bluuebunny/crossref_metadata_2025 huggingface dataset:
Defibrination Syndrome Developed after Replacement Therapy with PPSB in a Case of Hemophilia B.
Authors: Kazama M. , Iwakura H. , Nakajima M. , Abe M. , Abe T.
Published: May 2019

A case of Hemophilia B, 20y., had valgus osteotomy of the left femoral neck. The preliminary replacement with PPSB was revealed not to introduce inhibitor and no other abnormal enzyme activity was found except for the slight disturbance of liver function. The operation was gotten ready with injection of 10 vials PPSB and performed smoothly in 2 hours with 340ml of blood loss. PPSB administration was scheduled in a daily dosis of 20 vials divided in twice. But at the third postoperative day, large hematoma concreted in the femoral region with severe pain and was followed by the massive bleeding from the wound. Coagulation tests revealed decreased platelet count, prolonged.PTT and prothrombin time, decreased fibrinogen and increased FDP. The concentration of F.IX was not lifted so high as expected after the injection of 10 vials of PPSB, which, together with the above mentioned changes of coagulation factors, suggested the developement of defibrination syndrome.

The replacement of PPSB was continued together with 10,000 U of heparin and 800ml of fresh plasma per day. At the 7th postoperative day, the coagulation findings of defibrination syndrome were gradually improved, bleeding decreased and F. IX level elevated as could be calculated. The administration of PPSB was diminished and discontinued at 29th day and of heparin at 45th day without any bleeding complication thereafter.
A Method for Assessment and Grading of Osteoarthropathy in Hemophiliacs
Authors: Horoszowski H. , Seligsohn U. , Heim M. , Farine I.
Published: May 2019

Neither of the previously described methods for assessment of hemophilic osteoarthropathy has included all aspects, which we deem, are necessary for appropriate evaluation and follow-up of individual joints and the general state of the patient. We devised a simple method, expressed by scores, which differentially assesses the functional, the objective findings and roentgenologic state of the joints. For the last 4 years, we have been using this method in 110 hemophilic patients in Israel and have found it very efficient for: a) Quantitative comparison of the state of different joints in the same patient, b) Comparison of the state of similar joints in different patients, c) Comparison of the general state of different patients, d) Evaluation of the efficacy of treatment. The method can be easily applied by any physician and may provide means of comparing results achieved by various hemophilia centers.
Surgery in Hemophilic Patients with Inhibitors
Authors: Kelly P.E. , Penner J.A.
Published: May 2019

Major surgical procedures were performed in two hemophilic patients who had developed inhibitors. A total hip replacement was accomplished in one patient with an inhibitor to Factor IX, while a massive retroperitoneal pseudo-tumor was removed from another hemophilic with a Factor VIII inhibitor. Both patients received a single dose of cyclophosphamide prior to surgery. Blood replacement during the procedures reduced inhibitor activity to levels which permitted correction of thepatients’deficiencies with infusions of the appropriate factor. A subsequent rise in antibodies experienced by both patients was sufficient to neutralize the standard doses of factor at six days, and necessitated the use of an activated prothrombin concentrate, Auto IX (Hyland). Peak inhibitor activity was observed at 27 days in the individual with hemophilia B, and fell to pre-treatment levels at 7 months. Inhibitor patient, and has continued to fall slowly 2 months after surgery.
Home Care in Germany: Philosophy of Treatment, Results of Intensive Care
Authors: Brackmann H.H. , Hoffmann P. , Etzel F. , Hildenbrand Eqli H.
Published: May 2019

In the FRG the work of several centers is concerned with introducing a program of self-treatment for hemophi1iacso The general goal of a self-treatment-program is: avoidance of a time lag due to long distances and the expansion of personal freedom and life style possibilities.

In respect to the dosage and treatment duration various opinions exist, some of them differing quite noticably from ours. Our conception about the therapy, existing since the beginning of our program (June 1971), is based on an intensive cooperation with the department of orthopedics at the university. Through our teamwork the following results were achieved:

- the evaluation of 17.196 acute bleedings registered 93% joint and muscle bleedings

- 98% of the patients over 11 years of age with severe and semi-severe hemophilia A or B revealed at least one, in several cases more, arthropathic changes

- the pathophysiological process of a joint bleeding leads to an important electromyographic test as well as to new ideas about biomechanic.

Based on the general test results a specific dosage plan for each patient resulted, which, together with the orthopedic findings took into consideration the attained biological recovery. Since our goal is the strenghtening and training of muscle in general, every patient receives a specially adopted training program, which largely excludes bleeding. Our results have lead to a 90% improvement of the original orthopedic finding.
Personality Characteristics of Hemophiliac Children
Authors: Ackerman L.L. , Charney D.S. , Verrecchio J. , Eyster M.E.
Published: May 2019

The personality characteristics of hemophiliac children were assessed in 22 hemophiliacs, mean age of 12.2 years. Twelve had < 1%, 4 had 1-3%, 3 had 4-9%, and 3 had > 10% Factor VIII levels. Eleven boys, 8 to 11 years old were given the Children’s Personality Questionnaire, while the other eleven, ages 12 to 18 years were administered the Junior-Senior High School Questionnaire.

Both personality questionnaires measured 14 personality factors, each defining specific personality traits. Means for the 22 hemophiliacs were obtained and compared to values for a control population. Scores for factors B, F, G, M, O, and Q3 were found to differ from the normal range (40.0-60.0) and indicated that, as a group, the hemophiliac children were brighter (B, 72.4), more sober (F, 34.6), more timid (M, 36.8), and their inner feelings and overt behavior poorly integrated (G, 33.4 and Q3, 36.6).

