Additionally, the increased baseline levels of ADAMTS-13 inhibitor were further augmented by the dialysis session. Finally, pathological levels of PS and iROS were measured in red blood cells in close correlation with variations in several coagulation factors and platelet characteristics. This study provides evidence for a complex coagulation phenotype in ESRD. Signs of increased bleeding risk coexisted with prothrombotic features of soluble factors and blood cells in a general hyperfibrinolytic state. Hemodialysis seems to augment the prothrombotic potential, while the persisted platelet dysfunction might counteract the increased predisposition to thrombotic events post-dialysis. The interaction of red blood cells with platelets, the thrombus, the endothelium, the soluble components of the coagulation pathways, and the contribution of extracellular vesicles on hemostasis as well as the identification of the unknown origin ADAMTS-13 inhibitor deserve further investigation in uremia.

Trauma induced clotting factor depletion in severely injured children: a single center observational study

BackgroundCoagulopathy following severe trauma contributes significantly to mortality. Impaired clotting factors have been observed in adult trauma patients, but in pediatric trauma victims their activity has not yet been investigated.MethodsSixteen pediatric trauma patients were evaluated according to the ISS and assigned to two cohorts. An additional control group (CO; n = 10) was formed. Routine coagulation parameters and the soluble clotting factors (F) were tested. Nonparametric data was analyzed using the Mann-Whitney U test. Results are reported as median and interquartile range.ResultsThe ISS of severely (SI, n = 8) and mildly (MI, n = 8) injured children differed significantly (25 [19–28] vs. 5 [4–6]; p < 0.001). INR was elevated in the SI cohort only when compared to the CO (1.21 [1.04-1.58] vs. 0.96 [0.93-1.00]; p = 0.001). Differences between SI and MI were found for FII (67 [53-90] vs. 82 [76-114] %; p = 0.028), FV (76 [47-88] vs. 92 [82-99] %; p = 0.028), and FXIII (67 [62-87] vs. 90 [77-102] %; p = 0.021). Comparison of the SI with the CO (FII 122 [112-144] %; p < 0.001; FV 123 [100-142] %; p = 0.002; and FXIII 102 [79-115] %; p = 0.006) also revealed a reduction in the activity of these factors. Furthermore, fibrinogen (198 [80-242] vs. 296 [204-324] mg/dl; p = 0.034), FVII (71 [63-97] vs. 114 [100-152] %; p = 0.009), FIX (84 [67-103] vs. 110 [90-114] %; p = 0.043), and FX (70 [61-85] vs. 122 [96-140] %; p = 0.001) were reduced in the SI in comparison with the CO. Finally, FVIII was considerably, yet not significantly, increased in both patient cohorts (235 [91-320] % and 197 [164-238] %, respectively).ConclusionsThis study proves that children suffer a depletion of clotting factors following severe injury which basically reflects the findings for adult trauma patients. Attempts to correct the impaired clotting factor activity could be based on a specific hemostatic therapy involving administration of coagulation factors. Nevertheless, therapeutic implications need to be investigated in future studies.

Clinical Significance of Thrombin Blockade with Low Doses (2.5 mg) of Rivaroxaban in Ischemic Heart Disease Patients

Arterial thrombosis is a result of complex interaction between blood cells, soluble coagulation factors in plasma and vessel wall. Antiplatelet drugs do not always provide the necessary antithrombotic effect of sufficient strength, because their influence does not extend to all three factors involved in this process. Low doses of direct oral inhibitors of thrombin are able to potentiate antithrombotic effect of antiplatelet therapy. The combination of rivaroxaban in a dose of 2.5 mg and standard double antiplatelet therapy turned out to be the most promising for clinical use, since studies with dabigatran and apixaban at the II and III stages of the trials were found to be unsuccessful due to the unacceptably high frequency of bleeding. Studies of the combination of rivaroxaban at a dose of 2.5 mg and standard antiplatelet therapy conducted in previous years among patients with acute myocardial infarction showed a decrease in the frequency of complications of atherothrombosis associated with their ischemic nature, while at the same time there was a slight increase in hemorrhagic complications. In the COMPASS study the combination of rivaroxaban (2.5 mg) plus aspirin reduced the risk of the primary endpoint (myocardial infarction, ischemic stroke, cardiovascular death) more significantly than aspirin alone in patients with stable ischemic heart disease and ischemic brain disease. The pathophysiological rationales for the use of low doses of rivaroxaban when added to dual antiplatelet therapy are considered, and the significance of recent studies in patients with acute coronary syndrome, stable ischemic heart disease and in the prevention of ischemic stroke is discussed.

