8/20- Platelets

Question 1

Which cell is a platelet?

1. A
2. B
3. C

Answer 1

Which cell is a platelet?

1. A
2. B

3. C

Question 2

Describe the process of megakaryopoiesis

Answer 2

HSC -> myeloid SC -> committed progenitor -> megakaryoblast -> megakaryocyte

• Endomitosis results in polyploid, lobulated eccentric nucleus (characteristic of mature megakaryocyte)
• Megakaryocyte undergoes shedding (ctyoplasmic granulation and fragmentation) to create platelets

Question 3

What is this?

Answer 3

Platelets forming on the periphery of a megakaryocyte

• Large cell (about 50x RBC!)
• Eccentric multilobulated nucleus
• Granular cytoplasm

(Normally about 0.1% of all nucleated BM cells)

Question 4

How many platelets are made per megakaryocyte?

How many made per day?

Answer 4

1000-5000 platelets/megakaryocyte

10^11 each day

Question 5

Where do platelets get sequestered?

Consequences?

Answer 5

1/3 of platelet mass is sequestered in the spleen

• Liver dz -> splenomegaly -> increased sink size -> decreased platelet count

Question 6

What is thrombopoietin? Where is it made?

Answer 6

• Primary hematopoietic GF regulating megakaryocyte growth and number
• Made in liver (mostly) and kidneys

Question 7

Mechanism of TPO signaling?

Answer 7

• TPO binds c-MPL on megakaryocytes and platelets
• Platelet/megakaryocyte mass serves as skin: plasma levels increased with low platelet count, driving increased production

Question 8

What is the structure of a platelet?

• Diameter
• Nucleus?
• Shape
• Volume

Answer 8

• 1-4 um
• Anucleate
• Discoid
• MPV: 7-11 fL

Question 9

What membrane glycoproteins do platelets have?

Answer 9

- GPIIb-IIIa: fibrinogen receptor

- GPIb-IX-V: von Willebrand factor receptor

- GPIa-IIa, GPVI: collagen receptors

Question 10

What granules do platelets have?

Answer 10

Alpha granules:

• Larger and more abundant
• vWF, platelet factor 4, fibrinogen, factor V

Dense granules (delta):

• About 10x fewer than alpha
• Small mcls: ADP, ATP, serotonin, Ca, Mg

Question 11

What is GPIIb-IIIa?

• Amount
• Function
• Targeting drugs
• Associated diseases

Answer 11

• Most abundant platelet membrane protein (50-80K)
• Platelet activation -> conformational change with high affinity for fibrinogen -> aggregation
• Target of drugs in CAD: abciximab, tirofiban, eptafibatide
• Congenital defects: Glanzmann thrombasthenia

Question 12

The blood protein fibrinogen forms bridges between platelets by binding to what?

Answer 12

GpIIb/IIIa proteins

• Mediates platelet aggregation

Question 13

What is GPIb-IX-V?

Answer 13

Principal receptor for vWF

• vWF binds to subendothelial collagen
• GPIb-IX-V tethers platelets via vWF
• Binds other proteins: thrombin, P-selectin

Question 14

What disease is associated with GP Ib-IX-V? Characteristics?

Answer 14

Congenital defects: Bernard-Soulier

• Giant platelets
• Thrombocytopenia
• Bleeding

Question 15

What are the steps in the formation of a platelet plug?

Answer 15

Adhesion

Activation

• Shape change
• IIb-IIIa activation to fibrinogen receptor
• Secretion/release reaction (ADP, fibrinogen, vWF, calcium, TXA2)
• Phosphatidylserine expression (acceleration of Xase by 20M; acc of prothrombinase by 300K)

Aggregation

Question 16

Overall schematic of secondary hemostasis (picture)

Answer 16

Question 17

What is a “qualitative” platelet disorder?

Answer 17

Have enough platelets, but they’re not functioning correctly

Question 18

What are some inherited qualitative platelet disorders?

Answer 18

• Glanzmann thrombasthenia
• Bernard-Soulier syndrome
• Storage pool diseases
• Non-classic disorders more common, less defined

Question 19

Characteristics of Glanzmann thrombasthenia?

Answer 19

Qualitative platelet disorder

• Abnormal GP IIb/IIIa
• Purpura, epistaxis, gingival bleeding, and menorrhagia
• Defective aggregation to all agonists except ristocetin

Question 20

Characteristics of Bernard-Soulier syndrome?

Answer 20

Qualitative platelet disorder

• Abnormal GP Ib-IX-V
• Giant platelets and thrombocytopenia
• Decreased aggregation with ristocetin; normal to others

Question 21

Characteristics of storage pool diseases?

Answer 21

Qualitative platelet disorder

• Alpha-granule deficiency: gray platelet syndrome (alpha granules are most prominent component of platelets)
• Dense-granule deficiency: Hermansky-Pudlak

Question 22

What may cause acquired platelet dysfunction?

Answer 22

• Aspirin, NSAIDs
• Many other drugs: beta-lactam Abx, CCBs, SSRIs
• Renal failure
• Liver dz

(- Cardiopulmonary bypass)

(- MPDs/MDS)

(- Dysproteinemias)

Question 23

How does diabetes affect platelet function?

Answer 23

Increases reactivity

Question 24

What types of bleeding symptoms typically characterize platelet disorders?

Answer 24

Mucocutaneous bleeding

Question 25

What is this?

Answer 25

Petechiae

Question 26

What characterizes a quantitative platelet disorder?

Answer 26

Problem in the number of platelets (rather than functionality)

Question 27

Don't memorize these numbers: Conceptual framework for bleeding risk with acute (non-immune) thrombocytopenia

Answer 27

Need to have pretty decreased counts to have daily life affected

Question 28

Differential diagnosis (etiologies) of thrombocytopenia?

