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Biomedical subjects

B G Macik

Publications and source records attributed to B G Macik.

At least 19 recordsLinked to original sources
PubMed2001

Thrombophilia: what's a practitioner to do?

Management of thrombophilia is an ever-changing field as new disorders are described and additional clinical experience accrues. This paper addresses three common management issues in the care of patients with thrombophilia. The first two topics are updates for common but perplexing hypercoagulable states and the last topic introduces a new option for optimal management of oral anticoagulant therapy. Dr. Jacob Rand updates and organizes the approach to patients with antiphospholipid syndrome. This syndrome is a common acquired thrombophilic state, but the diagnosis and treatment of patients remains a challenge. Dr. Rand outlines his diagnostic and treatment strategies based on the current understanding of this complicated syndrome. Dr. Barbara Konkle addresses the special concerns of managing women with thrombophilia. Hematologists are often asked to advise on the risks of hormonal therapy or pregnancy in a woman with a personal or family history of thrombosis or with an abnormal laboratory finding. Dr. Konkle reviews the available data on the risks of hormonal therapy and pregnancy in women with and without known underlying thrombophilic risk factors. In Section III, Dr. Gail Macik will discuss a new approach to warfarin management. Several instruments are now available for home prothrombin time (PT) monitoring. Self-testing and self management of warfarin are slowly emerging as reliable alternatives to traditional provider-based care and Dr. Macik reviews the instruments available and the results of studies that support this new management option.

Blood Coagulation Tests↗
PubMed1999

Acquired autoantibodies to coagulation factors.

Acquired coagulation factor antibodies are either alloantibodies or autoantibodies. Alloantibodies are formed when the body reacts to an external antigen. Commonly, alloantibodies arise when a patient who has a congenital clotting factor deficiency is infused with a blood product. Alternately, patients exposed to a coagulation protein from a different species may develop alloantibodies to the animal protein that cross-reacts with their own protein. On the other hand, autoantibodies develop spontaneously in people without pre-existing factor deficiencies and without exposure to an external antigen. These antibodies may neutralize function of a clotting factor, promote rapid clearance of a clotting factor from the blood, or alter the clotting factor in such a way that the protein-antibody complex acquires a unique function. This review focuses on recent reports of autoantibodies directed against fibrinogen, prothrombin, factor V, factor VII, factor X, and von Willebrand factor, in which these various activities of autoantibodies are illustrated.

Autoantibodies↗
PubMed1995

Designing a point-of-care program for coagulation testing.

The prothrombin time and the activated partial thromboplastin time are routinely used to diagnose hemostatic disorders and to monitor anticoagulation therapy. Several coagulation test systems are now available that perform whole blood prothrombin time and activated partial thromboplastin time assays at the point of patient care. Many hospitals are evaluating point-of-care programs to satisfy the clinical demand for more expedient return of laboratory results. A successful point-of-care program requires the cooperation of laboratorians to assess validity of the methodology and clinicians to evaluate the clinical merit of the system. In this paper, the criteria for choosing a valid and appropriate point-of-care coagulation system are discussed and guidelines for implementing a coagulation point-of-care program are suggested.

