Biomedical subjects

T L Ortel

Publications and source records attributed to T L Ortel.

At least 55 records · Page 3Linked to original sources

PubMed1997

Subdural hematoma and lupus anticoagulants.

BACKGROUND AND PURPOSE: Patients with lupus anticoagulants do not typically have a bleeding tendency. However, a few reports of hemorrhage in patients with lupus anticoagulants in the absence of known risk factors for bleeding have been published, raising the question of an etiologic connection between lupus anticoagulants and certain types of hemorrhage. The presentation of three patients with subdural hematoma and lupus anticoagulants within only 1 year at our institutions and the report of two such patients in the literature led us to conduct a retrospective study to determine whether patients with lupus anticoagulants may have an increased risk for the development of subdural hematoma. CASE DESCRIPTIONS: All patients with a discharge diagnosis of nontraumatic subdural hematoma and lupus anticoagulant at three medical institutions between 1985 and 1996 were identified, and their medical histories and laboratory evaluations were reviewed. Of 733 patients with a discharge diagnosis of nontraumatic subdural hematoma, 5 were diagnosed as having a lupus anticoagulant (0.7%). All had known risk factors for the development of subdural hematoma: thrombocytopenia, hypoprothrombinemia, intracerebral venous hemorrhage, warfarin therapy, and advanced age with a history of a fall. CONCLUSIONS: This study suggests that presence of a lupus anticoagulant by itself is not associated with an increased incidence of nontraumatic subdural hematoma.

Adult↗

PubMed1997

Anticardiolipin antibodies and osteonecrosis of the femoral head.

The current study evaluated the prevalence of anticardiolipin antibodies, which have been associated with thrombotic phenomena, in patients with nontraumatic osteonecrosis of the hip and assessed whether the presence of such antibodies is associated with an increased risk for the development of bone necrosis. Forty consecutive patients (25 men and 15 women) with nontraumatic osteonecrosis of the hip were studied. Their ages ranged from 19 to 56 years (average, 34.3 years). Anticardiolipin antibodies were present in 37.5% (15 of 40) of the tested patients, a significantly higher rate than is seen in healthy subjects, of whom only one of 100 had low titer anticardiolipin antibodies (1%). Six of 40 patients tested positive for immunoglobulin M alone, and six of 40 patients tested positive for immunoglobulin A alone. Three of 40 patients tested positive for immunoglobulin M and immunoglobulin A isotype. The results of the current study indicate an increased incidence of anticardiolipin antibodies in patients with nontraumatic osteonecrosis of the femoral head, which may reflect that anticardiolipin antibodies play a role in the pathogenesis of bone necrosis by predisposing to thrombotic phenomena.

Adrenal Cortex Hormones↗

PubMed1996

Thrombocytopenia in association with a wandering spleen.

An ectopic, so-called wandering spleen is an uncommon occurrence. We present the case of a young woman who presented with abdominal pain and was found to have an enlarged spleen, located in the lower abdomen and pelvis. The possibility of lymphoma was entertained because of concomitant findings of thrombocytopenia and a possible mesenteric mass. The mass was subsequently found at laparotomy to be the tail of the malpositioned pancreas, and the thrombocytopenia resolved with splenectomy. Review of the literature indicates that lymphoma is an uncommon finding in wandering spleens, that wandering spleens are enlarged in most cases, and that thrombocytopenia, while uncommon, can be seen, in particular when associated with torsion of an elongated splenic pedicle.

Abdominal Neoplasms↗

PubMed1996

Patients with antiphospholipid antibodies: CT and MR findings of the brain.

OBJECTIVE: The purpose of this study was to determine the spectrum of neuroradiologic findings in patients with antiphospholipid antibodies (APA) and to compare findings in systemic lupus erythematosus (SLE) and non-SLE patients. MATERIALS AND METHODS: We identified 110 patients with APA who underwent CT or MR imaging, of whom 59 (54%) had abnormal studies. Of these 59 patients, abnormalities were categorized as large infarcts, cortical infarcts, lacunar infarcts, hyperintense white matter foci on T2-weighted images, or dural sinus thrombosis. White matter foci were designated as small (< 5mm) or large (> 5 mm). RESULTS: Large infarcts were the most common abnormality, seen in 24 of 110 (22%) patients, followed in frequency by hyperintense white matter foci, seen in 19 of 110 (17%) patients. Ninety-five percent of patients with hyperintense white matter foci had at least one large lesion, and 76% had five or more small foci, three or more large foci, or both. Small cortical infarcts and lacunar infarcts were seen in 11 of 110 (10%) and 10 of 110 (9%) patients, respectively. Dural sinus thrombosis was seen in five patients. The frequency of abnormalities was high in both the SLE (57%) and the non-SLE (41%) groups. Large infarcts were more common in the non-SLE group (26%) than in the SLE group (5%). Although hyperintense white matter foci and cortical infarcts were more common in SLE patients, the differences were not statistically significant. CONCLUSION: Infarcts of various sizes and hyperintense white matter foci are the most common abnormalities seen on CT and MR imaging in patients with APA. We found no significant differences in frequencies of abnormalities seen between non-SLE and SLE patients.

