M4 QUALITATIVE PLATELET DISORDERS (CONGENITAL) Flashcards by pink popcorn

Excessive bruising and superficial (mucocutaneous)
bleeding in a patient whose platelet count is normal
suggest an ____

acquired or a congenital disorder of platelet
function.

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2 TYPES OF QUALITATIVE PLATELET DISORDERS

I. Inherited Functional Defects
○ Congenital
II. Acquired Functional Defects

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With___, organs are just seldomly affected

platelet disorder

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Defects in
platelet-vessel wall
interaction

Adhesion

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Defects in
platelet-platelet interaction

Aggregation

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Disorders of platelet
secretion and
abnormalities of granules

Platelet secretion

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. Disorders of platelet
secretion and signal
transduction defects

Platelet activation
● G-protein binding
● Agonist

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Defects in cytoskeletal
regulation

Morphology: Size and shape

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Disorders of platelet
coagulant-protein
interaction

Secondary hemostasis
● Phosphatidylserine

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Important
____ and ___are contained in the platelet
granules, so if there would be defect in the secretion, it follows
that there are abnormalities in the granules

protein and non-protein mediators

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For the cytoskeletal regulation, we know that we have the
structural zone of the platelet so maybe there is a problem in
the ____, ___ and ___

microtubules, microfilaments and the intermediate
filaments

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For the problem on the platelet coagulant-protein
interaction, we know that the platelets are involved in the
secondary hemostasis so maybe there is a problem in the
flippin out of the____ from the inner membrane
to the outer membrane

phosphatidylserine

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2 types of adhesion defects

Bernard-Soulier Syndrome
von Willebrand’s Disease

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Involves qualitative and quantitative defects
qualitative:
quantitative:

BERNARD-SOULIER SYNDROME

Qualitative Defects
● Function
○ Adhesion
● Morphology
○ Giant platelets
Quantitative Defects
● Thrombocytopenia

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Autosomal recessive abnormality in the platelet
GPlb/V/IX complex

BERNARD-SOULIER SYNDROME

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Autosomal recessive abnormality in the platelet
GPlb/V/IX complex

Missing from the platelet surface or exhibits
abnormal function
○ Inability to bind to VWF
○ Inability of platelets to adhere to exposed
subendothelium

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💡 GPlb/V/IX complex

Indirect Platelet Adhesion defect

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BERNARD-SOULIER SYNDROME
Rare disorder of platelet adhesion that usually
manifests in____ with
hemorrhage characteristics of defective platelet
function: ecchymoses, epistaxis, and gingival
bleeding

infancy or childhood

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Rare disorder of platelet adhesion that usually
manifests in infancy or childhood with
hemorrhage characteristics of defective platelet
function: ___

-BERNARD-SOULIER SYNDROME
-ecchymoses, epistaxis, and gingival
bleeding

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bleeding of the joints

Hemarthrosis

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This complex is important in indirect platelet adhesion

GPlb/V/IX complex

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Because of this abnormality, this _____
is missing from the platelet surface and it would lead
to abnormal function affecting adhesion

glycoprotein complex

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The effect is that there would be inability to bind to
______ and inability of platelets to
adhere to ____

von Willebrand factor, exposed subendothelium

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It manifests thrombocytopenia with giant platelet because of the abnormalities that affect both platelet production and platelet structure

Bernard-Soulier Syndrome

Bernard-Soulier Syndrome LABORATORY FINDINGS

1. 40,000/uL to near normal

NORMAL - BS

ADP Arachidonic Acid Collagen Epinephrine

ABNORMAL -BS

Ristocetin Thrombin

Peripheral Blood Smear

○ 5 to 8 um in diameter ○ Can be as large as 20 um

Contain a larger number of cytoplasmic vacuoles and membrane complexes

Electron microscopy

Electron microscopy ○ Contain a larger number of ___ and ___

cytoplasmic vacuoles and membrane complexes

Electron microscopy ____ exhibit an irregular demarcation membrane system

Megakaryocytes

VON WILLEBRAND’S DISEASE ● Involves qualitative and quantitative defects Qualitative Defects ____ Quantitative Defects _____