Blood Coagulation Tests↗
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

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

Pharmacokinetics and pharmacodynamics of recombinant factor VIIa.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa). METHODS: Single-dose pharmacokinetics of three dose levels (17.5, 35, and 70 micrograms/kg) of rFVIIa were investigated in 15 patients with hemophilia with severe factor VIII or factor IX deficiency (with or without inhibitors) while they were in the nonbleeding state and during bleeding episodes. Factor VII clotting activity (FVII:C) was determined 5 minutes before and at 10, 20, and 50 minutes and 2, 4, 6, 8, 12, and 24 hours after rFVIIa administration. Model-independent pharmacokinetic analysis of FVII:C plasma concentration-time data included determination of plasma clearance, mean residence time, and volume of distribution. rFVIIa recovery was determined from the plasma FVII:C observed 10 minutes after administration. Pharmacodynamic assessments of prothrombin time, activated partial thromboplastic time, and Factor X values obtained concurrently with FVII:C samples were performed. RESULTS: Sufficient data to allow pharmacokinetic parameter calculation were available for 25 nonbleeding episodes in 11 patients (17.5 micrograms/kg, n = 8; 35 micrograms/kg, n = 9; 70 micrograms/kg, n = 8) and for five bleeding episodes in three patients (17.5 micrograms/kg, n = 2; 35 micrograms/kg, n = 2; 35 micrograms/kg, n = 1). Recovery was calculated during 27 nonbleeding and 17 bleeding episodes. rFVIIa distribution volume is two to three times that of plasma. Median clearance was low--31.0 ml/hr.kg in nonbleeding episodes and 32.5 mg/hr.kg in bleeding episodes. In nonbleeding episodes, median mean residence time was 3.44 hours and median half-life was 2.89 hours. In bleeding episodes, the elimination rate appears to be higher, with a median mean residence time of 2.97 hours and a median half-life of 2.30 hours. Recovery was 45.6% during nonbleeding conditions and 43.5% during bleeding episodes (p = 0.0006); it was statistically lower with the highest dose level than with the 17.5 and 35 micrograms/kg doses (p = 0.007). A significant statistical relationship was observed between values of the prothrombin time and activated partial thromboplastin time, and values of FVII:C with use of maximum effect model. CONCLUSIONS: The pharmacokinetics of rFVIIa are linear in the dose range evaluated. The results suggest potential value of prothrombin time determination in the monitoring of rFVIIa therapy.

Adolescent↗
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 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↗
PubMed1994

Evaluation of sensitivity and specificity of six D-dimer latex assays.

The results of six commercially available D-Dimer latex assays were compared with those obtained by two D-Dimer enzyme-linked immunosorbent assay; this comparison was done by assessing the sensitivity and specificity of the assays. Results indicated that five of the six latex assays were unable to detect consistently D-Dimer levels (ie, equal to the claims stated in the manufacturers' package inserts). Performance, in order of decreasing sensitivity ([true positive/(true positive+false negative)] as compared with the enzyme-linked immunosorbent assay results), was as follows: ACCUCLOT D-Dimer (Sigma Diagnostics, St Louis, Mo) (93.8%) greater than Fibrinosticon (Organon Teknika Corp, Durham, NC) (81.3%) greater than D-Di Test (Diagnostica Stago, Asnières, France) (68.8%) greater than Dade Dimer-test Latex Assay (Baxter Diagnostics Inc, Miami, Fla) (59.4%) greater than Dimertest Latex Kit (American Diagnostica Inc, Greenwich, Conn) and DimerKlone (Ortho Diagnostic Systems Inc, Raritan, NJ) (56.3%). The estimated sensitivity for the lowest sensitivity assays (group 1) (American Diagnostica Inc, Ortho Diagnostic Systems, and Dade Diagnostics) was approximately 1.5 mg/L; the estimated sensitivity for the moderate sensitivity assays (group 2) (Organon Teknika Corp and Diagnostica Stago) was approximately 1.0 mg/L; and the estimated sensitivity for the highest sensitivity assay (group 3) (Sigma Chemical Co) approached a detection limit in the 0.25- to 0.50-mg/L range.

Enzyme-Linked Immunosorbent Assay↗
PubMed1993

Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.

Although the majority of factor VII (FVII) circulates in the zymogen form, low levels of activated factor VII (FVIIa) have been postulated to exist in plasma and to serve a priming function for triggering of the clotting cascade. However, direct measurement of plasma FVIIa has not previously been possible. We have quantified plasma FVIIa levels using a novel, highly sensitive assay that is free from interference by FVII. Specificity of this clot-based assay results from the use of a mutant tissue factor that is selectively deficient in promoting FVII activation, but retains FVIIa cofactor function. In normal adults, FVIIa was found to be present in plasma (mean: 3.6 ng/mL) with considerable variation between individuals (range: 0.5 to 8.4 ng/mL). FVIIa levels were only loosely correlated with FVII coagulant activity, but were elevated in pregnancy and reduced with oral anticoagulant therapy. Incubation of plasma on ice in glass containers (cold activation) resulted in substantial FVIIa generation. Measurement of plasma forms of factor VII is of potential clinical importance because elevated FVII coagulant activity has been implicated as a significant risk predictor for ischemic heart disease. Clinically, this new assay will now permit direct assessment of the role of plasma FVIIa in thrombotic disorders.

