Hemostasis and Thrombosis/Coagulation

Question 1

Describe the differences among primary, secondary and tertiary hemostasis

Answer 1

primary - platelet aggregation and forming a “plug”

secondary - stabilizing the plug and adding fibrin/coag cascade

tertiary - breaking the plug down during repair (via plasmin)

Question 2

Under normal circumstances, endothelial cells secrete ___ which inhibits platelet function, and ___ which is a vasodilator to maintain blood flow and prevent clotting. ___ is also produced and converts plasminogen to plasmin which __

Answer 2

Under normal circumstances, endothelial cells secrete prostaglandin I2 (prostacyclin) which inhibits platelet function, and nitric oxide which is a vasodilator to maintain blood flow and prevent clotting. Tissue plasminogen activator (TPA) is also produced and converts plasminogen to plasmin which breaks down clots

Question 3

TFPI works by directly inhibiting factor __ and through TF, inhibits factor __ in the coag cascade

Answer 3

TFPI works by directly inhibiting factor 10a and through TF, inhibits factor 7 in the coag cascade

Question 4

On the surface of the endothelial cells are ___, which inhibits thrombin and factor 10a, and ___, which does what?

Answer 4

On the surface of the endothelial cells are heparan sulfate, which inhibits thrombin and factor 10a, and thrombomodulin, which binds to thrombin, ultimately leading to the breakdown of factors 5a and 8a

Question 5

Describe how thrombomodulin works. What are the roles of Protein C and S?

Answer 5

(see image below)

Question 6

Inside the dense granules of platelets are calcium, ___, and ___.

alpha granules contain von-Willibrand’s factor, ___, ___, fibrinogen and fibronectin, ___ and PF4

Answer 6

Inside the dense granules of platelets are calcium, ATP/ADP, and serotonin.

alpha granules contain von-Willibrand’s factor, platelet derived growth factor (PDGF), P selectin, fibrinogen and fibronectin, TGF-B, PF4, Protein S, PAT 1 and procoagulant factors

Question 7

What are the functions of the following factors released by platelets?

(vWF, fibrinogen, fibronectin, thrombospondin, P-selectin, GPIIb/IIIa)

(Factor V, XI and XIII)

(Protein S)

(Plasminogen activator inhibitor-1)

(Platelet Factor-4)

(Platelet derived growth factor)

(TGF β)

Answer 7

Question 8

The first step in forming a blood clot is ___, mediated by ___ which is released by endothelial cells

Answer 8

The first step in forming a blood clot is reflex vasoconstriction, mediated by endothelin which is released by endothelial cells

Question 9

The 2nd step in forming a blood clot is ___, which is mediated by ___ and ___ that are in the subendothelial matrix. Both of these help to tether the platelet to the damaged vessel

Answer 9

The 2nd step in forming a blood clot is platelet adhesion, which is mediated by vWF (bound by GPIb/9) and collagen (GP6) that are in the subendothelial matrix. Both of these help to tether the platelet to the damaged vessel

Question 10

Platelet activation and degranulation are mediated by ___ whose conformational change exposes the binding sites for vWF and fibrinogen. ___ and ___(platelet agonist) are also released

Answer 10

Platelet activation and degranulation are mediated by GPIIb/IIIa whose conformational change exposes the binding sites for vWF and fibrinogen. ADP and thromboxane (platelet agonist) are also released

Question 11

Step 4 in forming a blood clot is ___, which involves platelet binding to fibrinogen and can be inhibited by aspirin

Answer 11

Step 4 in forming a blood clot is platelet aggregation, which involves platelet binding to fibrinogen and can be inhibited by aspirin

Question 12

Describe a platelet aggregation study

What are 3 other ways you could measure platelet activity in a pts sample (measuring platelet quantity)?

Answer 12

• CBC: # of platelets
• Peripheral smear
• Bone marrow biopsy

Platelet aggregation study: Platelets in plasma >> measure baseline light transmission >> + platelet agonist >> wait for clot to form then measure second light transmission >> difference between initial and final transmission = amt of platelet clumping = degree of platelet function

Question 13

Describe the platelet function assay. How do you interpret the results of the study?