The personality profiles of these children are similar to the profiles of children frequently diagnosed as Overly Inhibited Personality Disorder, as defined by the Group for the Advancement of Psychiatry (GAP) classification.
Feasibility of Antifibrinolytic Treatment in Hemophilia: Preliminary Study
Authors: Scaraggi F A. , Ripa T. , Oreste A. , Schiavoni M. , Ciavarella N.
Published: May 2019

We present a randomized clinical trial of prophylactic antifibrinolytic treatment carried out for a period of 15 days in a summer camp (Rosamarina-Puglia-Italy) on 22 hemophiliacs: 11 were treated with A.M.C.H.A and 11 without. Both groups were homogeneous regarding age of patients, type and severity of the disease. The aims of study were: 1- Prophylaxis of the spontaneous recurrent hemarthrosis 2- Possible saving of hemoderivate after traumatic hemarthrosis 3- Possible acceleration of the recovery. The first group was treated with 500 mg of A.M.C.H.A per person given by mouth three times a day. The number of hemarthrosis were 26 in the prophylactic group and 20 in the control. The total amount of units of factor VIII or IX were 7600 in the treated group, while they were 13200 in the control. The average amount of plasma factor units per person in the treated group were 690, while they were 1200 in the control one. Finally in all but one of the treated patients we observed that only one infusion was sufficient to recover the hemorrhagic episode. Our results are encouraging and can stimulate a double-blind multicenter clinical trial on the prophylactic treatment in hemophilia.
Diagnostic and Therapeutic Problems in a Patient with Factor VIII Inhibitor
Authors: Sas G. , Petö I. , Csörgö M. , Köves Á , Kun L.
Published: May 2019

An old man was admitted to our hospital with the suspicion of acute abdomen. Sonography was used to visualize the psoas haematoma which accounted for the severe abdominal pain and made it possible to avoid an explorative laparotomy. We found a circulating anticoagulant against factor VIII /4 Bethesda units per ml plasma/. The antibody belonged to the IgG class. The patient was treated repeatedly by transfusions of fresh blood, large doses of cryoprecipitate and prednisolone. The improvement of the haemorrhagic symptoms was slow and a long term imtnuno - suppressive therapy was introduced. After a symptom-free year a massive bleeding occured in the thigh and in the psoas muscle. FEIBA therapy was introduced /plus prednisolone & azathioprine/. At first 15 units of FEIBA/kg were administered but the long clotting time did not change. In the following days the quantity of the FEIBA was gradually increased up to 60 units/kg but the coagulation time did not shorten significantly. The PTT became longer, the antithrombin III level decreased. At the same time a definite clinical improvement was observed.

In our case sonography has proved a very useful tool in the diagnosis of psoas haematoma. However, the value of therapy applied could not be judged just as unequivocally.
Von Willebrand Disease Combined with Factor V Deficiency: Variant Bari
Authors: Ciavarella N. , Scaraggi F.A. , Petronelli M. , Coviello M. , Oreste A. , De Mitrio V. , Schiavoni M. , Bonomo L.
Published: May 2019

We report a new variant of the von Willebrand’disease combined with a deficiency of Factor V. A 35 yr. old woman presented a history of severe hemorrhagic diathesis with prolonged epistaxis, gum bleeding and menometrorrhagias, one of which caused hysterectomy. PT 24"/15", aPTT 70"/33", F.V 8%; Template Ivy Bleeding Time (BT) 15'-10'; VIIIC 7%, VIIIRAG 76%, VIIIWF 48%; Platelet Retention (PR) 95%; Ristocetin-Induced Platelet Aggregation (RIPA) > 2.0 mg/ml; Electrophoretic mobility was normal. Other plasmatio and platelet assays were normal. The propositus has two female children. One presented: BT 5'30" - 6'30"; F.V 137%; VIIIC 54%, VIIIRAG 66%, VIIIWF 56%. The other. BT 5'-8"; F.V 107%; VIIIC 29%, VIIIRAG 30%, VIIIWF 37%. One of her two sisters has F.V 53%. The other was normal. One of her two brothers has VIIIC 84%, VIIIRAG 65%, VIIIWF 52%. The other was normal. As her father died of a severe hemorrhagic episode, we studied her three aunts. One has VIIIC 44%. Another has BT 7'30" and F.V “borderline. The third has F.V “borderline. In all the subjects presented PR was normal, while in all but two RIPA was reduced. This new variant may represent a genetical link between the von Willebrand’disease and a combined deficiency of F.VIII and F.V.
Hemophilia in a Chromosomal Female - An Extreme Example of Lyonization?
Authors: Lusher J.M. , Penner J.A. , Warrier I. , Evans R.K.
Published: May 2019

Severe Factor (F.) VIII deficiency is rare in females. We have previously reported two (unrelated) females with 1-3% F. VIII activity (Jour. Pediatr. 74:265-271, 1969). This report concerns a third Michigan female with Hemophilia A. Although this 12 year old girl’s F. VIII activity has ranged from 1-3% she has had only occasional hemarthroses. Her bleeding time is normal, her platelets aggregate normally with ristocetin and F. VIII antigen quantitation has varied from 1.02-1.40 μ/ml. In addition, platelet retention in a glass bead column has been normal. Her father has classical hemophilia A (F. VIII activity <1%, F. VIII antigen 1.61 μ/ml., normal bleeding time and normal platelet aggregation with ristocetin), while her mother appears to be normal (F. VIII activity 90-105% with corresponding values for F. VIII antigen, normal bleeding time and normal platelet aggregation with ristocetin). The child’s only sibling, a 9 year old sister has a F. VIII activity of 40-46%, F. VIII antigen of 1.40 μ/ml., normal bleeding time and normal platelet aggregation with ristocetin. While both girls are obligate carriers, one can only speculate on the reasons for the very low levels of F. VIII activity in the propositus. Although it is possible that there was a spontaneous mutation in the propositus’ maternal X chromosome, it seems likely that her 1-3% F. VIII activity reflects an extreme degree of lyonization.
Standartization of Heparin Therapy in Nyocardial Infarction
Authors: Zahavi J. , Smetana S.
Published: May 2019

