A 15 year old girl with apladic anemia developed a heparin-like anticoagulant during the course o... more A 15 year old girl with apladic anemia developed a heparin-like anticoagulant during the course of systemic candldiasis. This was inltlally detected In the laboratory by an elevation of the thrombin clotting time which corrected with toluidine blue but not by mixing with normal plasma. In vivo and in vitro the anticoagulant was remarkably resistant to neutralization by protamine sulfate. Nevertheless, its heparin-like nature was confirmed by its sensitivity to heparinaae and its dependence on antithrombin 111.
To evaluate the frequency of venous thromboembolism (VTE) in patients with advanced androgen-inde... more To evaluate the frequency of venous thromboembolism (VTE) in patients with advanced androgen-independent prostate cancer who were treated with docetaxel alone or in combination with thalidomide. Retrospective analysis of a randomized phase II trial. National Institutes of Health clinical research center. Seventy men, aged 50-80 years, with advanced androgen-independent prostate cancer. Each patient received either intravenous docetaxel 30 mg/m2/week for 3 consecutive weeks, followed by 1 week off, or the combination of continuous oral thalidomide 200 mg every evening plus the same docetaxel regimen. This 4-week cycle was repeated until there was evidence of excessive toxicity or disease progression. None of 23 patients who received docetaxel alone developed VTE, whereas 9 of 47 patients (19%) who received docetaxel plus thalidomide developed VTE (p=0.025). The addition of thalidomide to docetaxel in the treatment of prostate cancer significantly increases the frequency of VTE. Clinicians should be aware of this potential complication when adding thalidomide to chemotherapeutic regimens.
Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have t... more Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have tested its efficacy against the acquired immunodeficiency syndrome (AIDS) and various malignancies. Thromobocytopenia was observed in early trials with suramin in AIDS, but has been uncommon in patients treated for solid tumors. Here we describe 5 patients out of a total of 67 (7%) who developed severe thrombocytopenia while receiving suramin as part of a phase II clinical trial for metastatic prostate carcinoma refractory to hormonal therapy. IgG purified from one patient's plasma caused suramin-dependent platelet aggregation. There was also evidence of crossreactivity between suramin and heparin in this system. An immune mechanism, however, could not be documented in the other cases, suggesting that multiple mechanisms may be responsible for severe thrombocytopenia in this patient population.
Thrombosis is a recognized complication of inflammatory bowel disease (IBD). In contrast dissemin... more Thrombosis is a recognized complication of inflammatory bowel disease (IBD). In contrast disseminated intravascular coagulation (DIC) has rarely been described with IBD, and then only during periods of intense disease activity or during colectomy. However, we recently encountered a young woman with a 3-year history of ulcerative colitis (UC) and a 10-year history of recurrent thrombosis who presented with DIC when her disease appeared to be well controlled. For the previous two months she had been forced to discontinue her usual warfarin because of extreme over anticoagulation and extensive ecchymoses. Otherwise she felt well and was working full time. When she presented to us, the following laboratory data were obtained: pro time 18.7s, aPTT 43.6s, fibrinogen 56 mg/dL, D-dimer 8–16 μg/mL, platelet count 123K/μL, thrombin-antithrombin complexes 47 μg/mL (nl, 1.3–4.0), plasma endotoxin 6.3 EU/mL (control 0.1), positive prothrombin G20210A heterozygosity, negative FVLeiden, but positi...
Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic p... more Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am.
Little is known about the carbohydrate structure of the platelet von Willebrand factor (vWf). We ... more Little is known about the carbohydrate structure of the platelet von Willebrand factor (vWf). We have analyzed N-linked oligosaccharides from both plasma and platelet vWf by Fluorophore-Assisted-Carbohydrate Electrophoresis (FACE) and isoelectric focusing before and after digestion of the proteins with neuraminidase. We observed a greater variety of N-linked oligosaccharides derived from plasma vWf than from platelet vWf. Neuraminidase treatment reduced the oligosaccharides from both proteins to only two or three bands and produced significant increases in their isoelectric points.
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a clinico-pathological entity that presents... more BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a clinico-pathological entity that presents a diagnostic challenge, especially in medically complex patients. PATIENTS AND METHODS: In this observational and prospective study, 34 consecutive patients with suspected HIT were enrolled. They were clinically scored using two different clinical scoring systems and underwent testing for PVS-ELISA and 14C-SRA. 14C-SRA results were also available from 21 medical and surgical patients who had previously been tested. PURPOSE: The objective of our study was to evaluate the sensitivity and specificity of the PF4 ENHANCED (GTI Diagnostics) ELISA for HIT performed at two institutions using the serotonin-release assay (14C-SRA) and clinical scoring systems as reference methods. RESULTS: With the 14C-SRA as the reference method, the sensitivities and specificities of the ELISA were 100% and 57% respectively at one institution and 93% and 65% at the other. There was only one false-negative ELISA...
