Thrombocytopathies og blodplater

Thrombocytopathies

• Platelets adhere to exposed parts of the blood vessel wall, become activated, release their stored materials, and aggregate.
• Abnormalities in these stages can cause congenital platelet disorders.
• Affected patients often have prolonged bleeding times and normal platelet counts.
• Light transmission aggregometry is used to monitor platelet activation, but diagnosis can be challenging due to overlaps in healthy responses. Up to 40% of patients with supposed platelet function defects might have false-positive results with this method.

Disorders of Platelet Adhesion

• Platelet adhesion to the blood vessel wall involves receptors interacting with collagen, fibronectin, and other components.
• Important receptors include GPIB-IX and a2ß1 (GPIa-IIa). Other collagen receptors are GPIV and GPVI.
• Bernard-Soulier Syndrome (BSS) is an autosomal recessive disorder characterized by giant platelets, mild/moderate thrombocytopenia, and prolonged bleeding time disproportionate to the thrombocytopenia.
• BSS stems from abnormalities in the GP Ib-IX-V receptor complex.
• Bleeding can be severe, and cases of haemorrhages can be fatal.
• Platelet counts can range from very low to near normal, and over 80% of platelets may be larger than 2.5 µm (up to 8 µm) in diameter .
• Bone marrow megakaryocyte numbers are usually normal.
• Platelets in BSS show a lack of agglutination in the presence of ristocetin and human VWF, but normal aggregation, ATP secretion, and thromboxane B₂ formation.
• The defective binding with VWF impairs the ability of platelets to adhere to sites of vascular injury.

Disorders of Platelet Signaling Transduction

• Activated platelets release intracellular messengers that modulate responses like calcium mobilization, protein phosphorylation, and arachidonic acid production.
• Platelets release substances from granules to help form the primary haemostatic plug.
• Congenital defects in signaling mechanisms can cause issues with platelet function.
• Many platelet receptors interact with G-proteins, such as P2Y1 and receptors for thromboxane A2 and thrombin through Gaq. receptors for prostaglandins activate. Also P2Y12 inhibits adenylate cyclase through Gs and Gi2.
• Platelet activation can lead to the hydrolysis of phosphoinositide, producing inositol triphosphate and diacylglycerol. These contribute to intracellular calcium release and protein kinase C activation, respectively, important roles in platelet secretion and aIIb-B3 complex activation
• Deficiencies in phospholipase C activation, calcium mobilization, or protein phosphorylation have been observed in some patients, but defects in Gaq, Gs hyperfunction, and reduced phospholipase C-ẞ2 expression are less common findings.
• Platelet phospholipase A2 mobilizes arachidonic acid, which is then processed into thromboxane A2 by cyclo-oxygenase and thromboxane synthase. Thromboxane A2 is a strong aggregating agent.
• Deficiencies in arachidonic acid mobilization and thromboxane A2 production can lead to abnormal aggregation and secretion responses.
• Deficiencies in cyclooxygenase have also been linked to prolonged bleeding time and impaired aggregation.

Disorders of Platelet Aggregation

• Platelet aggregation is the interaction of activated platelets with one another after adhesion to the damaged vessel wall.
• Platelet aggregation is induced by primary and secondary aggregating agents.
• Glanzmann's thrombasthenia (GT) is a disorder with prolonged bleeding time, normal platelet count, and absent platelet aggregation in reaction to ADP, collagen, arachidonic acid, and thrombin. (but normal ristocetin and VWF response).
• GT has reduced/absent clot retraction and is an autosomal recessive disorder.
• Deficiencies in platelet ADP receptors P2Y1 and P2Y12 can lead to bleeding tendencies.
• Defects in epinephrine receptors and thromboxane A2 receptors have also been associated with bleeding.

Storage Pool Deficiency (SPD) Syndromes

• SPDs involve reductions in substances stored in platelet granules and often co-occur with other rare syndromes.
• 8-SPD (low dense granules), αδ-SPD (low dense and alpha granules), and α-SPD (low alpha granules) are subcategories.
• SPDs commonly showcase bleeding symptoms.
• Patients with 8-SPD or αδ-SPD often show absent secondary aggregation, with primary aggregation being present.
• Collagen-induced aggregation is reduced in SPDs.

Hermansky-Pudlak Syndrome (HPS)

• HPS is a rare, autosomal recessive disorder with oculocutaneous albinism, absent platelet dense granules, and specific organelle impairment.
• HPS often involves pulmonary fibrosis and inflammatory bowel disease.
• Several genes (HPS1, AP3B1—HPS2, etc) are linked to HPS.

Chediak-Higashi Syndrome (CHS)

• CHS is a rare, autosomal recessive disorder with variable oculocutaneous albinism, poor immune response to infections (usually fatal in early childhood), and potential chronic lymphohistiocytic infiltration.
• CHS is caused by mutations that often affect the LYST gene on chromosome 1q.