Platelet storage pool disorders
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- 1. Platelet Storage Pool Disease by: amirhossein heydarian
- 2. Introduction Platelets contain -granules, dense granules, and lysosomes. Platelet secretion or exocytosis releases molecules at sites of vascular injury to activate other cells or to facilitate cellular adhesion These secretory organelles have unique molecular contents, and genetic disorders
- 3. Platelet Storage Pool Disease The term SPD refers to patients with deficiencies in platelet content: dense granules (-SPD) -granules (-SPD) both types of granules (SPD)
- 4. Platelet granules -granules, dense bodies (granules),lysosomes.
- 5. Platelet granules con.. the term "alpha granules" is used to describe granules containing several growth factors Dense granules (also known as dense bodies or delta granules) are specialized secretory organelles
- 6. -granules -granules are the most numerous of the platelet organelles There are usually 40 to 80 -granules per platelet, but large and giant cells may have well over 100 -granules in resting platelets remain separated from each other
- 7. -granules
- 8. Contents of alpha-granules Contents include: insulin-like growth factor 1 platelet-derived growth factors (PDGF) platelet factor 4 (PF4) thrombospondin fibronectin factor V von Willebrand factor (vWF) P-selectin fibrinogen, albumin, immunoglobulin
- 9. Contents of alpha-granules con.. proteins that are either synthesized in megakaryocytes: platelet factor 4 [PF4], -thromboglobulin [TG], VWF, platelet-derived growth factor [PDGF] endocytosed from plasma: fibrinogen, albumin, immunoglobulin
- 10. a-Granule Disorders I. Gray Platelet Syndrome (GPS) II. Quebec Platelet Disorder
- 11. Gray Platelet Syndrome GPS is a heterogeneous disorder associated with abnormalities in - granule formation and maturation autosomal recessive inheritance mild thrombocytopenia A mild bleeding disorder (prolonged bleeding Time) characterized by: platelets inability to store -granule proteins platelets appearing gray on stained blood smears
- 12. Gray Platelet Syndrome con.. Under the electron microscope, platelets and megakaryocytes reveal absent or markedly decreased -granules or small and almost empty Platelets are severely and selectively deficient in -granule proteins Platelet aggregation responses have been variable: Responses to ADP and epinephrine were normal in most patients; however, in some patients, aggregation responses to thrombin, collagen, and ADP have been impaired.
- 13. Gray Platelet Syndrome con.. Inability of megakaryocytes to store newly synthesized growth factors and cytokines such as PDGF, and TGF-1 Plasma levels of PF4 and TG have been found to be raised in some patients, suggesting that the defect is not in their synthesis by megakaryocytes but in their packaging into granules
- 14. Gray Platelet Syndrome con.. The neutrophils from these patients also had decreased granules. Reticulin is increased in the bone marrow from GPS patients which can be attributed to elevated plasma PDGF levels
- 15. Gray Platelet Syndrome con..
- 16. Quebec Platelet Disorder autosomal dominant bleeding disorder was first described in two FrenchCanadian families normal to reduced platelet counts associated with delayed bleeding and abnormal proteolysis of - granule proteins caused by increased amounts of platelet urokinase- type plasminogen activator (u-PA)
- 17. Quebec Platelet Disorder con.. proteolytic degradation of soluble and membrane proteins of - granules Platelet factor V but not plasma factor V is degraded along with other -granule proteins, fibrinogen, vWF, thrombospondin, osteonectin, fibronectin, and P-selectin
- 18. Quebec Platelet Disorder con.. platelets are also severely deficient in multimerin. multimerin is a high molecular mass protein that is stored as a complex with factor Factor V in -granules platelets of these patients show protease related degradation of many -granule proteins (including P-selectin) even though -granule ultrastructure is preserved Thrombocytopenia is sometimes observed
- 19. Quebec Platelet Disorder con.. The platelet aggregation deficiency is, surprisingly, most striking with epinephrine (selective defective aggregation with epinephrine) the bleeding syndrome responds to fibrinolytic inhibitors rather than platelet transfusions Originally thought to involve factor V
- 20. Quebec Platelet Disorder con.. Patients with QPD suffer from mucocutaneous bleeding, which often is delayed by 1224 hours following injury This bleeding is unresponsive to platelet transfusions but responsive to fibrinolytic inhibitors
- 21. -granules Human platelet dense bodies are smaller than the granules, fewer in number, and have high morphological variability Normal platelets possess 3-8 dense granules/platelet
- 22. -granules con..
