252/254 - Too Much Bleeding

Question 1

How can a patient with a factor deficiency have normal PT/PTT?

Answer 1

PT and PTT only become abnormal when coagulation factors drop below 30-40%

=> Mild deficiencies can have normal PT and PTT

Measure specific clotting factor deficiencies if clinical suspicion is high

Question 2

Describe the amplification loop of the coagulation cascade

Answer 2

Initially, a small amount of thrombin is produced

Thrombin further activates V, VIII, XI

Results in lots of thrombin

Question 3

What is the only thrombocytopenia that will have platelets that are too small?

Answer 3

Wiscott-Aldrich

Defect in WAS gene; responsible for stabilizing actin cytoskeleton

Question 4

What clotting factor activates prothrombin -> thrombin?

Answer 4

Xa

Question 5

Deficiency of which clotting factor will result in elevated PT with normal PTT?

Answer 5

F VII

Question 6

What are the endogenous inhibitors of Factor Va and VIIIa? (2)

Answer 6

Activated protein C

with cofactor protein S

Question 7

Which factor deficiency is most likely to present with bleeding a few days after surgery?

Answer 7

Factor XI deficiency

Hemophilia C

Question 8

What are the treatments for hemophilia C?

Answer 8

Fresh frozen plasma

Anti-fibrinolytic agents

There is no factor XI concentrate available

Question 9

What is the most likely diagnosis in an adult patient, on no relevant medications, who has:

• Isolated thrombocytopenia
• Normal blood smear
• Increased megakaryocytes on bone marrow biopsy

Answer 9

Immune thrombocytopenia purpura

Question 10

List 5 treatment options for immune thrombocytopenia purpura (ITP)

Answer 10

According to boards…

• Corticosteroid
• IVIG
• Rituximab
• Thrombopoietin analog
• Splenectomy
  
  • -> no splenic macrophages to remove antibody-coated platelets

In real life, usually observe unless pt is bleeding or at high risk

Question 11

Which clotting factor is deficient in:

• Hemophilia A:
• Hemophilia B:
• Hemophilia C:

Answer 11

• Hemophilia A: FVIII
• Hemophilia B: FIX
• Hemophilia C: FXI

Question 12

What procoagulant factors are inhibited by tissue factor pathway inhibitor (TFPI)? (2)

Answer 12

Factor Xa

TF/Factor VIIa

Question 13

What endogenous substance initiates breakdown of a fibrin clot?

What are the subsequent steps?

Answer 13

tPA initiates

Activates plasminogen -> plasmin

Plasmin breaks down the fibrin clot

Results in D-dimer formation

Question 14

List the 2 major mechanisms of platelet destruction

Answer 14

• Antibodies
  
  • HIT
  • Drug-induced thrombocytopenia
  • Infection-related / immune
• Thrombotic microangiopathies
  
  • DIC
  • TTP
  • HUS
  • HELLP

Question 15

What is the mechanism and outcome of:

• Primary hemostasis:
• Secondary hemostasis:

Answer 15

• Primary hemostasis:
  
  • Vasoconstriction and platelet aggregation -> Platelet plug
• Secondary hemostasis:
  
  • Coagulation cascade -> Fibrin clot

Question 16

What is the treatment for vWF disease?

Answer 16

Desmopressin

vWF concentrate

Question 17

What duration defines each of the following thrombocytopenias?

• Acute:
• Persistenet:
• Chronic:

Answer 17

• Acute: < 3 months from dx
• Persistenet: 3-12 months since dx
• Chronic: >12 months since dx

Each time interval indicates time that platelet count has been low

Question 18

Which laboratory test is abnormal in a patient with severe hemophilia A?

Answer 18

PTT

Question 19

When is immune thrombocytopenia purpura treated?

Answer 19

Significant bleeding

High risk for traumatic bleeding
(toddlers, sports, phsysical demand)

Observation in adults w/ no history of bleeding >30k platelets

Observation in children ITP typically secondary to infection

Caused by antibodies against GpIIb/IIIa

Question 20

Describe the pathophysiology of heparin-induced thrombocytopenia (HIT)

Answer 20

• Heparin induces the production of autoantibodies against platelet factor 4 bind to platelets
• -> platelet activation
• -> clearance
• Tons of platelets are activated -> clotting*
• Then the platelets are used up -> thrombocytopenia*
• Tx: Remove heparin, give direct thrombin inhibitor*

Question 21

What are the endogenous inhibitors of thrombin? (2)

Answer 21

Antithrombin

Thrombomodulin

Question 22

What are the two most commonly mutated proteins in hereditary hemorrhagic telangiectasia?

Answer 22

Endoglin

ALK-1

Question 23

Which clotting factor cross-links fibrin

Answer 23

Factor XIII

Question 24

What is the most likely cause of prolonged PT or PTT that does NOT correct with a mixing study?

Answer 24

Inhibitor

Specific factor inhibitor or lupus anticoagulant

Question 25

What clotting factor levels define each level of hemophilia? * Mild: * Moderate: * Severe:

Answer 25

* Mild: **\>5%** * Moderate: **1-5%** * Severe: **\<1%** *Factors 30-40% of normal can still have normal PT/PTT*

Question 26

Deficiency of which clotting factors (6) will result in **elevated PTT with normal PT**?