Answer 13

Put sample of blood thru small opening surrounded by biologically active membrane; membrane is coated w/ collagen + adp/epinephrine (factors that help w/ clot formation) and a clot forms

You do the collagen/epi test first.

Normal closing time for collagen/epinephrine test= no defect; If closing time is prolonged, then you do the collagen/ADP test

If closing time for col/adp test normal, problem is aspirin induced platelet dysfunction (probably tell this from patient’s history); If closing time = prolonged, DDx = thrombocytopenia (check platelet count) or some other defect not due to aspirin

Question 14

Match the coagulation factors to their names:

I

Fibrinogen

Prothrombin

III

Thromboplastin

II

IV

Calcium

Answer 14

I Fibrinogen

II Prothrombin

III Thromboplastin

IV Calcium

Question 15

Number the following coagulation factors:

Proaccelerin

Same as V

Proconvertin

Antihemophilic

Answer 15

Proaccelerin: V

Same as V: VI

Proconvertin: VII

Antihemophilic: VIII

Question 16

Name the following coagulation factors:

IX

X

XI

XII

XIII

Answer 16

IX Christmas

X Stuart-Prower

XI Plasma thrombo-plastin antecedent

XII Hageman

XIII Fibrin stabilizing

Question 17

Outline the intrinsic pathway of the coag cascade

Answer 17

Question 18

Outline the extrinsic pathway of the coag cascade

Answer 18

Question 19

Describe the role of Calcium (aka Factor IV) in the coag cascade. What is the function of thrombin in the coag casade?

Answer 19

Calcium has a net + charge; PL scramblase creates negatively charged phosphotidyl serine rafts that bind to one of calcium’s +ve charges, and the coagulation factors (also –vely charged, can bind to the other +ve charge)

(basically calcium helps to bind the coagulation factors to the platelet membrane)

Thrombin acts as an activator >> promotes positive feedback

Question 20

Factors 2, __, __ and 10 are Vitamin K dependent

While the rest of the coag factors are made in the liver, only factor __ is made by endothelial cells

Answer 20

Factors 2, 7, 9 and 10 are Vitamin K dependent (remember 7+2=9 and 10 is Kind)

While the rest of the coag factors are made in the liver, only factor 8 is made by endothelial cells

Question 21

The prothrombin (PT) time test measures the activation of which pathway of thecoag cascade? Which factors are being measured in the test?

Briefly describe the test

Answer 21

Extrinsic (remember PT = 2 letters, extrinsic has 2 i’s in it)

Fcators 7, X, V, II and fibrinogen

(see below)

Question 22

Which pathway of the coag cascade does the PTT test?

The test will be prolonged with ___ and any other factor deficiency except __ and __

Answer 22

Intrinsic and common

Heparin; VII and XIII

Question 23

Thrombin time measures the conversion of ___ to ___ upon addition of ___ to a patient’s plasma sample

A prolonged thrombin time would suggest a deficiency in ___

Answer 23

Thrombin time measures the conversion of fibrinogen to fibrin upon addition of thrombin to a patient’s plasma sample

A prolonged thrombin time would suggest a deficiency in fibrinogen

Question 24

Patients lacking __, __, or __ have a long aPTT but no bleeding

Patients lacking FXI have a ___ aPTT and __

Patients lacking ___ or ___ have an equally long aPTT and ___ bleeding

Answer 24

• Patients lacking FXII, HMK, or PK have a long aPTT but no bleeding
• Patients lacking FXI have a long aPTT and may or may not have bleeding
• Patients lacking FVIII or FIX have an equally long aPTT and serious bleeding

Question 25

Describe the mixed study to determine the presence of a factor deficiency or the presence of a factor inhibitor. How would you interpret the results of the test?

