Therapeutic use of low molecular weight heparins.
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Angioplasty, Balloon, Coronary↗
Biomedical subjects
H L Messmore
Publications and source records attributed to H L Messmore.
Tracheal and bronchial cartilaginous rings: warfarin sodium-induced calcification.
Progressive calcification of the cartilaginous rings (CCR) of the trachea and bronchi has been observed in patients undergoing prolonged prophylactic anticoagulant therapy with warfarin sodium. The purpose of this study was to validate the relationship of warfarin sodium and CCR, as well as to present the appearance and sex and age distribution of the normal degenerative CCR seen in the elderly. Chest radiographs were scrutinized for evidence of CCR in 92 patients who underwent warfarin sodium therapy and in 105 patients used as a control group. CCR was classified as not present (scored as 0), subtle (scored as 1), and extensive (scored as 2). In the warfarin sodium study group, 47% of patients (43 of 92) exhibited level 1 or level 2 CCR. This proportion was 19% (20 of 105) in the control group. The difference was statistically significant (P less than .001). A significant positive correlation (P less than .001) was also present between the duration of warfarin sodium therapy and increased levels of CCR.
Aged↗
Acute venous thrombosis. Therapeutic choices for superficial and deep veins.
Superficial thrombophlebitis is common in varicose veins or veins that have undergone trauma from catheters or intravenous medications. Pain and tenderness, warmth, and erythema are diagnostic features. A compression bandage and nonsteroidal antiinflammatory agent are often all that is required for treatment. Deep vein thrombosis occurs in veins beneath the deep fascia of the leg or in the pelvis or abdomen. It is often asymptomatic but must be treated to prevent pulmonary embolization and postthrombotic syndrome. Standard therapy is administration of heparin sodium for 5 days, followed by tapering and discontinuation. Warfarin sodium (Coumadin, Panwarfin, Sofarin) is sometimes given simultaneously. Longer courses of anti-coagulation therapy are necessary in patients with an ongoing risk of recurrence.
Acute Disease↗
Potential use of recombinant hirudin as an anticoagulant in a cardiopulmonary bypass model.
Recombinant (r) hirudin is a potent thrombin-specific inhibitor derived from the natural hirudin of the leech (Hirudo medicinalis). We have studied the efficacy of r-hirudin compared with heparin in a canine model of cardiopulmonary bypass operations. Two administration regimens were used for r-hirudin: group 1, 1.0 mg/kg intracardiac bolus then intravenous bolus at 30 minutes (n = 10); and group 2, 1.0 mg/kg intracardiac bolus with 1.25 +/- 0.04 mg.kg-1.h-1 intravenous infusion (n = 8). Group 3 was given an intracardiac bolus of heparin, 1.66 mg/kg (n = 9). Aspiration of blood from the chest cavity revealed no significant difference between the three groups. Measurement of fibrin deposits in the pump line filter revealed higher amounts in the r-hirudin groups (p = 0.02). Decreases in platelets, fibrinogen, and hematocrit due primarily to hemodilution were the same in each group. The bleeding time assay showed less prolongation for r-hirudin than for heparin (p less than 0.001). No antagonist for r-hirudin was used; however, due to its short half-life all coagulation variables returned to baseline within 30 minutes after cardiopulmonary bypass. Because r-hirudin lacks effect on platelets, is a poor immunogen, does not require a plasma cofactor, and may not require an antagonist, it may provide an alternative anticoagulant to heparin in cardiopulmonary bypass. Additional studies are, however, needed to optimize the dose and to evaluate other clinical aspects of r-hirudin.
Animals↗
Comparison of recombinant hirudin and heparin as an anticoagulant in a cardiopulmonary bypass model.
Recombinant (r) hirudin is a potent thrombin-specific inhibitor originally derived from the natural hirudin of the leech (Hirudo medicinalis). We have studied the efficacy of r-hirudin compared to heparin in a dog model of cardiopulmonary bypass (CPB) surgery. Two administration regimens were used for r-hirudin: Group I received 1.0 mg/kg intracardiac (i.c.) bolus then intravenous (i.v.) bolus at 30 min (n = 10); Group II received 1.0 mg/kg (i.c.) bolus with 1.25 +/- 0.04 mg/kg/h (i.v.) infusion (n = 8). Group III was given heparin 1.66 mg/kg (i.c.) bolus (n = 9). Aspiration of blood from the chest cavity revealed no significant difference between the three groups. Measurement of fibrin deposits in the pump line filter revealed higher amounts in the r-hirudin groups (P = 0.02). Decreases in platelets, fibrinogen and haematocrit due primarily to haemodilution were the same in each group. The bleeding time was less prolonged for r-hirudin than for heparin (p less than 0.001). No antagonist for r-hirudin was used; however, due to its short half-life, all coagulation parameters returned to baseline within 30 min after CPB. Since r-hirudin has no effect on platelets, is a poor immunogen, does not require a plasma cofactor, and may not require an antagonist, it may provide an alternative anticoagulant to heparin in CPB. Additional studies are, however, needed to optimize the dose and to evaluate other clinical aspects of r-hirudin.
