Impaired hemostatic activity of healthy transfused platelets in inherited and acquired platelet disorders: Mechanisms and implications

Abstract

Platelet transfusions can fail to prevent bleeding in patients with inherited platelet function disorders (IPDs), such as Glanzmann’s thrombasthenia (GT; integrin αIIbβ3 dysfunction), Bernard-Soulier syndrome [BSS; glycoprotein (GP) Ib/V/IX dysfunction], and the more recently identified nonsyndromic RASGRP2 variants. Here, we used IPD mouse models and real-time imaging of hemostatic plug formation to investigate whether dysfunctional platelets impair the hemostatic function of healthy donor [wild-type (WT)] platelets. In Rasgrp2−/− mice or mice with platelet-specific deficiency in the integrin adaptor protein TALIN1 (“GT-like”), WT platelet transfusion was ineffective unless the ratio between mutant and WT platelets was ~2:1. In contrast, thrombocytopenic mice or mice lacking the extracellular domain of GPIbα (“BSS-like”) required very few transfused WT platelets to normalize hemostasis. Both Rasgrp2−/− and GT-like, but not BSS-like, platelets effectively localized to the injury site. Mechanistic studies identified at least two mechanisms of interference by dysfunctional platelets in IPDs: (i) delayed adhesion of WT donor platelets due to reduced access to GPIbα ligands exposed at sites of vascular injury and (ii) impaired consolidation of the hemostatic plug. We also investigated the hemostatic activity of transfused platelets in the setting of dual antiplatelet therapy (DAPT), an acquired platelet function disorder (APD). “DAPT” platelets did not prolong the time to initial hemostasis, but plugs were unstable and frequent rebleeding was observed. Thus, we propose that the endogenous platelet count and the ratio of transfused versus endogenous platelets should be considered when treating select IPD and APD patients with platelet transfusions.

Inherited Platelet Disorders: An Updated Overview

“…Moreover, platelet transfusions in these patients were only effective when more than 6 units of platelets were transfused [ 167 ]. In this regard, recent studies suggest that in diseases with significantly dysfunctional platelets (such as GT), a critical proportion of approximately 2:1 of endogenous (dysfunctional) to transfused (healthy) platelets is essential to prevent prolonged bleeding induced by hemostatic lesions [ 171 ].…”

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial

“… 11,12 Platelets are the largest cellular source of plasminogen activator inhibitors. Clots formed in the presence of thrombocytopenia are friable, lyse rapidly, and result in a poor hemostatic plug, 13 possibly due to plasminogen activator inhibitor deficiency. Therefore, TXA might be beneficial in thrombocytopenic bleeding.…”

Venous puncture wound hemostasis results in a vaulted thrombus structured by locally nucleated platelet aggregates

“…Experimentally, vascular damage has typically been visualized in mouse models, e.g., laser 1 – 4 and/or ferric chloride treatment [e.g., 5 ] or small needle pricks of arterioles 6 to induce vessel damage. Under these conditions, damage to the endothelial layer lining the vessel wall exposes the underlying collagen-rich adventitia, but often fails to puncture the adventitia to yield an open hole and more than very limited bleeding [for review, see 7 – 10 ].…”