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Hematological Disease > Platelats, Coagulation, Bleeding Disorders & Clinical Approach > Flashcards

Platelats, Coagulation, Bleeding Disorders & Clinical Approach Flashcards

1
Q

Where are platelets made?

A

In bone marrow

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2
Q

How are platelets made?

A

By fragmentation of megakaryocytic - breaking off cytoplasm

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3
Q

Define Endomitotic Synchronous Replication

A

DNA replication without nuclear & cytoplasmic division

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4
Q

Name 4 stages of platelet formation

A

1, Megakaryocytes in BM mature, via Endomitotic Synchronous Replication

  1. Multilobulation of nucleus
  2. ~8 lobulations of nucleus&raquo_space; development of granules in cytoplasm
  3. Platelets form by breaking off cytoplasm from megakaryocytic
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5
Q

What hormone regulates platelet production?

A

Thrombopoietin (TPO)

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6
Q

Where is TPO produced?

A

In the liver

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7
Q

TPO binds platelets via what receptor?

A

c-MPL receptor (this is target for Rx)

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8
Q

Platelet levels are ______ when free TPO levels are _________

A

Platelet levels are high when free TPO levels are low because it will be platelet bound.

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9
Q 
Normal platelet count = \_\_\_\_\_\_\_
Platelet lifespan = \_\_\_\_\_\_\_\_\_
A

150 - 400

7 - 10 days

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10
Q

What would cause a platelet to have a short lifespan? and why?

A

Thrombocytopenia&raquo_space; Increased utilization of platelets (ex: bleeding)

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11
Q

What would cause a platelet to have a long lifespan? and why?

A

Secondary thrombocythemia&raquo_space; splenic sequestration

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12
Q

What is the importance of glycoproteins on platelets?

A

Important for aggregation & adhesion

Receptors for binding (Ib, IIb & IIIa)

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13
Q

What are the important glycoprotein receptors on platelets & what do they bind?

A

Ib - wVF binding

IIb/IIIa - fibrinogen binding

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14
Q

What diseases are associated with missing glycoprotein receptors on platelets?

A

Ib - wVF binding (gone in Bernard-Soulier’s)

IIb/IIIa - fibrinogen binding (gone in Glanzman’s thrombasthenia)

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15
Q

Define Platelet Phospholipid

– Why is it important?

A

Infolded membrane for increased surface area

– Greater area for reaction with clotting factors

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16
Q

Which clotting factors are activated on the platelet surface?

A 
Factor II (prothrombin)
Factor X
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17
Q

Platelets contain 3 types of granules that are released upon activation. Name them and their contents.

A
  1. Alpha granule: clotting factors
  2. Dense granule: Ca+, ADP/ATP, serotonin
  3. Lysosome: hydrolytic enzymes
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18
Q

Name the clotting factors contained in the alpha granules of platelets.

A 
Fibrinogen
Factor V
vWF
Fibronectin
Beta-thromboglobulin
Heparin antagonist (PF 4)
Thrombosporidin
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19
Q

Name the key function of platelets

A
  1. Hemostatic response - Formation of mechanical plug in vascular injury
    - – “Adhesion, aggregation and release”
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20
Q

Describe the Big Picture of platelet function

A
  1. Upon vascular injury, platelet will be eexposed to subendothelial connective tissue (collagen fibrils)
  2. This allows platelet glycoproteins (Ib +IIb/IIIa) to interact w/ subendothelial components (vWF)
  3. Platelet binding ACTIVATES platelets
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21
Q

Name the platelet adhesion molecule

A

von Willebrand Factor (vWF)

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22
Q

Name the 2 functions of vWF

A

Platelet adhesion to vessel wall

Carries Factor VIII

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23
Q

Where is vWF synthesized

A

Synthesized in endothelial cells
— Stored in endothelial “Weible-Palade” bodies
Also synthesized in megs

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24
Q

Describe vWF formation, cleavage and associated diseases

A

vWF initially releases as large vWF
Cleaved by metalloprotease ADAMTS13
— TTP&raquo_space; ADAMTS13 is defective
— von Willebrand Disease&raquo_space; put in DDx for hemophilia symptoms

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25
Q

Name the platelet aggregation proteins

A

IIb/IIIa

Fibrinogen

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26
Q

Describe the process of platelet aggregation

A

Upon platelet binding, number of IIb/IIIa glycoproteins is increased&raquo_space; increased interaction and binding w/ fibrinogen

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27
Q

Activation of platelets cause degranulation&raquo_space; it’s contents are CRUCIAL for platelet aggregation:
— Describe the functions of ADP & TXA2

A

ADP&raquo_space; chemotactic activator of platelets
TXA2&raquo_space; AA metabolite important in platelet aggregation via vasoconstriction (less blood flow = more binding interaction)

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28
Q

The release of platelets is Ca/cAMP-dependent. Answer high or low?
— ______ cAMP = ______ Ca = ______ platelet function

A

High cAMP = Low Ca = Low Platelet function

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29
Q

Describe the effect of TXA2 on platelet function

A

TXA2 inhibits cAMP formation from ATP (inhibits Adenylate Cyclase)&raquo_space; increased platelet function

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30
Q

Describe the effect of PGI2 on platelet function

A

PGI2 (Prostacyclin formed in endothelial cells) activates Adenylate Cyclase&raquo_space; decreased platelet function

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31
Q

Define the coagulation cascade

A

Amplification of enzymatic/proteolytic pro-clotting factors

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32
Q

What is the main goal of the coagulation cascade?

