ITP is one of the immunologic thrombocytopenic purpura characterized by the development of autoantibodies reacting on platelet glycoproteins, which are then destroyed by phagocytosis primarily in spleen.
In the treatment of ITP, IVIG is used for patients with active bleeding or for whom major surgery is necessary (10
). High-dose IVIG was first used for treatment of childhood ITP by Imbach et al. (12
) in 1981. The six indications approved for the IVIG product in Canadian Consensus guideline (1999) (13
) include immune deficiency, idiopathic thrombocytopenic purpura, hypogammaglobulinemia, pediatric Human Immunodeficiency Virus (HIV) infection, bone marrow transplantation, and B cell chronic lymphocytic leukemia. However, the clinical use of IVIG is far from being restricted to the approved indications and off-label uses such as chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome are common (13
). In general, IVIG has been considered a safe medication, with minor adverse reactions such as fatigue, fever, headache, nausea, and myalgias, occurring in no more than 10% of patients (1
). With the wider use of IVIG, the reported rate of side effects has increased, some of them being potentially fatal (1
). The first report of thromboembolic events associated with IVIG therapy by Woodruff et al. (8
). described four older patients with ITP who developed myocardial infarction and cerebrovascular accident after IVIG therapy, resulting in death in three of them. Paran et al. (14
) described that 65 cases of IVIG-associated thrombosis had been reported in 33 articles published from 1966 to 2004 and 34 of these cases were reported in 2003. In the report, 51 cases had arterial thrombosis, including stroke, myocardial infarction, and limb ischemia. Thirteen cases had venous thrombosis, including deep vein thrombosis or pulmonary embolism, central retinal vein thrombosis, and sinus vein thrombosis. Two of the reported patients had both an arterial and a venous thrombotic event (14
). Thromboembolic complications occurred within two weeks after IVIG therapy had begun, and the 63% of them occurred within 24 hr of the infusion (1
Although the pathogenesis of thrombosis secondary to IVIG is not completely understood, several mechanisms have been proposed. One plausible mechanism for IVIG-related thrombosis is the increase in blood viscosity by IVIG. High-dose IVIG increases blood viscosity from normal (1.2-1.7 cp) by 0.5 to 0.7 cp, thus causing a hypercoagulable state (2
). Previous studies reported that serum viscosity increased up to 2.9 cp immediately, following infusion of IVIG and declined gradually over the next month (14
). In particular, IgG has been postulated to increase viscosity through molecular interactions between proteins (2
). The viscous effect of IVIG is dose-dependent and increases the susceptibility to thromboembolism in predisposed patients such as elderly patients and those with cardiovascular or cerebrovascular disease and atherosclerosis (1
). If such patients are planned to receive IVIG, pretreatment screening with lower extremity ultrasound for subclinical clots, very slow infusion rate (not exceeding 200 mL/hr or 0.08 mL/kg/min) and monitoring of serum viscosity are recommended (1
). In addition, IVIG induces platelet activation, increased fibrinogen levels and activation of the serum complement, which may further predispose patients to thrombosis and ischemia. Some IVIG preparations have increased concentrations of factor XI, which may potentially trigger intrinsic coagulation pathway activation and thrombin formation (5
). Besides, IVIG may induce localized production of vasoconstrictive cytokines and arterial vasospasm leading to thrombotic events (5
Irrespective of IVIG therapy, thromboembolic complications, such as portal vein thrombosis, pulmonary embolism, and deep vein thrombosis may occur following splenectomy for hematologic diseases (18
). However, in our case, the patient experienced thromboembolic complications immediately following IVIG before splenectomy, which excludes this possibility.
Although a direct underlying mechanism responsible for IVIG-induced thrombotic events needs to be clarified, IVIG should be given with precaution in patients with vascular risk factors such as advanced age, history of cerebrovascular or cardiovascular disease, hypertension, or hypercoagulable and hyperviscosity conditions.