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Flashcards in Hemostasis wk7t11 Deck (28):
1

3 stages in thrombus formation

- vascular constriction

- primary hemostasis- platelets

- secondary hemostasis- fibrin

2

hemostasis 

- immediate response

vasoconstriction

- endothelin release causes vasoconstriction

3

primary hemostasis

platelets

1. platelet adhesion via VWF

2. shape change/ activation (stick out adhesion molecules)

3. granule release (ADP, TXA2 potent vasoconstrictor)

4. recruitment

5. aggregation (hemostatic plug), assembly of factors in secondary hemostasis

4

secondary hemostasis

thrombin + fibrin

- rapidly formed

- localized to site of injury

- ultimately degradable

- formation of a temporary barrier at site of injury

- fibrin on top ok platelets, some trappen pmns and rbcs

5

Four enzymes in coagulation cascade

7,9,10,2 (thrombin)

serine proteases

synthesized in lover

vitamin K dependent

Ca2+ dependent

6

vitamin K

- co-factor for a liver carboxylase enzyme

- carboxylase adds COO- group to 4 proteases

- COO- on proteases alows Ca+2 binding 

- coumadin inhibits carboxylase reaction

- Vit K deficiencies seen in newborns, malnutrition, gut sterilization

7

Cofactors in coagulation cascade

Factor VIII, cofactor for factor IX

Factor V, co-factor for factor X

8

Corollaries

Neither enzymes nor co-factors are consumed in a reaction


Diminution of an enzyme or co-factor does not impair coagulation until the plasma level is very low (<30%) – phenotypes are recessive or X-linked


Fibrinogen and vWF are consumed in this reaction, so fibrinogen mutations and vWD can act as autosomal dominant

9

clinical findings of platelet defects

- petechiae and purapura- usually symetric

- hx of easy or spontaneous bruising

- mild to moderate mucosal membrane bleeding

10

Platelet disorders

- thrombocythemia- primary or secondary

- thrombocytopenia- production or destruction

- loss of platelet function- congenital (rare) vs. acquired (more common)

11

Thrombocythemia

 primary- a myeloproliferative disease, essential thrombocythemia

- platelets can have norma or abnormal function

secondary- increased release from bone marrow due to steriods or stress

- platelets have normal function

12

thrombocytopenia

production

- marrow replacement, aplasia, viral infections, drugs, rare congenital disorders

destruction

- prosthetic valves, hypersplenism, immune mediated, DIC

13

causes of immune thromocytopenia

autoImmune (ITP)- acute and chronic

Alloantibodies -  neonatal, transfusion (MHC)

Drug induced (drug as hapten), e.g. HIT

Disease associated

Other autoimmune

Lymphopholiferative

Solid tumors

Infection - viral, bacterial, parasitic

14

Acute vs chronic ITP

idiopathic thrombocytopenic purapura

acute:

2-9 years
Abrupt onset
Antecedent infection
<20,000 plts
2-6 weeks
80% spontaneous remission
variable response to immunosuppression or splenectomy

 

chronic:

20-40 yrs,  3F:1M
Gradual onset
no clear antecedent
20-100,000 plts
years
spontaneous remission rare
commonly respond to immunosuppression or splenectomy

 

15

Loss of platelet function

- uremia

- liver disease

- prosthetic valves

- aspirin or NSAIDS or other drugs

- essential thrombocythemia

- congenital- VWD, intrinsic platelet defects

 

16

lab tests to assess platelet type bleeds

- platelet count

- bone marrow evaluation: problem of production or destruction

- bleeding time- only if platelet count is >100K

- platelet aggregation assays- to test for specific defects

17

Thrombocytopenia ranges

- <5K imminent risk of GI or cerebral hemorrhage

- <20K risk of spontaneous bleeding

- <50K risk of excess bleeding with surgery

18

Bleeding time

- poor screening test

- bleeding time prlongs when platelet count <100K

- bleeding time abnormalities:

liver disease, uremia, collagen vascular disease, ess T'themia, VWD

 

19

Coagulation disorders- hemorrhagic

1. Decreased Factor production: 

Acquired -- liver disease, vitamin K deficiency
Congenital -- hemophilia (lack of specific factors)

2. Increased Factor consumption:

Acquired – DIC
Congenital --  some rare congenital deficiencies, e.g. a2-anti-plasmin (continue to degrade clots with plasmin, so more clots form and consume factors)
 

20

Congenital bleeding disorders

Von Willebrand’s Disease – autosomal dominant

Hemophilia A (F VIII) or B (F IX) – X-linked

All other factors – autosomal recessive

Fibrinogen – dominant or recessive, depending on mutation
 

21

Von Willebrand's factor

made in endothelial cells

glues platelets down to exposed collagen to start primary hemostasis (so consumed in reaction, acts as autosomal dominant)

also stabilizes FVIII- so can affect secondary  hemostasis

- mutations affect amount or affect function 

22

Hereditary hemorrhagic disease

Factor VIII- Hemophila A- x linked rec

factor IX- hemophila B- x-linked rec

VWF- VWD- auto dom

 

23

Clinical findings in factor deficiencies

common:

Bleeding in major muscles and joints
Large bruises

 

rare:

Mucosal hemorrhage
Intracranial bleeds
Bleeding from minor cuts and abrasions

24

regulators of coagulation

Plasmin – degrades fibrin

Protein C/Protein S – enzyme/co-factor that degrade FVIII and FV

Anti-thrombin III (ATIII) – serine protease inhibitor. In presence of heparin/heparan, inhibits FII, X, IX (not FVII).

25

Coagulation disorders- thrombotic

Antiphospholipid syndrome (autoimmune, often seen in lupus)

FVLeiden mutation- resistance to Protein C

Protein C deficiency

Protein S deficiency

ATIII deficiency

Prothrombin mutation

Homocysteinemia

All are autosomal dominant with incomplete penetrance - most symptomatic patients have >1 mutation and other contributing factors

26

Trigger mechs in DIC

Direct intravascular factor activation by proteases - snake venoms, proteases released in acute pancreatitis, crude factor concentrates

Release of cellular procoagulants, e.g. Tissue Factor  - intravascular cell lysis (hemolysis, leukemia, granulocyte lysis in sepsis), extravascular cell lysis (tumor, trauma, surgery), ascitic or amniotic fluid emboli

Vascular factors - endothelial cell damage by endotoxin, hypotension and stasis (shock), hemangiomas

27

Microvascular thrombi

- glomerular capillaries frequently affected

- fibrin-platelet thrombi in DIC

0 widespread focal ischemia

28

Lab tests to evaluate hemorrhagic and thrombotic diseases

Prothrombin Time (PT)   9-12 sec

Partial Thromboplastin Time (PTT) 22-33 sec

Fibrinogen     200-400 mg/dl

Specific factor/co-factor assays  >50% activity

APC resistance/ FVLeiden  negative

D-dimer assay  negative