Sixty patients with myocardial infarction were randomized for intravenous 10 days heparin therapy, 400 U/ kg/ 24 hrs. In 20 of them, sodium heparin was injected every 6 hours and in another 20, by a continuous infusion preceded by a bolus of 50 U/kg. The remaining 20 patients were used as controls. Blood was drawn pre and 1-4 hours post heparin injection and then twice daily for the following tests: heparin tolerance, activated partial thromboplastin time (APTT), heparin half life and level. During continuous drip, theurapeutic anticoagulation (TA), 1,5–2,5 time control APTT levels, was maintained most of the time with daily and interindividual variations. When heparin was injected intermittently (I), TA was achieved only in the first 3–4 hours. In addition, a significant negative correlation between plasma fibrinogen and APTT, as well as a positive one between APTT and plasma heparin level, were found. These results suggest that heparin dose should be individualized during continuous infusion and when it is injected I, frequency of injections should not exceed 4 hours and the daily dose must presumably be higher then 400 U/kg, Plasma fibrinogen seems to be an important factor influencing negatively the heparin activity and should be considered during anticoagulant therapy with heparin.
An in Vivo Model for the Study of Antithrombotic Drugs
Authors: Strachan C.J. L. , Hawker R.J. , Fejfar J.
Published: May 2019

A series of experimental animal models have been developed (a) to produce a model for double blind crossover assessment of new and existing antithrombotic drugs, and (b) to investigate the nature of the initiating factor in venous thrombosis. The following table describes results from 4 models in 80 dogs and 8 baboons.

Types I, II, III involved bilateral femoral vein dissection but type IV was unilateral, jugular and femoral and allowed crossover studies. The 2.5 milliamps for 10 minutes was standard but if no current passed in Type IV with jugular electrodes in situ, no thrombus was produced in the femoral vein indicating a third factor is required i.e. circulatory, as in Virchow’s triad. Partial thromboplastin time, euglobulin lysis, white blood count, haematocrit, platelet count, fibrinogen and fibrinogen turnover were followed for 7 days and reflected the clinical response. Low dose heparin prevented and an anti-factor XIII inhibited, thrombus formation. A series of anti-platelet drugs had little or no effect on thrombogenesis. We conclude that Types III and IV models reproduce the 3 factors in Virchow’s triad with minimal trauma.
Prostaglandin Endoperoxides and Thromboxanes: Role in Platelets
Authors: Samuelsson Bengt
Published: May 2019

Two groups of unstable (t1/2=5 min) endoperoxides, PGG and PGH compounds, have been isolated and shown to be precursors of the prostaglandins. The endoperoxides cause platelet aggregation and contract vascular and air-way smooth muscle.

A new group of compounds(thromboxanes) derived from the endoperoxides has been discovered. A highly unstable(t1/2=30-40 sec) intermediate, thromboxane A2, between the endoperoxides and thromboxane B2 has been detected. Structural work indicates that it has a bicyclic oxane-oxetane structure. Thromboxane A2 is a potent aggregating agent with pronounced effects on vascular smooth muscle. Studies on the mechanisms of actions of the endoperoxides and thromboxanes in human platelets will be discussed.
Hemophilia B: Genetic Variants and Carrier Detection
Authors: Kasper C.K. , Østerud B. , Rapaport S.I.
Published: May 2019

In 92 males with hemophilia B from 71 kindreds, we measured factor IX activity, prothrombin time using bovine thromboplastin (bovine tpln time), and factor IX antigen both by inhibitor neutralization using a human factor IX inhibitor and by electroimmunoassay using a precipitating rabbit anti-human-factor IX antiserum. Eighty patients with 3% or less factor IX activity could be divided into 4 groups:(1) 7 patients with greatly prolonged bovine tpln times and normal levels of factor IX antigen;(2) 17 patients with mildly prolonged bovine tpln times and factor IX antigen levels between about 25% and normal;(3) 8 patients with normal bovine tpln times and antigen levels between about 25% and normal; (4) 48 patients with normal bovine tpln times and no measureable antigen excess. Some of the latter group were also tested with a chicken anti-human-factor IX antiserum and no antigen was found. None of 12 patients with mild hemophilia B (factor IX activity of 4 to 22%) had a prolonged bovine tpln time although 4 patients had excess factor IX antigen over activity. Thus, about 1/3 of these 92 hemophilia B patients had evidence of an abnormal factor IX molecule. Factor IX activity was also measured in 48 normal women and in 51 definite carriers of severe hemophilia B. Probability curves were derived to estimate the chance of a woman being a carrier based upon her factor IX level and her degree of kinship to a definite carrier. The relation between factor IX activity and antigen was also delineated for normal women and for carriers. In kindreds in which affected males had excess antigen, some carriers could be distinguished from normal women on the basis of excess antigen over activity. In appropriate kindreds, prolonged bovine tpln times helped distinguish some carriers.
Thrombocytin, A Novel Platelet Activating Enzyme from Bothrops Atrox (MARAJOENSIS) Venom
Authors: Niewiarowski S. , Kirby E.P. , Stewart G.J. , Turna R. , Wiedeman M. , Millman M. , Stocker K.
Published: May 2019