A

Regardless of intrinsic/extrinsic activation, the main goal&raquo_space;> convert fibrinogen&raquo_space; fibrin (via thrombin)

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33
Q

Why and how is fibrin important to forming a stable blood clot?

A

Fibrin forms a mesh network on immature and unstable platelet clot
– By adding this meshwork (and eventually crosslinking w. Factor XIIIa) the clot becomes stable and withstand shear stress

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34
Q

Where are all clotting factors made?

A

vWF is made in endothelial cells

All others are made in the liver

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35
Q

Which clotting factors are Vitamin K dependent?

A

Factors 2, 7, 9, 10 need Vit. K

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36
Q

Why is Vit. K needed for clotting factors 2, 7, 9 and 10?

A

Vit. K is needed for gamma-carboxylation of these factors (important for Rx)

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37
Q

Vit. K is needed for pro-clotting factors 2, 7, 9 and 10.

Which anti-clotting proteins are Vit. K dependent?

A

Protein C and S are anti-coagulation proteins that are also Vit. K dependent

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38
Q

Name 2 Factors that are NOT clotting factors

A

Factors V and VII are NOT clotting factors – they are cofactors

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39
Q

How is the intrinsic pathway activated?

A

when plasma components recognize blood loss

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40
Q

How is the extrinsic pathway activated?

A

with vascular injury

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41
Q

Describe the 4 steps in the intrinsic pathway

A

Factor II (Hageman) > XI > IX (+cofactor factor VIII) > activates factor X

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42
Q

Describe the steps in the extrinsic pathway

A

vascular injury > TISSUE FACTOR exposed to blood > tissue factor + VIIA > activate IX (through intrinsic pathway) and X
* Cofactor Factor V required in Xa activation of I (fibrinogen&raquo_space; fibrin)

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43
Q

Which pathway is the key component of the coagulation pathway?

A

The Common Pathway

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44
Q

The Common Pathway is dependent on the Prothrombinase Complex. What are the 4 components of this complex?

A

Factor Xa
Factor Va (cofactor)
Phospholipid (need surface)
Calcium (for platelet function)

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45
Q 
Which pathway utilizes all of the following?
Factor Xa
Factor Va (cofactor)
Phospholipid (need surface)
Calcium (for platelet function)
A

The common pathway

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46
Q

What is the main function of the Prothrombinase Complex?

A

converts prothrombin > thrombin ( II > IIa )

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47
Q

What is the function of thrombin?

A

converts fibrinogen&raquo_space; fibrin ( I > Ia )

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48
Q

How does thrombin convert fibrinogen to fibrin ( I > Ia )?

A

thrombin clips fibrinopeptides A and B, forming Fibrin monomers

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49
Q

How are bonds formed between Fibrin monomers?

A
  1. weak H-bonds
  2. strong covalent bonds
    - - Thrombin activates Factor XIII > Factor XIIIa
    - - Factor XIIIa crosslinks fibrin w/ covalent bonds
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50
Q

Name the 3 stages of the Hemostatic Response & the time at which each stage starts

A
  1. Immediate Vasoconstriction (within seconds)
  2. Primary Hemostasis (within 60 seconds)
  3. Secondary Hemostasis (within few hours)
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51
Q

Describe what happens within the first seconds of the Hemostatic response

A

Immediate vasoconstriction

— Reduced blood flow allows for adhesion, aggregation and activation of platelets

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52
Q

Describe what happens within the first minute of the hemostatic response

A

Primary Hemostasis

    • Platelets (IIb/IIIa) adhere to exposed subendothelial layer (glycoprotein Ib + vWF)
    • Platelet binding > activation > release of TXA2 & ADP > aggregation
    • Weak platelet plug formation (large surface area)
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53
Q

Describe what happens within the first hour of the hemostatic response

A

Coagulation cascade is activated
– enhanced by epic amounts of platelet surface area
Fibrin mesh is successfully deposited on platelet plug
– strengthened by Factor XIII activation

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54
Q

Describe what happens to the formed blood clot after the hemolytic response is complete

A
    • Counter Regulation - Anti-Thrombosis

- - Fibrinolysis

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55
Q

Why are blood clots dissolved?

A

Excessive/continuous thrombosis would cause vaso-occlusive diseases

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56
Q

What are the ways in which your body prevents excessive clot-formation?

A
  1. Thrombin only has local effects
    - - thrombin > binds thrombomodulin > activates protein C
  2. Protein C and S destroy cofactors V, VII
  3. Increased blood flow clears away clotting factors
  4. Anti-thrombin 3 binds coagulation factors > inactivates coagulation > enhanced by Heparin
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57
Q

How does your body break clots down?

A

Fibrinolysis

  • Normal hemotological response during vascular injury
  • mediated by Plasminogen > Plasmin
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58
Q

Describe intrinsic Plasmin activation

A

Activators come from the vessel wall

  • Factor XII (Hageman)
  • Kallikrein
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59
Q

Describe extrinsic Plasmin activation

A

Activators come from Tissue (Endothelial cells)

  • Tissue Plasmin Activator (TPA)
  • Urokinase-like A (urinary system)
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60
Q

How do thrombin and plasmin interact when a clot needs to be formed?