Coagulation abnormalities and bleeding in pregnancy: an anesthesiologist's perspective.

During pregnancy, the procoagulant activity increases (manifested by elevation in factor VII, factor VIII, factor X, and fibrinogen levels), while the anticoagulant activity decreases (characterized by reduction in fibrinolysis and protein S activity), resulting in hypercoagulation. Standard coagulation tests, such as prothrombin time or activated partial thromboplastin time, are still used despite the lack of evidence supporting its accuracy in evaluating the coagulation status of pregnant women. Thromboelastography and rotational thromboelastometry, which are used to assess the function of platelets, soluble coagulation factors, fibrinogen, and fibrinolysis, can replace standard coagulation tests. Platelet count and function and the effect of anticoagulant treatment should be assessed to determine the risk of hematoma associated with regional anesthesia. Moreover, anesthesiologists should monitor patients for postpartum hemorrhage (PPH), and attention should be paid when performing rapid coagulation tests, transfusions, and prohemostatic pharmacotherapy. Transfusion of a high ratio of plasma and platelets to red blood cells (RBCs) showed high hemostasis success and low bleeding-related mortality rates in patients with severe trauma. However, the effects of high ratios of plasma and platelets and the ratio of plasma to RBCs and platelets to RBCs in the treatment of massive PPH were not established. Intravenous tranexamic acid should be administered immediately after the onset of postpartum bleeding. Pre-emptive treatment with fibrinogen for PPH is not effective in reducing bleeding. If fibrinogen levels of less than 2 g/L are identified, 2–4 g of fibrinogen or 5–10 ml/kg cryoprecipitate should be administered.

Evaluation of Potential Clinical Surrogate Markers of a Trauma Induced Alteration of Clotting Factor Activities

Objective. The aim of this study was to identify routinely available clinical surrogate markers for potential clotting factor alterations following multiple trauma. Methods. In 68 patients admitted directly from the scene of the accident, all soluble clotting factors were analyzed and clinical data was collected prospectively. Ten healthy subjects served as control group. Results. Patients showed reduced activities of clotting factors II, V, VII, and X and calcium levels (all P < 0.0001 to 0.01). Levels of hemoglobin and base deficit correlated moderately to highly with the activities of a number of clotting factors. Nonsurvivors and patients who needed preclinical intubation or hemostatic therapy showed significantly reduced factor activities at admission. In contrast, factor VIII activity was markedly elevated after injury in general (P < 0.0001), but reduced in nonsurvivors (P < 0.05). Conclusions. Multiple trauma causes an early reduction of the activities of nearly all soluble clotting factors in general. Initial hemoglobin and, with certain qualifications, base deficit levels demonstrated a potential value in detecting those underlying clotting factor deficiencies. Nevertheless, their role as triggers of a hemostatic therapy as well as the observed response of factor VIII to multiple trauma and also its potential prognostic value needs further evaluation.

Evaluation of clotting factor activities early after severe multiple trauma and their correlation with coagulation tests and clinical data

IntroductionTraumatic injuries are amongst the leading causes of death worldwide, frequently as a result of uncontrolled hemorrhage. Critical deficiencies in clotting factors have been noted in trauma-induced coagulopathy. However, the exact underlying conditions that result in devastating coagulopathies remain unclear. The purpose of this study was to elucidate these underlying deficiencies.MethodsBlood samples were drawn from 45 severely injured trauma patients on their arrival at the resuscitation room, and the activities of all soluble clotting factors and routine coagulation tests were assessed. The Mann–Whitney-U-test was used to assess differences in coagulation activity between the patients and healthy controls. Furthermore, Spearman’s rank correlation was used to analyze the blood work.ResultsAfter severe trauma the levels of serum fibrinogen and calcium were significantly reduced. Furthermore, traumatized patients had a significantly increased International Normalized Ratio (INR) compared to healthy controls. The median activities of all clotting factors were reduced after severe multiple trauma, with the exception of factor VIII, which was increased. Statistically significant differences were observed for factors II (80 vs. 122 %, P < 0.0001), V (76 vs. 123 %, P < 0.0001), VII (90 vs. 114 %, P = 0.002), VIII (200 vs. 108 %, P < 0.0001), and X (86 vs. 122 %, P < 0.0001). Spearman’s correlation indicated a significant negative correlation between INR on arrival with fibrinogen and levels of factors II, V, and VII, whereas Partial Thromboplastin Time was significantly negatively correlated with factor VIII (all P < 0.0001).ConclusionsThese findings suggest a general but rather moderate impairment of clotting factor activities following severe multiple trauma. In the concept of a calculated coagulation therapy, this could demand for the use of factor concentrates with higher ratios of clotting factors. Finally, the physiological importance of strongly elevated factor VIII activity remains unclear, but a possible interference with ex vivo measurements of Partial Thromboplastin Time has to be considered.