Thrombocytin (TCN) was purified from Bothrops atrox (BA) venom by precipitation with 1.2% Na-salicylate and chromatography on heparin-agarose column using increasing concentrations of lysine as eluent. It was homogeneous on SDS electrophoresis and had an apparent MW of 36,000. Immunoelectrophoresis with polyvalent anti-BA venom serum gave one cathodic arc indicating an isoelectric point higher than pH 8.6.TCN at a concentration of 1 yg/ml caused aggregation of human platelets, release of low affinity platelet factor 4 and serotonin, and stimulated platelets to retract fibrin.TCN was essentially free of fibrinogen clotting and fibrinolytic activities.TCN action on platelets was not mediated by the formation of thrombin since TCN did not activate Factor X or prothrombin and its action was not inhibited by hirudin.TCN is a serine protease since it was inhibited by DFP and it hydrolyzed a synthetic peptide, chromozyme UK (BZ-Val-Gly-Arg-pNA·HCl).TCN-induced aggregation of human platelets was completely inhibited by soy bean trypsin inhibitor, heparin, prostaglandin E1 and apyrase. Washed human platelets were 2-4 times less sensitive to TCN as compared to platelets in freshly prepared platelet rich plasma (PRP); their sensitivity to TCN gradually deteriorated during incubation of PRP at room temperature for 3 hours. Electron microscopic observations revealed formation of platelet aggregates characterized by pseudopod formation, centralization and partial loss of platelet granules. Infusion of TCN (3 yg) into the main artery of bat wing resulted in the formation of platelet aggregates seen on arterial and venous side which occasionally occluded small vessels.
Human Blood Platelet Factor VIII-Related Antigen: A Glycocalicin-Like Protein
Authors: Bouma B.N. , Graaf S.de , Zimmerman T.S.
Published: May 2019

The location of Factor VIII-Related Antigen (FVIII R:AG) in human blood platelets was evaluated by treating intact platelets with chymotrypsin and observing the effect on the relative distribution of FVIII R:AG in different platelet fractions. Platelets were fractionated using the glycerol gradient technique. In untreated platelets from 12 normal individuals 95.5% of total platelet FVIII R:AG was found in the soluble fraction, 4.5% in the granules and less than 0.01% in the membrane fraction. Treatment of washed platelets with chymotrypsin resulted in the appearance of FVIII R:AG outside the platelets, and the amount of FVIII R:AG in the soluble fraction decreased in parallel. This suggests that at least part of platelet FVIII R:AG is exposed on the surface of the platelets, and that this FVIII R:AG is released from the membranes during homogeniza-tion. FVIII R:AG present in the soluble fraction was analyzed on SDS-polyacrylamide gels in the presence of reducing agents. A PAS-positive band with an apparent mol wt similar to plasma FVIII R:AG was observed. This band was identified as FVIII R:AG by specific removal with insolubilized anti-factor VIII. Granule FVIII R:AG showed crossed immunoelectrophoretic and ultracentrifugational characteristics similar to plasma FVIII R:AG. In contrast studies of FVIII R:AG in the soluble fraction using the same techniques showed a smaller average size than plasma FVIII R:AG. Our results indicate that platelet FVIII R:AG, isolated in the soluble platelet fraction, originates in part from the surface of the platelet and is therefore a glycocalicin-like protein.
Inhibition of Fibrinolysis, Associated with Oncogenic Transformation, by Normal and Antiplasmin-Depleted Human Plasma
Authors: Collen D. , Billiau A. , Edy J. , Somer De P.
Published: May 2019

When mixed cultures of mouse fibroblasts and mouse fibroblasts transformed with Kirsten murine sarcoma virus (Arch. ges .Virusforsch. 43, 345, 1973) were grown in petri dishes and overlayed with plasminogen-enriched casein, they showed foci of caseinolysis induced by plasminogen activator secreted by the transformed cells. Caseinolysis was inhibited by the addition of human plasma or bovine pancreatic trypsin inhibitor (BPTI) to the overlay, I ml of plasma being equivalent to 67 ± 18 (mean ± S.E.), kallikrein inhibitor (Kl) units of BPTI.

The culture fluid from a human melanoma line (gift of Dr. G. Barlow, Abbott Labs, III..), induced lysis of a fibrin clot, I ml of cuIture fluid being equivalent to 25 CTA units of urokinase . Fibrinolysis was inhibited by addition of human plasma or BPTI, I ml of plasma being equivalent to 94 ± 34 Kl units of BPTI.

Specific removal of antiplasmin, the fast-reacting plasmin inhibitor from plasma, by immuno-absorption, completely abolished its inhibitory activity on caseinolysis and on fibrinolysis. This depleted plasma still contained normal levels of the known plasma protease inhibitors. It is conduced that antiplasmin is the only protein in human plasma capable of inhibiting the fibrinolysis associated with oncogenic transformation or neoplasia. Whether this effect is exclusively due to inhibition of formed plasmin or also to interference with plasminogen activation remains unsettled.
Binding of Dipyridamole of Human Platelets and to α-Acid Glycoprotein and its Significance for the Inhibition of Adenosine Uptake
Authors: Subbarao K. , Rucinski B. , Summers A. , Niewiarowski S.
Published: May 2019

