12-1: 1/6 - Coagulation Disorders

Front 1

What are the three main events of primary hemostasis?

Back 1

Vasoconstriction

Platelet adhesion (platelet-vessel wall) and aggregation (platelet-platelet)

Formation of unstable platelet plug

Front 2

How is vasoconstriction achieved in primary hemostasis?

What is the vasoconstriction in response to?

Back 2

Vessel injury!

Vasoconstriction caused by:
-Local reflexive neurogenic response
-Endoth cells releasing endothelin
-Platelets relasing Thromboxane A2

Front 3

How is platelet adhesion achieved in primary hemostasis?

Back 3

Injured vessel exposes subendothelial matrix proteins

Exposes collagen; vWF sticks to collagen (which carries factor VIII); and platelet binds to vWF via GpIb receptor

Front 4

What is Bernard Soulier syndrome?

Back 4

Defect/deficiency in GpIb receptor

Front 5

What is the platelet release reaction? When does it occur?

Back 5

When platelets adhere to damaged endothelium, undergo shape change and RELEASE REACTION, whereby agonists are released to recruit more platelets (AGGREGATION)

Front 6

Once a platelet is bound to vWF, how does it aggregate with other platelets?

Back 6

GpIIb/IIIa receptor binds fibrinogen, which binds to otehr GpIIb/IIIa receptors on other platelets.

Front 7

What is Glanzmann's Thrombasthenia?

Back 7

GpIIb-IIIa deficiency/defect

Front 8

What two events allow for an unstable platelet plug to be stabilized, i.e., activate coagulation cascade?

Back 8

-Once platelet shape changes, there's an alteration of platelet phospholipid surface.

-The release of tissue factor from damaged endothelial cells

Both of these activate blood coagulation cascade and deposition formation of fibrin (secondary hemostasis)

Front 9

What is the extrinsic pathway and how does it lead to the production of fibrin?

Why is this reaction localized?

Back 9

Tissue factor released from damaged endothelial cells and Factor VII released.

This activates the COMMON PATHWAY, which allow Factor X and Factor V to convert Prothrombin (Factor II) to Thrombin (Factor IIa)--10 divided by 5 is 2.

Thrombin converts fibrinogen to fibrin!

Extrinsic PW also activates Factor IX in the intrinsic PW which also activates common PW.

THIS ONLY HAPPENS ON ACTIVATED PLATELET PHOSPHOLIPID SO IT IS NOT A SYSTEMIC RESPONSE.

Front 10

Prothrombin Time test:
What is it?
Normal value?
What does it measure?
How are the results standardized between labs?

Back 10

Add Tissue Factor Equivalent to plasma and measure how long blood takes to clot

Normal PT ~12 seconds

Allows for assessment of EXTRINSIC PW

Time is then standardized against International Normalized Ratio (INR); normal INR is 1

Front 11

What ion is necessary for the extrinsic, intrinsic, and common pathways to occur?

Back 11

Ca2+

Front 12

What is a Partial Thromboplastin Time?
How is it performed?
Normal value?
What does it measure?

Back 12

PTT assesses intrinsic pathway through blod clotting test:

Contact-activating substances added to plasma and measure how long clot takes to form

Normal PTT ~30 sec

Front 13

What three things are required for fibrinogen conversion to fibrin (and cross-linking)?

Back 13

Thrombin
Factor XIII
Ca2+

Front 14

What is the role of plasmin?
What is its proenzyme form?
What converts it to its activate form?

Back 14

Limits extent of clot formation by cleaving fibrin (fibrinolysis)

TPA activates plasminogen to plasmin.

Front 15

List the required factors and appropriate tests for the following:
Common PW
Extrinsic PW
Extrinsic PW

Back 15

Common: X, V, II (10/5=2)

Extrinsic (PT--fewer factors, fewer letters): VII, TF (VII is all alone, EXtricated from the rest)

Intrinsic (PTT--more factors, more letters): VIII, IX, XI, XII (INcludes all the rest)

Front 16

Hemophilia A:
Factor involved
What tests will be abnormal?
Pattern of inheritance.
Mutation involved

Back 16

Deficiency of Factor VIII
PTT
X-linked recessive (females are carriers!)

45% of mutations = inversion of Factor VIII gene at intron 22***

Front 17

Factor ___ is carried by vWF.

Back 17

VIII

Front 18

Hemophilia B:
Factor Involved
What tests will be abnormal?
Pattern of inheritance.

Back 18

Factor IX
Abnormal PTT
X-linked recessive

Front 19

Clinical features of hemophilia.