A

When a clot needs to be formed, thrombin inhibits plasmin via thrombin-activated fibrinolysis inhibitor (TAFI)

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61
Q

What does Plasminogen activator inhibitor (PAI) do?

A

PAI inactivates tissue Plasmin Activator (TPA)

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62
Q

What does alpha2-antiplasmin do?

A

inactivates circulating TPA

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63
Q

Describe the difference between the inactivation of tissue TPA vs. blood TPA

A

Tissue TPA inactivated by plasminogen activator inhibitor

Blood TPA is inactivated by alpha2-antiplasmin

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64
Q

How does plasmin inhibit clot formation?

A

Plasmin breaks fibrin into fibrin split products > competitively inhibit thrombin/fibrin polymerization

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65
Q

How may endothelial cell disease affect clotting?

A

Endothelial cell disease might result in clotting abnormalities because of TPA release (too much or too little)

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66
Q

Describe the effect of plasmin on fibrinogen and fibrin

A

Plasmin digests fibrinogen and fibrin, generating D & E fragments

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67
Q

How can you distinguish if your patient can form a clot or is forming too many clots?

A
    • The only way to get D & E fragments is from a digested fibrin clot
    • Testing D & E fragments can help distinguish DIC and fibrinolysis from Liver Cirrhosis
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68
Q

Which clotting/anti-clotting molecules would be lost in diseases of endothelial cells?

A 
TPA
vWF
TF
Heparan sulfate
Thrombomodulin
PgI2
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69
Q

What questions do you ask a bleeding patient - History?

A
  1. What kind of bleeding, how much, how often?
  2. Recent trauma/surgery (secondary Thrombocythemia)
  3. Family history
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70
Q

What signs do you look for in a bleeding patient - Physical Exam?

A
  1. Purpura
  2. Petechia - ITP
  3. Ecchymoses (bruising)
  4. Hemarthroses - hemophilia (not vWF disease)
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71
Q

What medications would you ask a bleeding patient about?

A

Anticoagulants

Antiplatelets

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72
Q

What can the blood count and film of a bleeding pt. tell you about the cause of bleeding? Name follow up tests.

A

Blood count & film determines platelet count:

  • Low platelet count:
  • – Check bone marrow (malignancies)
  • – auto-antibodies (destruction
  • – DIC (increased thrombin)
  • Normal platelet count
  • – check platelet aggregation studies
  • – check bleeding time
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73
Q

Regarding the platelet aggregation lab test - graph shows a low optical density (normal) and high optical density (abnormal) - what diseases are indicated with a high optical density

A

IIb/IIIa deficiency (Glanzman’s)
Person taking warfarin
Person taking heparin

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74
Q

Regarding the PT/PTT (prothrombin/partial prothrombin time) tests - what pathways are tested with the PT test?

A

PT test = Plasma + Tissue Factor + Phospholipid + Ca

    • Adding tissue factor is key
    • This tests the Extrinsic Pathway & Common
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75
Q

Regarding the PT/PTT (prothrombin/partial prothrombin time) tests - what pathways are tested with the PTT test?

A

PTT test = Plasma + Phospholipid + Ca + NO tissue factor

– This tests the Intrinsic & Common Pathways

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76
Q

Patient has a long PT & normal PTT. What would be deficient?

A

Increased PT = deficient TF, Factor VI

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77
Q

Patient has long PTT & normal PT. What would be deficient?

A

Increased PTT = deficient XII, XI, IX, Factor VIII

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78
Q

Patient on warfarin or coumadin would have a ________ PT time.

A

Both PT & PTT increased

– Factor X & Factor V deficiencies may also cause both to be prolonged

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79
Q

Define INR and define the INR equation

A

INR - International normalized ratio

INR = (PT test / PT normal) /\ ISI

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80
Q

What is the normal INR & ISI value

A 
INR = 1
ISI = 1
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81
Q

What would be the INR value of a person on warfarin

A

a person on warfarin would have a long (high) PT time
INR = (PT test / PT normal) /\ ISI
Long (high) PT test would = high INR = >1

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82
Q

Transfusion Medicine (Dr. Stromm’s Lecture) - What is the current risk from blood transfusions?

A

1/100,000

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83
Q

What does blood donor screening entail?

A

Donor questionnaire
Serum test for infectious agents
– HIV, HBV, HCV, etc. (via PCR)

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84
Q

Outline the 3 steps in processing donated blood

A
  1. Separate RBC from plasma/platelets
    - - Packed RBC (prbc)
  2. Separate platelets from plasma
  3. Prepare plasma
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85
Q

Describe processing of packed RBCs

A

1 unit prbc = 250 mL = +1 Hg = +3 HCT

Irradiate to kill leukocytes (avoid rejection - Graft v. Host disease)

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86
Q

Describe processing of donated platelets

A
  1. Separate from plasma
    - - Cannot refrigerate
    - - Lasts 4-5 days
    - - Requires room temp. & constant agitation
  2. 2nd method - Apheresis
    - - platelets removed as blood is returned to donor
    - - 300 billion platelets vs. 55 billion from donated blood
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87
Q

Define plasma and describe the processing of plasma.

A

Fresh Frozen Plasma (FFP) = everything else that isn’t RBC or platelets
– Cryoprecipitate - precipitate proteins as you chill plasma

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88
Q

What is the usefulness of plasma with regards to clotting?

