4.1 Primary hemostasis and related bleeding disorders

Question 1

ITP:

Tx (3)

Answer 1

• Tx:
  1. corticosteroids, reduce immune system
  2. IVIG–“throwing sticks to dog to eat”–give Ab that attach to RBCs–macrophages eat those instead of platelets
  3. Splenectomy–remove Ab source and location of phagocytosis

Question 2

How do platelets aggregate?

Answer 2

Platelet GP2b3a receptors link with each, using fibrinogen as linking molecule.

Question 2

Petechiae, ecchymoses, purpura

Answer 2

skin bleeding: petechiae: 1-2mm purpura: >3mm ecchymoses: >1-2 cm

Question 3

TXA2, purpose in hemostasis

-how is it made?

Answer 3

Released by platelets:

TXA2–induce platelet aggregation via GP2b3a

-made from arachidonic acid via platelet COX

Question 4

MAHA lab findings:

1. platelet count
2. PT/PTT
3. blood smear
4. bone marrow biopsy

Answer 4

1. low, increased bleeding time
2. normal (no change in coag factors)
3. anemia, schistocytes
4. increased megakaryocytes

Question 5

Weibel-Palade bodies, what are they, what do they make?

Answer 5

• found in endothelial cells, secrete:
  1. vWF
  2. P-selectin
  mnemonic: W for vWF, P for P selectin

Question 5

Qualitative primary hemostasis disorders, list them (4)

Answer 5

• qualitative
  1. . Bernard-Soulier syndrome–GP1b deficiency
  2. Glanzmann thrombasthenia–GP2b3a deficiency
  3. Aspirin–irreversible COX inhibitor, lack of TXA2 impairs aggregation
  4. Uremia–disrupts platelet adhesion and aggregation

Question 7

Steps in primary hemostasis (4 main ones)

Answer 7

Endothelial damage:

1. Transient vasoconstriction, mediated by endothelin and neural reflexes
2. Platelet binding
   - vWF binds to subendothelial collagen
   - Platelets bind to vWF via GP1b
3. Platelet degranulation
   - ADP release, increases expression of GP2b3a
   - TXA2 release, induces aggregation via GP2b3a
4. Platelet aggregation
   - Fibrinogen is linking molecule, between GP2b3a

Secondary hemostasis stabilizes the fibrinogen by converting it to fibrin, using thrombin

Question 8

what do platelets release after binding to vessel surface?

Answer 8

1. ADP–increase expression of GP2b3a
2. TXA2–induce platelet aggregation via GP2b3a

Question 9

ITP:

• mech of disease
• divided into what 2 types

Answer 9

• Immune thrombocytopenic purpura
• Auto-Ab (IgG) binds to platelet antigens (eg via GP2b3a), making complexes eaten by macrophages in spleen. Ab made in spleen too.
• acute and chronic

Question 9

what is most common cause of thrombocytopenia in children and adults?

Answer 9

ITP

Question 9

schistocyte

Answer 9

• split RBC, caused by vessel microthrombi
• found in MAHA -“helmet cell”

Question 10

E Coli, why important in hemostasis

Answer 10

• HUS
• E Coli O157:H7 makes a verotoxin, which damages endothelium
• this results in microthrombi, leading to HUS (a form of MAHA)

Question 11

Bernard-Soulier syndrome

Answer 11

qualitative platelet disorder:

• genetic GP1b deficiency, so platelets not able to adhere to vWF.
• mild thrombocytopenia, enlarged platelets

Question 13

fibrinogen and fibrin

Answer 13

-linking molecule for platelet aggregation -link GP2b3a

Question 13

Thrombin

Answer 13

-final product of secondary hemostasis -converts fibrinogen to fibrin, stabilizing clot

Question 14

Hemostasis occurs in 2 stages: what are they?

Answer 14

1. primary–formation of platelet plug
2. secondary–coagulation cascade to stabilize the plug

Question 15

Pregnant pt with ITP:

what to be concerned about for baby? Why?

Answer 15

• short-lived thrombocytopenia in offspring
• The IgG Ab from the pt’s ITP can cross placenta, starting from week 20

Question 16

What are the conditions associated with these steps in primary hemostasis, and what are the mechs?

1. impaired platelet adhesion (3)
2. impaired platelet aggregation (3)

Answer 16

1. Bernard-Soulier syndrome – GP1b deficiency

Uremia

Von Willebrand disease– low vWF (also needed for Factor 8 stabilization)

2. Glanzmann thrombasthenia – GP2a3b deficiency

Aspirin – TXA2 deficiency

Uremia

Question 17

ADP, purpose in hemostasis

Answer 17

Released by platelets:

ADP–increase expression of GP2b3a

Question 19

ADAMTS13

Answer 19

• enzyme that cleaves vWF multimers into monomers for degradation
• TTP: decreased ADAMTS13 leads to large, uncleaved multimers of vWF, which leads to abnormal platelet adhesion, resulting in microthrombi (TTP–a form of MAHA)
• usually caused by autoAb to enzyme

Question 20

Acute vs chronic ITP

Answer 20

• acute:
• often occurs in children weeks after viral infection/immunization. Self-limited, usu resolves itself in weeks
• chronic:
• young women usually, autoimmune. Can be primary or secondary (SLE).
• can cause temporary thrombocytopenia in newborn since anti-platelet IgG can cross placenta.

