Can a drug-induced pulmonary hypersensitivity reaction be dose-dependent? A case with mesalamine.

Mesalamine-induced pulmonary adverse drug reactions (ADRs) in the course of therapy for inflammatory bowel diseases are rare events, having been reported in only 21 cases. This response, resembling hypersensitivity pneumonitis, is considered to be immunologically mediated and thus dose-independent. We report the case of a 70-year-old woman with ulcerative colitis (UC) who developed biopsy-proven interstitial pulmonary disease (lymphocytic alveolitis and mild interstitial pulmonary fibrosis) three months after starting mesalamine therapy. The usual treatment in cases of ADR is cessation of the drug and initiation of corticosteroids. In this case, we continued the mesalamine therapy but halved the dose, and did not add corticosteroids. This approach led to a remission of the pulmonary manifestations without a resurgence of UC symptoms. Based on a review of the literature and our own observation, we challenge the concept that mesalamine-induced pulmonary injury is always due to a hypersensitivity reaction. The evidence suggests that in some cases pulmonary ADR is dose-related; in such instances the most accepted therapy is not necessarily the most appropriate one.

The report of an Italian family with heterozygous protein C deficiency.

A heterozygote protein C deficit was found in 4 members of the same family. The propositus is a 40 year old male with a clear thrombotic tendency. This included repeated thrombophlebitis of the right leg, and one episode of pulmonary embolism. Arterial thrombosis was not noted. The anticoagulant therapy undertaken by the patient appears to be of some benefit in the sense that no recurrence of thrombotic manifestations occurred. One brother and two nephews of the propositus, even though asymptomatic showed reduced levels of Protein C both as activity and antigen. The parallel reduction of Protein C activity and antigen points towards a "true" deficit of Protein C. The normal, although reduced, pattern in the crossed immunoelectrophoresis supplies further confirmation to this interpretation.

Factor X antigen--factor X activity discrepancy in coumarin treated patients. No relationship with dilution curve.

The plasma of 12 patients on coumarin medication was investigated with regard to factor X antigen, factor X activity, factor X antigen--factor X activity difference (delta) and dilution curve. The plasmas were divided into 3 groups according to the level of anticoagulation (under anticoagulated, normally anticoagulated, over anticoagulated). The average factor X antigen and the average factor X activity were 56.7, 53.0, 34.6 and 25.5, 20.1, 11.1%, respectively for the three groups of patients. The antigen-activity differences (delta) were 21.2, 22.5 and 23.5%, respectively. The degree of inhibition in conventional units was 2.6, 1.7 and 0.4 units for the three groups of patients, respectively. The decrease of "inhibition" with the increase of anticoagulation is not in agreement with the presence of similar levels of pre-factors or delta antigen-activity in the plasma of the three groups of patients. These data are against the presence of inhibitors in coumarin treated patients.

Congenital heterozygous plasminogen deficiency associated with a severe thrombotic tendency.

Heterozygous plasminogen deficiency was found in 2 patients (mother and daughter). The mother, aged 55 years, was symptomatic while the daughter, aged 10 years, was asymptomatic so far. The thrombotic tendency presented by the proposita (mother) was severe and included recurrent superficial, portal, mesenteric, subclavian thrombophlebitis. No arterial thrombosis was noted. Oral anticoagulants have been of some benefit. The main laboratory features were: plasminogen activity about 50% of normal in two amidolytic methods and in a caseinolytic method. Plasminogen antigen was also about 50% of normal using electroimmunoassay and radial immunodiffusion. Crossed immunoelectrophoresis revealed a normal, even though reduced pattern, thus excluding dysplasminogenemia. Routine coagulation tests were negative. Euglobulin lysis time, fibrinogen level and fibrinogen degradation products (FDP) were within normal limits. Antithrombin III, protein C and protein S were also within normal limits.

Greater decrease of fibrinogen as compared to antithrombin III in L-asparaginase treated leukemia patients.

Fibrinogen and Antithrombin III (AT III) were studied sequentially during remission induction with L-asparaginase, prednisone and vincristine in 20 children with acute lymphoblastic leukemia (ALL). The first 2 weeks of therapy were characterized by significant decreases in plasma concentration of fibrinogen (p less than 0.05 or p less than 0.01). AT III (antigen and activity) decreased between the first and second week of therapy, but on an average, they remained a little above the lower limits of normal. However, at the second week, the difference was significant from basic values (p less than 0.05). All parameters gradually returned to normal after completion of L-asparaginase therapy.