A

Plasma is a good source of fibrinogen and other clotting factors

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89
Q

What is the only objective of an RBC transfusion?

A

to increase the patient’s oxygen carrying capacity

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90
Q

Regarding CHO surface antigens on RBCs:

What is the molecular composition of the O antigen and who has it?

A

O Antigen = Sphingosine + 5 sugars

Everyone has O Antigen

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91
Q

What does the ABO gene code for?

A

ABO glucosyltransferase

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92
Q

What does ABO glucosyltransferase do? What’s it importance?

A

it adds a 6th sugar to O antigen

– Depending on what ABO gene alleles you have will determine your blood type

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93
Q

Who does not have the ABO gene?

A

Your girlfriend Tanya.

All people with type O blood do not have this gene

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94
Q

Describe the ABO gene alleles in people with blood type A

A

Two A alleles = add GlcNac

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95
Q

Describe the ABO gene alleles in people with blood type B

A

Two B alleles = add Gal

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96
Q

Describe the ABO gene alleles in people with blood type AB

A

1 A + 1 B allele

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97
Q

Describe the ABO gene alleles in people with blood type O

A

enzyme’s taking a lifetime off - no ABO gene = no ABO glucosyltransferase enzyme

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98
Q

Most antigenic protein on RBC is _____

A

RhD

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99
Q

What is the genetic makeup of RhD-

A

two deleted alleles for RhD

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100
Q

Blood groups are immunogenic. What does this mean?

A

If you don’t have a blood group antigen, you will form an antibody to it without exposure due to normal gut flora

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101
Q

What is the reaction called, when someone receives the wrong blood type in a blood transfusion?

A

Acute Hemolytic Transfusion Reaction

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102
Q

For blood types A, B, AB and O - name the antigen each has and what blood types they may receive.

A

Type A has anti-B, receive A and O
Type B has anti-A, receive B and O
Type AB has no Ab, receive only O because donor Ab
Type O has anti-A/B, only receive O (can donate to all)

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103
Q

Compare mother vs. baby Rh & blood type

A

Blood type: Mother = Baby

Rh: Mother Rh-, Baby Rh+

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104
Q

In pregnancy, mother’s _____ is primed for _____

A

IgG, anti-RhD+

105
Q

In subsequent pregnancies, mother’s Ig andti-Rhd+ antibodies can do what to baby?
How do you treat this?

A

Cross and lyse fetal RBCs

* Treat with Rhogam (Ab targeted at IgG anti-RhD+ antibody)

106
Q

What is the only routinely screened protein antigen in donor and recipient?

A

RhD

107
Q

Which is more valuable, RhD+ or RhD-?

A

RhD-

108
Q

To save RhD- blood, RhD+ blood is given to men and older women for FIRST transfusions. Why is this ok?

A

Because first time transfusions only generates the anti-RhD+ antibodies; causes only mild lysis

109
Q

How do you test the patient before RBC transfusion?

A
  1. Type blood (ABO, Rh, Protein)

2. Screen recipient for preformed Ab

110
Q

Name 4 situations where you would give a patient a blood transfusion?

A
  1. During/immediately after acute MI (HCT>30)
  2. Acute blood loss
  3. Symptomatic patient (NOT NUMBERS)
  4. Decrease Hg trendline
111
Q

What are 4 situations where you would NOT perform a blood transfusion?

A
  1. Old/frail patient (recall PCM)
  2. Coronary Artery Disease
  3. Increase blood volume (saline/albumin)
  4. Increased coagulation
112
Q

When do you consider a patient transfusion in a patient?

A

When platelet count < 10K + GI bleeding

113
Q

Is a platelet transfusion considered in a patient with minor bleeding (nosebleeds)?

A

No

114
Q

Is a platelet transfusion considered in a patient with major bleeding or hemorrhage?

A

No (unless platelets <10K)

115
Q

Do platelets express ABO blood type?

A

Yes

116
Q

What is the consequence of an unmatched platelet transfusion?

A

Result is not major hemolysis, not a big deal.

– You’ll find that those unmatched platelets are just degraded a little bit sooner

117
Q

How many platelets and standard donation units can be obtained from 1 apheresis?

A

1 apheresis = 30k platelets = 6 std units

118
Q

How long do platelets last in storage?

A

4-5 days

119
Q

What conditions must be met to store platelets?

A

Must be agitated at room temp.

* High chance of contamination

120
Q

Are platelets more or less immunogenic than RBCs?

A

More immunogenic

* Significance: more transfusions result in less efficacy of transfused platelets over time

121
Q

What is the platelet refractory state and how do you prevent it?

A
  • Some individuals develop an immediate and strong response to platelets upon transfusion
  • Deplete platelets of leukocytes & avoid transfusions as much as possible
122
Q

Name 5 indications for a platelet transplant.

A
  1. t Tx Plat. in TTP)
123
Q

Plasma contains no RBCs and no platelets - does it need to be typed before transfusion?

A

Yes. Fresh Frozen Plasma = must be typed for patient or else you’ll kill them

124
Q

What is the main indication for Fresh Frozen Plasma?

A

INR > 2.0

125
Q

Name 5 situations in which FFP would be given to a patient.

A
  1. Coagulation factor replacement
  2. Antithrombin 3 replacement
  3. TTP (Plasma exchange)
  4. Reverse coumadin/warfarin quickly
  5. Replace plasma with massive transfusion
126
Q

What is a common risk with FFP treatments?

