A Comprehensive Review of Congenital Platelet Disorders, Thrombocytopenias and Thrombocytopathies

Abstract

Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet hemostatic mechanisms can be congenital or acquired. Congenital platelet disorders are rare and manifestations range from asymptomatic to sometimes severe bleeding. The disorders arise due to diverse mechanisms. Congenital platelet disorders include thrombocytopathies and thrombocytopenia (platelet count <150 x 10⁹/L) or thrombocytosis (platelet count > 450 x 10⁹/L). Congenital thrombocytopathies include disorders of adhesion like von Willebrand's disease or Bernard-Soulier syndrome. The disorders of aggregation include congenital afibrinogenemia and Glanzmann thrombasthenia. Disorders of storage granules are gray platelet syndrome and Quebec platelet disorder. Congenital thrombocythopathy and thrombocytopenia often occur in conjunction. In this article, we have a detailed literature review of these rare thrombocytopathies, their presentation and treatment.

Keywords: congenital abnormalities; inherited diseases; inherited platelet disorder; thrombocytopenia.

Figure 1. Overview of hemostasis

(A) Primary hemostasis: the formation of the primary platelet plug. When the endothelium is injured, the procoagulant subendothelial matrix (consisting of proteins, such as collagen, von Willebrand factor (vWF), fibrinogen (FBG), laminin, and fibronectin) is exposed, and the subendothelial matrix proteins bind to glycoprotein (GP) receptors on the platelet surface and immediately initiate primary hemostasis, consisting of (1) platelet adhesion, (2) platelet activation, and (3) platelet plug formation. vWF binding to the GPIb-IX-V complex, collagen binding to platelet GPVI, and integrin receptors trigger a signal transduction process resulting in the local release of platelet activation agonists from dense granules, such as thromboxane A2 (TXA2) and ADP. These agonists, along with thrombin produced from coagulation cascades and activated platelets, bind to platelet surface-bound G-coupled receptors, inducing further platelet activation. Dense granules also contain polyphosphates, which are both procoagulant (i.e., they promote the cofactor activity of factor V in the common pathway) and anti-fibrinolytic (i.e., they help to form dense fibrin fibrils that are more resistant to fibrinolysis). Activated platelets release vWF and coagulation factors from granules, which lead to platelet plug formation (vWF and fibrinogen) and fibrin formation (factor V and factor XIII). This helps platelets bind firmly to the endothelium and allows leukocytes to be incorporated into developing clots. The granule content also includes platelet-derived growth factor (PDGF), transforming growth factor (TGF-), and platelet factor 4 (PF4). Activation of platelet integrin IIb 3 induces platelet aggregation mediated by fibrinogen/vWF. (B) Secondary hemostasis (formation of fibrin by coagulation proteins). In the extrinsic pathway, vessel wall injury leads to the expression of tissue factor (TF) on endothelial cells. TF complexes with factor VIIa to activate factors X and Xa [5].

Figure 2. Disorders that mainly affect surface components of platelets

Figure 3. Disorders that mainly affect intracellular components of platelets

Figure 4. Giant platelets in Bernard Soulier syndrome

Giant platelets of Bernard Soulier syndrome in the peripheral smear

Figure 5. Hypogranular platelets in Gray platelet syndrome