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Hematology Block 2 > Platelets > Flashcards

Platelets Flashcards

1
Q

Platelets are normally made in the bone marrow from progenitor cells known as _____.

A

megakaryocytes

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2
Q

What is the normal platelet lifespan?

A

7-10 days

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3
Q

What is a normal platelet count?

A

150,000 - 450,000 mm^3

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4
Q

Megakaryocytes develop from _______ that reside mainly in the ____

A

Megakaryocytes develop from hematopoietic stem cells (HSCs) that reside mainly in the bone marrow

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5
Q

Megakaryocytes begin ____ in which DNA replication continues, but neither the nucleus nor the cell undergoes division - this produces a ____ cell.

A

Megakaryocytes begin endomitosis in which DNA replication continues, but neither the nucleus nor the cell undergoes division - this produces a polyploid cell.

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6
Q

After endomitosis, megakaryocytes undergo cytoplasmic maturation, in which they:

A
  • Increase in size
  • Fill with platelet-specific granules
  • Expand content of cytoskeletal proteins
  • Develop the highly tortuous invaginated membrane system
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7
Q

Describe what is happening in this image:

A

Schematic of platelet production.

(1) HSCs in the bone marrow differentiate into MKs in a TPO-dependent manner.
(2) MKs undergo endomitosis and develop nuclei ranging in DNA content from 2n to 128n.
(3) As MKs mature, they develop a highly invaginated membrane throughout their cytoplasm, which is continuous with the external plasma membrane. This membrane serves as a reservoir for proplatelet formation.
(4) MKs migrate to the vascular niche, where they extend proplatelets and release them into vascular sinusoids. The entire MK is converted into pre/proplatelets, and its nucleus is exuded and phagocytosed.
(5) Once in the bloodstream, proplatelets interconvert into preplatelets.
(6) A fission event creates two platelets from a barbell proplatelet.

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8
Q

What is thrombopoietin?

A

The physiologically relevent regulator of platelet production.

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9
Q

____ is the TPO receptor on megakaryocytes and platelets

A

C-Mpl

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10
Q

What is the effect of TPO binding to its receptor?

A

Prevents apoptosis of megakaryocytes and increases their number, size, and ploidy.

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11
Q

Addition of thrombopoietin to CD34+ cells in culture results in WHAT?

A

the majority of cells becoming megakaryocytes and then shedding platelets

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12
Q

Synthesis of TPO is ___. It is made mostly by the ____.

A

Synthesis of TPO is static. It is made mostly by the liver.

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13
Q

How are plasma thrombopoietin concentrations regulated?

A

By platelet production rates and platelet and MK mass

Platelets and MKs express c-Mpl receptors that bind and clear TPO from the circulation and thus regulate free TPO levels.

MPL binds to TPO - this complex gets invaginated and TPO levels in circulation fall. Free TPO levels are negatively regulated by the platelets. The more platelets, the lower the TPO level. TPO is cleared by its end product.

The fewer the platelets, the higher/more TPO.

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14
Q

What is the function of platelets?

A

Formation of a platelet plug

Phospholipid scaffold for the secondary hemostasis coagulation reactions

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15
Q

What are integrins?

A
  • Heterodimeric transmembrane molecules that cells use to both bind to and respond to extracellular matrix proteins
  • Composed of a and b subunits
  • Link the extracellular matrix to intracellular cytoskeleton
  • Clustering of the integrins leads to signalling into the cell
  • Some integrins get activated by signaling events that occur inside the cell (so called “inside out” signaling)

Some integrins are constitutively ready to bind. Some, esp. ones important in platelet activation, are closed to begin with and only with platelet activation are they opened up for binding.

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16
Q

Which integrins/platelet glycoproteins bind collagen?

A

alpha2beta1 aka GPIa-IIa

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17
Q

Which integrins/platelet glycoproteins bind fibrinogen?

A

alpha2beta3 - aka GPIIb-IIIa

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18
Q

What are some examples of platelet glycoproteins that are NOT integrins?

