Bl Week 2 Objective 2

Front 1

How can you generally classify the pathophysiology of a bleeding disorder?

Back 1

1. Hematologic
2. Non-hematologic

Front 2

How can you classify the pathophysiology of hematologic bleeding disorders?

Back 2

1. Platelet abnormalities
2. Coagulation factor abnormalities

Front 3

What are the two main pathophysiologic classifications of platelet disorders?

Back 3

1. Qualitatitive
2. Quantitative

Front 4

What are the two main pathophysiologic classifications of clotting factor disorders?

Back 4

1. Deficiency
2. Inhibitor present

Front 5

How can you further classify qualitative platelet abnormalities?

Back 5

1. congenital
2. acquired

Front 6

How can you further classify quantitative platelet abnormalities?

Back 6

1. increased consumption
2. decreased production
3. sequestration via spleen

Front 7

By what three primary means does the spleen sequester platelets?

Back 7

1. Infiltrative
2. Congestive (ie. increased blood flow to spleen means more platelets stay there)
3. Reactive (spleen reacts to and destroys platelets extravascularly ie. due to autoAb on platelet surface)

Front 8

To what can you attribute clotting factor deficiencies?

Back 8

1. Increased consumption
2. Decreased production

Front 9

What does ITP stand for? What is it analogous to in RBCs?

Back 9

IMMUNE (or idiopathic) thrombocytopenic purpura.
Autoimmune hemolytic anemia.

Front 10

Under which mechanistic classification of bleeding disorders would you categorize ITP?

Back 10

Quantitative platelet disorder - due to increased consumption

Front 11

ITP can be either chronic or acute. True or False?

Back 11

True.
1. Chronic ITP is more typical in adults (15-50)- escpecially women.
Usually idiopathic but can be seen with SLE, HIV, CLL, Hodgkin, AIHA.
Chronic ITP tends to relapse and remit.
2. Acute form seen in children.
Usually follows vaccination or infection with VZV or EBV.
5-10% of cases become chronic.

Front 12

What is the normal lifespan of a platelet? What is the lifespan in ITP?

Back 12

1. 7-10 days
2. few hours

** Megakaryocyte and platelet turnover are increased x5 to keep up with destruction of platelets

Front 13

What is the pathogenesis of ITP?

Back 13

IgG autoAb's attach to platelets which are then targeted for destruction in the spleen (and other parts of RES).

Front 14

ITP is associated with splenomegaly. True or False.

Back 14

FALSE. The spleen is not palpable unless there is another associated disease causing splenomegaly.

Front 15

Which other (more common) quantitative platelet disorders are due to increased consumption of platelets?

Back 15

1. HIT
2. DIC
3. HUS/TTP
4. Sepsis

Hint 15

Think 3 letter acronyms

Front 16

What is HIT?

Back 16

Heparin-induced thromboctyopenia

Front 17

How does HIT cause a comsumptive thrombocytopenia?

Back 17

Not due to direct action of drugs!
1. Immunogenic complex of PF4 (from alpha granules of platelet), Heparin and IgG binds to platelet surface.
2. Binding causes platelet activation, degranulation, and aggregation.
3. Promotes a severe thromboembolic predisposition.

Front 18

How are IgG-heparin-PF4 complexes cleared?

Back 18

Most are cleared extravascularly by RES.

If complement attaches before reaches RES, may be destroyed intravascularly.

Front 19

What is the incidence of HIT amongst patients exposed to heparin? When does HIT develop after initiation of heparin therapy?

Back 19

1-5% of patients exposed to heparin.
4-14 days after staring tx.

Front 20

DIC can be considered both a consumptive thrombocytopenia as well as a coagulopathy. True or false?

Back 20

True.

Front 21

What is the key event underlying the pathogenesis of DIC?

Back 21

increased activity of tissue factor (starts the extrinsic cascade)

Front 22

What is the general pathogenesis of DIC?

Back 22

1. Endothelial damage or entry of procoagulant material into circulation (ie. trauma, amniotic embolism, falciparum malaria, etc.)
2. Generalized platelet aggregation and widespread activation of coagulation.
3. Microthrombi in the circulation.
4. Leads to decrease in clotting factors, decrease in platelets, and increased fibrinolysis and fibrin degradation products which all contribute to bleeding.