The interactions of dipyridamole with α1-acid glycoprotein of plasma and with human platelets are related to inhibition of adenosine uptake by platelets. One mole of dipyridamole binds to one mole of α1-acid glycoprotein with a dissociation constant (Kd) of 1.3 μM. It was found that platelets contain both high and low affinity binding sites for the drug. The binding of dipyridamole to the high affinity sites follows a Michaelis Menten binding pattern with a Kd of 0.04 μM. Approximately 2x104 dipyridamole molecules are bound at the high affinity sites of each platelet. The lower affinity sites bind the drug with a Kd of 4 μM. In the presence of α1acid glycoprotein the binding of dipyridamole to platelets is inhibited. Correspondingly, the dipyridamole inhibition of adenosine uptake by platelets is reduced 1000-fold by α1acid glycoprotein. Binding of dipyridamole to human platelets is essential for its inhibition of adenosine uptake by platelets. Dipyridamole reduced the [14C]-ATP to [14C]-ADP ratio in the platelets. Purified α1acid glycoprotein reversed these effects of dipyridamole on adenosine metabolism of platelets in a concentration dependent manner. A correlationwas observed between the level of circulating dipyridamole in plasma and the inhibition of [14C]-adenosine uptake by platelets of PRP samples of 12 human volunteers given different amounts of dipyridamole. The in vitro and ex vivo effects of dipyridamole on the [14C]-adenosine uptake by platelets were found to be identical. Our data suggest the presence of dipyridamole binding sites in platelets that regulate adenosine transport across the cell surface.
Electron Microscopy of Globular Hyaline Micro-Thrombi
Authors: Bleyl U.
Published: May 2019

Globular hyaline micro-thrombi(GHM) are round or oval, eosinophilic, strongly PAS-positive intravascular coagulation products with a diameter between 3 and 60/u. Immunhistochemical investigations give strong evidence that they are composed of highly polymerized fibrinogen derivatives. The ultrastructure of these GHM is characterized by spherical space lattices of frequently interconnected bundles of fibres with a periodic transverse stria-tion and the fibrin-characteristic axial periodicity of 23 nm. The densely packed spherical space lattices are surrounded by a so-called corona, plump or slender bundles of fibrin fibres characterized by the same uniforme periodic axial striation of 23 nm that spread radially over the surface of the micro-thrombi. GHM apparently originate from the interlocking and internetting of intravascularly preformed, partly polymerized, filamentary intermediates of fibrinogen-fibrin conversion in the flowing blood. Part of these GHM, on the other hand, lack this axial periodicity and the fibrillary structure of the spherical space lattices is replaced by nearly amorphous finegrained precipitates. The disappearance of the axial periodicity and of the fibrillary structure of the spherical space lattices is considered to be the morphological equivalent of a secondary fibrinolysis in the centre of the GHM. The morphogenesis of GHM in states of hyperdynamic shock is discussed.
Effects of a Polyoxyethylene Detergent on Platelet Function
Authors: Barton P.G.
Published: May 2019

Low concentrations of a polyoxyethylene detergent, Brij 58, inhibited the secondary phase of platelet aggregation induced by ADP in human citrated platelet rich plasma but had no effect on primary aggregation.Thrombin-induced aggregation of washed human platelets suspended in Tyrode’s buffer was inhibited after incubation of cells with 4.5 × 10-6M detergent. Development of prothrombin-converting activity and efflux of [14C]-serotonin, 45Ca2+ ions and labile endoperoxides were abolished concomitantly. Aggregation of washed platelets by collagen or sodium arachidonate and the attachment of cells to clean glass surfaces were also inhibited by the same concentration of Brij 58 that inhibited thrombin aggregation. This concentration of Brij 58 did not itself produce any release of a cytoplasmic marker, lactate dehydrogenase, from platelets. Higher concentrations of Brij 58, exceeding 10-4 M, lysed the cells liberating all of their serotonin, Ca2+ and lactate dehydrogenase. These results suggest that low concentrations of Brij 58 stabilize a membrane conformation against the action of platelet stimulatory agents while high concentrations produce membrane destabilization and cell lysis. The presence of albumin (BSA) in the suspending fluid increased by tenfold the concentrations of detergent required to “elicit these effects and this could be attributed to competitive binding of the detergent to albumin, demonstrated with [14C]-acetylated Brij 58.
Blood Coagulation in High Altitude Pulmonary Oedema
Authors: Singh I. , Chohan I.S.
Published: May 2019

Blood coagulation studies were undertaken in patients of high altitude pulmonary oedema at 3,700 m, comparable controls, and sea level subjects to determine the possible causal connection between changes in fibrinolytic activity, blood coagulation factors, and formation of thrombi within the alveolar capillaries, venules and some branches of pulmonary arteries. The following changes have been observed: Fibrinolytic activity was reduced. Plasma fibrinogen and factor VIII were increased. Factor XII was decreased. Platelet adhesiveness and platelet factor 3 were increased and electrophoretic mobility of platelets reduced. The integrity of platelet plasma membrane, capacity of pseudopodia formation, and ability of degranulation remained intact. Both arterial and venous adenosine-5′-diphosphate (ADP) levels were low and there was evidence of excessive utilisation of ADP in the pulmonary bed. The findings suggest that sludging of RBCs and formation of thrombi possibly result from these changes, impede the pulmonary blood flow, and aggravate the disease.

Apart from inducing diuresis and reducing pulmonary blood volume, within 30 minutes of its administration intravenously, furosemide enhances fibrinolytic activity, decreases factors V, VIII and X and thrombotest activity, increases factor XII, reduces platelet factor 3 and adhesiveness, and improves clot retraction. It seems imoediments to blood flow at capillary and venuiar level, which occur on account or the hypercoagulable state, are removed and pulmonary oedema is relieved.
Antithrombin III Responses in Dogs to Various Stimuli
Authors: Takeda Y. , Kobayashi N.
Published: May 2019