Adult↗
PubMed1993

Treatment of factor VIII inhibitors: products and strategies.

Treatment of patients with inhibitors to FVIII remains a complex clinical problem. Although characterizing the individual patient may aid in the initial development of a care plan, no treatment is uniformly reliable for all patients. Experts in the field are as likely to disagree as agree when it comes to choosing treatment options; few randomized clinical trials exist on which to base decisions.

Autoantibodies↗
PubMed1993

Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a phase I study.

The safety and efficacy of recombinant DNA-produced factor VIIa (rFVIIa) was investigated in 15 haemophilic patients in non-bleeding states and during bleeding episodes (mild to moderate joint bleed). Patients with severe haemophilia A without inhibitors (n = 4), haemophilia A with inhibitors (n = 10), and haemophilia B with inhibitor (n = 1) received one or more doses of rFVIIa during 32 non-bleeding study episodes and 23 bleeding episodes. The study was an open, uncontrolled, dose-escalation (17.5 micrograms/kg, 35 micrograms/kg, 70 micrograms/kg) trial. Physical evaluation, laboratory assessment, and immunology testing were conducted at baseline, monthly for 3 months and every 3 months thereafter. The immediate safety of rFVIIa was assessed by monitoring of D-dimer, fibrinogen, platelet count, antithrombin III, thrombin-antithrombin complex, and alpha 2-antiplasmin 5 min before and at multiple times throughout the following 24 h. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values were also obtained. Pain, swelling, joint circumference, and range of motion were recorded before administration of the initial dose of rFVIIa in bleeding patients and at 6, 12, and 24 h. Haemostatic response to rFVIIa was observed in patients with severe VIII and IX deficiency with and without inhibitors. Therapy with rFVIIa was judged effective in 19 of the 22 evaluable bleeding episodes at one or more time points. The 35 micrograms/kg and 70 micrograms/kg doses were associated with higher response rates at 6 and 12 h compared to the 17.5 micrograms/kg dose level. A second dose of rFVIIa was administered in 20 of the 22 bleeding episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor X in the absence of tissue factor.

Clinical trials have recently begun using high concentrations of activated recombinant factor VII (rFVIIa) for the treatment of hemophilic patients with inhibitors. Unexpectedly, the activated partial thromboplastin time (aPTT) was observed to be significantly shortened during infusion of the rFVIIa. To determine the mechanism for this shortening, the effect of rFVIIa on both the prothrombin time (PT) and the aPTT of normal and various factor-deficient plasmas was examined. rFVIIa shortened the PT of all plasmas tested except FX and FV deficient plasmas. rFVIIa also shortened the aPTT of all plasmas tested except FX and FV deficient plasmas. Since there is no added tissue factor (TF) in aPTT reagents, rFVIIa appeared to shorten the aPTT in the absence of TF. To investigate this possibility, the activity of rFVIIa in a purified system containing only FX, phospholipid vesicles (1:1 PS:PC), and calcium was examined. In this system, rFVIIa activated factor X in the absence of TF. If any component of the purified system was omitted, there was no detectable activation of FX. Thus it appears that calcium and phospholipids are required for the activation of FX by rFVIIa in the absence of TF. Increasing the concentration of rFVIIa increased the rate of FX activation, but the rate of activation was always much lower than that observed with even trace amounts of tissue factor. We conclude that high concentrations of rFVIIa, in the presence of calcium and phospholipid, can directly activate FX in the absence of TF and hence account for the shortening of the aPTT in inhibitor patients treated with rFVIIa.

Blood Coagulation Tests↗
PubMed1989

Protein C inhibitor: purification and proteinase reactivity.