Front 23

What is the main clinical presentation of DIC?

Back 23

-bleeding
-although 5-10% manifest with microthrombotic lesions (eg. gangrene of limbs, organ dysfunction)

Front 24

What is TTP, and to which group of disorders does it belong?

Back 24

Thrombotic Thrombocytopenic Purpura.
Thrombotic microangiopathies/ microvascular occlusive disorders.

Front 25

TTP can occur in which two forms?

Back 25

1. Familial
2. Acquired

Front 26

What is the cause of the familial form of TTP?

Back 26

Deficiency of ADAMTS13 metalloprotease.

Front 27

What is the role of ADAMTS13 metalloprotease?

Back 27

- cleaves ultra large VWF monomers into more functional forms

Front 28

Why does a ADAMTS13 deficiency produce thrombosis?

Back 28

- passing platelets adhere to ultra long VWF; increasing platelet aggregation produces large, occlusive platelet thrombi

Front 29

What causes the acquired form of TTP?

Back 29

Autoantibody to ADAMTS13 metalloprotease so can't break down VWF

Front 30

What is the traditional pentad of TTP symptoms?

Back 30

1. thrombocytopenia**
2. microangiopathic hemolytic anemia **
3. fever
4. neurologic abnormalities
5. renal failure

**must have for dx

Front 31

TTP is a medical emergency. True or false?

Back 31

TRUE! Only treated at VGH via plasma exchange.

Front 32

What is HUS?

Back 32

Hemolytic uremic syndrome

Front 33

How is HUS related to TTP?

Back 33

HUS is very closely related to TTP and leads to same symptoms, but has normal ADAMTS13 levels.

The trigger for HUS is toxin-mediated enothelial damage (eg. E.coli O157 toxin)

Front 34

What are are common underlying causes of coagulation factor abnormalities?

Back 34

1. VWD
2. hemophilia
3. Vitamin K deficiency
4. Factor deficiency due to liver disease
5. DIC
6. Warfarin use
7. Heparin use
8. Lupus anticoagulant

Front 35

What are the 2 main roles of VWF?

Back 35

1. Promote platelet adhesion to endothelium.
2. Carry factor VIII in the blood.

Front 36

What is Von Willebrand Disease (VWD)?

Back 36

Most common inherited bleeding disorder.
Characterized by reduced level or abnormal function of VWF - from point mutation or deletion. (Autosomal dominant with varying expression).
Usually mucous membrane bleeding - hemarthroses and muscle hematomas are rare.
Three types of VWD have been described.
In rare cases may develop spontaneously.

Front 37

What are the 3 types of hemophilia and which factor is deficient in each type?

Back 37

1. Hemophilia A (classic hemophilia) - deficiency of Factor VIII (X-linked)
2. Hemophilia B (Christmas disease) -deficiency of factor IX (X-linked)
3. Hemophilia C (Jewish hemophilia) -deficiency of factor XI (autosomal)

Front 38

What type of bleeds are associated with coagulopathies like hemophilia?

Back 38

DEEP tissue bleeds - ie, hemarthroses, hematomas (not mucosal).

Severity of bleed depends on level of factor activity.

Front 39

Which are the Vitamin K dependent clotting factors?

Back 39

II, VII, IX, X

Front 40

Why is vitamin K essential for factors II, VII, IX and X?

Back 40

These factors require Vit K dependent gamma carboxylation (post-translational) in order to be active

Front 41

What is the significance of gamma-carboxylated clotting factors?

Back 41

They can bind Ca2+ ions leading to a conformational change. They can then bind to the phospholipid membranes supplied by platelets at the site of injury. This ensures that fibrin formation occurs at site of injury and not in circulating blood (ie. localized response)

Front 42

What happens if you can't gamma carboxylate clotting factors II, VII, IX and X? Why might this be the case?

Back 42

Those clotting factors will be biologically inactive.

Due to a Vitamin K deficiency.

Front 43

Why might you have a vitamin K deficiency?

Back 43

1. inadequate diet
2. sm. intestine malabsorption (Crohn's etc.)
3. inhibition by drugs (Warfarin)
4. fewer Vit K synthesizing bacteria (newborns, antibiotic use, etc.)