In vivo responses of antithrombin III (AT) to various stimuli were studied to characterize the AT system, using I-125-labeled AT (I-125-AT) as a tracer. Five dogs were used for each study and the radial immunodifussion was used to measure plasma AT concentration. A single intramuscular injection of 20 mg estradiol caused a 20% decrease of plasma AT concentration in 6 days without appreciable changes of plasma t½ of I-125-AT. A single intramuscular injection of 250 mg of progesterone did not produce any appreciable changes of plasma AT concentration or the plasma t½ of I-125-AT. However, intramuscular and intravenous injections of a total of 750 mg of Cortisol caused a 17% increase of plasma AT concentration in a day without alterations of plasma t½ of I-125-AT. Next, the AT responses to thrombophlebitis produced by a previous method were studied. The results indicated no appreciable changes of plasma AT concentration or of plasma t½ of I-125-AT. However, a single intravenous injection of 3 ml of typhoid vaccine showed a 25% decrease of. plasma AT concentration in a day with a moderate shortening of plasma t½ of I-125-AT. Further studies in heparinized dogs showed similar effects with typhoid vaccine, These results indicate that estradiol causes a decreased rate of AT synthesis, that progesterone has no appreciable effects on AT metabolism, that Cortisol increases the rate of AT synthesis, that localized thrombophlebitis has no appreciable effects on AT metabolism and that typhoid vaccine produces an increased catabolic rate of AT by unknown mechanisms other than accelerated coagulation processes.
Vasoactive Substances in Pulmonary Embolism
Authors: Todd M.H. , Forrest J.B. , Hirsh J.
Published: May 2019

Embolisation of the pulmonary vasculature with microspheres releases prostaglandin-1ike substances, PGLS (Piper and Vane, N.Y. Acad. Sei. 180: 363, 1971) but the capacity of autologous blood clots (ABC) to release pulmonary vasoactive substances is disputed. Ten normal mongrel dogs were anesthetised with pentobarbitone sodium and instrumented. Pulmonary venous blood was continuously superfused over isolated tissues for bioassay and then returned to the animal. Injection of ABC into the right atrium increased pulmonary artery pressure from 21 ± 6.5 mm Hg to 38 ± 15 mm Hg (mean ± S.D.), increased arterial pCO2 and decreased arterial pO2. No significant changes in heart rate, systemic arterial blood pressure or cardiac output occurred. In three animals contractions of the blood superfused assay tissues occurred following embolism. This effect was produced in normal assay tissues and those pretreated with antagonists of ACh, Serotonin, Histamine and Catecholamines and could therefore be attributed to PGLS. No cardiovascular or assay tissue tension changes were observed when equivalent volumes of saline or clot lysate were injected into the right atrium.Therefore, pulmonary embolism with ABC can release PGLS which may contribute to the pulmonary artery pressure rise. Vasoactive substances may normally be inactivated in the lung but in some animals appear in pulmonary venous blood.

(Supported by the Ontario Heart Foundation)
On the pathogenesis of “disseminated intravascular coagulation.”
Authors: Spaet Theodore H.
Published: May 2019

The following remarks introduce an alternative hypothesis to those conventionally held concerning the hemostatic changes of “disseminated intravascular coagulation (DIC).”

The concept that coagulant materials may enter the blood with sufficient rapidity to produce clotting within the vessels and reduction of various blood coagulation factors, particularly fibrinogen, has long been with us. In early animal experiments intravenous tissue factor or thrombin was administered; when these were given at sublethal rates, typical coagulopathies were observedoThe next step was to identify experimental situations or clinical conditions in which blood changes resembled those produced in coagulant-injected animals. These were readily found, and many tests were developed to achieve increased sensitivity in diagnosis of the process. In general, the most widely used have been those which demonstrate loss of certain clotting factors, and those which identify fibrinogen or fibrin fragments.“DIC” is now a generally accepted syndrome»

Some neglected observations suggest an alternative interpretation of the blood changes in “DIC.”These raise the possibility that in some, if not many or even most of these syndromes, the source of the blood changes is extravascular processing of the clotting factors. Products may return to the circulation via lymphatics. It is proposed that present methodology cannot resolve this alternative.

Supported by UoS. Public Health Service, NIH Grant #HL 16387.
Calcium Binding Sites on Human Blood Platelets
Authors: Heptinstall S.
Published: May 2019

Extracellular calcium ions are required for platelets to aggregate in response to various aggregating agents. Although magnesium ions can sometimes stimulate aggregation they only do so when a small amount of calcium is present. The calcium bound to washed human platelets suspended in buffered saline containing 0-200μM+5CaCl2 depends upon the extracellular calcium concentration. Scatchard analysis of the binding data suggests that a few (0,8 × 106) relatively high affinity (K = 85,000) calcium binding sites are present on each platelet. When 2.5mM MgCl2 is included in the saline suspensions the calcium bound to the platelets is only reduced at the higher calcium concentrations. Magnesium ions do not displace the tightly bound calcium. It is suggested that these specific calcium binding sites are involved in platelet aggregation.
Comparison of Methods of Assaying Factor VIII Antibody
Authors: Rhymes I. L. , Ghosh S. , Rizza C.R.
Published: May 2019

In assays of factor VIII antibody the patient’s antibody - containing plasma is allowed to react with factor VIII for a given length of time, the residual factor VIII assayed and the level of antibody calculated in arbitrarily defined units. The several methods of assay used throughout the word vary with regard to the source of factor VIII, the length of time the antibody is allowed to react with the factor VIII, the method of assay of residual factor VIII and the definition of the unit of antibody. A comparison has been made of 3 methods of antibody assay, namely, the method of Biggs & Bidwell, the method of Rizza & Biggs and the “Bethesda method”, the aim being to try to find out to what extent the results on any given sample varied with the method and to try to identify the main causes of variation. The investigation shows that the 3 methods record markedly different levels of antibody in any one sample. This is partly due to the different criteria for defining the antibody unit but in addition assays in which whole normal plasma is used as a source of factor VIII substrate show significantly higher levels of antibody compared with assays in which a concentrate of factor VIII is used as substrate. These results and their implications will be discussed.
Inhibitors of Urokinase-Induced Fibrinolysis in Pregnancy
Authors: Duthie J. E. , Campbell D. M. , Ogston D.
Published: May 2019

