Protein C and Antithrombin III in Polytransfused Thalassemic Patients

Abstract

Seventy-four patients with β-thalassemia major were studied to test the hypothesis that a deficiency of protein C (PC) and antithrombin III (AT III), both antithrombotic proteins, could contribute to the pathogenesis of CNS thromboembolic lesions. In 70 patients, PC levels were found to be significantly lower than normal, whereas AT III activity was found to be lower only in 41 patients. The lowest values of PC and AT III were found in older splenectomized patients, a low PC value only was found in chronic hepatitis patients. Prothrombin time and fibrinogen were found to be particularly abnormal in patients with chronic hepatitis and without spleen. A relatively poor correlation was observed between PC and AT III (p < 0.02). PC correlated with age (p < 0.001), transfusional iron (p < 0.001) and ferritin (p < 0.001). It also correlated with serum albumin (p < 0.001), prothrombin time (p < 0.001) and fibrinogen (p < 0.02) and with serum transaminases (GPT) (p < 0.001). The same indexes correlated less significantly with AT III activity. Nevertheless, only 2 of our patients had CNS thromboembolic complications. It is probable that low clotting factors, hyperfibrinolysis and thrombocytopenia (which are common in chronic liver disease) could have the opposite effect on hemostasis from that of low levels of anticoagulant proteins such as PC and AT III.

In‐vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with β‐thalassaemia major

“…Thus, sickle RBC were shown to display a procoagulant effect in in-vitro assays and were thought to be operative in the induction of a hypercoagulable state (Middelkoop et al, 1988;Hermann & Devaux, 1990). Although occlusive vascular complications are frequent in sickle cell disease, the existence of a hypercoagulable state in thalassaemia major and intermedia was recognized only recently (Eldor et al, 1987(Eldor et al, , 1991Musumeci et al, 1987;Del Principe et al, 1993;Cappellini et al, 1995Cappellini et al, , 1996. Despite the fact that none of our TM or TI patients had an overt thrombotic event, a chronic hypercoagulable state was evident by the increased fraction of circulating platelets expressing activation dependent neoantigens, p-selectin (CD62p) and the lysosomal glycoprotein CD63.…”

“…Despite the fact that none of our TM or TI patients had an overt thrombotic event, a chronic hypercoagulable state was evident by the increased fraction of circulating platelets expressing activation dependent neoantigens, p-selectin (CD62p) and the lysosomal glycoprotein CD63. Overt thromboembolic events occur only rarely in thalassaemic patients; however, laboratory tests have provided evidence for a chronic hypercoagulable state which already exists in early childhood (Eldor et al, 1991(Eldor et al, , 1992Musumeci et al, 1987;Del Principe et al, 1993;Cappellini et al, 1995Cappellini et al, , 1996. Low lung capacity, hypoxaemia and right ventricular heart failure are observed in many young and adult TM patients (Cooper et al, 1980;Grant et al, 1986).…”

“…Several platelet and coagulation anomalies, frequently observed in TM or thalassaemia intermedia (TI) patients, suggested the existence of a hypercoagulable state. These include changes in platelet aggregation (Eldor, 1978), shortened (by about 50%) mean platelet life-span (Eldor et al, 1989), increased urinary excretion of thromboxane (TX) A 2 metabolites (2,3-dinor-TXB 2 and 11-dehydro-TXB 2 ) (Eldor et al, 1991), enhanced expression of p-selectin (PADGEM/GMP 140) on intact thalassaemic platelets (Del Principe et al, 1993), elevated plasma levels of thrombin-antithrombin III (TAT) complexes and low plasma levels of the natural anticoagulants, protein C and protein S (Musumeci et al, 1987;Eldor et al, 1992;Cappellini et al, 1995).…”

The hypercoagulable state in thalassemia

“…53,54 Some thalassemic patients from Italy and Turkey had low antithrombin III (ATIII) levels in addition to protein C and protein S deficiencies, whereas no ATIII deficiency was found in the Israeli patients. 4,19,55 Low levels of heparin cofactor II (HCII), known to be associated with increased thrombotic risk, have been found in thalassemic patients. 56 Frequent blood transfusions resulted in a slow normalization of HCII levels, suggesting that the low HCII levels could be related to increased RBC turnover that had been suppressed by hypertransfusion.…”

Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia

“…Markers of thrombin generation such as thrombin antithrombin complexes (TAT) and D-dimers have been shown to be increased in thalassemia syndromes [6, 5]. From a pathophysiological point of view, the main factors involved in hypercoagulability of thalassemia are the procoagulant activity of red blood cells (RBC), due to exposure on the external membrane of phosphatidylserine, that promotes the formation of a prothrombinase complex [7,8,9], and the copresence of low levels of inhibitors especially protein C (PC) and protein S [6, 10]. …”