A

Volume overload

  • can increase blood volume by 20%
  • generates infiltrates in lung
127
Q

How do you avoid volume overload in FFP treatments?

A
  • Use vitamin K or cryoppt in place for warfarin toxicity to avoid volume overload
128
Q

What do you do if there is a transfusion reaction?

A

Stop the infusion

129
Q

Name 7 common adverse effects of transfusions.

A
  1. Graft vs. Host disease (immune run)
  2. Circulatory overload
  3. Transfusion-related Acute Lung Injury (TRALI)
  4. Acute Hemolytic reactions
  5. Delayed Hemolytic Reactions
  6. Allergic Reaction to plasma components
  7. CODE - can be transfusion reaction
130
Q

What causes Transfusion-related Acute Lung Injury (TRALI) and what are the symptoms?

A

Donor antibodies attack recipient HLA antigens

– Pulmonary edema but no cariogenic problems

131
Q

What are the signs & symptoms of Acute Hemolytic Reactions and what is the cause?

A

Hemolytic rections present with fever, dark urine, and other non-specific symptoms
– Type/screen mismatch because of ID error most commonly

132
Q

What is a delayed hemolytic reaction?

A

Antibody develops to minor antigen

- This means you have to educate patient when you send them home because it will develop later when they are at home

133
Q

Is it ok to do a transfusion if the patient has a mild fever?

A

Yes

134
Q

What is the best way to prevent adverse effects of transfusion?

A

Get fresh recipient sample and do complete transfusion workup

135
Q

Name 7 categories of bleeding disorders?

A
  1. Thrombocytopenia
  2. Vascular bleeding disorders
  3. Defective Platelets
  4. Defective Coagulation
  5. Defective Fibrinolysis
  6. Thrombophilia
  7. Iatrogenic
136
Q

Is defective coagulation a platelet disorder?

A

No

137
Q

What is thrombocytopenia?

A

Deficient thrombocytes = low number of platelets

138
Q

What is thrombophilia?

A

Hypercoagulable state

139
Q

What is the risk with thrombophilia?

A

Increased risk for thrombosis

140
Q

What is the cause of thrombophilia?

A

Inherited defect OR ongoing stimulus

141
Q

What are the two types of thrombophilia and what are their causes?

A

Arterial thrombosis
– caused by any lesion that exposes subendothelium to platelets in blood
Venous thrombosis
– caused by stasis of blood

142
Q

Arterial vs. Venous thrombosis: red or white clot and why for each.

A

Arterial clot
- white, high platelet component
Venous clot
- red, high fibrin component

143
Q

Arterial vs. Venous thrombosis: which is associated with atrial fibrillation?

A

Arterial thrombosis

144
Q

Arterial vs. Venous thrombosis: Which is associated with high blood flow?

A

Arterial thrombosis

145
Q

What causes a venous thrombosis? (think DVT)

A

Caused by immobility and hypercoagulation (thrombophilia)

146
Q

What does DVT stand for?

A

Deep Vein Thrombosis

147
Q

Where do DVTs occur and where do they spread?

A

DVT starts below the knee and grows up towards inguinal area

148
Q

Arterial vs. Venous thrombosis: which is more fatal?

A

Arterial thrombosis

149
Q

Arterial vs. Venous thrombosis: which is associated w/ MI > stroke > PAD

A

Arterial thrombosis

150
Q

What is the Holman’s Sign?

A

Dorsiflex foot with pain in back of calf

151
Q

Holman’s Sign is seen in what type of thrombosis?

A

DVT - deep vein thrombosis

*clotted veins are painful to stretc

152
Q

What is a common complication of DVT?

A

Pulmonary embolism

153
Q

What is the key symptom of pulmonary embolism?

A

shortness of breath

154
Q

What is the overall goal when treating blood clots?

A

keeping the clot south of the knee

155
Q

What is the acute management of an arterial thrombosis?

A
  1. Remove clot
  2. stent
  3. Anti-coagulation therapy
  4. Aspirin (decrease platelet aggregation)
  5. Clopidogrel ( decrease ADP receptors for aggregation)
156
Q

What is the chronic management of an arterial thrombosis?

A

Treat the underlying disease (hypertension, lipidemia, diabetes)

157
Q

Name 2 types of Iatrogenic bleeding disorders

A

Transfusion Related Disease

Anticoagulant toxicity

158
Q

What kind of diseases are categorized as a Thrombocytopenia?

A

Diseases where presentation involves lack of platelets

159
Q

Name 4 Diseases categorized as Thrombocytopenia disease

A
  1. Failure of platelet production
  2. ITP (idiopathic thrombocytopenia purpura)
  3. TTP
  4. DIC (disseminated intravascular coagulation)
160
Q

Name 3 causes of Failure of Platelet Production

A
  1. Bone marrow failure (radiation, aplastic, malignancy)
  2. Megs depression
  3. c-MPL receptor mutation
161
Q

Name 3 physical findings in Failure of Platelet Production

A
  1. Spontaneous skin purpura
  2. Mucosal hemorrhage
  3. Excess bleeding post-trauma
162
Q

What is the mechanism of ITP (idiopathic thrombocytopenia purpura)

A

IgG antibodies targeted at platelet Iv or IIb/IIIa binding regions > removed by RES system

163
Q

What causes ITP?