A

• GP Ib-IX-V binds von Willebrand factor

• GPVI activates platelets by binding to collagen

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19
Q

Describe the process of platelet plug formation:

A

•Adhesion - Platelets stick to injured vessel wall via GP Ib-IX-V binding to VWF

•Activation - Resting platelets come in contact with agonists that bind to receptors—signaling occurs—platelets change shape, secrete and activate their GP IIb-IIIa integrins

•Aggregation - Platelets stick to each other via fibrinogen bridges binding to activated GP IIb-IIIa

•Secretion - Platelets release granular contents and potentiate clotting

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20
Q

What stage of platelet plug formation is this image illustrating?

A

Adhesion

Platelets stick to injured vessel wall via GP Ib-IX-V binding to VWF

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21
Q

What stage of platelet plug formation is illustrated by this image?

A

Aggregation

Platelets stick to each other via fibrinogen bridges binding to activated GP IIb-IIIa

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22
Q

Describe how collagen serves as a platelet activator:

A
  • Platelet receptors are GP Ia/IIa (integrin) and GP VI (not integrin)
  • Adhesion to collagen is mediated thru GP Ia/IIa
  • GP VI acts in complex with FcRg to cause platelet activation
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23
Q

Describe how ADP serves as a platelet activator:

A
  • ADP is released by damaged RBCs and secreted by activated platelets
  • Two receptors: P2Y12, P2Y1—bind to a variety of purine and pyrimidine agonists and are G-protein coupled receptors
  • P2Y12 is the target of a number of antiplatelet drugs (clopidogrel, ticagrelor)—very important in cardiology
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24
Q

Describe how thrombin serves as a platelet activator:

A
  • PAR-1 is a GPCR whose ligand is its own proteolyzed N-terminus
  • Thrombin is the most potent platelet agonist

(Thrombin activates the thrombin receptor. Thrombin’s job is to clip off the N-terminus tail of the thrombin receptor. This terminus is its own ligand. Can get cross-activation after this, which is more efficient).

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25
Q

Describe how thromboxane serves as a platelet activator:

A
  • Arachidonic acid is converted into thromboxane (TxA2) by the action of cyclo-oxygenase 1 (COX1)
  • COX1 is blocked reversibly by NSAIDs and irreversibly by aspirin
  • The thromboxane receptor is a GPCR
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26
Q

What keeps the platelets from sticking to normal endothelium?

A
  • Nitric Oxide = vasodilator
  • Ecto-ADPase (CD39) chews up ADP to prevent platelet activation
  • Prostacyclin (PGI2)
  • Converted from arachidonic acid by action of cyclo-oxygenase 1 and 2 (COX-1 and COX-2)
  • Vasodilator
  • Inhibits platelet activation
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27
Q

Explain how platelets are the phospholipid scaffold for the coagulation reactions:

A
  • After activation, platelets turn their membrane inside out, so that the negative charges are now on the outside
  • Certain coag proteins (with gamma carboxyl groups) anchor themselves into the activated platelet membrane.
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28
Q

How are platelet disorders diagnosed?

A
  • Diagnose by a prolonged bleeding time. At UNC, we use a “Platelet function screen”, also known as the Platelet function analyzer-100 (PFA-100) which is an in vitro bleeding time
  • Follow-up by platelet aggregation studies.
  • PT/PTT/TCT should be entirely normal
29
Q

Bernard-Soulier:

A

A congenital defect in Ib/IX on platelet surface, so there’s no adhesion

30
Q

Glanzmann’s Thrombaesthenia:

A

Congenital defect in IIb/IIIa on platelet surface – so there’s no aggregation

31
Q

How are qualitative platelet disorders acquired?

A

•uremia

  • Drugs - ASA, NSAIDs, antibiotics, abciximab, integrelin, tirofiban, clopidogrel, ticagrelor
  • Herbs - ginkgo, garlic, Vitamin E

•Myeloproliferative diseases

32
Q

What are the symptoms of platelet dysfunction?

