Artur Wehmeier

A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders.

Abstract: Platelet function and the clinical course of the disease were prospectively investigated in 29 patients with myeloproliferative disorders. Serial determinations (median: 5 investigations per patient within 17 months) of platelet aggregation, plasma and intraplatelet concentrations of β‐thromboglobulin (βTG) and platelet factor 4 (PF4), and of fibrino‐peptide A (FPA) plasma levels were carried out. In the chronic phase of polycythaemia vera, patients with thrombohaemorrhagic complications during the study period had higher platelet count, more severe platelet aggregation defects, and increased plasma levels of βTG and FPA compared to patients without complications. However, thrombohaemorrhagic complications were not predicted by changes in these parameters in the individual patient during the chronic disease phase. When patients with chronic myelogenous leukaemia entered blast crisis, bleeding complications were related to thrombocytopenia, impaired platelet function and low intraplatelet concentrations of βTG and PF4. Cytoreduction by chemotherapy in the chronic phase of CML did not alter βTG and PF4 plasma levels, whereas treatment of polycythaemia rubra vera by venesection favourably influenced platelet α‐granule secretion and increased intraplatelet concentrations of βTG and PF4.

Bleeding and Thrombosis in Chronic Myeloproliferative Disorders: Relation of Platelet Disorders to Clinical Aspects of the Disease

Bleeding and thrombosis are a major cause of morbidity and mortality in myeloproliferative disorders (MPD). This study evaluates the relation between thrombohemorrhagic complications and platelet abnormalities in different subgroups of MPD. In 57 MPD patients thrombohemorrhagic complications occurred in 71% of patients with polycythemia rubra vera and 50% of patients with osteomyelofibrosis and primary thrombocythemia but in only 29% of patients with chronic myelogenous leukemia. Increased beta-thromboglobulin and platelet factor 4 plasma levels, platelet aggregation defects, and increased dispersion of the platelet volume distribution curve were most frequent in those subgroups where most serious thrombohemorrhagic complications were observed, and multiple platelet-related abnormalities were often found simultaneously. Fibrinopeptide A plasma levels were rarely elevated, however. Our results indicate that platelet abnormalities associated with bleeding and thrombosis are primarily determined by the clinical subgroup of myeloproliferative disease.

Coagulation factor V gene mutation associated with activated protein C resistance leading to recurrent thrombosis, leg ulcers, and lymphedema : successful treatment with intermittent compression

Activated protein C resistance is the most frequent cause of venous thrombosis. We describe a patient with extensive ulcerations and severe lymphedema of the legs after recurrent thrombosis. Laboratory tests revealed a pathologic activated protein C resistance and a reduced functional protein S. The underlying genetic defect was identified as a heterozygous coagulation factor V mutation. A combined therapeutic approach of intermittent compression, repeated debridements and systemic antibiotics resulted in marked improvement of both lymphedema and leg ulcers.

Plasma levels of D‐dimer and circulating endothelial adhesion molecules in veno‐occlusive disease of the liver following allogeneic bone marrow transplantation

Abstract: Veno‐occlusive disease (VOD) of the liver is a frequent and life‐threatening complication of BMT. Recently, successful treatment by t‐PA has been reported but has been compromised by fatal bleeding events. Therefore, t‐PA application should be restricted to patients with severe VOD. However, moderate and severe forms of VOD are difficult to distinguish in early stages. We analyzed plasma levels of cross‐linked fibrin degradation products (D‐dimer) and soluble endothelial adhesion molecules such as sE‐selectin, sVCAM‐1 and sICAM‐1 in 10 consecutive patients undergoing allogeneic BMT to evaluate their use in identifying severe forms of VOD. During the observation period, 4 episodes of VOD occurred, 2 of which were fatal due to early onset of multiorgan failure. Concentrations of D‐dimer generally increased after transplantation. However, there was an additional significant increase in D‐dimer levels during severe VOD. Thus, D‐dimer levels above 1000 μg/1 were only found in 2 cases with severe VOD and fatal outcome. When compared with bilirubin concentrations substantial increases of D‐dimers appeared earlier during the course of severe VOD. In contrast, VOD episodes were not accompanied by significant increases in sE‐selectin, sVCAM‐1 and sICAM‐1 levels. It is concluded that measurement of D‐dimer concentrations may aid accuracy to the early diagnosis of severe VOD.