Pregnancy plasma possesses inhibitory activity against urokinase measured on unheated fibrin plates. Antiurokinase activity in late pregnancy plasma subjected to gel filtration on Sephadex G-200 eluted with the high molecular weight proteins including α2-macroglobulin and, in greater quantity, with albumin. In all non-pregnancy plasmas the high molecular weight inhibitor activity was present in equivalent quantities; the lower molecular weight inhibitor was found in small amounts in only a proportion of plasmas. The anti-urokinase activity of pregnancy plasma could be separated from α1-antitrypsin and α2-antiplasmin by chromatography on DEAE-Sephadex. Within 1 hour of parturition plasma fibrinolytic activity increased and there was substantial reduction in the anti-urokinase activity of the lower molecular weight fractions; no change was seen in the high molecular weight inhibitory activity. It is concluded that anti-urokinase activity in pregnancy plasma resides in a protein distinct from established protease inhibitors; a placental source is postulated.
Changes in Platelet Function, Ultrastructure and Plasma Membrane-Associated Proteins (Actin and Tubulin) in Thrombocythemia
Authors: Podolsak B. , Wenzel E. , Morgenstern E. , Meiser R.J.
Published: May 2019

Five patients with thrombocythemia (two primary hemorrhagic cases and three symptomatic cases, one with generalised amyloidosis and two with splenectomies after hemoblastosis or hepatosplenomegaly) showed the following pathological platelet functions: platelet count, 8 × 105 - 1.4 × 106/μ1; bleeding time 4 min, 50 sec. - 20 min; adhesiveness (Hellem II) 1.5 - 27%; significantly decreased aggregation with collagen and ADP and decreased platelet spreading capacity.

In two patients, clot-retraction was less than normal. The distribution of platelet volumes was normal in all cases. Electron microscopic studies on platelets from these patients showed an increase in microtubular structures and a decrease in electron dense hyaloplasma.

Analyses of the platelet membrane proteins from each patients, by SDS-PAGE and staining showed a band at ca. 50,000 daltons (probably tubulin) which was stronger, while in only three cases there was a significant decrease in membrane-associated actin, as compared to normal platelet membranes. In the other patients, the decrease was smaller. In two patients, there was a discrete decrease in the bands corresponding to heavy myosin chains. No essential changes were found in membrane glycoproteins. The changes in the relation between the different cytosoeletal elements could partially explain the impaired platelet function in thrombocythemia.
Platelet Antibodies and Circulating Immune Complexes in Thrombocytopenic Purpura
Authors: Wautier J.L. , Kadeva H. , Wautier M.P. , Boizard B. , Caen J.P.
Published: May 2019

Forty five patients with thrombocytopenia (Platelet count below 105/ul) have been studied. Platelet associated IgG (Plat IgG) was determined by the method of Dixon et al (Normal range 38 ± 16 × 10-16g). Circulating immune complexes were detected by the [3H] Clq precipitation and the PEG precipitation techniques.

The sera were also tested for their thrombo-agglutinating activity (Aggl.). The results were:

The [3H] Clq test and the PEG test were significantly more frequently positive in patients with high level of Plat IgG.

The thramboagglutination seems to be independant of the level of Plat IgG. It could be correlated with the presence of circulating immune complexes in the serum.
Evaluation of Trials of Antithrombotic Agents in Acute Myocardial Infarction
Authors: Blackburn B.A. , Chalmers T.C. , Smith H.
Published: May 2019

Forty randomized control trials dealing with antithrombotic therapy in the treatment and secondary prevention of myocardial infarction were evaluated for quality of trial design, implementation and analysis. To reduce bias, methods sections were differentially xeroxed before evaluation. Two quality scores were obtained: 1) one reflects the authors’ description of patients and treatments; blinding of randomization and of patients, physicians and observers; measurements of efficacy of randomization, blinding, and compliance; and prior estimate of appropriate sample sizes. 2) The other reflects appropriateness and adequacy of statistical analysis. Hiqher quality scores were obtained by large multi-centered trials (P=.03); those with credit given to a biostatistician (P=.02); and those done recently (P=.04). Decrease in control CFR was found across time (P=.03). Results obtained for anticoagulant treatment showed 8 of the 11 trials with reduction in CFR, 2 with no difference and one with an increase in CFR. 5 of the 10 trials of fibrinolyses were positive. 5 of 9 secondary anticoagulant trials were positive. Two large trials with a trend in favor of aspirin plus a positive sulfinpyrazone (P<.02) trial suggest that antiplatelet agents may be prophylactic. No association between above results and the quality score of the trials was found. This study indicates that anticoagulants but not fibrinolysins reduce acute mortality, and antiplatelet agents are potentially useful in prophylaxis.
Fibrinopeptide-A (FPA) Generation by Factor IX Concentrates (F-IX-C) and Feiba (factor VIII inhibitor bypassing activity)
Authors: Hofmann V. , Ermanni M. , Straub P.M.
Published: May 2019

