scholarly journals The Natural History of “Inhibitors” to Factors VIII and IX in Hemophiliacs

1977 ◽  
Author(s):  
C.E.C. Harris
Keyword(s):  
Factor Viii ◽  
Room Temperature ◽  
Factor Ix ◽  
Standard Dosage ◽  
The Past ◽  
Frequent Administration ◽  
Life Threatening ◽  
History Of ◽  
Viii And Ix

Since 1954 an increasing number of adult hemophiliacs have been followed and “inhibitors” have been found in a minority of patients. A retrospective study was made of 9 factor-VIII and of 9 factor-IX cases who have attended with sufficient regularity for adequate documentation. The presence of this complication was, until recently, suspected because of failure clinically to respond to replacement therapy and confirmed by the original Biggs’ technique in the laboratory. In the past k years, this has been replaced by her method using serial dilutions at room temperature and at 37°C, incubated for 1 hour. In addition, studies have been made of factor recovery and survival following infusions.In no case were immuno-suppressive agents used. There were no deaths. Life-threatening crises were met by conservative measures, including hypothermia, and by the use of porcine factor-VIII. Instances when in vivo survival of infused concentrate was shortened were usually managed successfully by more frequent administration of equal or lesser dosage quantities; it was exceptional in such cases to witness enhancement of “inhibitor” potency as a consequence.In no less than 6 of the 9 patients would it seem that the “inhibitor” has disappeared and full clinical response is now being obtained with standard dosage schedules. The nature of “inhibitors” would not seem to be well understood.

Heated Lyophilized Factor VIII And Factor IX Concentrate Preliminary In Vitro Studies

1981 ◽  
Author(s):  
A Rubinstein
Keyword(s):  
Factor Viii ◽  
Hepatitis Virus ◽  
Heating Time ◽  
Significant Loss ◽  
Factor Ix ◽  
Factor Viii Activity ◽  
Viii And Ix ◽  
Plasma Protein Fraction

It has been known that albumin and plasma protein fraction (PPF) do not transmit hepatitis since these products are heated at 60°C for 10 hours. This heating is sufficient for inactivation of hepatitis virus. It has been previously tried to heat the Cohn Fractions leading to Factor VIII and Factor IX Concentrates in solution, however, this has resulted in significant loss of Factors VIII and IX.We have taken lyophilized Factor VIII Concentrate powder and heated it in a waterbath at 60°C for 10 hours and have demonstrated no significant change in in vitro recovery of Factor VIII activity four hours following the heating. The same was shown for recovery of Factor IX activity after heating lyophilized Factor IX concentrate for 10 hours at 60°C. In addition Factor IX activity was not destroyed following heating of the lyophilized powder for 20-30 minutes at 100°C. This is significant because now potentially this heated lyophilized powder of Factor VIII and Factor IX is free of previous risk of transmission of hepatitis. However, the effect of heating on the thrombogenic effects in vivo of the concentrates and complications was not assessed in this study. Chimpanzee studies are planned to determine whether the heating has inactivated the hepatitis virus.It is possible that a longer heating time will be needed to sufficiently inactivate the hepatitis virus in the lyophilized state.

THE MODE OF ACTION OF PENTOSAN POLYSULPHATE IN PLASMA

1987 ◽  
Author(s):  
S Béguin ◽  
H C Hemker
Keyword(s):  
Factor Viii ◽  
Linear Increase ◽  
Factor Ix ◽  
Factor X ◽  
Heparin Cofactor Ii ◽  
Normal Plasma ◽  
Viii And Ix ◽  
Pentosan Polysulphate ◽  
Lag Times ◽  
Prothrombinase Activity

We developed a method which enables as to compute the course of prothrombinase activity in clotting plasma (H.C. Hemker, G.M. Willems, S. Béguin: Thromb. Haemostas. 56, 9-17, 1986) and used this for a study of the effect of pentosan polysulphate (PPS) on thrombin generation.When added to normal plasma in the concentration range of 0-8 μg/ml PPS induces a linear increase of the pseudo first order decay constant of endogenous thrombin like heparin does, 1 ug of PPS being equivalent to 0.045 Aig of heparin. Contrary to heparin this action is partly (∼ 65%) dependent upon AT III and partly (∼ 35%) upon heparin cofactor II.In normal plasma PPS causes an inhibition of both extrinsic and intrinsic prothrombinase formation. Only in the intrinsic system an increase of the lag time of prothrombinase appearance is observed. Unlike heparin, PPS does not inhibit factor IXa induced thrombin formation neither does it inhibit prothrombinase formation in the presence of preactivated factor VIII. The prolongation of the lag times must therefore be ascribed to inhibition by PPS of the activation of factor VIII.The inhibition of extrinsic prothrombinase formation by PPS increases with progressive dilution of thromboplastin and is not seen in haemophilia A or B plasma. This demonstrates the existance of a factor VIII and IX dependent process in extrinsic coagulation that gains in importance when the potency of factgr VII-tissue factor complex decreases, i.e. the Josso pathway.PPS, but also heparin causes an unexplained increase of prothrombinase action in haemophIIic plasma. The same phenomenon may be expected to exist in normal plasma, be it obscured by a concomitant inhibition. This, together with the incomplete inhibition of factor VIII activation by PPS makes that we cannot use this inhibitor as a means to quantitate the Josso pathway. The best estimate that we can obtain is that, in the presence of 2% thromboplastin, the factor IX dependent activation of factor X contributes more then 20% to prothrombinase generation.