Because central venous catheters often become blocked by clot at their tip despite heparin flushe... more Because central venous catheters often become blocked by clot at their tip despite heparin flushes, a more effective anticoagulant is needed. We hypothesize that lepirudin, a recently introduced protein anticoagulant, might be more effective than heparin because of its tendency to adsorb to silicone, a commonly used catheter material. We preliminarily tested this hypothesis in vitro by measuring residual lepirudin and heparin activity at the tip of a catheter that had been submerged in a flowing stream of water for various periods of time. We observed that lepirudin is less readily removed than heparin from the catheter by fluid washing over it. This "slow-release" property of lepirudin might provide prolonged protection against clot formation at the catheter tip. A clinical trial will be necessary, however, to determine whether this property translates into significant improvement in catheter function.
The carbohydrate structure of human thrombin has been determined by direct probe mass spectrometr... more The carbohydrate structure of human thrombin has been determined by direct probe mass spectrometry of the oligosaccharides released by trifluoroacetolysis from the asialo glycoprotein. The free oligosaccharides were studied as permethylated and N-trifluoroacetylated oligosaccharide alditols. The structure was confirmed by sequential exoglycosidase digestion of intact thrombin and sugar and methylation analysis of the oligosaccharides by gas-liquid chromatography-mass spectrometry. The results indicate the following structure: (formula; see text) with Fuc present on only about 50% of the oligosaccharides.
Cancer patients with venous access devices (VADs) often receive daily flushes of heparin. Even th... more Cancer patients with venous access devices (VADs) often receive daily flushes of heparin. Even this relatively small heparin exposure has been reported to induce immune-mediated thrombocytopenia. To estimate how frequently this occurs we tested for heparin-related antibodies in 49 patients receiving daily heparin flushes of their VADs. Although one-third of the patients showed evidence of heparin sensitization on at least one occasion during their surveillance, their antibody titers were generally low and typical of those found in other cohorts of patients who become sensitized to heparin but do not develop secondary thrombocytopenia. However, one patient developed a positive serotonin release assay indicative of a more significant sensitization, but without thrombocytopenia. Therefore, our observations suggest that heparin-induced thrombocytopenia (HIT) related to heparin flushes of VADs is uncommon but still an important diagnosis to entertain.
Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in ... more Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.
The extent to which platelets can metabolize galactose has been unknown. We have studied this que... more The extent to which platelets can metabolize galactose has been unknown. We have studied this question by incubating platelets with radiolabeled galactose for periods of time and analyzing the cells for radioactive metabolites. The sugar was observed to accumulate quickly in cells isolated by filtration. Within seconds at room temperature, galactose metabolites were detectable by thin-layer chromatography, and within 20 minutes at 37 degrees C, radioactivity appeared in trichloroacetic acid (TCA) precipitates of the suspensions. The TCA-precipitable radioactivity was degraded by alpha-amylase as well as by protease. However, the TCA-soluble material released by protease digestion had an elution volume on Sepharose CL-4B too small for glycopeptides and in addition was degraded by alpha-amylase. The majority of the galactose metabolized by platelets, therefore, becomes incorporated into glycogen, rather than glycoprotein. The reversibility of the galactose metabolic pathway was demonstrated by the addition of an excess of the unlabeled sugar to the labeled platelets and by the effect of thrombin and collagen on the TCA-precipitable radioactivity.
... MCDONALD K. HORNE MI, MD; MICHAEL R. WATERMAN, PH.D.; LAVERNE MCELROY SIMON, MA; JAMES C. GAR... more ... MCDONALD K. HORNE MI, MD; MICHAEL R. WATERMAN, PH.D.; LAVERNE MCELROY SIMON, MA; JAMES C. GARRIOTT, Ph.D.; and EH FOERSTER, MS Baylor University Medical Center; Dallas, Texas ... 5th ed. New York: MacMil-lan Publishing Co.; 1975:727. 5. JAFFE ER. ...
Microangiopathic hemolytic anemia developed in two patients with metastatic malignancy, one with ... more Microangiopathic hemolytic anemia developed in two patients with metastatic malignancy, one with primary carcinoma of the colon and the other with ovarian carcinoma. There was no evidence of consumptive coagulopathy except severe thrombocytolysis in one patient. Both patients improved remarkably after chemotherapy. The colonic carcinoma responded to 5-fluorouracil delivered into the hepatic artery, and the ovarian tumor to multiagent systemic therapy.