Adult↗

PubMed1996

Effect of heterologous factor V heavy chain sequences on the secretion of recombinant human factor VIII.

Factor VIII and factor V share a repetitive domain structure of A1-A2-B-A3-C1-C2. To define the region(s) within the factor VIII heavy chain that result in inefficient expression of the recombinant protein, we expressed a series of factor VIII/factor V chimeras that contained heterologous sequences from the A1 and/or A2 domains. Substitution of the factor VIII A1 domain dramatically reduced secretion of factor V approximately 500-fold, whereas substitution of the factor VIII A2 domain had minimal effect on secretion. Conversely, substitution of the factor V A1 domain increased secretion of factor VIII approximately 3-fold, whereas substitution of the factor V A2 domain actually reduced secretion approximately 4-fold. Pulse chase experiments confirmed that reduced expression levels were due to decreased secretion rather than instability of secreted protein. Smaller substitutions did not further localize within the A1 domain the regions responsible for inefficient secretion.

Amino Acid Sequence↗

PubMed1995

Thrombin-catalyzed activation of recombinant human factor V.

Proteolytic activation of human factor V by thrombin results from the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545. In order to define the functional importance of these sites, mutants with isoleucine substitutions blocking thrombin cleavage at one, two, or all three activation sites were expressed in COS-7 cells. The wild type protein is activated approximately 10-fold by thrombin or Russell's viper venom (RVV-V). Thrombin cleavage at Arg709 alone did not result in an increase in procoagulant activity. Cleavage at both Arg709 and Arg1018 resulted in an approximately 3.4-fold increase in activity. Cleavage at these sites was required for rapid cleavage by thrombin at Arg1545, however, which resulted in maximal activation of the factor V molecule. In contrast, isolated cleavage at Arg1545 by RVV-V was sufficient for efficient and complete activation of factor V. The effect of isoleucine substitutions at one or both thrombin cleavage sites in a B-domain deletion mutant lacking amino acids 811-1491 was also investigated. The specific activity of all four mutants was approximately 30% compared to thrombin activated factor V, indicating that these isoleucine substitutions do not drastically alter the structure of the protein and that cleavage at these sites is not required for the expression of partial procoagulant activity.

Amino Acid Sequence↗

PubMed1995

Adrenal hemorrhage in patients with primary antiphospholipid syndrome: imaging findings.

OBJECTIVE: The primary antiphospholipid syndrome consists of recurrent thromboses, early stroke, recurrent fetal loss, and livedo reticularis in patients with antiphospholipid antibodies and without systemic lupus erythematosus. The purpose of this study was to analyze the imaging findings in patients who had this syndrome as well as adrenal hemorrhage. MATERIALS AND METHODS: The medical records and reports of radiologic examinations of 228 patients with elevated titers of lupus anticoagulant or anticardiolipin antibodies from January 1992 to April 1994 were examined for indications of adrenal hemorrhage. Four patients (two men and two women 38-78 years old) were identified as having adrenal hemorrhage. The abdominal CT and MR imaging findings for three patients and autopsy data for the fourth patient were analyzed. RESULTS: Adrenal hemorrhage was seen in all three patients who underwent abdominal CT and in one patient who underwent MR imaging. Adrenal hemorrhage was bilateral in three patients. Extension of hemorrhage into the perinephric space was present in two patients. Associated clinical findings probably attributable to the presence of antiphospholipid antibodies included amaurosis fugax (two patients), deep venous thrombosis (three patients), and transient ischemic attacks or stroke (two patients). CONCLUSION: Antiphospholipid antibodies appear to be a risk factor for adrenal hemorrhage. The presence of these antibodies should be suspected in patients who have adrenal hemorrhage as well as recurrent thromboses and early stroke.

Abdomen↗

PubMed1995

Anatomic distribution of venous thrombosis in patients with antiphospholipid antibody: imaging findings.