● Function ○ Adhesion ● Thrombocytopenia

Mutations result in spontaneous binding of plasma VWF to the mutated GP Ib/IX/V complex

VON WILLEBRAND’S DISEASE

With regards to von Willebrand’s disease, if it is related with the platelet function then it is called ____

platelet-type VWD or pseudo-VWD

____ is related to coagulation disorder

True-VWD

The spontaneous binding of the von willebrand factor to the mutated GP Ib/IX/V causes these complexes to continuously be removed from the circulation which will result to ____ and ___

thrombocytopenia and reduced factor VIII clotting activity

And there is ____ of clot even if there is binding of the von willebrand factor with GP Ib/IX/V

no formation

VWD subtypes: Quantitative deficiency

Type 1 and 3

VWD subtypes: Qualitative deficiency

Type 2

Type 2A

Deficiency of HMW multimers 2A(A= Absence)

Type 2B

Binding of vWF and GPIb 2B (Binding)

Type 2M

With HMW multimers 2M (M= Multimers)

Type 2N

No binding of vWF and FVIII

Diff of Type 1 and 3

type 1: partial deficiency type 3: complete

2 Types AGGREGATION DEFECTS

1. Glanzmann thrombasthenia 2. Inherited Giant Platelet Syndromes

Quantitative or qualitative defect in the GPIIb/IIIa complex

Glanzmann thrombasthenia

Inability of fibrinogen to bind with platelets: von willebrand factor (VWF), fibronectin, and other adhesive ligands

Glanzmann thrombasthenia

Glanzmann thrombasthenia Lack ____: clot retraction defect

thrombosthenin/actomyosin

Glanzmann thrombasthenia Qualitative Defects ____ Quantitative Defects ____

● Present GPIIb/IIIa but non-functional ● Missing GPIIb/IIIa in platelet

Glanzmann thrombasthenia Hemorrhagic manifestations:

○ Petechiae ○ Purpura ○ Menorrhagia ○ Gastrointestinal bleeding ○ Hematuria

Glanzmann thrombasthenia Severity of the bleeding episodes seems to _____ with age

decrease

Aggregation Test - GT Normal

Ristocetin

Aggregation Test - GT Abnormal

ADP Collagen Epinephrine Thrombin

📑 So the problem with Glanzmann is the defect in the GP IIb/IIIa

● Hereditary Afibrinogenemia ● Hereditary Hypofibrinogenemia

➔ With defect, if the level of fibrinogen is low or is absent in the plasma, it will lead to___

aggregation defects

Fibrinogen is from the ___

liver

Exhibit large platelets and thrombocytopenia

INHERITED GIANT PLATELET SYNDROMES

Abnormal microtubule distribution

● May-Hegglin anomaly

Spherical and have a prominent surface-connected canalicular system

Epstein syndrome

A. Decreased platelets B. Giant platelets

Macrothrombocytopenia

TYPES PLATELET SECRETION DEFECTS

1. Dense granules deficiencies 2. Alpha granules deficiencies 3. Alpha-dense storage pool deficiency

Most common hereditary platelet function defects ● Manifestations

○ Mucocutaneous hemorrhage and hematuria ○ Epistaxis ○ Easy and spontaneous bruising ○ Less common petechiae ○ Rare hemorrhage

Two granules that is contained in the platelet ultrastructure

Dense granule ⍺-granule

DENSE GRANULES DEFICIENCIES

1. Hermansky-Pudlak Syndrome 2. Wiskott-Aldrich Syndrome 3. Chediak-Higashi 4. TAR (Thrombocytopenia with absent radius)

➔ Dense granules deficiencies are only responsive in ____of collagen

high concentration

💡 For aggregation tests: 💡 For coagulation tests:

Platelet plasma rich Platelet plasma-poor

HERMANSKY-PUDLAK SYNDROME

💡 Mutation: HPS (HPS 1 & HPS 3)

HPS1 (Hermansky-Pudlak Syndrome 1) & HPS3 (Hermansky-Pudlak Syndrome 3) Defect in___

Defect in chromosome 19

____ vesicular trafficking, ___ of organelles

intracellular, biogenesis

Marked dilation and tortuosity of the surface connecting tubular system

“Swiss-cheese platelet”

“Swiss-cheese platelet” ● Oculocutaneous albinism ● Prone to hemorrhage

HERMANSKY-PUDLAK SYNDROME

CHEDIAK-HIGASHI SYNDROME Defect in __

● Chromosome 1 (1q42.3)

Nonsense and frameshift mutations ○ Nonsense mutations are also k

CHEDIAK-HIGASHI SYNDROME

Gives rise to a disorder of generalized cellular dysfunction involving fusion of cytoplasmic granules

CHEDIAK-HIGASHI SYNDROME

CHEDIAK-HIGASHI SYNDROME Involved are ___, ___ and ___ 💡 Affected are also giant platelets

Involved are monocytes, lymphocytes, and neutrophils 💡 Affected are also giant platelets

WISKOTT-ALDRICH SYNDROME

💡 Mutation: WAS gene

other name : WISKOTT-ALDRICH SYNDROME

Eczema Thrombocytopenia Immunodeficiency Syndrome

WAS gene mutations: lack of any functional ___

WASP (Wiskott-Aldrich Syndrome Protein)

WAS

X chromosome Xp11.23

WAS is related to ___

Related with T-lymphocytes

Relaying signals from the surface of blood cells to the actin cytoskeleton ◆ There is a problem with the structure or in the Sol Gel because the affected actin skeleton

WAS

____ has also problem in platelet adhesion, actin cytoskeleton and leading to reduce size and early cell death.

Wiskott-Aldrich Syndrome

💡 3 Defects: ____ 💡 Small platelets = WAS

Adhesion defect, Secretion defect, SizE

The only one with small platelets

WAS

two types of ⍺-GRANULES DEFICIENCIES

Gray Platelet Syndrome Quebec Platelet Syndrome

GRAY PLATELET SYNDROME

NbEAL2 gene

QUEBEC PLATELET SYNDROME

📑 Alpha granules are present, but plasmin degrades or destroys the contents of alpha granules

Gray platelet disorder

absent alpha granules

Both 𝛼-granules and dense granules are deficient

⍺-DENSE STORAGE POOL DEFICIENCY

___ has also no alpha and dense granules

WAS

INHERITED DISORDERS OF RECEPTORS AND SIGNALING PATHWAYS

1. Scott Syndrome 2. Stormorken Syndrome

Collagen receptors

○ ⍺2 (GP Ia/IIa), GP VI

Adenosine diphosphate receptors

○ P2Y1 And P2Y12 (P2 TAC)

Other receptors

○ ⍺2-adrenergic (epinephrine) receptor

Calcium mobilization defects

○ Insufficient calcium is released ○ Abnormal G protein s-ubunits ○ Phospholipase C isoenzymes

💡 Decreased calcium scramblase

Scott syndrome

Calcium is released from

dense tubular system

SCOTT SYNDROME Phospholipid asymmetry is primarily maintained by ____

aminophospholipid translocase

Defective translocating ____ to the platelet membrane inner to outer leaflet

SCOTT SYNDROME phosphatidylserine and phosphatidylethanolamine

Impaired thrombin formation

SCOTT SYNDROME

💡 Uncontrolled phosphatidylserine

STORMORKEN SYNDROME

DIFF OF SCOTT AND STORMORKEN

● In Scott Syndrome, scramblase has low activity ● In Stormorken Syndrome, scramblase has overactivated activity

Defective aminophospholipid translocase

STORMORKEN SYNDROME

M4 QUALITATIVE PLATELET DISORDERS (CONGENITAL) Flashcards

(104 cards)