A 15 year old girl with apladic anemia developed a heparin-like anticoagulant during the course o... more A 15 year old girl with apladic anemia developed a heparin-like anticoagulant during the course of systemic candldiasis. This was inltlally detected In the laboratory by an elevation of the thrombin clotting time which corrected with toluidine blue but not by mixing with normal plasma. In vivo and in vitro the anticoagulant was remarkably resistant to neutralization by protamine sulfate. Nevertheless, its heparin-like nature was confirmed by its sensitivity to heparinaae and its dependence on antithrombin 111.
To evaluate the frequency of venous thromboembolism (VTE) in patients with advanced androgen-inde... more To evaluate the frequency of venous thromboembolism (VTE) in patients with advanced androgen-independent prostate cancer who were treated with docetaxel alone or in combination with thalidomide. Retrospective analysis of a randomized phase II trial. National Institutes of Health clinical research center. Seventy men, aged 50-80 years, with advanced androgen-independent prostate cancer. Each patient received either intravenous docetaxel 30 mg/m2/week for 3 consecutive weeks, followed by 1 week off, or the combination of continuous oral thalidomide 200 mg every evening plus the same docetaxel regimen. This 4-week cycle was repeated until there was evidence of excessive toxicity or disease progression. None of 23 patients who received docetaxel alone developed VTE, whereas 9 of 47 patients (19%) who received docetaxel plus thalidomide developed VTE (p=0.025). The addition of thalidomide to docetaxel in the treatment of prostate cancer significantly increases the frequency of VTE. Clinicians should be aware of this potential complication when adding thalidomide to chemotherapeutic regimens.
Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have t... more Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have tested its efficacy against the acquired immunodeficiency syndrome (AIDS) and various malignancies. Thromobocytopenia was observed in early trials with suramin in AIDS, but has been uncommon in patients treated for solid tumors. Here we describe 5 patients out of a total of 67 (7%) who developed severe thrombocytopenia while receiving suramin as part of a phase II clinical trial for metastatic prostate carcinoma refractory to hormonal therapy. IgG purified from one patient's plasma caused suramin-dependent platelet aggregation. There was also evidence of crossreactivity between suramin and heparin in this system. An immune mechanism, however, could not be documented in the other cases, suggesting that multiple mechanisms may be responsible for severe thrombocytopenia in this patient population.
Thrombosis is a recognized complication of inflammatory bowel disease (IBD). In contrast dissemin... more Thrombosis is a recognized complication of inflammatory bowel disease (IBD). In contrast disseminated intravascular coagulation (DIC) has rarely been described with IBD, and then only during periods of intense disease activity or during colectomy. However, we recently encountered a young woman with a 3-year history of ulcerative colitis (UC) and a 10-year history of recurrent thrombosis who presented with DIC when her disease appeared to be well controlled. For the previous two months she had been forced to discontinue her usual warfarin because of extreme over anticoagulation and extensive ecchymoses. Otherwise she felt well and was working full time. When she presented to us, the following laboratory data were obtained: pro time 18.7s, aPTT 43.6s, fibrinogen 56 mg/dL, D-dimer 8–16 μg/mL, platelet count 123K/μL, thrombin-antithrombin complexes 47 μg/mL (nl, 1.3–4.0), plasma endotoxin 6.3 EU/mL (control 0.1), positive prothrombin G20210A heterozygosity, negative FVLeiden, but positi...
Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic p... more Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am.
Little is known about the carbohydrate structure of the platelet von Willebrand factor (vWf). We ... more Little is known about the carbohydrate structure of the platelet von Willebrand factor (vWf). We have analyzed N-linked oligosaccharides from both plasma and platelet vWf by Fluorophore-Assisted-Carbohydrate Electrophoresis (FACE) and isoelectric focusing before and after digestion of the proteins with neuraminidase. We observed a greater variety of N-linked oligosaccharides derived from plasma vWf than from platelet vWf. Neuraminidase treatment reduced the oligosaccharides from both proteins to only two or three bands and produced significant increases in their isoelectric points.
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a clinico-pathological entity that presents... more BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a clinico-pathological entity that presents a diagnostic challenge, especially in medically complex patients. PATIENTS AND METHODS: In this observational and prospective study, 34 consecutive patients with suspected HIT were enrolled. They were clinically scored using two different clinical scoring systems and underwent testing for PVS-ELISA and 14C-SRA. 14C-SRA results were also available from 21 medical and surgical patients who had previously been tested. PURPOSE: The objective of our study was to evaluate the sensitivity and specificity of the PF4 ENHANCED (GTI Diagnostics) ELISA for HIT performed at two institutions using the serotonin-release assay (14C-SRA) and clinical scoring systems as reference methods. RESULTS: With the 14C-SRA as the reference method, the sensitivities and specificities of the ELISA were 100% and 57% respectively at one institution and 93% and 65% at the other. There was only one false-negative ELISA...