Animals↗
Interaction of heparinoids with platelets: comparison with heparin and low molecular weight heparins.
Heparin interacts with platelets to impair collagen-induced aggregation and adhesion to collagen. Low molecular weight heparin and heparinoids have little or no inhibitory activity in these platelet-collagen interactions. Thrombin-induced aggregation of platelets is inhibited by any of the glycosaminoglycans that will block the action of thrombin on fibrinogen. However, heparin is a much more potent inhibitor than low molecular weight heparins or heparinoids at equigravimetric concentrations in these reactions. The inhibition of ristocetin or asialo-von Willebrand factor aggregation of platelets is partially blocked by high dose heparin but not by low molecular weight heparin or heparinoids. The heparin-induced IgG antibody, produced to a heparin-platelet complex, aggregates platelets strongly in the presence of heparin, less strongly in the presence of low molecular weight heparins and pentosan polysulfate and not at all with dermatan sulfate or the pentasaccharide. Heparan sulfate does interact with platelets and this antibody, which is of interest because of the heparan sulfate on endothelial cells. Clinical information to date suggests a low incidence of heparin antibodies in patients receiving only low molecular weight heparin of the depolymerized type. Whether long-term clinical use of low molecular weight heparins, heparan sulfate, and dermatan sulfate will give rise to specific antibodies that would cause a similar problem as heparin remains to be seen.
Autoantibodies↗
Risk of thromboembolism during diagnostic and interventional cardiac procedures with nonionic contrast media.
To investigate the relationship between clot formation and thromboembolism, canine blood was withdrawn into catheter-syringe or catheter-steerable wire systems containing either contrast medium or normal saline as used in debubbling techniques. The contrast media used were iohexol, iopamidol, ioxaglate, and diatrizoate. Without the use of heparin, after a 30-minute incubation, blood clots were harvested from all catheter-syringe systems except those with diatrizoate and from all catheter-steerable wire systems. Significantly more blood clot was harvested from the catheter-steerable wire system. With use of heparinized blood, no clot was found in any system. Twelve dogs that underwent coronary angiography were divided into two groups; one received heparin (5,000 IU) and the other did not. Thromboembolism occurred in all nonheparinized dogs that underwent angiography with iohexol or iopamidol but not in any other group. The authors found that in a dog model nonionic contrast media are more thrombogenic than ionic contrast media, especially in the catheter-steerable wire system. The blood clot in the catheters is associated with thromboembolism during angiography. The authors maintain that in this setting, blood clotting and thromboembolism with nonionic agents can be eliminated with heparin.
Animals↗
Thromboembolic disease during pregnancy: problems with anticoagulant therapy.
Thromboembolic complications of pregnancy and the puerperium deserve renewed attention not only because they are the most frequent nonobstetrical complications encountered in these circumstances, but also because of current litigious attitudes, the greater survival of women with prosthetic heart valves, and the inadequacy of current treatment regimens that put the physician, as well as the patient, in special peril. New techniques are available to the clinical laboratory for studying the coagulation and hypocoagulant proteins, coagulation inhibitors, and the fibrinolytic system. They provide fresh insight into this perplexing medical problem. Attention to the details of current investigations, efforts to control the risk factors, and the perspicacious use and suitable monitoring of pharmacological agents can be expected to reduce the risks for both the pregnant patient and her attending physicians.
Anticoagulants↗
Clinical potential of low molecular weight heparins.
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Cardiopulmonary Bypass↗
In vitro studies of the interaction of heparin, low molecular weight heparin and heparinoids with platelets.
Heparin, low molecular weight heparins, and heparinoids were studied for their ability to inhibit the aggregation of platelets by various agonists and for their ability to adhere to collagen. Heparin was a very effective inhibitor of aggregation with collagen and with ristocetin as it was with adhesion to collagen. The heparinoids showed little effect on aggregation or adhesion. Heparan sulfate and pentosan polysulfate did show slight inhibitory activity against collagen aggregation and adhesion and both interacted with the antibody induced by heparin therapy. It is of interest that dermatan sulfate and the pentasaccharide were almost inert in these experiments, and are unlikely to induce bleeding by inhibition of platelet function. It is highly probable that interference with the interaction of von Willebrand factor with platelets and collagen is a major mechanism for bleeding in the heparinized patient.