A
  1. Can be Rx induced
    - – antibody-drug-protein complex deposits on platelets (ex. Heparin-PF4)
    - – HIT Syndrome (only w/ unfractioned Heparin)
164
Q

What is the clinical presentation of ITP?

A

Young women
Thrombocytopenia
Petichia
* NO neutropenia or anemia (appears healthy)

165
Q

How do you treat ITP?

A
  1. Common w/ URI in children
    - – do nothing other than avoid injury for 6 wks
  2. Must treat in adults
    - – Steroids
    - – IV-Ig
    - – TPO agonists
    - – Splenectomy
166
Q

Name congenital and acquired causes of TTP

A
  1. Congenital
    - – absence/defective ADAMTS13
  2. Acquired
    - – auto-IgG antibody that is anti-ADAMTS13
167
Q

What is ADAMTS13?

A

metalloprotease that cleaves large vWF

168
Q

What is the mechanism of TTP?

A

no/low/defective ADAMTS13&raquo_space; cannot cleave large vWF&raquo_space; large vWF binds to platelets via Ib+IIb/IIIa&raquo_space; occlusion due to platelet aggregation&raquo_space; microangiopathic anemia

169
Q

What is the clinical presentation of TTP?

A 
TTP Triad
---Thrombocytopenia
---Microangiopathic hemolytic anemia
---Neurological symptoms
Young woman
Renal insufficiency
Fever
170
Q

What is seen on the peripheral stain of a patient with TTP?

A

Schistocytosis

171
Q

How do you treat TTP?

A

Plasma exchange

NOT PLATELETS!!

172
Q

What is the DDx of TTP?

A
  1. Thrombocytopenia
  2. Schistocytes (MAHA)
  3. Increased LDH (hemolysis/necrosis)
173
Q

Name 3 causes of DIC

A
  1. Infection (gram (-), sepsis)
  2. Malignancies (ex. overproduction tissue factor)
  3. OB complications
174
Q

What is the mechanism of DIC?

A

Excess thrombin production&raquo_space; excess/abnormal fibrin deposition&raquo_space; clot formation&raquo_space; MAHA

175
Q

How do you treat DIC?

A
  1. Underlying cause (infection, malignancy)

2. Platelets

176
Q

What is the clinical presentation of DIC?

A

Thrombocytopenia
Purpura
Peripheral gangrene

177
Q

What does the peripheral smear show in DIC?

A

Schistocytes

178
Q

What is the DDx of DIC?

A

Low platelets
Low fibrinogen
Low clotting factors (depleted/exhausted)
High D-dimer (fibrin split product)

179
Q

Name 4 blood vessel disorders

A
  1. Hereditary Hemorrhagic Telenglectaria (HHT)
  2. Senile Purpura
  3. Ehlers Danlos Syndrome
  4. Henoch Schoenlein Purpura (Vasculitides)
180
Q

Hereditary Hemorrhagic Telangiectaria (HHT) is inherited in what pattern?

A

Autosomal dominant

181
Q

Hereditary Hemorrhagic Telangiectaria (HHT) occurs in what type of blood vessels?

A

Arterioles/small venules

182
Q

In Hereditary Hemorrhagic Telangiectaria (HHT) , are the platelets normal or abnormal?

A

Platelets are normal

183
Q

What is the clinical presentation of Hereditary Hemorrhagic Telangiectaria (HHT)?

A 
Easy bruising
Spontaneous bleeding from small vessels
Mucosal bleeding
*look for bleeding on edge of tongue, inside nose
*recurrent bleeding >> iron-deficiency
184
Q

What causes Senile Purpura?

A

Age-associated atrophy of blood vessels and vasculature support

185
Q

What is the clinical presentation of Senile Purpura?

A

Old

Bruising on forearms

186
Q

What is the mechanism of Ehlers Danlos Syndrome?

A

Defective synthesis in connective tissue (Collagen I/III)

187
Q

What is the clinical presentation of Ehlers Danlos Syndrome?

A 
Hyperflexible skin
Double jointedness
Poor wound healing
Arterial rupture 
Difficulty breathing
188
Q

Wat is the mechanism of Henoch Schoenlein Purpura (Vasculitides)?

A

IgA mediated vasculitis

189
Q

What is the clinical presentation of Henoch Schoenlein Purpura (Vasculitides)?

A

Purpura you can “feel”

— it has a rough feeling

190
Q

Name 2 platelet diseases that cause dysfunctional platelets, and identify their defective proteins

A
  1. Bernard Soulier - deficient in glycoprotein Ib

2. Glanzman’s Thrombasthenia - deficient in IIb/IIIa

191
Q

What are acquired causes of Dysfunctional platelets?

A

Drugs

Liver/renal metabolic failure

192
Q

What is the clinical presentation for all those with dysfunctional platelets?

A

Superficial bleeding

193
Q

How do you treat patients with dysfunctional platelets?

A

Treat the underlying cause
Platelet transfusions
* platelet transfusions can cause autoimmune thrombocytopenia – if this happens then there is no treatment option left

194
Q

Name 3 Coagulation Disorders

A

They are all hereditary disorders:

    • Hemophilia A
    • Hemophilia B
    • von Willebrand Disease
195
Q

What is the inheritance pattern of Hemophilia A?

A

X-linked recessive

196
Q

What clotting component is defective in Hemophilia A?