Plasma and Plasma Protein Product Transfusion: A Canadian Blood Services Centre for Innovation Symposium.

Plasma obtained via whole blood donation processing or via apheresis technology can either be transfused directly to patients or pooled and fractionated into plasma protein products that are concentrates of 1 or more purified plasma protein. The evidence base supporting clinical efficacy in most of the indications for which plasma is transfused is weak, whereas high-quality evidence supports the efficacy of plasma protein products in at least some of the clinical settings in which they are used. Transfusable plasma utilization remains composed in part of applications that fall outside of clinical practice guidelines. Plasma contains all of the soluble coagulation factors and is frequently transfused in efforts to restore or reinforce patient hemostasis. The biochemical complexities of coagulation have in recent years been rationalized in newer cell-based models that supplement the cascade hypothesis. Efforts to normalize widely used clinical hemostasis screening test values by plasma transfusion are thought to be misplaced, but superior rapid tests have been slow to emerge. The advent of non-vitamin K-dependent oral anticoagulants has brought new challenges to clinical laboratories in plasma testing and to clinicians needing to reverse non-vitamin K-dependent oral anticoagulants urgently. Current plasma-related controversies include prophylactic plasma transfusion before invasive procedures, plasma vs prothrombin complex concentrates for urgent warfarin reversal, and the utility of increased ratios of plasma to red blood cell units transfused in massive transfusion protocols. The first recombinant plasma protein products to reach the clinic were recombinant hemophilia treatment products, and these donor-free equivalents to factors VIII and IX are now being supplemented with novel products whose circulatory half-lives have been increased by chemical modification or genetic fusion. Achieving optimal plasma utilization is an ongoing challenge in the interconnected worlds of transfusable plasma, plasma protein products, and recombinant and engineered replacements.

The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients

The international normalized ratio (INR) was developed to assess adequacy of Coumadin dosing. Its use has been generalized to guide fresh frozen plasma (FFP) therapy in stable patients. Thrombelastography (TEG) is a whole-blood assay measuring the viscoelastic properties of the clot in near real time. This study hypothesized that INR does not reflect coagulopathy and should not be used to guide FFP therapy in stable trauma and surgical patients. Prospective observational data were collected from stable trauma and surgical patients (n = 106) who received FFP transfusions. Pretransfusion and posttransfusion blood samples were obtained to assess complete blood count, standard coagulation parameters (INR, partial thromboplastin time, fibrinogen and D-dimer), soluble clotting factors (II, V, VII, VIII, IX, X, XI, XII, proteins C and S) and TEG. Data were analyzed using a Mann-Whitney U-test. Significance was defined as p < 0.05. A total of 262 U of FFP were transfused, with 78% of 106 patients receiving two or more units. Despite a reduction in INR, median TEG values remained within normal limits, while clotting factor levels retained adequate function to produce normal clotting before and following FFP transfusion. The use of FFP in this population did not affect coagulation status in a clinically relevant manner based on TEG values and coagulation factor function. INR is not a predictor of coagulopathy and should not be used to guide coagulation factor replacement in stable trauma and surgical patients. Diagnostic study, level III.

A Phase I Study Of KB004, a Novel Non-Fucosylated humaneered® Antibody, Targeted Against The Receptor Tyrosine Kinase EphA3, In Advanced Hematologic Malignancies

