250/252 - 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

• Factor Xa and factor Va form a complex (mediated by calcium) that cleaves prothrombin (factor II) to thrombin (factor IIa).*
• Small amounts of prothrombin are activated by factor Xa alone. The resulting thrombin activates factor V, which then builds the complex with factor Xa, activating more thrombin in the process.*

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

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: type of thrombocytopenia involving the formation of autoantibodies against platelets.

Question 10

List 2 treatment options for immune thrombocytopenia purpura (ITP)

Answer 10

According to boards…

• IVIG
• Corticosteroid

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 pathologies:

Answer 14

• Antibodies
  
  • HIT
  • Drug-induced thrombocytopenia
  • Infection-related / immune
• Thrombotic microangiopathies (mechanical destruction?)
  
  • 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:
• Persistent:
• Chronic:

Answer 17

• Acute: < 3 months from dx
• Persistent: 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)

Caused by antibodies against GpIIb/IIIa

Question 20

Describe the pathophysiology of heparin-induced thrombocytopenia (HIT)

Answer 20

• IgG antibodies are made against the heparin-platelet factor 4 complex
• IgG-heparin-PF4 immune complex bind to platelets
• -> platelet activation and aggregation
• -> consumption of platelets AND formation of thrombi (clotting)

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 or ALK-1 gene

HHT: hereditary, systemic vasculopathy characterized by telangiectasia on the skin and mucosa, particularly in the area of the face (nose, lips, tongue)

Question 23

Which clotting factor cross-links fibrin

Answer 23

Factor XIII (Fibrin stabilizing factor)

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 recessive**

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 ## Footnote * 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 platelets** =\> **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

**HUS:** * hemolytic anemia * thrombocytopenia * renal failure **TTP:** * hemolytic anemia * thrombocytopenia * renal failure --\> *Renal failure is usually not as bad in TTP; rarely requires dialysis* * fever * altered mental status

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) (Common pathway)

Question 39

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

Answer 39

Protease Nexin 2

Question 40

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

Answer 40

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

Question 41

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

Answer 41

* 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 42

What is the treatment for heparin-induced thrombocytopenia?

Answer 42

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

Question 43

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

Answer 43

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

Question 44

Which part of the clotting cascade is evaluated with PT?

Answer 44

Extrinsic and common

Question 45

Where is von Willebrand Factor stored? (2)

Answer 45

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

Question 46

List 4 manifestations of severe hemophilia A

Answer 46

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

Question 47

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

Answer 47

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

Question 48

List 2 functions of von Willebrand factor

Answer 48

* 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*