Back 19

Mucocutaneous bleeding

Hemarthrosis: joint bleeds (knees, elbows); can lead to deformity

Muscle bleeds

Intracranial bleeding

Front 20

In patients with hemophilia, is excessive bleeding seen after minor cuts or abrasions? Why or why not?

Back 20

No, primary hemostasis is normal in hemophilia. Secondary hemostasis is abnormal.

Can plug up hole.

Front 21

How are hemophilia A and B distinguished clinically?

Back 21

Measure factor VIII, and IX levels.

Factor VIII low in hemophilia A; Factor IX low in hemophilia B.

Front 22

Hemophilia:
Treatment

Back 22

-Recombinant factor replacement to about 30% activity

-Prophylaxis replacement

Front 23

DDAVP (desmopressin):
Treatment role in hemophilia
Treatment role in VW Disease

Back 23

Causes release of factor VIII from endothelium and can be used for low-risk bleeding in patients with mild hemophilia.


Causes release of stored vWF from endothleium in pts w/VW Dz.

Note, this only works acutely bc all Factor VIII/vWF will be used up.

Front 24

Von Willebrand Disease:
What is it?
Why does it affect both primary and secondary hemostasis?

Back 24

Abnl/deficient VWF protein

VWF impt for platelet adhesion and is a carrier for FVIII

Front 25

How is VW Disease differentiated from hemophilia A clinically?

Back 25

In addition to low factor VIII levels, patients will have low vWF levels.

Front 26

VW Disease:
Type I
Type II (general)
Type II A
Type II B
Type II N
Type III

Back 26

Type I: deficiency of VWF (most common)

Type II: qualitative defect of VWF:
IIA: no high molecular multimers

IIB: VWF binds platelets super well and use up platelets and large multimers (THROMBOCYTOPENIA)

IIN: VWF can't bind factor VIII (looks like hemophilia)

Type III: rare; severe or even complete VWF deficiency

Front 27

Utility of ristocetin in diagnosis of VW Disease.

Back 27

Upon administration, there will be defective platelet aggregation in pts w/VW Dz.

Platelet aggregation is the normal response for ristocetin (bc requires large multimers of vWF)

Front 28

VW Disease:
Treatment

Back 28

High-purity vWF concentrates with pts w/very low vWF

Factor VIII replacement

Front 29

Vitamin K:
Role in coagulation
Site of production in body
Requirements for production

Back 29

Required for final synthetic step for factors II, VII, IX, and X

Produced by bacterial gut flora

Vit K is fat soluble and requires bile salts for absorption

Front 30

Warfarin:
MOA

Back 30

Blocks reduction of vitamin K epoxide-->vitamin K so it can't participate in final step of coagulation

Front 31

Vitamin K Deficiency:
Causes
Test Abnormalities
Treatment

Back 31

Poor nutrtion, malabsorption, anything affecting GI flora (broad spectrum abx)

Elevations in PT, can see elevations in PTT with more severe deficiencies

Tx: Vit K supplementation

Front 32

Hemorrhagic Disease of Newborn:
Cause

Back 32

Vitamin K deficiency secondary to:
-No bacterial colonization
-Low Vit K in breast milk
-Liver still developing (liver responsible for production of coagulation factors)

(prophylaxis dose of vit K given at birth)

Front 33

All coagulation factors are made by ______ except ____, which is made in ____.

Back 33

All coag factors made by liver except factor VIII, which is made by endothelium and bound to vWF.

Front 34

Effect of liver disease on PT and PTT. Why?

Back 34

Will see elevations in both PT and PTT because liver makes clotting factors measured by both tests.

Front 35

Disseminated Intravascular Coagulation:
Pathophys
Test Abnormalities

Back 35

Overwhelming stimulus to coaguln system (ex: bacterial sepsis)-->massive triggering of blood coagulation cascade

Paradoxically results in bleeding (consumptive coagulopathy) bc:
-Dec'd clotting factors
-Dec'd platelets
-Dec'd fibrin production (inc'd fibrinolysis, inc'd fibrin splid prods--D-Dimer)

Elevated PT and PTT

Front 36

How can liver disease be distinguished from disseminated intravascular coagulation?

Back 36

Similarities:
Inc PT and Inc PTT
Dec platelets
Inc'd Fibrin Degradation Products (D-Dimer?)
Dec'd factor levels

DIFFERENCE:
FVIII normal in liver disease (only factor NOT made in liver)
FVIII depleted in DIC

Front 37

List the three coagulation factor inhibitors.
What do they promote?