Adenosine Diphosphate↗
Validity of the newly established low-molecular-weight heparin standard in cross-referencing low-molecular-weight heparins.
Four low-molecular-weight-heparin (LMWH) preparations have recently become available for clinical usage. Some ten preparations are currently under preclinical development. The safety/efficacy profile of each of these LMWHs is now known to be quite distinct from one and other. In order to minimize the variations in the pharmacologic responses and to cross-reference different products on a common scale, the WHO has recently introduced a LMWH standard. This standard is a nitrous-acid-depolymerized product provided by KabiVitrum (Stockholm, Sweden) with a specific physiochemical and biological profile. Although the in vitro characteristics of this standard are comparable to other LMWH, the in vivo behavior of this reference and the parent product, Fragmin, are quite different in comparison to other products. In a well-defined uniform biochemical and pharmacologic screening, seven LMWH were compared at WHO reference-adjusted potency using pharmacologically valid dose-response curves. Cross-referencing of various LMWHs against the WHO standard in terms of anti-Xa activity resulted in a marked elevation of the anti-IIa component of some of the LMWHs. Establishment of this WHO standard stipulated that the clinical performance of cross-referenced LMWHs would be equivalent to one another and variation in potency could be minimized. Our data suggest that utilizing the WHO, standard individual potency (anti-Xa)-adjusted LMWHs exhibit distinct safety/efficacy profiles which were not related in their observed in vitro potency. Each LMWH has distinct multiparametric molecular and biochemical characteristics which determine the pharmacologic activities of individual agents. Thus cross-referencing of LMWHs by one in vitro assay is of questionable value as it may result in serious dosimetric errors, resulting in serious thrombotic and bleeding complications.
Animals↗
Medical treatment of abnormal endothelial cell function.
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Endothelium, Vascular↗
Soft tissue infections in the compromised host.
Soft tissue infections were seen in 25 patients with underlying malignancy and immunosuppressive disease. The primary disease included leukemia, lupus, aplastic anemia, lymphoma, carcinoma and myeloma. Infectious sites included the perianal area, gluteal, chest wall, extremity and the vulva. Eighty per cent of the infectious episodes occurred in patients who were granulocytopenic. Initial presentation was of local tenderness and redness. Fluctuation and discoloration were present in nine patients who were also hypotensive. Local drainage in five patients resulted in the death of two (20%). Overall, the mortality was 3/25 (12%). Wide debridement and drainage and appropriate antibiotic therapy resulted in the death of 1/20 (5%) patients. Hypotension, discoloration and fluctuation were found to be late signs in these patients. Soft tissue infections in the compromised host present subtly and progress to death if treatment is delayed. Temperature elevation and localized tenderness and erythema are indications for broad spectrum antibiotics and extensive intraoperative drainage and debridement.
Adolescent↗
Heparin-associated thrombocytopenia in maintenance hemodialysis patients.
Thrombocytopenia associated with the presence of a heparin-dependent platelet aggregating factor developed in two patients after hemodialysis with heparin. It resolved in one patient after heparin was stopped; but persisted in the other during a two-week heparin-free period and intermittently thereafter. We suggest that when heparin causes thrombocytopenia in dialysis patients the heparin should be stopped whenever possible, but this may not be necessary in all patients.
Heparin↗
A case of TdT-positive B-cell acute lymphoblastic leukemia.
The phenotypic marker profile of a patient with B-cell acute lymphoblastic leukemia (B-ALL) is described. The blast cells showed typical FAB L3 morphology, had the characteristic t(8;14) chromosomal abnormality, and were monoclonal in the expression of surface immunoglobulins. The clinical course of this patient is consistent with the poor prognosis described for B-ALL cases. Surface marker analysis identified cells positive for surface immunoglobulins, Ia-like antigen, common ALL-antigen, and terminal deoxynucleotidyl transferase. This marker profile shows immunologic characteristics of the two B-cell leukemia subtypes, pre-B-ALL and B-ALL. This "intermediate" immunologic phenotype might either be the result of an uncoupling of the sequential immunologic maturation processes or of an arrest of the cells at an intermediate stage between the two otherwise clearly defined leukemia subtypes, but closer to the typical B-ALL stage. This latter observation is supported by isoenzyme marker analysis, as the cells were negative for the hexosaminidase I isoenzyme, which is positive in pre-B-ALL but negative in B-ALL.