Possible GoLytely-Associated Cardiac Arrest: A Case Report and Literature Review

2019 ◽  
Vol 33 (3) ◽  
pp. 364-367 ◽  
Author(s):  
Yoonsun Mo ◽  
Shiv Gandhi ◽  
Jose Orsini
Keyword(s):  
Cardiac Arrest ◽  
Abdominal Pain ◽  
Sudden Cardiac Arrest ◽  
Lower Abdominal Pain ◽  
The Past ◽  
Life Threatening ◽  
History Of ◽  
Artery Disease ◽  
Possible Cause

Purpose: To report a case of sudden cardiac arrest possibly associated with the administration of GoLytely® (polyethylene glycol 3350 and electrolytes). Summary: A 60-year-old male with a history of hypertension, hyperlipidemia, type 2 diabetes, and coronary artery disease presented to the emergency department with complaints of constipation and lower abdominal pain over the past week, and the inability to urinate over the past day. The patient had received GoLytely as treatment to alleviate symptoms of constipation and abdominal pain. However, several hours after administration of the bowel prep solution, the patient suffered an episode of cardiac arrest. After ruling out other possible etiologies, GoLytely was suspected as a possible cause of cardiac arrest. The patient had suffered an anoxic brain injury and remained intubated and unconscious until he eventually expired, 20 days after the event. Conclusion: Although GoLytely appears to be a safe agent with fewer side effects, clinicians need to be mindful of potential life-threatening adverse events following GoLytely administration and monitor patients closely during and after administration.

scholarly journals Preliminary Report of the Cooperative Study of Spontaneously Occuring Factor VIII Inhibitors in Patients with Hemophilia

1977 ◽  
Author(s):  
S.S. Shapiro
Keyword(s):  
Factor Viii ◽  
The United States ◽  
General Information ◽  
Factor Ix ◽  
Cooperative Study ◽  
Computer Center ◽  
Hbsag Positivity ◽  
Blood Institute ◽  
National Heart Lung ◽  
History Of

A cooperative study was started in July 1975, sponsored by the Division of Blood Diseases, National Heart, Lung and Blood Institute, National Institutes of Health. The study includes 11 cooperating Centers throughout the United States as well as a computer center. All patients with Factor VIII coagulant levels below 0.10 u/ml (or even higher, if transfused often) are eligible for entry. Currently more than 1200 patients have been entered, including more than 200 with Factor VIII inhibitors. General information concerning the natural history of hemophilia is being collected, including a comparison of severity assessed clinically and in the laboratory, the incidence and degree of liver dysfunction, HBsAg positivity, and hypertension. More than 200 patients with Factor VIII inhibitors have been identified, falling clearly into categories of “strong” and “weak” antibody producers. More than 200 treatment episodes have been documented in inhibitor patients, over 100 treated with Factor VIII and an equal number treated with Factor IX concentrates. Among the latter, some 20% have resulted in secondary rises in Factor VIII antibody titer. A controlled, blinded study of the efficacy of several Factor IX concentrates will begin shortly, and should be completed within a year.

An Enzyme-Linked Immunosorbent Assay (ELISA) For Factor VIII Inhibitors

1981 ◽  
Author(s):  
C H Miller ◽  
M W Hilgartner ◽  
D R Lopez
Keyword(s):  
Factor Viii ◽  
Color Change ◽  
Factor Ix ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Igg ◽  
Elisa System ◽  
Microtiter Plates ◽  
Enzyme Substrate ◽  
Normal Individuals ◽  
History Of