Back 37

Anti-thrombin III
Prot C
Prot S

Promote fibrinolysis

Front 38

Factor V Leiden:
Pathophysiology
Testing

Back 38

Point mutation in factor V leading to Activated Protein C Resistance (Prot C promotes fibrinolysis)

Resistance to APC-->unopposed clotting

Testing:
PCR for point mutation at 506 on Factor V

OR

Test for APC resistance:
Perform PTT by adding APC to tube. If mutation present, PTT will not increase as expected.

Front 39

Activated Protein C:
Function

Back 39

Inactivates Factor Va, and VIIIa

Front 40

What is the most common inherited cause of increased risk of venous thrombosis?

Effect of heterozygous and homozygous genotypes on increased risk.

Back 40

Factor V Leiden

However, 90% of persons who are heterozygous for FVL will never have clot!!! DOn't need lifelong anticoaguln.

50% of homozygotes will have clot by age 50.

Front 41

Protein S:
Function
Risk of thrombosis with deficiency

Back 41

Cofactor for Protein C; needed to activate prot C to inactivate FV and FVIII

50% will have thrombosis by age 35!

Front 42

Protein C Deficiency:
Effects (general)
Effects in infants

Back 42

50% will develop clot by age 50!

Can result in Neonatal Purpura Fulminans (Presents as DIC at birth. Tret w/Protein C concentrate and anticoaguln)

Front 43

Warfarin Skin Necrosis:
Pathophys
Treatment

Back 43

Patients with Prot C Def have further decrease in Prot C upon administration of warfarin (bc warfarin inhibits protein C)

Results in paradoxical coagulation and dermal vessel occlusion

Tx: vit K (counteracts warfarin's effects) and heparin (to prevent further coagulation)

Front 44

This deficiency may present with migraines or mesenteric vein thrombosis.

If this patient were a woman, what would exacerbate this deficiency?

Back 44

Protein S deficiency

Pregnancy and those on OCP's have lower protein S levels.

Front 45

A child with purpura fulminans in setting of varicella infection, is likely to have ________.

Back 45

An auto-ab against Prot S

Front 46

Heparin:
MOA

Back 46

Heparin boosts antithrombin activity by 1000x

Antithrombin = anticoagulant

When heparin added, AT binds and inactivates clotting enzymes (II, X, XII, XI, IX)

Front 47

Women who are pregnant or post-partum are at greatest risk of this deficiency.

Back 47

Antithrombin Def

Often need tx w/heparin or AT to prevent clot

Front 48

Patients with nephrotic syndrome are at risk for renal vein thrombosis because ______.

Back 48

They lose antithrombin in the urine.

Front 49

Antithrombin deficiency:
Treatment

Back 49

Heparin
Estrogens

Front 50

Protein C Deficiency:
Treatment

Back 50

Warfarin

Front 51

Protein S Deficiency:
Treatment

Back 51

Warfarin
Estrogens

Front 52

Prothrombin Gene Mutation (G20210A):
Effects

Back 52

Mutation leading to inc'd levels of prothrombin

Weak risk factor for cloting (like FVL), so no need for lifelong anticoaguln

Front 53

A woman with cerebral vein thrombosis while pregnant (or on OCPs) likely has __________.

Back 53

Prothrombin Gene Mutation

Front 54

Antiphospholipid Anitbodies:
Pathophys
Presents with [bleeding/clotting]

Back 54

Ab's directed against phospholipids, clotting doesn't occur bc have no phospholipids to activate cascade

CLOTTING; it's paradoxical. no one knoooows why.

Front 55

This condition has an elevated PTT that corrects with viper venom. Why?

Back 55

Antiphospholipid Ab's

Venom uses excess phospholipid to provide clotting cascade medium (can't have clotting without phospholipids. pts w/auto-ab's against phospholipids won't have phospholipids for clotting to occur on!)

Front 56

Venous Thrombosis:
Virchow's Triad
Utility of D-Dimer assay

Back 56

1) Hemostasis
2) Hypercoag--inherited or ac'd
-Vessel wall damage

Can lead to DVT or PE

Negative D-dimer usually r/o DVT and PE

Front 57

Arterial thrombosis is most commonly due to _________.

Pathophys?

Back 57

Atherosclerosis-->plaque rupture and endothelial injury exposing collagen and TF

-->platelet nidus forms, adhere, aggregate

Front 58

Criteria for weak vs strong thrombophilia.

How does screening differ between the two?

Back 58

Weak: 1st clot after age 50 and no famhx clotting

Strong: 1st clot before age 50 or hx of recurrent clots
or 1st degree relative w/clot before age 50

If weak, screen for APC-R, Prothrombin Mutation, Antiphospholipid Ab's

If strong: all of the above, in addition: Antithrombin Def, Prot S Def, Prot C Def