Answer 28

_Increased Destruction/Consumption:_ **- Immune-mediated (including drugs)** **- Thrombotic microangiopathy (TTP/HUS, HELLP)** - Disseminated intravascular coagulation (DIC) - Kassabach-Merritt syndrome - Extracorporeal circulation _Decreased Production:_ - Alcohol - Chemotherapy - Aplastic anemia - Nutritional deficiencies (e.g. B12) - Infections (including sepsis) - Inherited disorders - MDS, fibrosis, leukemia, metastatic dz _Other:_ - Spurious (increased platelet clumping) - Hypersplenism - Massive transfusions (dilutional) - Anaphylaxis

Question 29

What is ITP? What causes it?

Answer 29

**Immune-Mediated Thrombocytopenia** - Accelerated platelet destruction due to phagocytosis of Ab-coated platelets by reticuloendothelial system (Mphages in spleen, liver, and BM) - Auto-antibodies (mainly **IgG**) vs. common platelet glycoproteins cross-react with autologous and transfused platelets

Question 30

Immune thrombocytopenias can be broken down into what main causes?

Answer 30

**Neoplasia** - Hodgkin's dz - NHL - CLL - Solid tumors **Autoimmune Disease** - Lupus - Antiphospholipid syndrome - AIHA (Evan's syndrome) - Thyrotoxicosis *_- Primary ITP (esp kids)_* **Immune dysregulation** - HIV - Common variable immunodeficiency - ALPS - BMT **Alloimmune thromboctyopenias** - Post-transfusion purpura - Neonatal alloimmune thrombocytopenia

Question 31

What are some treatment options for ITP?

Answer 31

_Acutely:_ - Observation - Steroids (may take a few days) - Intravenous immune globulin (IVIg) (quicker) - Anti-D immune globulin - Platelet transfusion generally ineffective _Chronically:_ - Splenectomy - Rituximab - Additional immunosuppressive agents - Thrombopoietin mimetic agents (romiplostim, altrombopag)

Question 32

What are some sources of drug-induced immune thrombocytopenias?

Answer 32

HIT: heparin induced thrombocytopenia!

Question 33

Case) - 40 yo teacher can't find words at black board and confused at home - Seems clear in ER but has seizure - Petechiae on her legs - Post-ictal CBC: - Hct = 25 - WBCs normal - Platelets = 25,000 - PT and PTT normal - BUN and creatinine are 35/2.0 - LDH significantly elevated - Temp = 100.8

Answer 33

PBS: - Evidence for hemolytic anemia (MAHA)

Question 34

What is the classic pentad of clinical elements present in TTP? Diagnostic triad?

Answer 34

_Classic pentad:_ 1. Fragmentation hemolysis 2. Thrombocytopenia 3. Fluctuating neurological changes 4. Renal insufficiency 5. Fever _Diagnostic triad:_ 1. Fragmentation hemolysis 2. Thrombocytopenia 3. Elevated LDH

Question 35

Do's and Dont's of acute therapy for TTP?

Answer 35

_Do:_ - Plasma exchange - Corticosteroids - Plasma infusion (for congenital TTP) _Don't:_ - Platelet transfusion - Anti-platelet drugs - DDAVP

Question 36

What are some inherited thrombocytopenia abnormalities?

Answer 36

- May-Hegglin - Bernard-Soulier, Grey Platelet Syndrome - Wiskott-Aldrich (small platelets) - Fanconi anemia, congenital amegakaryocytic thrombocytopenia - Other disorders and mutations being ID'd

Question 37

Characteristics of **May-Hegglin** disorder?

Answer 37

Form of inherited thrombocytopenia - MYH9 class of disorders - Non muscle heavy chain of myosin - Dohle-like inclusions - Giant platelets

Question 38

Case) - 23 yo female with rash on ankles/shins and easy bruising for 10 days on her arms and sides (no trauma) - Nosebleeds, gum bleeding with flossing, unusually heavy menses 1 wk ago that persists - Upper respiratory infection 3 weeks ago now resolved - Normal PE but her stool is guaiac positive - Some petechiae/blood blisters (wet purpura) in mouth - CBC normal except for platelet count (3,000) What is the most likely diagnosis? A. Acute leukemia or lymphoma B. TTP C. Immune thrombocytopenia (ITP) D. Lupus E. Pseudothrombocytopenia

Answer 38

What is the most likely diagnosis? A. Acute leukemia or lymphoma B. TTP **C. Immune thrombocytopenia (ITP)** D. Lupus E. Pseudothrombocytopenia - Not TTP because red blood cells look nice

Question 39

Case cont'd) How would you treat this patient? A. Observation B. Platelet transfusion C. Oral steroids D. Oral steroids and IVIg E. Splenectomy

Answer 39

How would you treat this patient? A. Observation B. Platelet transfusion C. Oral steroids **D. Oral steroids and IVIg** E. Splenectomy

Question 40

What is the key GF for megakaryopoiesis and the primary bone marrow cell it affects?

Answer 40

- Thrombopoietin - Megakaryocytes

Question 41

What is the avg platelet lifespan in circulation and the typical proportion of platelet mass sequestered in the spleen?

Answer 41

- **7-10 day** lifespan in circulation - **1/3** of mass sequestered in spleen

Question 42

What are the 3 mechanisms that can lead to thrombocytopenia and examples of each?

Answer 42

1. Increased destruction 2. Decreased production 3. Sequestration

Question 43

What are some thrombyctopenic conditions for which platelet transfusion is not considered first line therapy?

Answer 43

- HIT - TTP - "ITP"