A

Absence/lower plasma factor VIII

197
Q

In Hemophilia A disease, what is the key problem?

A

Once it starts, they don’t stop bleeding

198
Q

What is the clinical presentation of a patient with Hemophilia A ?

A

Deep bleeding
Bleeding into joints (hemarthrosis)
Fusion of joints
* bleeding can be spontaneous

199
Q

What is the DDx for Hemophilia A?

A
  1. Long PTT (b/c VIII)
  2. Normal PT
  3. Check for inhibitors
  4. Confirm VIII deficiency w/ factor assay
200
Q

How do you treat a patient w/ Hemophilia A?

A

Education
Local; pressure, topical thrombin
Systemic: Desmopressin (DDAVP)
— increase vWF
— only works in pts that can produce some VIII
— E-Aminocaproic Acid - inhibits fibrinolysis

201
Q

What is the inheritance pattern of Hemophilia B?

A

x-linked recessive

202
Q

What clotting component is missing/reduced in Hemophilia B?

A

plasma factor IX

203
Q

What is the clinical presentation, DDx and treatment for Hemophilia B?

A

Same as for Hemophilia A

204
Q

What is the inheritance pattern of von Willebrand Disease?

A

autosomal dominant

205
Q

What is the blood clotting component missing/reduced in von Willebrand Disease?

A

vWF is absent or reduced

206
Q

What are the 2 functions of vWF?

A

platelet binding

VIII carrier

207
Q

How many subtypes of von Willebrand Disease are there? Which is the most common?

A

4 types

Type I is most common

208
Q

What is the clinical presentation of von Willebrand Disease?

A

Common when young women begin menstruating
Bruising
mucosal bleeding

209
Q

What is the DDx for von Willebrand Disease?

A

Long PTT b/c vWF deficiency lowers VIII
Measure vWF
Ristoceitin Test

210
Q

What is the treatment for von Willebrand Disease?

A

DDAVP + E-Aminocaproic Acid

211
Q

What are the 2 causes of Fibrinolysis?

A
  1. Liver cirrhosis (alcoholics, Hep C)
  2. Prostate cancer/ surgery
    * Hep C due to blood transfusions
212
Q

What is the clinical presentation of Fibrinolysis?

A

Liver disease
Prostate issues
*Liver disease = red palms despite pallor, jaundice

213
Q

What is the DDx for Fibrinolysis?

A

CBC, PS, PT/PTT, D-dimer test
Complete Metabolic Profile - Liver function tests
Antibody to HepB/C

214
Q

Name 7 Thrombophilia/Hypercoagulable states

A
  1. Inherited Factor V Leiden Mutation
  2. Inherited Antithrombin 3 Deficiency
  3. Inherited Protein C and Protein S Deficiency
  4. Inherited PRothrombin Gene Mutation
  5. Inherited Hyperhomocysteinemia
  6. Acquired Thrombophilia
  7. Acquired Anti-Phospholipid Syndrome
215
Q

What is the most common inherited thrombophilia?

A

Factor V Leiden Mutation

216
Q

What super powers do you get from Factor V Leiden Mutation?

A

Protein C Resistance

217
Q

What is the mechanism of Factor V Leiden mutation?

A

Mutation in Factor V makes it resistant to degradation from Protein C

218
Q

What is the clinical presentation of Factor V Leiden mutation?

A

thrombosis (variable)

219
Q

How do you diagnose Factor V Leiden mutation?

A
  1. Add activated PRotein C and observe thrombin time
    - – if factor V is resistant (Leiden) then the PT/PTT will both be normal
    - – if prolonged, Factor V is not resistant
  2. PCR screen for mutation
220
Q

What is the treatment for Factor V Leiden mutation?

A

If no thrombosis, don’t start on anticoagulant therapy

—- unless high risk situation (long flights)

221
Q

What is the inheritance pattern of inherited antithrombin 3 deficiency?

A

Autosomal dominant

222
Q

What is the mechanism of antithrombin 3 deficiency?

A

Deficiency in antithrombin 3&raquo_space; tissue factors are not inactivated or bound&raquo_space; hypercoagulable state

223
Q

What is the clinical presentation of antithrombin 3 deficiency?

A

Recurrent venous thrombosis starting in early adult life

224
Q

How do you test for antithrombin 3 deficiency?

A

Inject heparin and look at PTT

— There should be no change in PTT because heparin has nothing to bind to

225
Q

How do you treat a patient with antithrombin 3 deficiency?

A

Antithrombin replacement

226
Q

What is the inheritance pattern of Protein C and Protein S deficiency?

A

Autosomal dominant

227
Q

What is the mechanism of Protein C and Protein S deficiency?

A

no activated anti-coagulant proteins to bind/destroy thrombin&raquo_space; hypercoagulable state

228
Q

How can an infection complicate patients with Protein S deficiency?

A

Protein S also binds to C4b.

  • – This means if you have an infection and you are protein S deficient
  • – the little PS you have will be bound by increased acute phase C4b
  • – Increased clotting will occur
229
Q

What is the clinical presentation of patients with Protein C or Protein S deficiency?

A

Skin necrosis

Thrombosis

230
Q

How do you treat patients with Protein C or Protein S deficiency?

A

Activated Protein C & S concentrate for replacement

231
Q

How does Prothrombin Gene Mutation (G20210A) create a hypercoagulable state?

