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44 Cards in this Set

  • Front
  • Back
Occurrence of arterial thrombosis is closely linked to...?
atherosclerotic vessel disease
Arterial thrombosis is epidemiologically assoc w/...?
sedentary life style
specific coag factor levels (fibrinogen, factor VII)
Acquired/genetic risk factors associated w/ arterial thrombosis?

heparin induced thrombocytopenia

lupus anticoagulants
Pathogenesis of arterial thrombosis involves?
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
The clinical presentation of arterial thrombosis depends on?
1. The specific vascular bed involved

2. Acute vs. chronic nature of the arterial obstruction
Venous thromboembolism (VTE) is a _____ disease in which the interaction of _____ and _____ risk factors determines likelihood of occurence.


In contrast to bleeding d/o's, VTE is a ________ d/o.
The factors involved in the development of a venous thrombi?

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

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

3. Intrinsic "hypercoagulability" of the blood
-- 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
-- deficiency or abnormal platelet fxn
Acquired conditions of Venous Stasis associated w/ VTE?
1. bed rest/immobility (lower extremity casts)

2. Obesity

3. CHF

4. Venous obstruction/post-phlebotic syndrome

5. Advanced age
Acquired conditions of endothelial/vessel injury assoc w/ VTE?
1. trauma

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

3. vasculitis/infection
Acquired conditions of intrinsic hypercoagulability associated w/ VTE?
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
What are lupus anticoagulants (LAC)?
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)
What are antiphospholipid antibodies (APA)?
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
What is antiphospholipid antibody syndrome?
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)
What is heparin induced thrombocytopenia (HIT)?
Induced by heparin therapy

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

-- 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
What is the mechanism of HIT?
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
Therapy for HIT?
Discontinue ALL heparin and institute alternative anticoag w/ use of argatrobin or hirudin
HIT assays?
Serotonin release assay (GOLD STANDARD)
-- measures release of radioactively labeled serotonin from platelets in response to activation and destruction
What is DIC?
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
DIC Assays?
1. Check intravascular fibrin deposition, fibrinolysis
-- ↑ PT/PTT, d-dimers
-- ↓ fibrinogem

2. look for microangiopathy
-- shearing of RBCs

3. ↓ platelet count
DIC treatment?
1. treat primary disease

2. replacement therapy
-- cryoprecipitate

3. heparin
That is TTP?
Thrombotic thrombocytopenic purpura

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

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
Hallmark of TTP?
TTP treatment?

FFP infusion

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

AVOID platelet transfusions b/c may exascerbate the disease
What is HUS?
Similar pathophys of TTP

1. thrombocytopenia
2. microangiopathy
3. renal failure

Frequently assoc w/ verocytotoxin producing E.coli -- this variant responds poorly to plasmapheresis
What are the myeloproliferative/bone marrow disorders?
1. polycythemia vera

2. essential thrombocytopenia

3. paroxysmal nocturnal hemoglobinuria (PNH)
Describe polycythemia vera.
assoc w/ increased incidence thrombosis, especially in pts treated w/ phlebotomy
Describe essential thrombocytopenia.
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
Describe paroxysmal nocturnal hemoglobinuria (PNH).
Stem cell d/o characterized by complement dependent destruction of RBC
-- assoc w/ increased incidenc of DVT
How is hypercoagulability assoc w/ nephrotic syndrome?
Results from urinary loss of natural anticoag proteins such as antithrombin
-- may be assoc w/ renal vein thrombosis
List the inherited risk factors for VTE.
1. AT deficiency

2. Protein C deficiency

3. Protein S deficiency

4. Factor V Leiden

5. Prothrombin 20210A
Describe AT deficiency.
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)
Describe Protein C deficiency.
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
Describe Protein S deficiency.
rare -- no good estimates of prevalence or relative risk VTE

Homozyg also assoc w/ neonatal purpura fulminans
Describe Factor V Leiden.
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
Describe Prothrombin 20210A
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
List VTE risk factors that may be genetic OR acquired.
1. hyperhomocystinemia

2. elevated factor VIII levels

3. dusfibrinogenemia
Describe hyperhomocysteinemia
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
hyperhomocysteinemia treatment?
B vitamins
-- folate
-- B6
-- B12
Describe result of elevated factor VIII levels.
may be inherited differences, but increased levels commonly assoc w/ inflamm states
Dysfibrinogenemia is assoc w/...?
bleeding or thrombophilia equally
Major complications of VTE?
post-phlebotic syndrome

pulmonary insufficiency

sudden death from pulmonary embolism
Anticoag therapy and VTE?
Tx demonstrates signif clinical benefits, but is allso assoc w/ signif risk of bleeding comolications
What is the risk of recurrence of VTE?
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)