BackgroundEphA3 is involved in cell positioning in fetal development. In the adult it is an oncofetal antigen re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors (tumor stem cells, neovasculature and stroma) and may be prognostic. KB004 is a humaneered® high affinity antibody targeted against EphA3 with 3 putative mechanisms of action: direct induction of apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature by induction of endothelial cell rounding and subsequent blood vessel infarction. Herein, we describe results of an ongoing, phase 1 dose-escalation study of KB004 in adult patients with advanced hematologic cancers. Objectives1) primary: to determine safety and MTD for KB004 in patients with hematologic malignancies refractory to or unfit for chemotherapy; 2) secondary: to examine PK profile, immunogenicity, and clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. MethodsThis is a multicenter phase 1 study. Key eligibility criteria include: 1) relapsed or refractory hematologic malignancy 2) ECOG PS 0-1; 3) adequate end-organ function. Additional eligibility criteria amended later to protect against hemorrhagic events, included platelets ≥ 10,000/uL (untransfused) and normal coagulation times. A standard 3 + 3 escalation study design (amended to allow up to 6 pts. per cohort in the absence of a DLT) was utilized. KB004 was administered as a 1 or 2 hr infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 mg and thereafter 33% increments up to a planned maximum of 700 mg. At 70 mg and above infusion reaction (IR) prophylaxis included an H1 blocker, H2 blocker, acetaminophen and IV steroids. Peripheral blood and bone marrow biopsy specimens for PK analysis and EphA3 expression, respectively, were collected during cycle 1. ResultsTo date, 37 patients (AML 32, MDS 2, lymphoma 1, myelofibrosis 2) received KB004; 20 mg: 9 pts, 40 mg: 3pts, 70 mg: 8 pts, 100 mg: 7pts, 140 mg: 5pts, 190 mg 5pts. At 70 mg, two patients had intracranial hemorrhages 5 and 18 days after last KB004 dose in the context of thrombocytopenia and hyperleukocytosis. A causal relationship to KB004 could not be excluded. One occurred in course 1 and was considered a DLT. KB004 blood levels were near the limit of quantitation at 48 and 96 hours. Following the change to entry criteria no further episodes of serious bleeding or other DLTs or significant changes in soluble clotting factors have been observed.Overall KB004 is well tolerated. The most common toxicity was mild to moderate transient IRs in 28 (76%) patients characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension, transient hypoxia (in 2 cases). Fourteen % of infusions were slowed due to an adverse event, two (1.2%) were prematurely discontinued but no patient discontinued KB004 secondary to an IR. No other significant KB004-related toxicity has been observed. KB004 Cmax at all dose levels was above the predicted effective concentration (1 ug/ml) and was approximately dose proportional. However at dose levels below 190 mg sustained exposure to cover the entire interval between doses was not achieved.One CRp was observed at the 20mg dose level in a 78 yr-old patient with relapsed AML, who remains on study and in sustained remission for over a year. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. A > 50% reduction in marrow blast percentage was seen in 14% of AML patients, and 59% had overall stable disease beyond 1 cycle.Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in 75% of AML patients. EphA3 was expressed in at least 30% of nucleated cells in the baseline sample of the patient with an ongoing CRp. ConclusionKB004 is a novel agent targeted against EphA3 that is well tolerated with evidence of clinical activity. It is anticipated that 190 mg given over 2 hours will provide sufficient plasma exposure to achieve sustained efficacy over the interval between doses. The study is ongoing. Additional PK, PD, and clinical data will be presented. Disclosures:Durrant:KaloBios: Research Funding. Yarranton:KaloBios: Employment, Equity Ownership; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; StemLine Therapeutics: Equity Ownership. Walling:KaloBios: Consultancy; Corcept Therapeutics: Consultancy; Prothena: Consultancy; New Gen Therapeutics: Consultancy; Valent Technologies: Consultancy; LBC Pharmaceuticals: Consultancy; Amgen: Equity Ownership; BioMarin: Equity Ownership; Crown BioScience: Membership on an entity's Board of Directors or advisory committees.

Mutation of the fiber shaft heparan sulphate binding site of a 5/3 chimeric adenovirus reduces liver tropism.

Natural tropism to the liver is a major obstacle in systemic delivery of adenoviruses in cancer gene therapy. Adenovirus binding to soluble coagulation factors and to cellular heparan sulphate proteoglycans via the fiber shaft KKTK domain are suggested to cause liver tropism. Serotype 5 adenovirus constructs with mutated KKTK regions exhibit liver detargeting, but they also transduce tumors less efficiently, possibly due to altered fiber conformation. We constructed Ad5/3lucS*, a 5/3 chimeric adenovirus with a mutated KKTK region. The fiber knob swap was hypothesized to facilitate tumor transduction. This construct was studied with or without additional coagulation factor ablation. Ad5/3lucS* exhibited significantly reduced transduction of human hepatic cells in vitro and mouse livers in vivo. Combination of coagulation factor ablation by warfarinization to Ad5/3lucS* seemed to further enhance liver detargeting. Cancer cell transduction by Ad5/3lucS* was retained in vitro. In vivo, viral particle accumulation in M4A4-LM3 xenograft tumors was comparable to controls, but Ad5/3lucS* transgene expression was nearly abolished. Coagulation factor ablation did not affect tumor transduction. These studies set the stage for further investigations into the effects of the KKTK mutation and coagulation factor ablation in the context of 5/3 serotype chimerism. Of note, the putative disconnect between tumor transduction and transgene expression could prove useful in further understanding of adenovirus biology.