Protein C inhibitor was purified from human plasma by a modification of a published procedure (Suzuki, K., Nishioka, J., and Hashimoto, S. J. Biol. Chem. 258, 163-168, 1983). Approximately 1 mg of pure protein was obtained from 1 L plasma, a yield of about 17%. The protein C inhibitor preparation did not lose activity over 4 weeks at 4 degrees C. Second order rate constants were measured for the inhibition of activated protein C, thrombin, and urokinase, and bimolecular complexes of protein C inhibitor with activated protein C and thrombin were visualized by denaturing polyacrylamide gel electrophoresis. Heparin accelerated the inhibition of the three proteinases in a manner consistent with a template mechanism. Plasma or pure protein C inhibitor (at the same concentration) showed the same effect of heparin on activated protein C inhibition, indicating that protein C inhibitor accounts for all the heparin-dependent inhibition of activated protein C in vivo.

Blood Proteins↗
PubMed1989

Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor.

Treatment options during an acute hemorrhage for a hemophilic patient who has an inhibitor (antibody) to factor VIII (FVIII) are limited. If the inhibitor titer is high, even massive doses of FVIII are not sufficient to neutralize the antibody. Likewise, immunoadsorption techniques or plasmapheresis cannot remove enough antibody to permit treatment with FVIII. Allergic reactions and cross-reacting inhibitors complicate therapy with porcine FVIII. Prothrombin complex concentrates (PCC) may be effective but the mechanism is unclear. The theory that activated factor VII (FVIIa) is the active principle in PCC prompted our treatment of a patient with a recombinant FVIIa (rFVIIa) product (NOVO Industries). The patient presented with a large retropharyngeal hemorrhage and an initial inhibitor titer of 129 Bethesda units (BU). Despite Autoplex therapy (100U/kg), tracheal compression by the hematoma increased and asphyxiation was imminent. RFVIIa therapy (60 micrograms/kg) was substituted for Autoplex and nine doses were given without complication. The hemorrhage was controlled. By 18 hr breathing was normal and swallowing and speech were greatly improved. Clinically, the patient dramatically responded to rFVIIa. In addition, the purity, the lack of known infectious agents, and the ease of administration make rFVIIa a potentially attractive new therapy. Use of this product also promises to further our understanding of in vivo hemostasis.

Adult↗
PubMed1988

The heparin flush syndrome: a cause of iatrogenic hemorrhage.

The anticoagulant drug heparin is used extensively in modern hospital practice. The major therapeutic use of this drug remains treatment and prevention of systemic thrombosis. However, an increasing amount of heparin is being used in nontherapeutic protocols to implement newer, more invasive technology when the body's protective clotting mechanism would otherwise interfere. Buried in protocols, heparin has become ubiquitous in standard hospital practice. One such protocol is the use of heparinized solutions to "flush" arterial and venous catheters in order to maintain patency and thus, vascular access. Often these flush solutions are considered to be as innocuous as "simple saline." We report a patient who experienced post-operative bleeding resulting from overuse of "heparin flushes," and necessitating a second surgery. The excessive hemorrhage following this inadvertent anticoagulation has been named the "heparin flush syndrome," to call attention to the serious and sometimes fatal side-effects of heparinized solutions.

Aged↗
PubMed1988

The use of high-dose intravenous gamma-globulin in acquired von Willebrand syndrome.

Acquired von Willebrand syndrome has been reported in patients with a variety of primary diseases, many immunologic in nature. Usually, an autoantibody to von Willebrand factor can be identified. These patients often experience severe hemorrhages requiring large doses of cryoprecipitate or factor VIII concentrates, thus exposing them to viral and allergic complications. The success of intravenous gamma-globulin in the treatment of other autoimmune diseases prompted us to treat two patients with acquired von Willebrand syndrome with high-dose intravenous gamma-globulin. Two days after initiation of therapy, von Willebrand factor and factor VIII rose to normal levels in both patients. Patient 1 underwent dental surgery, and patient 2 underwent a splenectomy without increased bleeding and without additional factor coverage or desmopressin acetate therapy. Thus, intravenous gamma-globulin is efficacious for acquired von Willebrand syndrome and obviates the need for replacement therapy with its attendant complications.

Aged↗