A
  • Symptoms of platelet hypofunction are the same as defects in Primary Hemostasis- epistaxis, gum bleeding, bruising, heavy menses, petechiae, i.e. mucocutaneous bleeding. “Oozing and bruising” NOT hematomas or bleeding into joints.
  • Abnormal platelet activation results in arterial occlusion–if in the CNS, these are strokes. If in the coronary arteries, these are heart attacks, and if in the peripheral arteries, these become gangrenous limbs.
33
Q

When the spleen gets enlarged, platelets like to go there to hang out, instead of being in the circulation. The platelet counts then fall. What do TPO levels do in response to the lower platelet count?

A

TPO levels remain constant.

Spleen is still in circulation, so platelets still bind and sequester the TPO. This is a design flaw.

34
Q

Name 5 important disorders of peripheral destruction of platelets

A

DIC

TTP

HUS

ITP

HIT

35
Q

Pseudothrombocytopenia:

A
  • Certain pts make a substance that causes platelets to clump when blood is added to EDTA-anticoagulated test tubes
  • Plt count artifactually low
  • Plt count is higher in vivo than what is reported.
  • No bleeding consequences
  • No treatment needed
36
Q

What are the 3 broad causes of thrombocytopenia?

A

Underproduction

Peripheral Destruction

Splenic sequestration

37
Q

What might cause an underproduction of platelets?

A

•Marrow failure: myelodysplasia, aplastic anemia, vitamin deficiencies

•Marrow infiltration: tumor, granulomatous diseases, fibrosis, leukemias, lymphomas

•Marrow toxins: drugs (especially chemotherapy), radiation, infections, alcohol

38
Q

What might cause peripheral destruction of platelets?

A
  • Non-immune mechanisms: e.g. DIC, TTP
  • Immune Mechanisms: antibody-mediated platelet destruction:
  • can be provoked by drugs
  • can be associated with HIV
  • can be associated with other autoimmune disease
  • can be idiopathic
39
Q

What is Disseminated Intravascular Coagulation (DIC)?

A

A process, characterized by abnormal activation of coagulation, generation of thrombin, consumption of clotting factors, destruction of platelets, and activation of fibrinolysis.

40
Q

How is DIC diagnosed?

A

•Elevated PT - due to consumption of Factor VII, which has the shortest half-life (4 hrs) of all clotting factors.

  • When advanced, DIC can cause the aPTT to be prolonged as well, as the other clotting factor levels fall.
  • Low platelets

•Low/falling fibrinogen

•Elevated D-Dimers

•Can see a few schistocytes on the peripheral smear in most cases.

41
Q

What are the etiologies of DIC?

A

Can be associated with gram negative sepsis, severe burns, obstetrical disasters, certain leukemias, shock, insect or snake venoms

42
Q

How is DIC treated?

A
  • TREAT THE UNDERLYING CAUSE
  • Supportive measures can include transfusion of platelets, clotting factors (FFP), fibrinogen (cryoprecipitate)
43
Q

What is Thrombotic Thrombocytopenic Purpura (TTP)?

A

A process, characterized by abnormal activation of platelets and endothelial cells, with von Willebrand factor (VWF) and fibrin deposition in the microvasculature, and peripheral destruction of platelets and red cells.

44
Q

What is the “pentad” of features used to diagnose TTP?

A

•Microangiopathic Hemolytic Anemia (MAHA)

  • Elevated LDH, elevated bilirubin
  • Schistocytes on the peripheral smear MUST BE PRESENT

•Low platelets - MUST BE PRESENT

•Fever

•Neurologic Manifestations - headache, sleepiness, confusion, stupor, stroke, coma, seizures

•Renal Manifestations - hematuria, proteinuria, elevated BUN/Creatinine

45
Q

What disease is indicated by this smear?