Coagulopathy in Critically III Patients: Part 2 — Soluble Clotting Factors and Hemostatic Testing

This manuscript provides an overview of how to interpret in vitro clotting studies and how to select studies to evaluate patients with bleeding disorders in the ICU. It provides a practical approach to understanding the complex subject of clotting factor abnormalities, including the most common problems of preanalytical error and anticoagulation therapy. Limitations and pitfalls of diagnostic testing are highlighted.

Effect of Blood Soluble Clotting Factors on Coagulation Profile

Recently, mechanical thrombolytic therapy has been introduced as an alternative or adjunct to pharmaceutical thrombolytic therapy in removing thrombus from vascular system. Recurrent thrombosis has been a challenge for thrombolytic therapies. We hypothesize that soluble clotting factors released during a mechanical thrombectomy procedure may be responsible for creating a localized hypercoagulable state and could be one of the underlying causes of recurrent thrombosis. Blood samples were obtained from 20 participants with no history of hypertension, vascular disease, and antiplatelet/anticoagulation therapy. For each whole blood (WB) sample, we measured activated clotting time (ACT) and clotting rate (CR) at the baseline and then with added agitated and nonagitated clot serums. The same set of measurements was performed on platelet-rich plasma (PRP) samples of each participant. We tested for changes in coagulation profile between baseline samples and those with added supernatant serums obtained from autologous blood clot. We observed a significant decrease in ACT for WB with agitated and nonagitated clot serums (49%, P < .0001 and 25%, P = .01, respectively) compared to the baseline WB. The same trend was observed for PRP samples with agitated and nonagitated clot serums (28%, P = .002 and 18%, P = .05, respectively). The CR was increased (a steeper slope) by 83% for samples with added agitated clot serum only (P = .007). We observed a significant change for ACT in WB samples with added clot serums as compared to the baseline WB samples. The results of this study suggest that the soluble substances released from clotting blood have profound procoagulant effects.

Flow Effects on Coagulation and Thrombosis

Thrombosis occurs in a dynamic rheological field that constantly changes as the thrombus grows to occlusive dimensions. In the initiation of thrombosis, flow conditions near the vessel wall regulate how quickly reactive components are delivered to the injured site and how rapidly the reaction products are disseminated. Whereas the delivery and removal of soluble coagulation factors to the vessel is thought to occur via classic convection-diffusion phenomena, the movement of cells and platelets to the injured wall is strongly augmented by flow-dependent cell-cell collisions that enhance their ability to interact with the wall. In addition, increased shear conditions have been shown to activate platelets, alter the cellular localization of proteins such as tissue factor (TF) and TF pathway inhibitor, and regulate gene production. In the absence of high shearing forces, red cells, leukocytes, and platelets can form stable aggregates with each other or cells lining the vessel wall, which, in addition to altering the biochemical makeup of the aggregate or vessel wall, effectively increases the local blood viscosity. Thus, hemodynamic forces not only regulate the predilection of specific anatomic sites to thrombosis, but they strongly influence the biochemical makeup of thrombi and the reaction pathways involved in thrombus formation.

Recurrent Embolism in the Course of Marantic Endocarditis

Marantic or nonbacterial thrombotic endocarditis (NBTE) associated with systemic embolism is usually a complication of advanced or terminal malignancies. We report on the case of a 46-year-old woman in whom nonbacterial thrombotic endocarditis (NBTE)-related cerebral embolism was the first clinical sign of ovarian neoplasm, which was diagnosed after cardiac surgery. Marantic endocarditis should alert the physician to make every effort to diagnose the possible background of this clinical phenomenon. Early identification of NBTE, treatment of the underlying disease, and the associated coagulopathy could possibly prevent cardiac surgery.

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model.

Antiphospholipid antibodies (aPL) have thrombogenic properties in vivo, through their interactions with soluble coagulation factors and their ability to modulate the functions of cells involved in coagulation homeostasis. These antibodies have also been shown to enhance the adhesion of leukocytes to endothelial cells (ECs) in vivo. New lipophilic statins such as fluvastatin have antiinflammatory and antithrombogenic effects. This study uses an in vivo mouse model to investigate whether fluvastatin has an effect on decreasing both the adhesion of leukocytes to ECs and the thrombus formation induced by aPL. Two groups of CD-1 male mice, each comprising approximately 18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay. IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo. These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.