The increase of FPA from 0.4-2.4 to 5.6-80 mg/ml after infusion of F-I-C in 5 hemophiliacs B prompted a study whether thrombin is present or genera ted in F-IX-C and in FEIBA rasp. Purified dialysed fibrinogen served as substrate, FPA-release was measured by RIA and expressed as % of the total FPA in fibrinogen. F-IX-C + fibrinogen produced only traces of FPA. The addition of Ca++ led to a time-dependent increase of FPA-release. 8 batches F-IX-C from 2 sources (Immuno, SwissRedCross) were preincubated with Ca++ for 2 hrs, added to fibrinogen with and without heparin, and FPA measured after 60 s. In absence of heparin 7 F-IX-C produced 5 to 80% FPA, in its presence no FPA was liberated. FEIBA + fibrinogen produced clotting and an 80% FPA-release in 5 min, prevented by prior heparin addition. Preincubation of FEIBA with Ca++ increased FPA-release from 80 to 100%, however, prevention required an ll-fold heparin conc. Hirudin more effectively blocked FPA-release probably due to low AT III in concentrates. Thus, in F-IX-C thrombin is absent or blocked by heparin added by the manufacturer; however, thrombin is rapidly generated in presence of Ca++. The coagulant activity of FEIBA is due to thrombin rather than to a “factor VIII inhibitor bypassing activity”.
Factor VIII-Related Activities in therapeutic concentrates
Authors: Barrowcliffe T.W. , Kemball-Cook G. , Morris G. , Holt J.C. , Peake I.R.
Published: May 2019

Levels of Factor VIII clotting activity (VIII:C), VIII clotting antigen (VIII: CAg), VIII related antigen (VIII R:Ag) and ristocetin co-factor (RCF) have been compared in several batches of the various concentrates used therapeutically in the U.K. The mean ratio of VIII R:Ag to VIII:C ranged from 2 to 4, but a major problem in VIII R:Ag assays of concentrates against a plasma standard was non-parallelism of the dose-response curves. This reflects the abnormality of the antigen in the concentrates, as shown by its more rapid mobility on crossed immunoelectrophoresis. Ratios of VIII: CAg to VIII:C ranged from less than 1 to about 2; the higher ratios indicate denaturation of the clotting part of the molecule during purification. All concentrates had RCF levels at least equivalent to their clotting activity, but lower than their VIII R:Ag levels. At high dilutions, most concentrates gave an acceptable parallel line bioassay against a plasma standard, but as the concentration of ristocetin co-factor was increased, non-parallelism was observed, due to a failure of the plasma response to increase with increasing dose. In treatment of patients with haemophilia and von Willebrand’s disease, it should be recognised that concentrates which are equivalent in VIII:C potency may nevertheless display a wide spectrum of other Factor VIII-related activities.
Antithrombin III and Platelet Volume in Correlation with Hemolysis after Valve Replacements Using Xenografts.
Authors: Volkmer I. , Nienhaus Kh. , Wenzel E. , Jäger H. , Welsch J. , Meiser J. , Vief B.
Published: May 2019

Blood corpuscles as well as plasma proteins are traumatized, when blood comes in contact with surfaces of artificial heart valves. 30 patients who had received valve replacement (N = 18, Edwards Xenografts in aortic position; N = 12, Hancock Xenografts in mitral position) in addition to the parameters for hemolysis (haptoglobin, LDH, erythrocyte count, hemoglobin), platelet count, platelet volume distribution (Coulter Counter equipment) and coagulation parameters (PTT, PTZ, fibrinogen, plasmathrombin- and thrombincoagulase times, thrombelastography) were controlled. Antithrombin III was evaluated immunologically (Mancini) and photometrically (Chromozym TH). Laboratory and clinical investigations were performed postoperatively after 6 weeks and thereafter every 3 months (19.5 months). A significant higher rate of hemolysis was observed in patients with an aortic valve replacement. Antithrombin III was found to be significantly decreased, especially in patients with aortic valve replacements. A significant and comparable increase in small platelets (< 4.3 μ3) was observed in both patients’ groups.
Human Pharmacology Studies in Volunteers with Indobufen (K 3920), Inhibitor of Platelet Aggregation
Authors: Fuccella L.M. , Corvi G. , Pogliani E. , Tamassia V. , Tosolini G. , Tremoli E.
Published: May 2019

Given by the i.v. route to healthy volunteers, indobufen has an half-life of 7-9 h. After oral administration of tablets, the drug is completely absorbed. Excretion occurs through the kidney and the drug is present in the urine as glucoronide and in unchanged form. The maximum inhibitory effect on collagen-induced platelet aggregation was observed 1 to 4 h after i.v. and p.o. administration but activity at 8 h was more marked after p.o. administration in accordance with the higher plasma levels found at that time. During repeated administration at the dose of 100 mg b.i.d. for 7 days, no important changes in kinetic parameters and activity of indobufen was observed. Indobufen is rapidly absorbed also when given by the i.m. route, giving at 30 min peak levels comparable to those observed after oral administration. These data suggest that indobufen is active by the i.V., p.o. and i.m. routes, that its effect on platelets, unlike ASA, is reversible, and that its kinetics is linear.
Molecular Characterization of Human Foetal Fibrinogen
Authors: Witt Irene , Tesch Rudolf
Published: May 2019

Until eiqht days after birth, the human newborn synthesizes a molecular variant of fibrinogen. This foetal fibrinogen is characterized by several biochemical and functional properties.

Previous results led to the assumption that the peculiarities of the foetal protein are caused by a special sequence of amino acids.

Comparison of the tryptic peptide maps showed the identity of foetal and adult Bβ- and γ-chains, whereas the Aα-chain tryptic peptides and cyanogen bromide fragments are different. By thin layer chromatographic and sequence analyses the special amino acid sequence of the foetal Aα-chain can be localized in the amino acid sections 50 - 250 and/or 500 - 620. Because it could be ruled out that posttranslational constituents of the molecule are the cause of the “foetal” features it is quite probable that the foetal fibrinogen is genetically determined.