Inherited disorders of platelet function

Platelets play a critical role in hemostasis by forming the primary plug that initially seals vascular defects and by providing a surface that binds and concentrates activated coagulation factors.

Platelets are disc-shaped anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the bloodstream. Their function depends on several glycoprotein receptors, a contractile cytoskeleton, and two types of cytoplasmic granules. α-Granules: have the adhesion molecule P-selectin on their membranes and contain proteins involved in coagulation, such as fibrinogen, coagulation factor V, and vWF, as well as protein factors that may be involved in wound healing, such as fibronectin, platelet factor 4 (a heparin-binding chemokine), platelet-derived growth factor (PDGF), and transforming growth factor-β. Dense (or δ) granules: contain adenosine diphosphate (ADP) and adenosine triphosphate, ionized calcium, serotonin, and epinephrine.

After a traumatic vascular injury, platelets encounter constituents of the subendothelial connective tissue, such as vWF and collagen. On contact with these proteins, platelets undergo a sequence of reactions that culminate in the formation of a platelet plug:

1- Platelet adhesion: is mediated largely via interactions with vWF, which acts as a bridge between the platelet surface receptor glycoprotein Ib (GpIb) and exposed collagen. 2- Platelets rapidly change shape following adhesion, being converted from smooth discs to spiky “sea urchins” with greatly increased surface area. This change is accompanied by alterations in glycoprotein IIb/IIIa that increase its affinity for fibrinogen, and by the translocation of negatively charged phospholipids to the platelet surface. These phospholipids bind calcium and serve as nucleation sites for the assembly of coagulation factor complexes.

3- Secretion (release reaction) of granule contents occurs along with changes in shape; these two events are often referred to together as platelet activation. Platelet activation is triggered by a number of factors, including the coagulation factor thrombin and ADP. Thrombin activates platelets through a special type of G-protein– coupled receptor referred to as a protease-activated receptor (PAR), which is switched on by a proteolytic cleavage carried out by thrombin. Activated platelets also produce the prostaglandin thromboxane A2 (TxA2), a potent inducer of platelet aggregation. 4- ADP is a component of dense-body granules; thus, platelet activation and ADP release begets additional rounds of platelet activation, a phenomenon referred to as recruitment.

5- Platelet aggregation follows their activation 5- Platelet aggregation follows their activation. The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. 6- The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets.

7- In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug. Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to P-selectin expressed on activated platelets.

Qualitative defects of platelet function can be inherited or acquired Qualitative defects of platelet function can be inherited or acquired. Several inherited disorders characterized by abnormal platelet function and normal platelet count have been described.

Inherited disorders of platelet function can be classified into three pathogenically distinct groups: (1) defects of adhesion (2) defects of aggregation (3) Disorders of platelet secretion (storage pool disorders

Bernard-Soulier syndrome illustrates the consequences of defective adhesion of platelets to subendothelial matrix. caused by an inherited deficiency of the platelet membrane glycoprotein complex Ib-IX. This glycoprotein is a receptor for vWF and is essential for normal platelet adhesion to the subendothelial extracellular matrix. Inherited in an autosomal recessive fashion.

It is rare disorder. Characterized by: Thrombocytopenia Giant platelets Qualitative paltelet defects resulting in bleeding tendency

Signs and symptoms: Easy bruising Nosebleeds Menorrhagia GI bleeding (occasional) Purpura and petechial rash

Diagnosis: CBC: Thrombocytopenia, giant platelets Bleeding time: prolonged PT, PTT: Normal - Platelet aggregation study: platelets do not aggregate in response to ristocetin (antibiotic that normally causes platelets to aggregate) even after adding normal plasma but do have normal aggregation in response to adenosine diphosphate, epinephrine, and collagen Flow cytometry

Management: - Mainly supporative, in most cases no medications are needed. - Restriction of activity. - Antiplatelets medications should be avoided. - Antifibrinolytic agents for mucosal bleeding. - Platelets transfusion for surgery and life-threatening hemorrhage. - Desmopressin for minor bleeding.

Glanzmann thrombasthenia Rare genetic platelets disorder in which the platelets have qualitative or quantitative deficiencies of fibrinogen receptor glycoprotein IIb-IIIa . Bleeding due to defective platelet aggregation. The associated bleeding tendency is often severe. But prognosis remains good with appropriate supporative care. The majority of the patients have normal platelets size/morphology and count. Transmitted as an autosomal recessive trait.

Signs and symptoms: - Bleeding tendency is variable (minimal to severe) - Typically present with mucocutaneous bleeding at birth or early in infancy. - Mucosal bleeding - Gingival bleeding - Menorrhagia - GI bleeding (occasional) Petechiae and ecchymoses Hemarthrosis is very rare

Diagnosis: - CBC: no thrombocytopenia, no giant platelets Bleeding time: prolonged PT, PTT: Normal - Platelet aggregation study: platelets aggregate in response to ristocetin, but fail to aggregate in response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin because of deficiency or dysfunction of glycoprotein IIb-IIIa, an integrin that participates in “bridge formation” between platelets by binding fibrinogen. - Flow cytometry

Management: - Antiplatelets medications should be avoided. - Iron/folate for anemia - Hepatitis B vaccine. - Antifibrinolytic agents. - Desmopressin . - Platelets transfusion.