PLATELET FACTOR-4 INJECTION PRODUCES ACUTE PULMONARY-HYPERTENSION IN THE AWAKE LAMB

Background: Reversal of heparin anticoagulation by intravenous protami ne sulfate consistently produces acute pulmonary vasoconstriction medi ated by the release of thromboxane in the awake lamb. Recently, recomb inant platelet factor 4 (rPF4) has been cloned, expressed in Escherich ia coli, and infused to reverse heparin anticoagulation in the rat, wi thout producing adverse hemodynamic or pulmonary morpholopic effects. The authors sought to learn whether intravenous administration of PF4 is devoid of side effects in the pulmonary circulation of lambs. Metho ds: The authors evaluated the hemodynamic response and plasma release rates of thromboxane during intravenous challenges with heparin-rPF4 ( n = 2), rPF-free carrier (n = 5), rPF4 (n = 5), rPF4 after indomethaci n (n = 5), protamine (n = 5) and heparin-protamine (n = 5) in 17 awake , hemodynamically monitored lambs. Each lamb underwent up to three ran dom challenges with a 2-h recovery period between each challenge. Resu lts: In two lambs, systemic anticoagulation with heparin followed by r eversal of anticoagulation with an intravenous bolus of rPE4 (4 mg/kg) led to acute pulmonary vasoconstriction and hypertension with the rel ease of thromboxane (peak pulmonary artery pressure [Ppa] 40 and 33 mm Hg and peak plasma thromboxane B-2 50 and 30 ng/ml, respectively). Int ravenous administration of rPF4 (1.5 mg/kg) alone increased the Ppa fr om 17.2 +/- 0.7 mmHg (mean +/- SEM) at baseline to 31.2 +/- 2 mmHg at 1 min (n = 5, P < 0.05). This was associated with an increase of plasm a thromboxane B-2 from 0.06 +/- 0.02 to 3.96 +/- 1.21 ng/ml. Acute pul monary vasoconstriction lasted approximately 5 min and was completely prevented by pretreatment with oral indomethacin (10 mg/kg). Intraveno us bolus administration of rPF4 carrier (n = 5) or protamine (2 mg/kg) alone (n = 5) did not induce pulmonary hypertension or the release of thromboxane. In five lambs, intravenous heparin (200 U/kg) followed b y protamine (2 mg/kg) consistently produced acute pulmonary vasoconstr iction and hypertension. Conclusions: Intravenous injection of human r PE4 into the awake lamb produces acute pulmonary vasoconstriction and hypertension associated with thromboxane release into circulating bloo d. The effects of rPF4 on the pulmonary vasculature should be evaluate d in primates before rPF4 is substituted for protamine in reversing he parin anticoagulation in humans.