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What arm of the clotting cascade does secondary hemostasis involve?
Coagulation factors
What clotting factor is involved in the most common heriditary clotting factor deficiency?
FVIII
What are the pathways of the coagulation cascade?
Intrinsic

Extrinsic

Common
What is the only measurable factor in the extrinsic coagulation cascade?
F VII
What does prothrombin time (PT) provide a measurement of?
Extrinsic and common coagulation cascade factors
What does activated partial thromboplastin time provide a measurement of?
Intrinsic and common coagulation cascade factors
What diagnostic information do these measurements provide:
- Normal PT, prolonged PTT
- Prolonged PT, normal PTT
- Prolnged PT, prolonged PTT
Normal PT, prolonged PTT:
- Problem with intrinsic coagulation factors

Prolonged PT, normal PTT:
- Problem with extrinsic coagulation factors

Prolonged PT, prolonged PTT:
- Problem with intrinsic or extrinsic factors
- Problem with common pathway
How is a mixing study done and what diagnostic information does this provide?
Mix normal plasma with patient plasma and examine condition:
- If normalizes: factor deficiency
- If PT or PTT or both still prolonged, inhibitor of factors present
What factors are involved in the intrinsic pathway of the coagulation cascade?
F VIII

F IX

F XI

F XII
What factors are involved in the extrinsic pathway of the coagulation cascade?
F VII
What factors and molecules are involved in the common pathway of the coagulation cascade?
F II

F V

F X

Thrombin

Fibrinogen

Fibrin
Clinically, how do factor deficiencies in the coagulation cascade present compared with platelet disorders?
Factor deficiencies:
- Deep bleeding
- Hematomas
- Joint bleeding

Platelet disorders:
- Superficial bleeding
- Mucosal bleeding
- Capillary bleeding
How are factor deficiencies classified?
Severe:
- Factor < 1% of normal
- Spontaneous hemorrhage

Moderate:
- Factor 1-5% of normal

Mild:
- Factor >5% of normal
- Bleeding only with trauma or surgery
What are the factor VIII and factor IX deficiencies?
Hemophilia A (F VIII)

Hemophelia B (F IX)
What genetic problem can cause factor VIII deficiency hemophilia A and what types of problems cause which severity?
High spontaneous mutation rate of intron 22
- Inversion: Severe
- Missense: Mild/moderate
How are factor VIII and factor IX deficiencies inherited?
Sex-linked recessive:
- Males manifest
- Females carry
How are factor VIII levels in female carriers of hemophilia A?
~50% of normal
What are clinical manifestations of factor VIII and factor IX deficiencies?
Hemarthrosis (bleeding in joints)

Hematoma

Intercranial bleed

Other sites of hemorrhage:
- Mouth
- GI
- Kidney
What are treatment options for factor VIII and factor IX deficiencies and for what conditions are these used?
Factor replacement (treatment of choice)
- Severe disease

Desmopressin (DDAVP)
- Mild F VII deficiency only

Aminocaproic acid:
- Mouth bleeding

Prophylaxis
What are complications of factor replacement therapy when treating factor VIII and factor IX deficiencies?
Allergic reaction

Inhibitor (antibody) development
How does aminocaproic acid help treat factor VIII and factor IX deficiencies?
Inhibition of fibrinolysis
- Decreases effect of plasmin on fibrin
How are factor VIII and factor IX deficiencies diagnosed?
Prolonged PTT only

Carrier detection via:
- DNA probes
- CVS
How is factor XII deficiency inherited?
Autosomal recessive
How is factor XII deficiency diagnosed?
Prolonged PTT
- Corrected in mixing study
What are symptoms of factor XII deficiency?
Thrombosis

NO BLEEDING
How is factor XI deficiency inherited?
Autosomal dominant

(High prevalence in Ashkenazi Jews)
What are symptoms of factor XI deficiency?
Bleeding after trauma or surgery
How is factor XI deficiency treated?
Fresh frozen plasma infusion