OBJECTIVE: Antiphospholipid antibodies are immunoglobulins that cross-react with phospholipid within cell membranes. These antibodies have been associated with a hypercoagulable state manifested by early stroke, frequent arterial and venous thromboses, recurrent fetal loss, thrombocytopenia, and livedo reticularis (antiphospholipid syndrome). The purpose of this study was to determine the anatomic distribution of venous thrombosis in patients with antiphospholipid antibodies as seen on imaging examinations. MATERIALS AND METHODS: We retrospectively reviewed the laboratory results of patients tested for antiphospholipid antibodies at a tertiary referral center during the period January 1992 to April 1994. This review revealed 228 patients with antiphospholipid antibodies. We excluded patients with systemic lupus erythematosus or any other medical condition associated with a hypercoagulable state and patients over 65 years old. Thirty-one of the remaining 73 patients had undergone imaging studies of the CNS or non-CNS venous system. Radiologic studies (contrast angiography or venography, MR angiography or venography, or Doppler sonography) were examined for the presence of venous thrombosis. Nineteen patients--11 men and eight women, 18-62 years old (average age, 38 years)--with venous thromboses were identified. RESULTS: Twelve patients had non-CNS thrombosis alone, three had CNS thrombosis alone, and four had both CNS and non-CNS thromboses. Locations of non-CNS thromboses included deep veins of the legs (nine occurrences), pulmonary vessels (five), and large veins in the thorax or abdomen (six). Three of these patients had documented thromboses at other sites. Twelve patients had recurrent thrombotic events (six with multiple recurrences), including five with arterial thromboses and two with both venous and arterial thromboses and stroke. Among patients with CNS involvement, five had documented thromboses (four dural sinus, one arterial) and two had arterial distribution strokes demonstrated by CT. Two patients with only non-CNS thromboses had either seizures or migraines. CONCLUSION: Deep veins of the leg were the most common site of venous thrombosis. The thoracic and abdominal venous system and the dural sinuses--unusual sites of thrombosis in the general population--are other common sites. Antiphospholipid antibodies should be suspected when thromboses are found in these locations in the absence of other known risk factors, or when found in combination with arterial thromboses or CNS ischemic disease in young or middle-aged patients.

Adolescent↗

PubMed1995

Clinical and laboratory evaluation of the hypercoagulable states.

In summary, every patient presenting with a new (or recurrent) thromboembolic event should be carefully assessed for potential predisposing factors. This starts with a thorough patient history and complete physical examination. If indicated, the clinical assessment is then used to guide the clinical laboratory evaluation for a potential hypercoagulable state. Identification of a specific hypercoagulable state, primary or secondary, is extremely important in the prognosis and therapeutic management of the individual patient.

Blood Coagulation Disorders↗

PubMed1994

Localization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras.

Coagulation factor V, an integral component of the prothrombinase complex, possesses two C-type domains at the carboxyl-terminal end of the molecule. Homologous C-type domains are present in factor VIII as well as several non-coagulation proteins. Deletion of the second C-type domain of factor V results in the loss of procoagulant activity and the ability to bind phosphatidylserine. We now report the effect of substitution of all or a portion of the C2 domain of factor V with the corresponding regions of factor VIII or the human breast carcinoma protein BA46. Substitution of the entire domain with a heterologous C2 domain does not restore significant procoagulant activity, although smaller, exon-size substitutions do result in chimeras with partial activity (approximately 10% of factor Va). Using chimeras with partial substitutions, we determined that the amino-terminal region of the domain is involved in binding to phosphatidylserine. In contrast, the central region of the domain is not involved in phosphatidylserine binding, but an antibody binding at or near this site inhibits procoagulant activity, suggesting that this region is involved in a separate function. Lastly, the molecular basis for the light chain doublet, which is important in the expression of full procoagulant activity, is located within the carboxyl-terminal region of the C2 domain.

Animals↗

PubMed1994

Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis.

Topical bovine thrombin preparations are used extensively in cardiovascular, neurosurgical, and otolaryngologic procedures. Patients who are treated with these topical thrombin preparations may develop antibodies to bovine coagulation factors that may cross-react with the endogenous human clotting proteins. We have identified four patients with acquired factor inhibitors following exposure to topical thrombin at Duke University Medical Center and summarize these cases in addition to 13 patients previously reported in the literature. In most cases, the inhibitor developed following a second (or subsequent) exposure to topical thrombin. The clinical course was extremely variable, ranging from totally asymptomatic to life-threatening hemorrhage. The most consistent laboratory abnormality was a prolonged bovine thrombin clotting time, which corrected, at least partially, when human thrombin was substituted for bovine thrombin. Some of these patients also developed factor V inhibitors with prolonged prothrombin and activated partial thromboplastin times. Although these patients have prolonged clotting times, they should not be considered "autoanticoagulated," since thromboembolic complications can still occur. Therapeutic intervention is largely empirical and depends on the clinical manifestations of the individual patient.