Front 44

How does Warfarin affect hemostasis?

Back 44

Competitive inhibitor of Vitamin K. Blocks gamma-carboxylation therefore making factors II, VII, IX and X inactive.
People taking Warfarin must monitor their PT/INR to make sure they have the proper degree of clotting activity. (PTT will also be abnormal)

Front 45

How can liver disease affect hemostasis?

Back 45

1. Biliary obstruction can lead to impaired absorption of Vit K, and therefore decreased synthesis of factors II, VII, IX and X.
2. Hepatocellular disease can lead to deficiency of all factors.
3. Decreased thromobopoietin production by liver contributes to thrombocytopenia.
4. Hypersplenism from portal HTN leads to thrombocytopenia.
5. May develop DIC - due to release of thromboplastins from damaged cells, reduced concentrations of anti-clotting factors (antithrombin, Protein C), impaired removal of activated clotting factors, increased fibrinolytic activity.

Front 46

How does heparin contribute to hemostasis?

Back 46

Heparin is a potentiator of antithrombin III, which irreversibly inactivates factors XIIa, XIa, IXa, Xa, IIa (thrombin).
Heparin is not a coagulator itself - requires ATIII.
Heparin also impairs platelet function.

Front 47

What is the lupus anticoagulant?

Back 47

An anti-phospholipid antibody initially found in patients with SLE. (Do not need to have SLE to have lupus anticoagulant, and not all people with SLE have lupus anticoagulant).

Front 48

How might patients with lupus anticoagulant manifest clinically?

Back 48

Repeat miscarriages, thrombosis.

Front 49

Why is the term lupus anticoagulant a misnomer?

Back 49

1. Because most people with LA do not have SLE.
2. It is NOT an anticoagulant - rather, it causes thrombosis.

Front 50

Which lab test is commonly used to test for the lupus anticoagulant?

Back 50

PTT with mixing test.

Front 51

What is a mixing test?

Back 51

Looks for inhibitors to clotting factors. If a patient has a prolonged clotting time, then you can mix their blood with "normal" plasma, which should have clotting factors present. If the clotting time corrects, then you know that the extended time was due to a deficiency. If not, then there is an inhibitor present! (antibodies against specific factors, heparin, lupus anticoagulant, etc.)

Front 52

The lupus anticoagulant is the most common non-iatrogenic inhibitor. True or False?

Back 52

TRUE! If a drug is not responsible for inhibition, suspect this next.

Front 53

What is the pathophysiology of the lupus anticoagulant?

Back 53

Not entirely clear. Binds to platelets and proteins and stimulates thrombosis in vivo (including in placental vasculature leading to miscarriage).

Front 54

Lupus anticoagulant is an anticoagulant in vitro and a procoagulant in vivo. True or False?

Back 54

TRUE!

Front 55

If a patient has lupus anticoagulant and a prolonged PTT, then this is not an accurate reflection of clotting status. True or False?

Back 55

True. While in vitro, the PTT will be prolonged as the LA is acting as an anti-coagulant, in the patient, there is a tendency towards thrombosis!

Front 56

What is secondary thrombocytopenia?

Back 56

Low platelet count is secondary to some other disease or process. ie. something "external" happening to an otherwise normal marrow which can lead to a platelet production problem (usually other cell lines as well).

Front 57

What are common causes of secondary thrombocytopenia?

Back 57

1. metastatic cancers to the bone marrow.
2. chemotherapy.
3. {others: Paget's disease leading to bony trabeculae disrupting marrow; extensive granulomatous infiltration of marrow; storage disease filling up marrow with abnormal macrophages.}

Front 58

How does metastatic cancer lead to thrombocytopenia?

Back 58

Infiltrates the marrow and takes up space so that production of cell lines is inhibited.
(May be other abnormalities, ie. secretion of chemokines which suppress hematopoiesis).

Front 59

How does chemotherapy lead to thrombocytopenia?

Back 59

Chemotherapy kills any rapidly dividing cells, including benign cells. Benign cells such as marrow cells, hair follicle cells and those lining the GI tract are especially vulnerable.