William P. Webster

Strategies for anticoagulation with synthetic protease inhibitors. Xa inhibitors versus thrombin inhibitors

Abstract In our series of synthetic inhibitors of arginine-specific esteroproteases we have identified 1,2-di(5-amidino-2-benzofuranyl)ethane (DABE) as a preferential inhibitor of bovine factor Xa (Ki = 5.73 × 10−7 M) and α,α′-bis(4-amidino-2-iodophenoxy)-p-xylene as a preferential inhibitor of human thrombin (Ki = 3.79 × 10−7 M). With the help of those compounds it was demonstrated that a hypocoagulable state of human plasma can be established much more effectively with a Xa inhibitor than with a thrombin inhibitor. This was in contrast to the findings with canine plasma where suppression of factor Xa presented no advantage over suppression of thrombin. With porcine plasma the situation was similar to the experience with human plasma and led us to select the pig over the dog for in vivo testing of DABE. Infusion experiments in the pig confirmed the usefulness of DABE, and only 0.1 mg/kg/min. was needed for full anticoagulation, i.e., for maintaining the partial thromboplastin time at 2 1/2 times the control value.

Continuous Intravenous Infusion of Factor VIII in Classic Haemophilia

The effects of continous intravenous infusion of factor VIII were studied under varied conditions in five children with classic haemophilia. Factor‐VIII activity was stable at room temperature (73–76°F) up to 12 hr in cryoprecipitates from fresh plasma and up to 27 hr in glycine‐precipitated fractions (Fraction AA and Method 4, Hyland). Constant infusion (17 ml/hr) of different concentrations of these fractions produced levels of plasma factor‐VIII activity which were proportional to the dose‐rate and became relatively steady after 12‐18 hr. In separate studies of two of the subjects, dental extraction and laminectomies were uneventfully supported by an initial dose of factor VIII followed by continuous infusions. It is suggested that continuous intravenous infusion of factor VIII is useful for studying the regulation of factor‐VIII levels in plasma and for maintaining steady plasma factor‐VIII activity during replacement therapy.

Liver biopsy in hemophilia A.

Hepatitis is a significant complication of the treatment of hemophilia A with factor VIII concentrates. Chronic liver disease in these patients is infrequently documented in the literature. The results of percutaneous liver biopsy, under the coverage of glycine-precipitated factor VIII, in six patients with hemophilia A who had the persistence of abnormal liver-function tests for at least 6 months, are described. Three patients had chronic active hepatitis, and three had chronic persistent hepatitis. No complications were encountered as a result of the biopsy procedure. These results suggest that percutaneous liver biopsy should be considered in patients with hemophilia A with continuously abnormal liver-function tests to establish a histologic diagnosis and to guide further therapy.

American Burkitt's lymphoma: A 10-year review and case study

Burkitts lymphoma is a malignancy of B-lymphocyte origin that was initially described in African children with jaw tumors. These tumors often spread to involve abdominal viscera and other sites, have rapid growth kinetics, and are principally responsive to chemotherapy. Prolonged survival is predicted by site and extent of tumor, with bone marrow and central nervous system involvement being indicators of a poor prognosis. The dental practitioner plays an important role in diagnosis of jaw lesions and treatment throughout the course of the disease. An examination of 17 cases of Burkitts lymphoma diagnosed at The North Carolina Memorial Hospital, University of North Carolina at Chapel Hill, North Carolina, over a 10-year period is undertaken and an illustrative case study is presented to demonstrate the challenge of caring for the patient with Burkitts lymphoma.

Release of Factor VIII (Antihaemophilic Factor) from Perfused Organs and Tissues

IT has been known for many years that patients with classic haemophilia bleed because they lack a plasma factor required for normal blood coagulation. This factor, factor VIII (antihaemophilic factor) of normal plasma, has been extensively investigated, but its exact site of origin is unknown. Recent developments in organ transplantation have stimulated us to look for the specific organ source of this procoagulant. If the site of synthesis of factor VIII could be identified, permanent replacement of the deficient factor in haemophilia might be possible. In the past, a variety of experimental approaches has been used to investigate the bodys mechanisms for maintaining haemostatic levels of factor VIII: organ ablation1, total body irradiation2, administration of hepatotoxins3,4, reticulo-endothelial blockade5, physical exercise6, hormone administration7, and thromboplastin injections4. Several recent investigations have suggested that the spleen may play a part in the regulation of concentrations of factor VIII in the plasma of normal individuals. Weaver et al. demonstrated that factor VIII is maintained at normal concentrations when intact normal dogs are crosscirculated with haemophilic dogs, but that the concentrations decrease if a splenectomy is first performed on the normal animals8. In humans, Libre et al.9 have observed that splenectomy abolishes the rise in factor VIII that is known to follow injection of adrenaline into normal subjects10. Pool was able to recover antihaemophilic activity in extracts of splenic tissue, but not from a variety of other tissues11.

Glanzmann's thrombasthenia: Report of two oral surgical cases using a new microfibrillar collagen preparation and EACA for hemostasis☆

Glanzmanns thromboasthenia is a rare congenital platelet disorder characterized by a prolonged bleeding time, a qualitative platelet defect, and severe hemorrhagic episodes. Patients with this disorder have been managed by administration of blood and blood components (most recently, platelet-rich plasma and platelet concentrates) to control hemorrhage resulting from trauma or surgical procedures. The two case reports presented here illustrate the use of a local hemostatic agent (microfibrillar bovine collagen, Avitene) and a systemic fibrinolytic inhibitor (epsilon aminocaproic acid, Amicar) to control postoperative hemorrhage secondary to elective extraction of teeth. The clinical results demonstrate excellent postoperative hemostasis and support recent in vitro observation of platelet adherence to the collagen preparation. This provides an alternate therapeutic modality in the management of patients with Glanzmanns disease and possibly other disorders of platelet function.

Radium therapy appliance

A device for holding Ra capsules in the mouth is described. The device enabled the local irradiation with 10500 r of a maxilliary carcinoma without exposing the eyes to excessive doses. (H.H.D.)

Dental management of mild hemophilia with polycythemia vera.

Classic hemophilia (hemophilia A. Factor VIII deficiency, antihemophilic factor deficiency) and polycythemia vera were diagnosed in a patient who presented for management of his dental disease. This case report summarizes the history, laboratory findings, and clinical course and discusses the various diagnostic considerations in the management of two rare disorders. A review of current concepts of hemophilia and polycythemia vera is presented.