Administration, Topical↗

PubMed1994

Antiphospholipid antibodies in patients without systemic lupus erythematosus: neuroradiologic findings.

PURPOSE: To study neuroradiologic findings in patients with hypercoagulability due to antiphospholipid antibodies (APAs). MATERIALS AND METHODS: Retrospective review of abnormal angiographic, computed tomographic, and magnetic resonance imaging findings was performed over a 14-month period in patients with APAs, no diagnosis of systemic lupus erythematosus, age less than 65 years, and no other cause of a hypercoagulable state. RESULTS: Fourteen patients (age range, 22-62 years) with APAs had abnormal results at neuroradiologic examination. Abnormal findings on cross-sectional imaging studies included large-artery (n = 3), lacunar (n = 5), and venous infarctions (n = 2); cortical atrophy (n = 5); white matter abnormalities (n = 3); and dural sinus thrombosis (n = 4). Abnormal angiographic findings included large-artery occlusions (n = 2), arterial narrowing that simulated vasculitis (n = 2), and transverse sinus thrombosis (n = 1). CONCLUSION: Presence of APAs should be suspected when no cause is apparent for either (a) an ischemic cerebrovascular event in young and middle-aged adults or (b) dural sinus or cerebral venous thrombosis (c) in patients with recurrent systemic arterial or venous thromboses, especially women with recurrent miscarriages.

Adult↗

PubMed1994

Evaluation of a modified procedure for Staclot LA for the confirmation of lupus anticoagulants.

Staclot LA is a hexagonal (II) phase phospholipid clotting assay used to confirm the presence of lupus anticoagulants (LA). However, there have been complaints that the procedure contains several incubation steps requiring 15 min of operator time. The authors were able to shorten this procedure to a single 5 min incubation without affecting assay sensitivity. Both procedures were performed on 45 known lupus anticoagulant positive specimens, 25 normal donors, eleven plasmas from patients with known factor VIII or factor V inhibitors and ten other specimens submitted for lupus anticoagulant or anticardiolipin antibody testing but without complete testing to confirm the presence of LA prior to testing with Staclot LA. Excellent agreement was observed between the two procedures with concurrence in 87 of 91 specimens (95.6%). Each method detected 39 of 45 LA positive specimens giving a sensitivity of 86.7%. This modification shortens technologist time by two-thirds without compromising assay sensitivity, which will allow for automation on commonly used coagulation analysers.

Automation↗

PubMed1994

Evaluation of preanalytical variables associated with measurement of prothrombin fragment 1.2.

We have used a monoclonal antibody-based ELISA for plasma prothrombin fragment 1.2 (F1.2) to establish appropriate sample collection and storage conditions for this biomarker of thrombin generation. F1.2 concentrations were not altered by exogenous factor Xa, thrombin, or thromboplastin if blood was collected by routine venipuncture into tubes containing heparin as anticoagulant (but not citrate, acid-citrate-dextrose, EDTA, or oxalate) and if plasma antithrombin III concentration was > or = 30% of normal. Heparinized plasma F1.2 was stable for > or = 8 h at 20-25 degrees C, and if premixed with a stabilizing reagent, for > or = 4 years at -70 degrees C. Mean values for heparinized plasma F1.2 collected and stored by recommended procedures were increased in patients with thrombosis and conditions of increased thrombotic risk, and were sensitive to heparin and oral anticoagulant therapies. We conclude that plasma obtained by routine venipuncture into tubes with heparin as anticoagulant is an appropriate specimen for F1.2 measurements for most patients.