Answer 26

HMWK PK FXII FXI FIX FVIII

Question 27

What is the inheritance of: * Hemophilia A: * Hemophilia B: * Hemophilia C:

Answer 27

* Hemophilia A: **X-linked recessive** * Hemophilia B: **X-linked recessive** * Hemophilia C: **Autosomal dominant**

Question 28

Which clotting factor cleaves fibrinogen -\> fibrin?

Answer 28

Thrombin (Factor II)

Question 29

Describe the bleeding associated with Hemophilia C deficiency

Answer 29

Delayed post-surgical bleeding * A few days after surgery* * FXI is important for the thrombin burst; no FXI -\> no burst -\> weaker clot*

Question 30

Which part of the clotting cascade is evaluated with PTT?

Answer 30

Intrinsic pathway

Question 31

Describe the negative feedback loop that regulates thrombopoietin

Answer 31

Thrombopoietin = signal to make more platelets Thrombopoietin is constituitively expressed in the liver **Thrombopoietin is cleared when it binds to the cMPL receptor on bplatelets** =\> **More platelets = less thrombopoietin = less platelet production**

Question 32

What is the cause of Aplasia vs. Myelophthisis? ## Footnote *What is the bone marrow doing differently?*

Answer 32

* Aplasia = **bone marrow is not making platelets** * Aplastic anemia * Myelodysplasia * Secondary bone marrow suppression * Myelophthisis = **Bone marrow is making platelets, but they are not healthy** * **​**Cancer * Myelofibrosis * Oseoporosis

Question 33

Which coagulation factor deficiency will have normal PT and normal PTT?

Answer 33

Factor XIII deficiency *Results in a weak clot that dissolves more easily*

Question 34

What is the most common congenital bleeding disorder?

Answer 34

Von Willebrand's disease

Question 35

List 4 causes of secondary ITP

Answer 35

* Lupus * Malignancy * HIV * Hepatitis C *This was a "boards alert" question from this lecure (which I think means it won't appear on our exam) but figured it might be good to remember*

Question 36

What is the difference in presentation between HUS and TTP?

Answer 36

TTP will have **altered mental status and fever**, HUS will not Both will have renal failure, hemolytic anemia, thrombocytopenia *Renal failure is usually not as bad in TTP; rarely requires dialysis*

Question 37

List 2 anti-fibrinolytic agents

Answer 37

Aminocaproic acid Tranexamic acid

Question 38

Deficiency of which clotting factors (4) will result in **elevated PTT and PT**?

Answer 38

FX FV Prothrombin (FII) Fibrinogen (FI)

Question 39

Which coagulation disorder? ## Footnote **No platelet aggregation when mixed with ristocetin**

Answer 39

Von Willebrand Disease

Question 40

What is the endogenous inhibitor of **Factor XIa?**

Answer 40

Protease Nexin 2

Question 41

Which thrombocytopenia is caused by antibodies against GP IIb/IIIa?

Answer 41

Immune thrombocytopenia purpura (ITP) *Glanzman thrombasthenia = hereditary mutation in GPIIb/IIIa*

Question 42

What is the difference in etiology of immune thrombocytopenia purpura in children vs. adults

Answer 42

* Children * Usually preceded by a viral illness * Self-limited * Bleeding is rare * Adults * Usually idiopathic * HIgh relapse rate * Treat if platelet count \<30,000 or actively bleeding

Question 43

What is the treatment for heparin-induced thrombocytopenia?

Answer 43

**Discontinue ALL heparin** (heparin, enoxaparin, fondaparinux) **Give direct thrombin inhibitor** (Agatroban or bivalirudin)

Question 44

List 3 clotting factor deficiencies **NOT** associated with bleeding? Which lab abnormality will be present?

Answer 44

Contact activation factors * Factor XII * High-molecular weight kininogen * Prekallikrein **Elevated PTT** *Results in elevated PTT but no bleeding*

Question 45

Which part of the clotting cascade is evaluated with PT?

Answer 45

Extrinsic and common

Question 46

Where is von Willebrand Factor stored? (2)

Answer 46

* Endothelial: **Weible-Palade bodies** * Platelets: **Alpha granules**

Question 47

List 4 manifestations of severe hemophilia A

Answer 47

* Spontaneous joint hemorrhage * Intramuscular hemorrhage * Intracranial hemorrhage * Serious bleeding after trauma or injury *Severe Hemophilia A = \<1% of normal FVIII*

Question 48

What platelet counts correspond with each level of thrombocytopenia? * Mild: * Moderate: * Severe:

Answer 48

* Mild: **100k-149k** * Moderate: **50k-99k** * Severe: **\<50k**

Question 49

List 2 functions of von Willebrand Disease

Answer 49

* Bind platelets to the endothelium * Binding protein for FVIII * *vWF carries FVIII; without it, VIII is rapidly degraded* * *Mutation in vWF presents like hemophilia A*