Module 6 Ics

Front 1

Occurrence of arterial thrombosis is closely linked to...?

Back 1

atherosclerotic vessel disease

Front 2

Arterial thrombosis is epidemiologically assoc w/...?

Back 2

age
smoking
HTN
obesity
hyperlipidemias
DM
sedentary life style
specific coag factor levels (fibrinogen, factor VII)

Front 3

Acquired/genetic risk factors associated w/ arterial thrombosis?

Back 3

hyperhomocysteinemia

heparin induced thrombocytopenia

lupus anticoagulants

Front 4

Pathogenesis of arterial thrombosis involves?

Back 4

1. development arterial atherosclerosis

2. endothelial injury and lipid hypotheses

3. platelet activation and rheology of blood flow (shear stress)

4. loss of antiplatelet (NO, ecto-ADPase) and pro-fibrinolytic properties of normal endothelium

Front 5

The clinical presentation of arterial thrombosis depends on?

Back 5

1. The specific vascular bed involved

2. Acute vs. chronic nature of the arterial obstruction

Front 6

Venous thromboembolism (VTE) is a _____ disease in which the interaction of _____ and _____ risk factors determines likelihood of occurence.

Back 6

multicausal

acquired

genetic

Front 7

In contrast to bleeding d/o's, VTE is a ________ d/o.

Back 7

multigenic

Front 8

The factors involved in the development of a venous thrombi?

Back 8

VIRCHOW's TRIAD

1. Endothelial/vessel wall abnormalities
-- trauma/surgery
-- vasculitis/infection
-- atherosclerosis
-- others

2. Venous stasis
-- decreased mobility
-- vessel obstruction

3. Intrinsic "hypercoagulability" of the blood
ACQUIRED
-- inflamm states
-- Lupus-type anticoag and antiphospholipid syndrome
-- Reduced natural coagulants: DIC, nephrotic syndrome
-- Abnormal platelet fxn: myeloprolif d/o's, HIT w/ thrombosis syndrome
INHERITED
-- deficiency or abnormal platelet fxn

Front 9

Acquired conditions of Venous Stasis associated w/ VTE?

Back 9

1. bed rest/immobility (lower extremity casts)

2. Obesity

3. CHF

4. Venous obstruction/post-phlebotic syndrome

5. Advanced age

Front 10

Acquired conditions of endothelial/vessel injury assoc w/ VTE?

Back 10

1. trauma

2. surgery (espec hip and knee fracture/replacement)

3. vasculitis/infection

Front 11

Acquired conditions of intrinsic hypercoagulability associated w/ VTE?

Back 11

1. pregnancy
2. antiphospholipid Ab
-- lupus anticoag
-- anticardiolipin Ab
3. pharmacologic estrogen doses
-- oral contraceptives
-- hormone replacement therapy
4. malignancy
-- adenocarcinoma
5. heparin induced thrombocytopeia (HIT)
6. myeloprolif d/o's
-- polycythemia vera
-- essential thrombocytopenia
7. Nephrotic syndrome
8. Microangiopathic syndomes
-- DIC, TTP, HUS

Front 12

What are lupus anticoagulants (LAC)?

Back 12

Phospholipids/protein dependent Ab that inhibit IN VITRO coagulation
-- prolong aPTT in an inhibitor pattern (mixing studies do not correct)
-- can be neutralized by the addition of excess lipid or platelets
-- may also be assoc w/ thrombocytopenia

**do not require SLE dx
** are associated w/ arterial and venous thrombosis (NOT bleeding)

Front 13

What are antiphospholipid antibodies (APA)?

Back 13

They represent a larger category of phospholipid/protein dependent Ab which may not affect in vitro coag assays
-- detection of these Ab is relatively comon in general pop, and path signif is unclear unless high titers present or assoc w/ other autoAb or evidence of antiphospholipid antibody syndrome

Front 14

What is antiphospholipid antibody syndrome?

Back 14

presence of antiphospholipid Ab (LAC or ACA) in assoc w/ syndrome of:
-- arterial or venous thrombosis
-- recurrent fetal wastage
-- thrombocytopenia

May occur w/ underlying SLE or no assoc condition (primary syndrome)

Front 15

What is heparin induced thrombocytopenia (HIT)?

Back 15

Induced by heparin therapy

EARLY:
-- 1 to 3 days
-- mild thrombocytopenia which is usually of no pathological significance

LATE:
-- 5 to 14 days
-- immune response to heparin
-- moderate to severe (>50% reduction platelet count) thrombocytopenia which may be assoc w/ arterial or venous thrombosis

**dx assoc w/ very high 30 day mortality and occurrenc of life or limb threatening thrombotic episodes

Front 16

What is the mechanism of HIT?

Back 16

heparin induces an immunologic response that generates Ab that recognize platelet factor 4 (PF4)-heparin complex

-- PF4 is a platelet protein that binds w/ high affinity to heparin/heparan sulfate chains and may serve a procoag fxn

-- formation of the Ab-PF4/heparin cmpls on the platelet surface results in Fc dependent platelet activation and destruction
-- release of additional PF4 from platelet granules

**marked platelet activation can trigger fuminant arterial or venous thrombosis

Front 17

Therapy for HIT?

Back 17

Discontinue ALL heparin and institute alternative anticoag w/ use of argatrobin or hirudin

Front 18

HIT assays?

Back 18

Serotonin release assay (GOLD STANDARD)
-- measures release of radioactively labeled serotonin from platelets in response to activation and destruction

Front 19

What is DIC?

Back 19

Disseminated Intravascular Coagulation
-- secondary mech of disease that results in the intravascular generation of thrombin and plasmin at a rate that exceeds their natural inhibitors

Can cause thrombosis OR hemorrhage

Front 20

DIC Assays?