A

TTP

46
Q

Describe the etiology of TTP:

A
  • Sporadic (i.e. not familial or from secondary causes) cases are due to an autoantibody against the protease which cleaves the ultra-large molecular weight multimers of von Willebrand factor.
  • The protease is called ADAMTS-13, (A Disintegrin And Metalloprotease with Thrombospondin-like repeats).
  • We can measure activity levels of ADAMTS-13, as well as the presence of an inhibitor to ADAMTS-13.
47
Q

Sporadic cases of TTP are due to an autoantibody against the protease, _____, which cleaves the ultra-large molecular weight multimers of _______.

A

Sporadic cases of TTP are due to an autoantibody against the protease, ADAMTS-13, which cleaves the ultra-large molecular weight multimers of von Willebrand factor.

48
Q

The antibody against ADAMTS-13 blocks the function of the protease, leading to WHAT

A

The accumulation of the ultra-large molecular weight vWF multimers.

These ultra-large vWF multimers lead to abnormal platelet activation.

(This is characteristic of TTP)

49
Q

How can TTP be induced?

A

•TTP can be induced by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, gemcitabine.

  • Drug-induced TTP may not be related to problems with ADAMTS-13

•Increased incidence with pregnancy or HIV/AIDS

50
Q

Describe the course and prognosis of TTP:

A

•Incidence 1 in 50,000

> 90% fatal without therapy.

80-90% survive with therapy

  • One third of patients will relapse within 10 yrs, most within one month of diagnosis.
  • Accurate and prompt diagnosis and treatment is key to survival
51
Q

How is TTP treated?

A
  • Treatment relies on PLASMA EXCHANGE (PLEX).
  • Remove all inciting agents.
  • We also use corticosteroids, but these are of limited benefit without PLEX.
  • Secondary measures if no response to plasma exchange include splenectomy, vincristine. Rituximab has been used in cases of relapse.

•AVOID PLATELET TRANSFUSIONS - THEY “FUEL THE FIRE”

52
Q

What is Hemolytic Uremic Syndrome (HUS)?

A
  • Usually classified along with TTP as “TTP/HUS”
  • Has fewer neurologic sequelae, more renal manifestations.
  • Usually precipitated by diarrheal illness, especially E. coli O157:H7 or Shigella which produce shiga toxin
  • Shiga toxin binds to endothelial cells in the kidney, leading to cell death.
  • Seen more in pediatric patients, usually has better prognosis.
53
Q

Shiga toxin binds to endothelial cells in the ____, leading to cell death and causing HUS.

A

kidney

54
Q

Atypical HUS:

A

•This is HUS without the diarrheal prodrome

•Two hits to get it started:

  • Inherited disorder of complement regulation (unopposed activation, or deficient inactivation)
  • Trigger—either infection or pregnancy

•Diagnosis/clinical features:

  • MAHA and thrombocytopenia
  • Renal failure
  • Evidence of complement activation

•Treatment:

  • PLEX
  • Eculizumab (remember this drug from its use to treat PNH)
55
Q

How is atypical HUS diagnosed?

A
  • MAHA and thrombocytopenia
  • Renal failure
  • Evidence of complement activation
56
Q

How is atypical HUS treated?

A

PLEX

Eculizumab

57
Q

What drugs can induce thrombocytopenia?

A

•Beta-lactam antibiotics

•Trimethoprim-sulfamethoxazole and other sulfa drugs

•Quinine/quinidine

•Heparin

•Abciximab and other GP IIb-IIIa inhibitors

58
Q

Describe Heparin-Induced Thrombocytopenia:

A
  • Seen in 1-3% of patients treated with heparin
  • Usually, 7-10 d after heparin started, platelets fall by at least 30-50%
  • Caused by antibodies against the complex of heparin/PF4

•IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY.

•Can lead, paradoxically, to THROMBOSIS, in some patients (the pathogenic antibodies lead to platelet activation).

59
Q

How is ITP diagnosed?

A
  • Diagnosis of exclusion. There is no diagnostic test (Unlike AIHA)
  • Suspect this in patients with isolated thrombocytopenia
  • In children, usually provoked by viral illness.
  • Spontaneously remits
  • No specific therapy usually required.
60
Q

In adults with ITP, specific therapy is required if platelet count is less than ____ or if the patient is experiencing ____

A

In adults with ITP, specific therapy is required if platelet count is less than 20-30 or if the patient is experiencing bleeding.