Pseudomonas aeruginosa blepharoconjunctivitis during cytoreductive chemotherapy in a woman with acute lymphocytic leukemia.

Abstract Patients undergoing chemotherapy regimens for hematologic malignancies are prone to develop unusual and potentially life-threatening infections during periods of leukopenia- induced immunosuppression. We report the case of a woman who received consolidation chemotherapy for acute lymphocytic leukemia and acquired necrotizing Pseudomonas aeruginosa blepharoconjunctivitis of the right eye during a period of mild leukopenia. The infection led to severe orbital and periorbital inflammation, spreading down to the neck. High-dose antibiotic treatment with ceftazidime and tobramycin combined with granulocyte cell-stimulating factor cleared the infection after several days, but plastic surgery was needed to restore normal eye closure.

Increases of sICAM-1 during neutropenic pneumonia in leukemic patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Incidence and Severity of Amphotericin B-induced Acute Toxicity in Leukemic Patients After Treatment with Three Different Formulations (Amphotericin B, AmBisome and Amphotericin B/lntralipid) — A Pilot Study

Intravenous amphotericin B (AmB) is the most potent drug for treatment of systemic fungal infections in leukemic patients. However, use of this drug is often limited by renal side effects and acute toxicity (fever, chills, nausea, vomiting). A far better tolerance has been reported with the use of AmBisome, a liposomal preparation of AmB, but this formulation is extremely expensive. In search of a cheaper AmB preparation with a better tolerance than conventional AmB, french scientists recently reported that AmB mixed in fat emulsion (Intralipid) has a significantly better tolerance profile compared to conventional AmB (Caillot et al., 1992, Chavanet et al., 1992). Our pilot study was performed to get information about the tolerance of the three different AmB preparations in individual patients.

Drugs or diet: do they protect against degenerative cardiovascular disease?

Summary: Early observations that the regular use of aspirin (acetylsalicylic acid, ASA), a nonsteroidal anti-inflammatory agent, seemed to protect against myocardial infarction and reduce platelet aggregation made this substance the most frequently used drug in large clinical trials. The objectives of these studies were to reduce thromboembolic complications in arterial cardiovascular diseases (prevention of myocardial infarction in unstable angina, secondary prevention of acute myocardial infarction, and increased patency of aortocoronary bypass grafts) and to reduce platelet deposition on artificial surfaces (artificial heart valves and hemodialysis shunts). Despite the recent synthesis of more selective inhibitors of arachidonic acid metabolism in blood platelets, and a multitude of questions concerning optimal dose, schedule, and mode of action that still remain open, ASA continues to be the most frequently used drug in arterial vascular disorders. Because of the frequent and potentially serious side effects of aspirin, mainly on the gastrointestinal tract, less toxic ways of inhibiting eicosanoid metabolism in blood platelets are attracting more and more interest. Among these, the alimentary substitution of ω-3 fatty acids for a competitive inhibition of the ω-6-ar-achidonic acid metabolism seems the most promising. Results with fish-oil diet raise the question of whether substitution of polyunsaturated lipid acids influence only platelet metabolism, or whether the action of “antiplatelet” drugs or diet in cardiovascular disorders is mediated primarily by leukocytes or monocytes. This new dietary principle, which possibly corrects only a poor alimentary habit of civilization, could open simple and adequate ways for even a primary prophylaxis of vascular disease by diet alone or, at least for therapeutic aims, in combination with drugs.