Back 20

1. Check intravascular fibrin deposition, fibrinolysis
-- ↑ PT/PTT, d-dimers
-- ↓ fibrinogem

2. look for microangiopathy
-- shearing of RBCs

3. ↓ platelet count

Front 21

DIC treatment?

Back 21

1. treat primary disease

2. replacement therapy
-- cryoprecipitate

3. heparin

Front 22

That is TTP?

Back 22

Thrombotic thrombocytopenic purpura

Endothel injury suspected to trigger diffuse deposition of platelets and fibrin w/in vasculature, resulting in RBC fragmentation

PENTAD:
1. thrombocytopenia
2. microangiopathy (RBC fragmentation)
3. fever
4. renal failure
5. neuro involvement (change in mental status, seizures)

Assoc w/ number of different triggering events including: infection, toxins, drugs, pregnancy

Front 23

Hallmark of TTP?

Back 23

Schistocytes

Front 24

TTP treatment?

Back 24

Steroids

FFP infusion

Plasmapheresis (w/ exchange) -- dramatic improvements in mortality rates

AVOID platelet transfusions b/c may exascerbate the disease

Front 25

What is HUS?

Back 25

Similar pathophys of TTP

1. thrombocytopenia
2. microangiopathy
3. renal failure

Frequently assoc w/ verocytotoxin producing E.coli -- this variant responds poorly to plasmapheresis

Front 26

What are the myeloproliferative/bone marrow disorders?

Back 26

1. polycythemia vera

2. essential thrombocytopenia

3. paroxysmal nocturnal hemoglobinuria (PNH)

Front 27

Describe polycythemia vera.

Back 27

assoc w/ increased incidence thrombosis, especially in pts treated w/ phlebotomy

Front 28

Describe essential thrombocytopenia.

Back 28

Assoc w/ BOTH bleeding and thrombotic episodes
-- Venous and microvascular arterial events are most common

Must be differentiated from reactive thrombocytosis that generally poses little to no risk

Front 29

Describe paroxysmal nocturnal hemoglobinuria (PNH).

Back 29

Stem cell d/o characterized by complement dependent destruction of RBC
-- assoc w/ increased incidenc of DVT

Front 30

How is hypercoagulability assoc w/ nephrotic syndrome?

Back 30

Results from urinary loss of natural anticoag proteins such as antithrombin
-- may be assoc w/ renal vein thrombosis

Front 31

List the inherited risk factors for VTE.

Back 31

1. AT deficiency

2. Protein C deficiency

3. Protein S deficiency

4. Factor V Leiden

5. Prothrombin 20210A

Front 32

Describe AT deficiency.

Back 32

rare - 1/5000 blood donors

Autosomal dominant condition in which AT activity levels are about 50% of normal
--homozygous not compatible w/ life

Relative risk of VTE ~50-fold higher than gen pop, especially high-risk during pregnancy (up to 40% frequency VTE)

Front 33

Describe Protein C deficiency.

Back 33

More common (1/350 blood donors)

Autosomal dominant in which protein C activity is about 50%

Relative risk VTE for heterozy is ~8-10-fold higher than gen pop

Homozyg results in neonatal purpura fulminans

Front 34

Describe Protein S deficiency.

Back 34

rare -- no good estimates of prevalence or relative risk VTE

Homozyg also assoc w/ neonatal purpura fulminans

Front 35

Describe Factor V Leiden.

Back 35

Most common deficiency (5% Caucasian pop)

Relative risk VTE similar to PC deficiency (5 fold) for heterozygotes

Assoc w/ large porportion of venous thromboembolism cases (15-30%)

Molecular defect: Pt mutation (Arg 506) that eliminates a protein C cleavage site in factor Va, resulting in resistance to activated protein C
-- results in defective termination of coag by APC

Front 36

Describe Prothrombin 20210A

Back 36

Relatively common -- heterozyg in approx 2% of pop

Risk of VTE approx 3-5 fold for heterozyg

Assoc w/ 15-30% higher levels of prothrombin Ag in the plasma

Polymorphism/mutation in 3'UTR of prothrombin gene; molec mech undefined

Front 37

List VTE risk factors that may be genetic OR acquired.

Back 37

1. hyperhomocystinemia

2. elevated factor VIII levels

3. dusfibrinogenemia

Front 38

Describe hyperhomocysteinemia

Back 38

Risk factor for BOTH venous and arterial thrombosis

Severe elevations result from homozyg cystathionine synthetase deficiency

Mild elevations may result from additional defects in homocysteine metab

Precise mech unclear, but may involve induction of endothelial procoag activity

Clinical impact unclear unless marked elevation is identified due to the effect of diet, and gradual increase in risk w/ levels

Front 39

hyperhomocysteinemia treatment?

Back 39

B vitamins
-- folate
-- B6
-- B12

Front 40

Describe result of elevated factor VIII levels.

Back 40

may be inherited differences, but increased levels commonly assoc w/ inflamm states

Front 41

Dysfibrinogenemia is assoc w/...?

Back 41

bleeding or thrombophilia equally

Front 42

Major complications of VTE?

Back 42

post-phlebotic syndrome

pulmonary insufficiency

sudden death from pulmonary embolism

Front 43

Anticoag therapy and VTE?

Back 43

Tx demonstrates signif clinical benefits, but is allso assoc w/ signif risk of bleeding comolications

Front 44

What is the risk of recurrence of VTE?

Back 44

varies signif depending on the clinical and genetic risk factors present in a partic patient

Clinical risk factors may be transient or reversible (surgery, estrogens) OR chronic, ongoing conditions (CHF, venous insuff)