- 23. Contents of dense granules Contents include: adenosine diphosphate (ADP) (more than ATP) adenosine triphosphate (ATP) ionized calcium magnesium histamine serotonin pyrophosphate
- 24. Dense () Granule Disorders Patients with -SPD have a mild to moderate bleeding diathesis associated with prolonged bleeding time In platelet studies the second wave of aggregation : Response to ADP and epinephrine is absent or blunted The collagen response is markedly Impaired Both impaired and normal aggregation responses to arachidonic acid have been noted
- 25. Dense () Granule Disorders con.. Under the electron microscope, dense granules are decreased in -SPD platelets in -SPD platelets, the ratio of total ATP to ADP is increased (>2.5) compared with that in normal platelets.
- 26. Dense () Granule Disorders con.. -SPD has been reported in association with other inherited disorders such as the: Hermansky-Pudlak syndrome (HPS) Chdiak-Higashi syndrome (CHS) WiskottAldrich Syndrome (WAS) Thrombocytopenia with absent radii syndrome (TAR) Griscelli syndrome
- 27. Hermansky-Pudlak syndrome Is a rare autosomal recessive disorder There are eight classic forms of the disorder, based on the genetic mutation from which the disorder stems HPS can be caused by mutations in several genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6 and HPS7(dysbindin)
- 28. HPS Symptoms Albinism (decrease amounts of skin pigment (melanin)) light sensitivity (photophobia) strabismus (crossed eyes) Bleeding disorders (platelet dysfunction) Cellular storage disorders (wax-like substance (ceroid) to accumulate in the body tissues and cause damage, especially in the lungs and kidneys)
- 29. ChediakHigashi syndrome is a rare autosomal recessive disorder mutation of a lysosomal trafficking regulator protein (also called LYST) leads to a decrease in phagocytosis The disease is characterised by large lysosome vesicles in phagocytes (neutrophils), which thus have poor bactericidal function, abnormalities in nuclear structure of leukocytes, anemia, and hepatomegaly
- 30. CHS Symptoms light skin and silvery hair (partial albinism) complain of solar sensitivity and photophobia frequent infections are common Neuropathy often begins in the teenage years organ failure Most children ultimately reach a stage known as the accelerated phase, also known as the lymphoma-like-syndrome Bone marrow transplants appear to have been successful in several patients
- 31. WiskottAldrich Syndrome (WAS) is an X-linked recessive disease mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein gene (WASp). The WASp gene codes for the protein WASp, which is 502 amino acids long and is mainly expressed in hematopoietic cells WAS platelets show a decreased aggregation response to ADP, epinephrine, and collagen and have a reduced dense granule number
- 32. WAS Symptoms most patients are male petechiae and bruising, resulting from a low platelet count Epistaxis and bloody diarrhea are common Eczema develops within the first month of life Recurrent bacterial infections The majority of WAS children develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated
- 33. TAR syndrome This syndrome may occur as a part of the 1q21.1 deletion syndrome is a rare genetic disorder that is characterized by the absence of the radius bone dramatically reduced platelet count
- 34. Griscelli Syndrome rare autosomal recessive disorder is a disorder of melanosome transport, and divided into several types:
- 35. Griscelli Syndrome Symptoms Hypopigmentation Frequent pyogenic infection Hepatosplenomegaly Neutropenia Thrombocytopenia Impaired NK cell activity