61
Q

How is ITP treated?

A
  • Initial therapy relies on use of corticosteroids (e.g. prednisone, methylprednisolone). These can take 48-72 hrs to take effect.
  • If platelet count is <10K or if patient is bleeding, need more rapid therapy–use IVIg
  • 2/3 of adult patients will relapse after steroid taper, or will fail to respond to steroids. In this case, we need second line treatment. This can include:
  • Rituximab—off label use. Kills CD20 positive B cells
  • Splenectomy. 2/3 of pts will respond to splenectomy and remain in remission for >10 years.

•There are two new agents which stimulate more platelet production by the bone marrow—

  • These are useful for refractory cases.
  • They are agonists for the TPO receptor
62
Q

Normally, ___ of the total platelet mass resides in the spleen. Splenic enlargement, from any cause, can lead to ____ of platelets from peripheral circulation into splenic pool.

A

Normally, 1/3 of the total platelet mass resides in the spleen. Splenic enlargement, from any cause, can lead to displacement of platelets from peripheral circulation into splenic pool.

63
Q

What are some common causes of splenectomy?

A
  • Cirrhosis (30%)
  • Lymphoma (27%)
  • Infection (AIDS, endocarditis) (23%)
  • Congestion or inflammation (CHF) (8%)
  • Primary splenic disease (splenic vein thrombosis) (4%)
  • Other/unknown (5%)
64
Q

Platelet transfusion can be used WHEN?

A
  • Can be used to raise the platelet count prophylactically to prevent bleeding or to treat acute bleeding in patients with low platelet counts.
  • Blood bank will have a platelet count above which they will not release platelets–this is not the same as a magic number that should serve as a trigger to transfuse platelets.
65
Q

What patients with thrombocytopenia should get platelet transfusions?

A

•In ITP, transfused platelets will not raise platelet counts, so use only if severe bleeding (ie bleeding causing a rapid Hgb drop or bleeding severe enough to cause end-organ damage)

•In TTP–contra-indicated

•In DIC—give to treat bleeding

•In splenic sequestration, transfused platelets also get warehoused in the spleen, so reserve transfusions for severe bleeding, since the transfusion will not cause the platelet count to rise

•In hypo-production - there tends to be a numerical trigger (10K) to transfuse.

66
Q

Which of the following patients should receive a platelet transfusion? (Normal platelets 150-450)

  1. 55 y.o. man, plts 7, nl Hgb, WBC, nl PT/aPTT, no schistos, no bleeding
  2. 35 y.o. woman, plts 22, nl Hgb, WBC , prolonged PT/aPTT, low fibrinogen, serious vaginal bleeding
  3. 45 y.o. man with acute leukemia, plts 7, no bleeding
  4. 45 y.o. man with splenomegaly, plts 23, no schistos, massive bleeding
  5. 45 y.o. man plts 7, no bleeding, 2+ schistos
A

***2, 3, 4 MAYBE, DOUBLE CHECK

1 - Seems like ITP, so it wouldn’t help (no bleeding)

2 - Maybe? Sounds like hypoproduction (need <10) - BUT bleeding

3 - Low platelets, acute leukemia?

4 - Massive bleeding, despite sequestration should get it

5 - Seems like TTP - platelet transfusion contraindicated

67
Q

Describe diseases of primary thrombocytosis:

A

Primary - i.e. myeloproliferative syndromes

  • Diseases include Essential Thrombocythemia, Polycythemia Vera, CML and myelofibrosis
  • These platelets are both hyper- and hypo-functional
  • May lead to thrombosis and/or bleeding
68
Q

Describe diseases of secondary thrombocytosis:

A

Secondary - i.e. reactive

  • Causes include inflammation, infection, bleeding, iron deficiency, post-splenectomy
  • Treat the underlying cause.
  • Usually does not lead to thrombosis

Hematology Block 2 (7 decks)

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