ELISA microtechniques are suitable for measurement of a variety of antigens and antibodies. They are sensitive, safe, and easy to perform. Enzyme-labeled antibodies to factor VIII and factor IX can be used to measure antigen in a “sandwich” assay analogous to the immunoradiometric assay (IRMA). Likewise, specific antibodies can be easily quantitated in plasma samples. Quantitation of F. IX inhibitors by ELISA has been performed by Orstavik and colleagues. We have studied use of the ELISA system for measurement of inhibitors to factor VIII. Purified factor VIII prepared from concentrate is bound to plastic microtiter plates, which are then incubated with plasma dilutions. After washing to remove non-bound material, heterologous anti-human IgG labeled with alkaline phosphatase is added. It binds to any hyman IgG remaining on the plate. Following incubation and washing, the enzyme substrate, p-nitro- phenyl phosphate, is added. Degradation of the substrate produces a color change which is read spectrophoto-metrically. A “through-the-plate” reader allows rapid OD measurements without transfer of the well contents. Ten or more samples in dilution series can be tested simultaneously. The inhibitor titer may be quantitated by comparison with a standard inhibitor measured in Bethesda units by a clotting assay or by direct comparison with the OD curve produced by known quantities of human IgG. Twelve known inhibitors from hemophilia patients and two acquired non-hemophilic inhibitors showed good correlation with the Bethesda unit method. Five normal individuals and five hemophiliacs with no history of inhibitor by clotting assay showed no anti-IX inhibitor by this test.

A Non-Stasis Rabbit Model for the Detection of Factor IX Concentrate Thrombogenicity.

1979 ◽  
Author(s):  
C.V. Prowse ◽  
A.R. Williams
Keyword(s):  
Platelet Count ◽  
Factor Viii ◽  
Partial Thromboplastin Time ◽  
Rabbit Model ◽  
Factor Ix ◽  
In Vitro Activity ◽  
Blood Samples ◽  
Intravascular Coagulation

A method has been developed whereby aerial blood samples can be obtained from a rabbit over a period of four hours following infusion of potentially thrombogenic solutions. Infusion of 50 uAg thrombin over JO minutes produced intravascular coagulation for up to three hours after infusion as demonstrated by a decrease in factor VIII, increase in partial thromboplastin time and fibrin(ogen) degradation producta and a positive ethanol gelation teat. No change in fibrinogen, factor DC or platelet count was found. Saline infusion produced no change in any of these parameters.Infusion of a variety of factor IX concentrates at 100 u/kg shewed that those concentrates active in in vitro thrombogenicity teste produced a similar effect to thrombin in vivo and in addition may result in a drop in platelet count. Infesion of concentrates with low in vitro activity did not induce intravascular coagulation.

Use of Digoxin-Specific Fab Fragments in the Treatment of Digitalis Intoxication

1986 ◽  
Vol 20 (4) ◽  
pp. 267-270 ◽  
Author(s):  
Patricia L. Cole ◽  
Thomas W. Smith
Keyword(s):  
Digitalis Intoxication ◽  
High Affinity ◽  
The Past ◽  
Fab Fragments ◽  
Homogeneous Product ◽  
Intact Antibody ◽  
Life Threatening ◽  
Antibody Population

The narrow margin between therapeutic and toxic effects of digitalis glycosides renders patients taking these drugs particularly susceptible to serious consequences of accidental or deliberate overdosage, including life-threatening arrhythmias. Until recently, the treatment of digitalis intoxication has been largely supportive. In the past decade, however, digoxin-specific antibodies have been developed and have proven to be effective in rapidly reversing the electrophysiologic and metabolic manifestations of digitalis intoxication, both in vitro and in vivo. Enzymatic cleavage of the intact antibody population into Fab fragments results in a more rapidly effective and less immunogenic antidote to digitalis excess. More recently, monoclonal antibodies with high affinity and specificity for digoxin have been produced by the technique of somatic cell fusion; application of this technique to the production of anti-digoxin antibodies has potential implications for the production of a highly purified homogeneous product, but this approach has not yet been tested clinically.

Effect of Stanozolol on Factors VIII and IX and Serum Aminotransferases in Haemophilia

1985 ◽  
Vol 53 (03) ◽  
pp. 386-389 ◽  
Author(s):  
I A Greer ◽  
M Greaves ◽  
R Madhok ◽  
K McLoughlin ◽  
N Porter ◽  
...  
Keyword(s):  
Factor Viii ◽  
Anabolic Steroid ◽  
Anabolic Steroids ◽  
Factor Ix ◽  
Chronic Liver Diseases ◽  
Oral Agent ◽  
Interesting Possibility ◽  
Consistent Change ◽  
Viii And Ix ◽  
Serum Aminotransferases

SummaryThe treatment of haemophilia has been dramatically improved since the introduction of factor VIII and IX concentrates, however these concentrates have brought new problems such as hepatitis and A.I.D.S. An oral agent which could raise endogenous levels of factor VIII and IX would be of great benefit. Danazol, an anabolic steroid, has recently been shown to increase levels of factors VIII and IX in haemophilia. We therefore studied the effect of stanozolol, a closely related anabolic steroid, in 15 patients with haemophilia A or Christmas disease over a 2-4 week period. There was no consistent change in factor VIIIc or factor IX, and fibrinolysis was significantly enhanced. No effect was apparent on the incidence of spontaneous bleeds. However serum aminotransferases which were abnormal in 11 of the 15 patients at the start of the study fell significantly with stanozolol therapy. This raises the interesting possibility that anabolic steroids may be beneficial in patients with chronic liver diseases.