Because central venous catheters often become blocked by clot at their tip despite heparin flushe... more Because central venous catheters often become blocked by clot at their tip despite heparin flushes, a more effective anticoagulant is needed. We hypothesize that lepirudin, a recently introduced protein anticoagulant, might be more effective than heparin because of its tendency to adsorb to silicone, a commonly used catheter material. We preliminarily tested this hypothesis in vitro by measuring residual lepirudin and heparin activity at the tip of a catheter that had been submerged in a flowing stream of water for various periods of time. We observed that lepirudin is less readily removed than heparin from the catheter by fluid washing over it. This "slow-release" property of lepirudin might provide prolonged protection against clot formation at the catheter tip. A clinical trial will be necessary, however, to determine whether this property translates into significant improvement in catheter function.
The carbohydrate structure of human thrombin has been determined by direct probe mass spectrometr... more The carbohydrate structure of human thrombin has been determined by direct probe mass spectrometry of the oligosaccharides released by trifluoroacetolysis from the asialo glycoprotein. The free oligosaccharides were studied as permethylated and N-trifluoroacetylated oligosaccharide alditols. The structure was confirmed by sequential exoglycosidase digestion of intact thrombin and sugar and methylation analysis of the oligosaccharides by gas-liquid chromatography-mass spectrometry. The results indicate the following structure: (formula; see text) with Fuc present on only about 50% of the oligosaccharides.
Cancer patients with venous access devices (VADs) often receive daily flushes of heparin. Even th... more Cancer patients with venous access devices (VADs) often receive daily flushes of heparin. Even this relatively small heparin exposure has been reported to induce immune-mediated thrombocytopenia. To estimate how frequently this occurs we tested for heparin-related antibodies in 49 patients receiving daily heparin flushes of their VADs. Although one-third of the patients showed evidence of heparin sensitization on at least one occasion during their surveillance, their antibody titers were generally low and typical of those found in other cohorts of patients who become sensitized to heparin but do not develop secondary thrombocytopenia. However, one patient developed a positive serotonin release assay indicative of a more significant sensitization, but without thrombocytopenia. Therefore, our observations suggest that heparin-induced thrombocytopenia (HIT) related to heparin flushes of VADs is uncommon but still an important diagnosis to entertain.
Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in ... more Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.
The extent to which platelets can metabolize galactose has been unknown. We have studied this que... more The extent to which platelets can metabolize galactose has been unknown. We have studied this question by incubating platelets with radiolabeled galactose for periods of time and analyzing the cells for radioactive metabolites. The sugar was observed to accumulate quickly in cells isolated by filtration. Within seconds at room temperature, galactose metabolites were detectable by thin-layer chromatography, and within 20 minutes at 37 degrees C, radioactivity appeared in trichloroacetic acid (TCA) precipitates of the suspensions. The TCA-precipitable radioactivity was degraded by alpha-amylase as well as by protease. However, the TCA-soluble material released by protease digestion had an elution volume on Sepharose CL-4B too small for glycopeptides and in addition was degraded by alpha-amylase. The majority of the galactose metabolized by platelets, therefore, becomes incorporated into glycogen, rather than glycoprotein. The reversibility of the galactose metabolic pathway was demonstrated by the addition of an excess of the unlabeled sugar to the labeled platelets and by the effect of thrombin and collagen on the TCA-precipitable radioactivity.
... MCDONALD K. HORNE MI, MD; MICHAEL R. WATERMAN, PH.D.; LAVERNE MCELROY SIMON, MA; JAMES C. GAR... more ... MCDONALD K. HORNE MI, MD; MICHAEL R. WATERMAN, PH.D.; LAVERNE MCELROY SIMON, MA; JAMES C. GARRIOTT, Ph.D.; and EH FOERSTER, MS Baylor University Medical Center; Dallas, Texas ... 5th ed. New York: MacMil-lan Publishing Co.; 1975:727. 5. JAFFE ER. ...
Microangiopathic hemolytic anemia developed in two patients with metastatic malignancy, one with ... more Microangiopathic hemolytic anemia developed in two patients with metastatic malignancy, one with primary carcinoma of the colon and the other with ovarian carcinoma. There was no evidence of consumptive coagulopathy except severe thrombocytolysis in one patient. Both patients improved remarkably after chemotherapy. The colonic carcinoma responded to 5-fluorouracil delivered into the hepatic artery, and the ovarian tumor to multiagent systemic therapy.
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Papers by McDonald Horne