Acute Disease↗
Neurotoxicity associated with systemic high-dose cytosine arabinoside.
High doses of cytosine arabinoside (ara-C) have been used in the treatment of refractory forms of acute nonlymphoblastic leukemia (ANLL) and ANLL occurring after previous antineoplastic therapy. In addition to the usual toxicities associated with antimetabolites, neurotoxicity, mainly in the form of cerebellar dysfunction, develops in a significant proportion of patients receiving high-dose cytosine arabinoside HDara-C. This study was performed to determine the incidence of cerebellar dysfunction in our patients and to determine any factors that predict its development. In this series of 30 consecutive patients receiving HDara-C, confusion with cerebellar signs and symptoms developed in seven (23%). Factors that appear to predispose patients to the development of neurotoxicity are (1) past history of neurologic dysfunction and (2) preexisting and progressive hepatic dysfunction. No peripheral neuropathy was seen. In contrast to previous reports, we did not find neurotoxicity to be dose related. Prophylactic use of pyridoxine does not prevent neurotoxicity.
Acute Disease↗
Clinical efficacy of heparin fractions: issues and answers.
The recent development of heparin fractions and fragments for clinical use has created the prospect of some new agents at our disposal for the treatment of thrombotic disorders. The development of a drug that will block thrombosis but will not impair hemostasis now appears to be a possibility. Due to lack of understanding of all of the mechanisms of the pathology of thrombosis, we are not certain what the properties of the ideal anticoagulant should be. Of the heparins and heparin fractions, fragments, and heparinoids now available to us, we have yet to fully understand the mechanism of their pharmacologic activity. It has been amply demonstrated that decreasing the average molecular weight decreases the antithrombin activity while retaining the anti-Xa activity of heparin derivatives. Studies on animal models have proven the antithrombotic potency of some of these low molecular weight heparins to be equal to that of unfractionated heparin. There has been some evidence that these fractions are less likely than unfractionated heparin to cause hemorrhage in animal models as well as in at least one human clinical trial. A recently published human clinical trial revealed an unexpected incidence of hemorrhage following major surgery when a certain heparin fraction was given as prophylaxis against thrombosis. We are desperately in need of heparin derivatives, heparinoids or other anticoagulants that can be used in place of standard heparin in patients who are allergic to heparin or who have heparin-induced thrombocytopenia. Patients with these problems not infrequently require cardiopulmonary bypass surgery in which the use of heparin has been mandatory. There is now evidence from animal and human studies that such a procedure is possible with a heparin fraction or a heparinoid. This is true for hemodialysis as well. Studies in progress offer hope that a low molecular weight fragment with potent anti-Xa activity will not cause thrombocytopenia in patients with heparin-induced thrombocytopenia. Whether this agent, a pentasaccharide, will have sufficient antithrombotic potency for clinical use remains an important question. An important property of some of the newer heparin fractions is a prolonged duration of action which may permit fewer doses, thus reducing the cost as well as patient discomfort and inconvenience.
Animals↗
Correlation of surface marker expression with morphologically and immunologically defined subclasses of acute myeloid leukaemias.
The expression of myeloid-associated cell surface antigens detected by monoclonal antibodies (MoAb: MCS-2, MCS-1, MY7, MY9, Leu-M1, OKM1, VIM-D5, Mol, My-1, MY8, MY4, Leu-M3, VIM-D2, Mo2) of the HLA-DR/Ia-like antigen and of the Fc-receptor was determined on the blast cells from 91 patients with acute myeloid leukaemias classified as M1-M5 in the French-American-British (FAB) system. The surface antigen analysis revealed a highly heterogeneous reaction profile. Nevertheless, distinctive patterns of marker expression referring to morphologically defined subgroups were delineated. Several MoAb (especially MCS-2 and MY7 which were positive in most cases of the five FAB subgroups) appear to be useful for the recognition of myelomonocytic cells regardless of the commitment to either the granulocytic or monocytic cell lineage whereas other Mo Ab (especially MY4, Leu-M3, VIM-D2, Mo2) react predominantly with the monocytic variants and are helpful in the identification of monocytic commitment. The 91 cases could be divided into three immunologically defined phenotypes (Types I-III) corresponding to sequential differentiation levels. Correlations of these MoAb-defined phenotypes with the FAB subtyping showed that immunological and morphological classifications are not completely concordant and that only the parameters Type I and FAB M1 were significantly related. A scheme of early myeloid differentiation sequences based on the expression of surface antigens is presented.
Adult↗