Answer 25

(see image below) Mix patient plasma (sans deficiency) w/ normal plasma \>\> if clotting time is prolonged, there’s a factor inhibitor (right, b/c you should see normal clotting time a longer time suggests that they’re inhibitors in the pt sample that are blocking the clotting process) Mix patient plasma (+ clotting factor deficiency) w/ normal plasma \>\>if clotting time is normal or goes down to near normal, this suggests a clotting factor deficiency (which makes sense because if there is a deficiency, the only reason we’re able to form a clot is because of the normal plasma which has normal levels of clotting factors in it)

Question 26

Is there any way to measure how all the parts of the coagulation system work together? Explain how this works.

Answer 26

Sure, the #TEG Basically the pin is spun until the clot forms and restricts spinning of pin. The pressure against the pin = tracing

Question 27

Match the following conditions and tracings

Answer 27

Question 28

The disorders of platelet dysfunction include ___ and \_\_\_

Answer 28

Platelet defects and von Willibrands disease

Question 29

Describe the clinical presentation of platelet defects

Answer 29

Petechiae (small, unraised patches on skin or mucus membranes) Mucosal bleeding Bruising

Question 30

\_\_\_, also known as low platelet count is a qauantitative platelet defect that can arise from decrased marrow production of platelets, increased consumption or splenic sequestration

Answer 30

**Thrombocytopenia**, also known as **low platelet count** is a quantitative platelet defect that can arise from **decrased marrow production of platelets**, **increased consumption** or **splenic sequestration**

Question 31

\_\_\_ and ___ are examples of inherited qualitative platelet disorders Which of these is characterized by a deficiency in GP1b, resulting in impaired platelet adhesion? Which of these is characterized by GPIIb/IIIa deficiency, leading to impaired platelet aggregation?

Answer 31

**Bernard-Soulier syndrome** and **Glanzmann thrombasthenia** are examples of inherited qualitative platelet disorders **Bernard-Soulier syndrome** is characterized by a **deficiency in** **GP1b**, resulting in **impaired platelet adhesio**n? **Glanzmann thrombasthenia** is characterized by **GPIIb/IIIa** deficiency, leading to **impaired platelet aggregation**?

Question 32

In Bernard-Soulier syndrome, ___ is dificient, which impairs platelet adhesion due to inability to bind vWF In Glanzmann thrombasthenia, we can't bind ___ due to adeficienciy in GPIIb/IIIa, thus impairing platelet \_\_\_

Answer 32

In **Bernard-Soulier syndrome,** **GP1b** is dificient, which impairs **platelet adhesion** due to **inability to bind vWF** In G**lanzmann thrombasthenia,** we can't bind **fibrinogen** due to a deficienciy in **GPIIb/IIIa**, thus impairing **platelet aggregation**

Question 33

Type I and 3 von Willebrand's disease are characterized by a (defect/deficiency) in ___ vWF, resulting in impaired platelet adhesion Type 2 von Willebrand's disease is characterized by a (defect/deficiency) in ___ vWF, resulting in impaired platelet adhesion

Answer 33

**Type I and 3** von Willebrand's disease are characterized by a **deficiency** in vWF, resulting in impaired platelet adhesion **Type 2** von Willebrand's disease is characterized by a **defect** in vWF, resulting in impaired platelet adhesion

Question 34

What kind of graphs would you expect to see in a platelet aggregation study to distinguish between Bernard-soulier syndrome and Glanzmann thrombastenia?

Answer 34

Question 35

How does aspirin work to prevent platelet aggregation?

Answer 35

Aspirin inhibits COX which mediates the production of prostaglandins (PGH2) that later become thomboxane, which is necessary for platelet aggregation

Question 36

Besides its role in platelet aggregation, von Willebrand's factor also does what with factor 8? What is the inheritance pattern of vW disease? T/F: vW disease is the most common inherited bleeding disorder

Answer 36

Binds factor VIII and extends its halflife/prevents its inactivation Autosomal dominant Truth

Question 37

How would you treat von Willebrand's disease? What kind of results would you expect with PTT,PT and ristocetin tests?

