Hemostasis wk7t11 Flashcards
3 stages in thrombus formation
- vascular constriction
- primary hemostasis- platelets
- secondary hemostasis- fibrin
hemostasis
- immediate response
vasoconstriction
- endothelin release causes vasoconstriction
primary hemostasis
platelets
- platelet adhesion via VWF
- shape change/ activation (stick out adhesion molecules)
- granule release (ADP, TXA2 potent vasoconstrictor)
- recruitment
- aggregation (hemostatic plug), assembly of factors in secondary hemostasis
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
Four enzymes in coagulation cascade
7,9,10,2 (thrombin)
serine proteases
synthesized in lover
vitamin K dependent
Ca2+ dependent
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
Cofactors in coagulation cascade
Factor VIII, cofactor for factor IX
Factor V, co-factor for factor X
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
clinical findings of platelet defects
- petechiae and purapura- usually symetric
- hx of easy or spontaneous bruising
- mild to moderate mucosal membrane bleeding
Platelet disorders
- thrombocythemia- primary or secondary
- thrombocytopenia- production or destruction
- loss of platelet function- congenital (rare) vs. acquired (more common)
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
thrombocytopenia
production
- marrow replacement, aplasia, viral infections, drugs, rare congenital disorders
destruction
- prosthetic valves, hypersplenism, immune mediated, DIC
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
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
Loss of platelet function
- uremia
- liver disease
- prosthetic valves
- aspirin or NSAIDS or other drugs
- essential thrombocythemia
- congenital- VWD, intrinsic platelet defects
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
Thrombocytopenia ranges
- <5K imminent risk of GI or cerebral hemorrhage
- <20K risk of spontaneous bleeding
- <50K risk of excess bleeding with surgery
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
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)
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
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
Hereditary hemorrhagic disease
Factor VIII- Hemophila A- x linked rec
factor IX- hemophila B- x-linked rec
VWF- VWD- auto dom
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
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).
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
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
Microvascular thrombi
- glomerular capillaries frequently affected
- fibrin-platelet thrombi in DIC
0 widespread focal ischemia
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
