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_MS2 HemeOnc > 8/20- Platelets > Flashcards

8/20- Platelets Flashcards

1
Q

Which cell is a platelet?

  1. A
  2. B
  3. C
A

Which cell is a platelet?

  1. A
  2. B

3. C

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2
Q

Describe the process of megakaryopoiesis

A

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
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3
Q

What is this?

A

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)

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4
Q

How many platelets are made per megakaryocyte?

How many made per day?

A

1000-5000 platelets/megakaryocyte

10^11 each day

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5
Q

Where do platelets get sequestered?

Consequences?

A

1/3 of platelet mass is sequestered in the spleen

  • Liver dz -> splenomegaly -> increased sink size -> decreased platelet count
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6
Q

What is thrombopoietin? Where is it made?

A
  • Primary hematopoietic GF regulating megakaryocyte growth and number
  • Made in liver (mostly) and kidneys
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7
Q

Mechanism of TPO signaling?

A
  • TPO binds c-MPL on megakaryocytes and platelets
  • Platelet/megakaryocyte mass serves as skin: plasma levels increased with low platelet count, driving increased production
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8
Q

What is the structure of a platelet?

  • Diameter
  • Nucleus?
  • Shape
  • Volume
A
  • 1-4 um
  • Anucleate
  • Discoid
  • MPV: 7-11 fL
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9
Q

What membrane glycoproteins do platelets have?

A

- GPIIb-IIIa: fibrinogen receptor

- GPIb-IX-V: von Willebrand factor receptor

- GPIa-IIa, GPVI: collagen receptors

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10
Q

What granules do platelets have?

A

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
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11
Q

What is GPIIb-IIIa?

  • Amount
  • Function
  • Targeting drugs
  • Associated diseases
A
  • 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
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12
Q

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

A

GpIIb/IIIa proteins

  • Mediates platelet aggregation
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13
Q

What is GPIb-IX-V?

A

Principal receptor for vWF

  • vWF binds to subendothelial collagen
  • GPIb-IX-V tethers platelets via vWF
  • Binds other proteins: thrombin, P-selectin
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14
Q

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

A

Congenital defects: Bernard-Soulier

  • Giant platelets
  • Thrombocytopenia
  • Bleeding
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15
Q

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

A

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

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16
Q

Overall schematic of secondary hemostasis (picture)

A
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17
Q

What is a “qualitative” platelet disorder?

A

Have enough platelets, but they’re not functioning correctly

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18
Q

What are some inherited qualitative platelet disorders?

A
  • Glanzmann thrombasthenia
  • Bernard-Soulier syndrome
  • Storage pool diseases
  • Non-classic disorders more common, less defined
19
Q

Characteristics of Glanzmann thrombasthenia?

A

Qualitative platelet disorder

  • Abnormal GP IIb/IIIa
  • Purpura, epistaxis, gingival bleeding, and menorrhagia
  • Defective aggregation to all agonists except ristocetin
20
Q

Characteristics of Bernard-Soulier syndrome?

A

Qualitative platelet disorder

  • Abnormal GP Ib-IX-V
  • Giant platelets and thrombocytopenia
  • Decreased aggregation with ristocetin; normal to others
21
Q

Characteristics of storage pool diseases?

A

Qualitative platelet disorder

  • Alpha-granule deficiency: gray platelet syndrome (alpha granules are most prominent component of platelets)
  • Dense-granule deficiency: Hermansky-Pudlak
22
Q

What may cause acquired platelet dysfunction?

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

(- Cardiopulmonary bypass)

(- MPDs/MDS)

(- Dysproteinemias)

23
Q

How does diabetes affect platelet function?

A

Increases reactivity

24
Q

What types of bleeding symptoms typically characterize platelet disorders?

A

Mucocutaneous bleeding

25
Q

What is this?

A

Petechiae

26
Q

What characterizes a quantitative platelet disorder?

A

Problem in the number of platelets (rather than functionality)

27
Q

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

A

Need to have pretty decreased counts to have daily life affected

28
Q

Differential diagnosis (etiologies) of thrombocytopenia?

A

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
29
Q

What is ITP? What causes it?

A

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
30
Q

Immune thrombocytopenias can be broken down into what main causes?

A

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
31
Q

What are some treatment options for ITP?

A

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)
32
Q

What are some sources of drug-induced immune thrombocytopenias?

A

HIT: heparin induced thrombocytopenia!

33
Q

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
A

PBS:

  • Evidence for hemolytic anemia (MAHA)
34
Q

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

Diagnostic triad?

A

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
35
Q

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

A

Do:

  • Plasma exchange
  • Corticosteroids
  • Plasma infusion (for congenital TTP)

Don’t:

  • Platelet transfusion
  • Anti-platelet drugs
  • DDAVP
36
Q

What are some inherited thrombocytopenia abnormalities?

A
  • May-Hegglin
  • Bernard-Soulier, Grey Platelet Syndrome
  • Wiskott-Aldrich (small platelets)
  • Fanconi anemia, congenital amegakaryocytic thrombocytopenia
  • Other disorders and mutations being ID’d
37
Q

Characteristics of May-Hegglin disorder?

A

Form of inherited thrombocytopenia

  • MYH9 class of disorders
  • Non muscle heavy chain of myosin
  • Dohle-like inclusions
  • Giant platelets
38
Q

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

A

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
39
Q

Case cont’d)

How would you treat this patient?

A. Observation

B. Platelet transfusion

C. Oral steroids

D. Oral steroids and IVIg

E. Splenectomy

A

How would you treat this patient?

A. Observation

B. Platelet transfusion

C. Oral steroids

D. Oral steroids and IVIg

E. Splenectomy

40
Q

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

A
  • Thrombopoietin
  • Megakaryocytes
41
Q

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

A
  • 7-10 day lifespan in circulation
  • 1/3 of mass sequestered in spleen
42
Q

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

A
  1. Increased destruction
  2. Decreased production
  3. Sequestration
43
Q

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

A
  • HIT
  • TTP
  • “ITP”

_MS2 HemeOnc (33 decks)

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