Answer 37

Give desmopressin (DDavp) which increases vWF release from Weibel-Palade bodies PTT: increased; PT: normal; Ristocetin: abnormal

Question 38

Types 2A and 2M vW disease both involve a ___ vWF-dependent platelet adhesion, with type __ having deficient HMW multimers and type ___ having normal levels of multimers

Answer 38

Types 2A and 2M vW disease both involve a **decreased** vWF-dependent platelet adhesion, with **type 2A** having **deficient HMW multimers** and **type 2M** having **normal levels** of multimers

Question 39

Type ___ vW disease is a partial vWF deficiency, whereas type ___ vW disease is a complete deficiency

Answer 39

**Type 1** vW disease is a **partial vWF deficiency**, whereas **type 3** vW disease is a **complete deficiency**

Question 40

Type 2B vW disease involves increased affinity for which protein? Type 2N involves patients presenting hemophilia symtpoms because?

Answer 40

**Type 2B** vW disease involves increased affinity for **GPIb alpha** **Type 2N** involves patients presenting hemophilia symtpoms because patients can’t prevent **deactivation of factor 8** since they have **decreased vWF binding affinity for factor 8** (inheritance pattern doesn’t fit hemophilia though)

Question 41

What are the ways in which you could test for vW disease?

Answer 41

Check vW antigen level Measure factor 8 activity Measure vWF activity using ristocetin Multimer assay

Question 42

PT is used to monitor \_\_\_, whereas PTT is used to monitor \_\_\_

Answer 42

PT is used to monitor warfarin, PTT is used to monitor heparin

Question 43

Disease of secondary hemostasis include \_\_\_, anti-coagulation, and \_\_\_

Answer 43

Disease of secondary hemostasis include Vitamin K deficiency, anti-coagulation, and hemophilia (genetic/acquired)

Question 44

Common causes of prolonged PT include Vit K deficiency, \_\_\_, ___ and DIC

Answer 44

Common causes of prolonged PT include Vit K deficiency, warfarin, liver disease and DIC

Question 45

How does warfarin work to block clot formation?

Answer 45

Clotting factors have glutamate residue, which becomes carboxylated (gives clotting factor negative charge necessary for binding calcium) Warfarin blocks effects of epoxide reductase (which recycles Vit K back to functional form so we can get carboxyl group to bind calcium) Inability to bind calcium \>\> can’t proceed with clotting cascade

Question 46

Common causes of prolonged PTT include factor defects, esp those in factors \_\_\_, \_\_\_, ___ and \_\_\_; heparin use; antiphospholipid antibody and DIC

Answer 46

Common causes of prolonged PTT include factor defects, esp those in **factors 8, 9, 11** and **12**; **heparin use**; **antiphospholipid antibody** and **DIC**

Question 47

Primary targets of heparin are factor ___ and \_\_\_, and secondary targets are factor ___ and \_\_\_ How does heparin work?

Answer 47

Primary targets of heparin are factor 12a and 11a, and secondary targets are factor 10a and thrombin Heparin inactivates thrombin and activated factor X (Xa) through antithrombin (AT)-dependent mechanism

Question 48

What patterns of PT and PTT results would you see in defects in the extrinsic, intrinsic or common pathway? which factors are affected?

Answer 48

Question 49

Explain what happens with disseminated intravascular coagulation What are the downstream effects of DIC and how do they occur?

Answer 49

Systematic activation of clotting system due to existing illness (in this case, clotting is activated by sepsis, which the body responds to by activating inflammatory mechanisms that then shut down anti-coagulation mechanisms so clotting is constantly on) End organ damage due to clot travelling to smaller and smaller vessels, resulting in occlusion, and bleeding due to platelet depletion (coz we're clotting so much)

Question 50

Why would you see prolonged thrombin time, PTT and PT in the case of DIC?

