Hematin: unique effects of hemostasis

Abstract

Hematin is clinically useful in the treatment of acute intermittent porphyria. Recently, hematin-induced coagulopathy has been reported, and a patient we treated bled during hematin therapy. On 3 separate occasions, infusions of hematin (4 mg/kg) induced thrombocytopenia, prolongation of the prothrombin time, partial thromboplastin time. Reptilase time, and apparent decreases in fibrinogen and increases in fibrin(ogen) degradation products (FDP). However, fibrinogen assayed by heat precipitation was unchanged, the protamine paracoagulation test was negative, there was no red blood cell fragmentation, and plasminogen and antithrombin III remained normal, excluding the presence of disseminated intravascular coagulation. Furthermore, premedication with heparin, 5000 U i.v., failed to prevent the lengthening of the Reptilase time and exacerbated the thrombocytopenia. In vitro studies revealed that hematin, 0.1 mg/ml, aggregated platelets and induced the release of 14C-serotonin and adenosine triphosphate (ATP). Hematin also aggregated washed or gel-filtered platelets but had no effect on formalin-fixed platelets. Aggregation was inhibited by aspirin (0.12 mg/ml), adenosine triphosphate, and apyrase, suggesting that hematin aggregated platelets by inducing adenosine diphosphate (ADP) release. Hematin (0.07 mg/ml) progressively inactivated thrombin and 0.1 mg/ml prolonged the Reptilase time. Thus, hematin is unique in that it both induces platelet aggregation and inhibits coagulation.

Mechanism and characteristics of platelet activation by haematin

“…This paper focuses on the mechanism of haematin-induced platelet aggregation and defines some of the characteristics of the aggregation reaction. We elected to use platelets suspended in a low-protein artificial medium, rather than in plasma, to minimize haematin-protein interaction (Green et al, 1983) which may render the interpretation of certain haematinplatelet interactions more difficult. With washed platelets, a concentration of 5 ,ug/ml or less of haematin was sufficient to cause platelet aggregation, whereas with PRP, 20-50 times the concentration of haematin was required (Glueck et al, 1983).…”

“…Haematin, the ferric hydroxide of haem, is an effective agent for the treatment of patients in acute porphyric crisis (Bonkowsky et al,19 71). Recently, a coagulopathy characterized by thrombocytopenia and prolonged clotting times has been described in association with haematin therapy (Morris et al, 1981;Glueck et al, 1983). Although clinical bleeding is uncommonly encountered, the drug clearly compromises the haemostatic capability of the patient.…”

“…Although clinical bleeding is uncommonly encountered, the drug clearly compromises the haemostatic capability of the patient. Following our observation (Glueck et al, 1983) of the development of a coagulopathy involving several haemostatic components in a porphyric patient receiving therapeutic doses of haematin, we investigated the effects of haematin on clotting factor and plasmin activities (Green et al, 1983) and on endothelial cells and endothelial cell-platelet interactions (Neely et al, 1984). We found that haematin directly inhibited clotting factors and plasmin, damaged endothelial cells in tissue culture, and promoted platelet interaction with haematin-treated endothelial cell monolayers.…”

Effect of the Heme Oxygenase Inducer Hemin on Blood Haemostasis Measured by High‐frequency Ultrasound

“…Heme compounds are the most efficient in the treatment of acute porphyria, 1,2 a well-defined autonomic dominant disorder of heme biosynthesis with a genetic frequency of 1 : 10 000-1 : 50 000 and characterized by acute life-threatening attacks of non-specific neurological symptoms. [3][4][5][6] Given intravenously at moderate doses (3-4 mg/kg per day), heme compounds usually result in a rapid clinical improvement, often within 1-2 days, especially when therapy is started early in an attack. 4,7,8 Such compounds are now available as heme arginate (Normosang ® ; Orphan Europe, Puteaux, France) and as haematin (Panhematin; Ovation Pharmaceuticals, Deerfield, IL, USA), which is a lyophilized powder of hemin.…”

Pharmacokinetics of intravenously administered haem arginate.

“…normally performed on drug preparations before clinical use. Haematin infusions in porphyric patients are associated with a high risk of thrombophlebitis (McColl etal., 1981) and coagulation disturbances (Morris et al, 1981, Glueck et al, 1983, which are possibly caused by degradation products of haematin (Mustajoki, 1985). Transitory renal failure after a relatively large dose of haematin has been reported (Dhar et al, 1978).…”