Question 21

What is vWF derived from?

Answer 21

1. Weibel-Palade bodies, in endothelial cells
2. Platelet alpha-granules

Question 22

Pt with kidney disease:

-what to be concern about with platelets?

Answer 22

Increased bleeding, b/c uremia disrupts:

1. platelet adhesion
2. platelet aggregation

Question 23

TTP - mech - etiology

Answer 23

- Thrombotic Thrombocytopenic Purpura - reduced ADAMTS13 enzyme, which cleaves vWF multimers into monomers for degradation. - causes microthrombi, leading to MAHA - usually caused by auto-Ab against ADAMTS13, usually young women.

Question 24

MAHA - what is it - causes (2)

Answer 24

- Microangiopathic hemolytic anemia - microthrombi in vessel wall causes RBCs to lyse, forming schistocytes (helmet cells) - caused by 1. TTP--low ADAMTS13 enzyme 2. HUS--O157:H7 verotoxin

Question 24

Pt with SLE: What to be concerned about for pt's platelets?

Answer 24

Possible ITP: autoimmune destruction of platelets by splenic macrophages from production of auto-platelet Ab

Question 26

Role of spleen in ITP

Answer 26

1. site of auto-Ab production from plasma cells 2. site of phagocytosis of Ab-platelet complex by macrophages - splenectomy is tx in severe cases of ITP.

Question 27

HUS, TTP - clinical presentation (5) - which is more common in HUS, and which is more common in TTP?

Answer 27

1. skin, mucosal bleeding 2, MAHA 3. Fever 4. Renal insufficiency (HUS--thrombi involve renal vessels) 5. CNS abnormalities (TTP--thrombi involve CNS vessels)

Question 27

TTP: Tx

Answer 27

1. plasmapheresis (remove auto-Ab to platelets) 2. steroids

Question 28

HUS: -tx

Answer 28

-usu supportive, sometimes with hemodialysis

Question 30

HUS - mech - etiology

Answer 30

- Hemolytic uremic syndrome - Verotoxin of E Coli O157:H7 dysentery causes endothelial damage, leading to microthrombi formation - this E Coli comes usually from undercooked beef

Question 32

What symptom is seen in thrombocytopenia but not usu seen in a qualitative hemostatic disorder?

Answer 32

petechiae

Question 33

What immediately happens when endothelial cells are damaged?

Answer 33

Transient vasoconstriction, mediated by 1. neural reflexes 2. endothelin

Question 33

Disorders of primary hemostasis: 1. divided into what 2 categories? 2. clinical presentation - most feared complication

Answer 33

1. Quantitative, Qualitative 2. Bleeding: - mucosal and skin bleeding (epistaxis is most common) - hemoptysis, GI bleeding, hematuria, menorrhagia - most feared: intracranial hemmorhage

Question 35

HUS -most common population

Answer 35

-Children, after eating underocoked beef exposed to E Coli O157:H7 verotoxin

Question 36

TTP: -most commonly seen in what population, why?

Answer 36

- adult female - autoimmune--Ab against ADAMTS13 enzyme, which normally cleaves vWF multimers to prevent excessive thrombosis

Question 37

How do platelets adhere to vessel surface?

Answer 37

1. vWF binds to subendothelial collagen 2. Platelets bind to vWF via GP1b

Question 38

ITP lab values/findings - platelet count - PT, PTT - bone marrow biopsy

Answer 38

- labs: 1. platelet count low 2. PT, PTT normal--coag factors not affected 3. bone marrow--increased # of megakaryocytes trying to replace platelets

Question 40

Endothelin

Answer 40

- vasoconstrictor - secreted by endothelial cells in response to injury

Question 41

Quantitative primary hemostasis disorders, list them (3)

Answer 41

1. ITP 2. TTP (MAHA) 3. HUS (MAHA)

Question 42

Glanzmann thrombasthenia

Answer 42

- qualitative platelet disorder - genetic deficiency in GP2b3a receptors, impairing platelet aggregation through fibrinogen.

Question 43

vWF - what are its functions? (2) - what disorders are related to it? (2)

Answer 43

1. bind to platelet GP1b receptors for platelet adhesion 2. needed to stablilize Factor 8 in coagulation 1. TTP (auto-Ab to ADAMTS13, which normally breaks apart vWF multimers) 2. Von Willebrand disease (lack of vWF means imparied adhesion and impaired coagulation)

Question 44

When NOT to give platelets to pt with thrombocytopenia? (2)

Answer 44

1. TTP 2. HIT - more platelets may be used to make more thrombi, increase risk of MI or other thrombotic events