Answer 50

You're using up too many of your platelets with these pathologic clots that you're forming so your fibrinogen drops, which prolongs all of these measures (in other ords, b/c you're clotting so much, your levels of fibrinogen and platelet ct drop, which prolongs all those test times)

Question 51

Morphologically, what kinds of cellswould you see in a smear of a pt who has DIC?

Answer 51

Helmet cells and schistocytes

Question 52

\_\_\_ is an X linked recessive disorder of Factor 8 caused by a partial inversion of intron 22 on the X chromosome Hemophilia B (aka Christmas disease) is caused by a deficiency in Factor __ due to a missense mutation.

Answer 52

Hemophilia A (Ate rHymes with 8) Factor 9 (remember factor 9 is Christmas factor; also if you turn 9 around and add a bottom hump, it looks like a B)

Question 53

\_\_\_ deficiency presents with milder symptoms compared to Hemophilia A and B, and is an AR disorder Patients w/ ___ deficiency experience delayed bleeding and have NORMAL PT and PTT. (why are these both normal?)

Answer 53

factor 11 deficiency factor 13 deficiency. Both tests measure variables that are outside of factor 13's function/activation so both values will be normal

Question 54

Factor __ dificiency arises from consanguinity and can be combined w/ factor 7 deficiency, whose symptoms are unrelated to factor 7 levels Contact factor deficiency is a deficiency is factor \_\_, HMWK or prekallikrein, and is characterized by long PTT w/o clinical bleeding

Answer 54

**Factor V** dificiency arises from consanguinity and can be combined w/ factor 7 deficiency, whose symptoms are unrelated to factor 7 levels Contact factor deficiency is a deficiency is **factor XII, HMWK or prekallikrein**

Question 55

One key characteristic of ___ deficiency is umbilical cord hemorrhage

Answer 55

Fibrinogen deficiency

Question 56

Treating hemophilia w/ factor 8 concentrates can result in \_\_\_, preventing the use of factor 8 when treated with it again \_\_\_ is an autoimmune disorder that results from antibodies against phospholipid-binding proteins and is characterized by thromboembolic events and pregnancy morbidities

Answer 56

Acquired factor 8 inhibitors (antibodies against factor 8) Antiphospholipid syndrome

Question 57

Some antibodies seen in APS are anti-\_\_\_ and \_\_\_, which normally bind the phospholipid membrane of platelets and inhibit platelet aggregation

Answer 57

Anti-cardiolipin and anti-beta 2 glycoprotein

Question 58

The lupus anticoagulant phenomenon describes what? How would you test for lupus anticoagulant?

Answer 58

Prolongation of clotting times in vitro but thrombosis in vivo Basically do the same corrected mixing test and if it fails, that suggests the presence of an inhibitor. You woulc also add phospholipid to establish phospholipid dependence (so if the time shortens upon addition of phospholipids = phospholipid dependence)

Question 59

Common causes of inherited thrombophilia ass'd with low bleeding risk include ___ (Activated Protein C Resistance) and \_\_\_

Answer 59

Common causes of inherited thrombophilia ass'd with low bleeding risk include factor V leiden (Activated Protein C Resistance) and Prothrombin 20210 (Factor V Leiden is a proclotting disease - Factor V resistant to Activated Protein C so clotting cascade doesn't stop)

Question 60

Protein __ and ___ deficiency result in an inability to inactivate factors 5 and 8

Answer 60

**Protein C and S** deficiency result in an inability to inactivate factors 5 and 8

Question 61

\_\_\_ deficiency results in recurring venous thrombosis (fialure to inhibit factors 2, 9, 10, 11, 12) \_\_\_\_ disorder is caused by a mutation in the thrombin gene (G to A)that results in increased production of thrombin

Answer 61

Antithrombin III deficiency results in recurring venous thrombosis (fialure to inhibit factors 2, 9, 10, 11, 12) Prothrombin G20210A disorder is caused by a mutation in the thrombin gene (G to A)that results in increased production of thrombin