Adult↗

PubMed1993

Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem-cell disorder in which the glycolipid-anchored membrane proteins, including the cell-surface complement inhibitors, CD55 and CD59, are partially or completely deleted from the plasma membranes of mature blood cells. To gain insight into the pathogenesis of thrombosis that is frequently observed in this disorder, the procoagulant responses of PNH platelets exposed to the human terminal complement proteins C5b-9 were investigated. C5b-9 complexes were assembled on gel-filtered platelets by incubation with purified C5b6, C7, C9, and limiting amounts of C8. Platelet microparticle formation and exposure of plasma membrane-binding sites for coagulation factor Va were then analyzed by flow cytometry. PNH platelets exhibiting undetectable levels of surface CD59 antigen showed an approximately 10-fold increase in sensitivity to C5b-9-stimulated expression of membrane-binding sites for factor Va when compared with platelets from normal controls. Expression of catalytic surface for the prothrombinase complex (VaXa) paralleled the exposure of factor Va-binding sites; the rate of prothrombin conversion by C5b-9-treated PNH platelets exceeded that of C5b-9-treated normal controls by approximately 10-fold at the maximal input of C8 tested (500 ng/mL). These data indicate that PNH platelets deficient in plasma membrane CD59 antigen are exquisitely sensitive to C5b-9-induced expression of prothrombinase activity, and suggest that the tendency toward thrombosis in these patients may be due, at least in part, to the deletion of this complement inhibitor from the platelet plasma membrane.

Adult↗

PubMed1992

Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis.

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Anticoagulants↗

PubMed1992

Deletion analysis of recombinant human factor V. Evidence for a phosphatidylserine binding site in the second C-type domain.

Human coagulation factor V is an integral component of the prothrombinase complex. Rapid activation of prothrombin is dependent on the interactions of this nonenzymatic cofactor with factor Xa and prothrombin in the presence of calcium ions and a phospholipid or platelet surface. Factor V is similar structurally and functionally to the homologous cofactor, factor VIII, which interacts with factor IXa to accelerate factor X activation in the presence of calcium and phospholipids. Both of these cofactors, when activated, possess homologous heavy and light chains. Binding to anionic phospholipids is mediated by the light chains of these two cofactors. In bovine factor Va, a phosphatidylserine-specific binding site has been localized to the amino-terminal A3 domain of the light chain. In human factor VIII, on the other hand, a region within the carboxyl-terminal C2 domain of the light chain has been shown to interact with anionic phospholipids. We have constructed a series of recombinant deletion mutants lacking domain-size fragments of the light chain of human factor V (rHFV). These mutants are expressed and secreted as single-chain proteins by COS cells. Thrombin and the factor V activator from Russell's viper venom process these deletion mutants as expected. The light chain deletion mutants possess essentially no procoagulant activity, nor are they activated by treatment with factor V activator from Russell's viper venom. Deletion of the second C-type domain results in essentially complete loss of phosphatidylserine-specific binding whereas the presence of the C2 domain alone (rHFV des-A3C1, which lacks the A3 and C1 domains of the light chain) results in significant phosphatidylserine-specific binding. The presence of the A3 domain alone (rHFV des-C1C2) does not mediate binding to immobilized phosphatidylserine. Increasing calcium ion concentrations result in decreased binding of recombinant human factor V and the mutant rHFV des-A3C1 to phosphatidylserine, similar to previous studies with purified plasma factor V and phospholipid vesicles. These results indicate that human factor V, similar to human factor VIII, possesses a phosphatidylserine-specific binding site within the C2 domain of the light chain.

Base Sequence↗

PubMed1992

Characterization of an acquired inhibitor to coagulation factor V. Antibody binding to the second C-type domain of factor V inhibits the binding of factor V to phosphatidylserine and neutralizes procoagulant activity.

Coagulation Factor V is an essential component of the prothrombinase complex, which activates the zymogen prothrombin to thrombin. A patient was described who developed a Factor V inhibitor that neutralized the procoagulant activity of Factor V and resulted in a fatal hemorrhagic diathesis (Coots, M. C., A. F. Muhleman, and H. I. Glueck. 1978. Am. J. Hematol. 4:193-206). This inhibitor was shown to be an IgG antibody that bound to the light chain of Factor V. Using a series of light chain deletion mutants, we have found that this antibody binds to the second C-type domain of the light chain. Both inhibitor IgG and Fab fragments rapidly neutralized the procoagulant activity of Factor Va, implying that the neutralization resulted from specific binding to the C2 domain. We have previously demonstrated that deletion of the C2 domain results in loss of procoagulant activity, as well as loss of phosphatidylserine-specific binding. Confirming these results, both inhibitor IgG and Fab fragments interfered with phosphatidylserine-specific binding of Factor V. Conversely, preincubation of Factor Va with procoagulant phospholipids protected the cofactor from inactivation by the inhibitor. Our results suggest that this inhibitor neutralizes the procoagulant activity of Factor Va by interfering with the C2-mediated interaction with phospholipid surfaces, thereby disrupting formation of the prothrombinase complex.

Antigen-Antibody Reactions↗