Pathogenic mechanisms mediating antiphospholipid syndrome

Antiphospholipid antibodies are the marker for antiphospholipid syndrome. There is evidence that these autoantibodies lead to both thrombotic diathesis and obstetrical manifestations. Besides the known interaction with soluble coagulation factors, in vitro and in vivo experimental models and studies in humans recently have shown the ability of antiphospholipid antibodies to modulate functions of cells involved in coagulation homeostasis. These findings support a new hypothesis to explain the paradox of the prolongation of coagulation assays in vitro and the association with thrombophilic diathesis in vivo. Obstetrical manifestations have been linked to a direct antibody effect on the trophoblast leading to defective placentation that is not necessarily associated with thrombotic phenomena. Phospholipid binding proteins such as beta 2 -glycoprotein I appear to behave as a bridge between circulating antiphospholipid antibodies and cellular targets.

Role of red blood cells in thrombosis.

Most biomedical textbooks teach that coagulation and thrombosis are primarily a function of endothelial cells, platelets, and soluble coagulation factors. Red blood cells, in contrast, are generally regarded as innocent bystanders, passively entrapped in a developing thrombus as they flow through the vasculature. This review summarizes evidence that demonstrates an active role for red cells in normal and pathologic hemostasis. We then evaluate the possible molecular mechanisms whereby a usually inert erythrocyte can actively contribute to the processes of clot formation.

Extracorporeal Left Ventricular Assistance with Prostacyclin and Heparinized Centrifugal Pump

A temporary left ventricular assist system utilizing an improved left atrial catheter and centrifugal pump was developed and tried in 22 anesthetized sheep to test the hypothesis that prostacyclin (PGI 2) and ionically bound heparin-coated surfaces could prevent thrombosis in this perfusion system without inhibiting soluble, circulating coagulation factors. Sheep were perfused at 53.6 ml/kg/min (standard error, 1.5) from left atrium to aorta for two hours. The pump maintained flow at left atrial pressures of 3 to 4 mm Hg. As expected, systemic heparin inhibited coagulation, mildly activated platelets, and prevented thrombosis in uncoated perfusion circuits and wounds. Infusion of PGI 2 (30 ng/kg/min) without systemic heparin or heparin-bonded extracorporeal surfaces prevented platelet activation and did not alter coagulation measurements; however, bleeding times increased and thrombi formed in every circuit. When heparin was ionically bound to all extracorporeal surfaces, infusion of PGI 2 completely prevented thrombosis within the circuit, inhibited platelet activation, and did not alter coagulation measurements. Blood spontaneously clotted in three of six thoracotomy wounds during perfusion. When PGI 2 infusion was stopped, heparin-coated surfaces alone failed to prevent thrombosis within the system in 3 of 5 animals. The combination of PGI 2 infusion and heparin-coated extracorporeal surfaces prevents thrombosis within the perfusion circuit without inhibiting soluble coagulation factors. This method, using the assist system, overcomes many of the implementation and bleeding problems associated with other temporary left ventricular assist devices.

Diabetes and atherosclerosis: an overview.

Atherosclerosis is the most common complication of diabetes. Epidemiologic and pathophysiologic evidence suggest a number of possible reasons for this. They include alterations in lipoproteins, platelets, soluble clotting factors, the balance of prostacyclin-thromboxane, blood pressure regulation, and arterial smooth muscle cell metabolism and proliferation. Many of these alterations may accompany hyperinsulinemia and may account for the recent evidence that hyperinsulinemia is a risk factor for atherosclerosis. Advances in this area will require the recognition that neither diabetes nor atherosclerosis are single disorders. Furthermore, new approaches are needed to study these disorders in which there may be many years of very subtle changes before any end point is apparent.

Effects of -(p-(Fluoren-9-ylidenemethyl)phenyl)-2-piperidineethanol (RMI 10,393) on Platelet Function

SummaryRMI 10,393 is a new compound which inhibits aggregation of human platelets in plasma. It is effective against aggregation induced by ADP, thrombin, collagen, epinephrine, and serotonin. In the effective concentration range it also inhibits clot retraction, but does not cause activation of platelet factor 3. In an attenuated system activation of a platelet-derived procoagulant effect occurs, but this is not seen in the standard clotting system. RMI 10,393 has no effect on soluble clotting factors. A compound with such activity may have potential as an antithrombotic agent.