A
  1. Increased thrombosis
    - - Sustained generation of thrombin in the plasma&raquo_space; increased thrombosis
  2. Decreased fibrinolysis
    - - Activated thrombin stimulates secretion of anti-tPA
232
Q

What is the clinical presentation of a patient with Prothrombin Gene Mutation (G20210A)?

A

Thrombosis

233
Q

What is the DDx for Prothrombin Gene Mutation (G20210A)?

A
  1. Analyze for genetic mutation

2. Analyze levels of clotting factors + PT/PTT

234
Q

What is the mechanism of Hyperhomocysteinemia (bad MTHFR gene)?

A

Bad MTHFR&raquo_space; no re-methylation of THF&raquo_space; no substrate for conversion of homocysteine&raquo_space; methionine&raquo_space; homocysteine build-up&raquo_space; thrombosis

235
Q

What is the clinical presentation of Hyperhomocysteinemia?

A

Young children

    • Look for unusual thrombosis or CVD
    • ex. 8 y/o with MI
236
Q

What 10 diseases/conditions are associated with acquired Thrombophilia?

A
  1. Pregnancy/post-partum
  2. Immobilization (foot in a cast)
  3. Trauma
  4. Advanced Age
  5. Antiphospholipid
    - – Increased B-thromboglobulin (pro-thrombus)
    - – Decreased antithrombin (pro-thrombus)
  6. cancer
  7. Essential Thrombocythemia
  8. Nephrotic Syndrome
  9. Estrogen - increased risk for DVT
  10. Birth control
237
Q

What is the clinical presentation of acquired Thrombophilia?

A

Thrombosis

Idiopathic

238
Q

What is the DDx for acquired thrombophilia?

A

For birth control - check b thromboglobulin and antithrombin 3

239
Q

What is Anti-Phospholipid syndrome?

A

Condition where antibodies are directed at phospholipid components

240
Q

What phospholipid components are targeted in Anti-Phospholipid syndrome?

A
  1. Anti-cardiolipin

2. Anti-phosphatidyl serine

241
Q

What proteins are associated with Anti-phospholipid syndrome?

A

B2 GP + Thrombin

242
Q

What is common finding in Anti-Phospholipid syndrome?

A

Common finding is lupus anticoagulant

243
Q

What is the clinical presentation of Anti-Phospholipid syndrome?

A

Thrombosis
Fetal loss in 2nd Trimester
Dermatological issues (Livedo reticularis)
Blurred vision
Stroke
Thrombosis w/ lupus anticoagulant, but no SLE diagnosis

244
Q

What is the DDx for Anti-Phospholipid syndrome?

A
  1. High PTT that is not corrected in 50/50
    - – shows that this is an inhibitor of coagulation and not a deficiency of clotting factor
  2. Corrected in hexagonal phase because this competes for binding of Lupus Anticoagulant
  3. Russell Viper Venom Test
245
Q

Name 2 Iatrogenic/Drug Related conditions?

A
  1. HIT Syndrome

2. Coumarin/Coumadin Induced Necrosis

246
Q

What is the mechanism of HIT Syndrome?

A
  1. Autoantibody develops for Heparin-PF4 complex
  2. Antibody+Complex binds to platelet via platelet’s Fc receptor
  3. Causes platelet aggregation and activation
247
Q

Is HIT Syndrome a bleeding disorder or clotting disorder?

A

HIT syndrome is THROMBOSIS, not bleeding

248
Q

What triggers HIT syndrome?

A

common in unfractionated heparin

249
Q

What is the clinical presentation of HIT syndrome?

A

Heparin use

250
Q

What will labs show in HIT syndrome?

A
  1. Thrombosis - aggregation of platelets

2. Thrombocytopenia - increased use of platelets

251
Q

What does the peripheral smear show in HIT syndrome?

A

Abnormal platelets

All other cells normal

252
Q

What is the DDx for HIT syndrome?

A
  • Look for anti-Heparin/PF4 antibody via ELISA
  • Sensitive (test will find the Ab)
  • NOT specific (Ab is common)
253
Q

What is the treatment for HIT syndrome?

A

Take patient off Heparin
Give DTI
– Cannot give other type of Heparin b/c there is 80% cross reactivity w/ this Ab
– Don’t give DTI via IV if kidney disease

254
Q

What type of medication is warfarin?

A

Coumarin

255
Q

What is Coumarins mechanism of action?

A

Inhibits VitK Epoxide Reductase

256
Q

What is the mechanism of Coumarin/Coumadin induced necrosis?

A

Anti-coagulation factors, protein C and protein S, have shorter half lives
Therefore, inhibition of PC/PS formation generates clots&raquo_space; tissue necrosis

257
Q

What is the clinical presentation in Coumarin/Coumadin induced necrosis?

A

Warfarin therapy

Tissue necrosis of skin/fatty areas

258
Q

How do you treat a patient with Coumarin/Coumadin induced necrosis?

A
  1. Remove warfarin
  2. Administer Vit K (replaces VitK-dep factors)
  3. Administer Prothrombin Complex (replace all Vit K factors including PS/PC
  4. FFP (replace all clotting factors)
  5. Recombiant VIIa
259
Q

How do you prevent Coumarin/Coumadin induced necrosis?

A

Give heparin and warfarin at the same time

— Heparin can have immediate effects and protect from necrosis

Hematological Disease (3 decks)

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