Associated von Willebrand disease as a possible cause of lack of thrombosis in an AT III abnormality (AT III Trento).

In a family with a known antithrombin III abnormality (AT III Trento) an associated von Willebrand defect (Type I) was found. The two defects seem to segregate independently. In fact four types of individuals were present, namely: subjects with isolated AT III abnormality, subjects with isolated von Willebrand defect, patients with double defect and normal subjects. Only one of the two patients with isolated AT III abnormality showed a thrombotic tendency. None of the patients with double defect showed thrombotic disease, indicating a possible protective action of the von Willebrand defect against thrombotic manifestations. Patients with isolated von Willebrand defect showed neither thrombotic nor bleeding manifestations. The study emphasizes the need for a careful evaluation of the hemostatic balance of patients with AT III abnormalities before concluding that they are symptomatic or asymptomatic.

Fibrinolytic study in plasma and ascitic fluid of cirrhotic patients before and after ascites concentration; reinfusion technique.

Management of cirrhosis with massive ascites involves particular difficulties. The introduction of a peritoneovenous shunt and reinfusion of concentrated ascitic fluid techniques allows increased diuresis and improves renal function. However, these procedures have frequently been associated with disseminated intravascular coagulation and/or activation of fibrinolysis. Factor VIII activity, antigen and ristocetin cofactor, plasminogen, antiplasmin, plasminogen activator activity and plasmin-antiplasmin complex were investigated both in the ascitic fluid and plasma of cirrhotic patients before and after the concentration-reinfusion technique. Our results indicated that no hyperfibrinolysis was seen in the plasma of cirrhotic patients and that activation of fibrinolysis exists in ascites. Significantly higher levels of plasmin-antiplasmin complex and plasminogen activator activity were found in ascitic fluid than in plasma. In post-reinfusion much higher levels of all three Factor VIII components were observed in cirrhotic plasma than in normal plasma. In conclusion, activation of fibrinolysis could explain coagulation complications occurring after ascites reinfusion. Antifibrinolytic treatment could render the concentration-reinfusion technique more acceptable.

Platelet factor 4 release induced by intravenous administration of heparin.

When heparin is injected intravenously, it can induce an immediate release of platelet factor 4 PF4), probably from the non-platelet pool of endothelial cells. We evaluated this release in a group of normal subjects and patients with cardiovascular disorders or thrombocytosis after an intravenous injection of a bolus of 5,000 I.U. of a commercial mucous heparin. The mean level in normals was 102 +/- 32 (range 50-160) ng/ml and no correlation was found before and after heparin injection between PF4 and heparin level, body weight or platelet count. Only three cardiovascular patients had an elevated level of PF4 released by heparin (HR-PF4) that could be the expression of an increased platelet turnover, whereas all the patients with thrombocytosis had an extremely elevated level of HR-PF4. These patients have much more PF4 available for the binding sites of endothelial cells since only a small percentage of potential binding sites are normally occupied "in vivo". Although no correlation could be found between platelet count and HR-PF4 in subjects with a normal platelet count or in patients with thrombocytosis there was a positive correlation, however, when all the cases were considered together. The other proteins with heparin affinity, B-thromboglobulin, antithrombin III and fibronectin were not influenced by a bolus of heparin and did not correlate in normals as well in patients with HR-PF4.

Antithrombin III deficiency: a report of 14 cases belonging to three different kindreds.

A hereditary deficiency of AT III is described in 14 subjects belonging to three different kindreds. There is no consanguineity in any of the families investigated. The pattern of inheritance of defect appears autosomal dominant. Seven of the affected subjects presented thrombotic episodes (deep vein thrombosis, splanchnic thrombosis, pulmonary embolization). The main laboratory features were: normal routine clotting tests, decreased AT III activity in all assay systems and concomitantly reduced AT III antigen levels. Crossed immunoelectrophoresis showed only reduced peaks with respect to normal in both plasma and serum. No correlation was found between age of patients and AT III levels.