scholarly journals Clinical Use of Factor IX Concentrates

1977 ◽  
Author(s):  
D. Ménaché
Keyword(s):  
Beneficial Effect ◽  
Factor Viii ◽  
Radical Change ◽  
Factor Ix ◽  
Severe Bleeding ◽  
Factor Viii Inhibitor ◽  
Anamnestic Response ◽  
Viii Inhibitor ◽  
Factor Ix Deficiency

The clinical efficacy of Factor IX concentrates in the treatment of patients with Factor IX deficiency is well recognized. The availability of such concentrates has brought a radical change in the management of these patients. The basis for treatment is to obtain an effective Factor IX hemostatic level in vivo. In these conditions, concentrates have been used to reduce the incidence of hemorrhagic episodes in patients particularly exposed and more often to control hemorrhagic episodes or to prevent hemorrhage in the post operative period. Although thromboembolic complications have occured in some instances the major indication of Factor IX concentrates still remains replacement therapy in patients with Factor IX deficiency.More recently Factor IX concentrates have been used for the treatment of patients with antibody to Factor VIII. Although the therapeutic principle(s) responsible for the Factor VIII inhibitor bypassing activity has not yet been characterized several beneficial effect of both “activated” and non activated Factor IX concentrates have been observed in such patients experiencing minor or severe bleeding episodes. On the other hand we are aware of some cases without beneficial effect of Factor IX concentrates in patients with Factor VIII inhibitor. The major complication would seem to be an anamnestic response in some patients resulting in either a moderate or a considerable increase of the Factor VIII inhibitor titer when compared to the initial level before Factor IX concentrates therapy. If Factor IX concentrates prove to be efficacious in the treatment of patients with Factor VIII antibody special attention would be required in the manufacturing processing in order to avoid an anamnestic response.

Prevalence of Coronary Heart Disease in Patients with Hemophilia: a Nationwide Study in Brazil.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3495-3495
Author(s):  
Claudia Bley ◽  
Fabio P S Santos ◽  
Antonio E P Pesaro ◽  
Ricardo Helman ◽  
Sergio A Oliveira ◽  
...  
Keyword(s):  
Risk Factors ◽  
Surgical Treatment ◽  
Factor Viii ◽  
Antiplatelet Therapy ◽  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor Activity ◽  
Positive History ◽  
History Of

Abstract Abstract 3495 Poster Board III-432 Background It is well known that patients with hemophilia (both A and B) have a lower incidence of coronary artery disease (CAD). However, patients with hemophilia may develop atherosclerosis, and with increases in life expectancy it is possible that the incidence of CAD may increase in these patients. There are no studies analyzing the prevalence of CAD in patients with hemophilia and possible risk factors. Aims To determine the prevalence of CAD in patients with hemophilia treated in Brazil. Methods All patients with hemophilia in Brazil receive therapy with Factor VIII or Factor IX at government-designed hemophilia centers. We thus contacted all centers in Brazil by e-mail and information from databases concerning health information for all patients was reviewed by the responsible physician at each center. A questionnaire about risk factors for CAD and history of coronary events was sent to patients that had a positive history of CAD. Results There are 6,881 patients registered with a diagnosis of hemophilia A and 1,291 patients with a diagnosis of hemophilia B in Brazil. Fifty-six percent of hemophilia centers answered the query, and information on 71.7% of patients with hemophilia A (4,934 patients) and 61.4% of patients with hemophilia B (792 patients) was reviewed. There were only 3 patients (0.05%) with a positive history of CAD. Their clinical characteristics are summarized in Table 1. During surgical treatment for CAD, replacement with Factor VIII and Factor IX was done by continuous infusion to increase Factor activity to 80-100%. Antiplatelet therapy was used in all patients at some point, and one patient (#1) developed hemarthrosis after two months of ASA. Patient #3 did not start antiplatelet therapy after CABG, and developed thrombosis of the graft. ASA and clopidogrel were started after percutaneous coronary angioplasty. Conclusion We found a very low incidence of CAD in hemophiliac patients, even after doing a nationwide survey that included more than 5,000 patients. No information about risk factors can be gleaned due to the small number of patients. Surgical treatment after increasing factor activity appears to be safe in such patients. Despite a theoretical risk for increased bleeding, therapy with antiplatelet agents appears to be necessary in hemophiliac patients with CAD. Disclosures: No relevant conflicts of interest to declare.

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