(No F XI available)
How is factor VII deficiency inherited?
Autosomal dominant
How is factor VII deficiency diagnosed?
Prolonged PT, normal PTT
What are symptoms of factor VII deficiency?
Symptomatic bleeding when F VII < 15%
What is cryoprecipitate and what factors and molecules are in cryoprecipitate
Cold, insoluble plasma proteins:
- F VIII
- F XIII
- vWF
- Fibrinogen
- Fibronectin
What is von Willebrand Factor (vWF) and where is it synthesized?
Large glycoprotein

Synthesized from:
- Endothelial cells
- Megakaryocytes
What are the functions of von Willebrand Factor (vWF)?
Assist in platelet adhesion to area of vessel injury

Carrier of F VIII (stabilizer)
What are the types of von Willebrand Disease (vWD) and how are they grouped?
Quantitative deficiency:
- Type 1 (decreased vWF)
- Type 3 (no vWF)

Qualitative deficiency:
- Type 2 (LOF, GOF, F VIII binding mutation)
What is the most common inherited bleeding disorder?
Type 1 von Willebrand disease
How is von Willebrand Disease (vWD) diagnosed and why do these signs come about?
Normal PT, prolonged PTT
- vWF carries F VIII

Abnormal bleeding time
- vWF bridges platelets with subendothelium of blood vessels
What tests are done to investigate von Willebrand Disease (vWD)?
Decreased F VIII levels

Decreased vWF antigen

Decreased vWF activity
How is type 1 von Willebrand Disease (vWD) inherited?
Autosomal dominant
What are symptoms of type 1 von Willebrand Disease (vWD)?
Decreased vWF

Decreased F VIII

Prolonged bleeding time
How is type 3 von Willebrand Disease (vWD) inherited?
Autosomal dominant
What are symptoms of type 3 von Willebrand Disease (vWD)?
Extremely low vWF

Extremely low F VIII

Spontaneous bleeding

Hemarthrosis

Prolonged bleeding time
What are treatment options for types 1, 2, and 3 von Willebrand Disease (vWD) and how do these work?
Type 1 von Willebrand Disease (vWD):
- DDAVP: stimulates release of vWF from endothelial cells

Type 2 and Type 3 von Willebrand Disease (vWD):
- vWF concentrate

Also cryoprecipitate if needed
How can liver disease affect hemostasis and the coagulation cascade?
Decreases vitamin K dependent factors: F II, F VII, F IX, F X

Decreases all other factors and molecules

Activates fibrinolysis
How are PT and PTT affected in liver disease?
Both prolonged
How are platelet levels affected in liver disease?
Decreased
How are problems with hemostasis and the coagulation cascade associated with liver disease treated?
Fresh frozen plasma (FFP)

Platelets

Cryoprecipitate (considered)
How does vitamin K deficiency affect hemostasis and the coagulation cascade?
Decreases vitamin K dependent factors: F II, F VII, F IX, F X
Why is vitamin K deficient in newborns?
Immature liver does not synthesize vitamin K
What can cause vitamin K deficiency?
Immature liver at birth

Biliary disease and malabsorption

Malnourishment

Coumadin overdose
Why are biliary disease and malabsorption causative of vitamin K deficiency?
Vitamin K is fat soluble
How do coumadin and warfarin affect the coagulation cascade?
Inhibit vitamin K's carboxylation of vitamin K dependent factors: F II, F VII, F IX, F X

Inactivates them
How are vitamin K deficiencies treated?
Give vitamin K

GIVE VITAMIN K TO NEWBORNS
What does disseminated intravascular coagulation (DIC) cause?
Hematologic and immunologic/inflammatory abberations
What is the pathophysiological basis and mechanism of disseminated intravascular coagulation (DIC)?
Pathological activation of coagulation, via increased generation of thrombin

1. Thrombin is generated from tissue factor-dependent pathway via activation of F VII

2. Thrombin activates:
- Platelets
- Clotting factors
- Fibrinolysis
What is the major cause of the pathological activation of coagulation seen in disseminated intravascular coagulation (DIC)?
Underlying disease that activates tissue factor

Secondary to:
- Trauma
- Burns
- Embolism
- Increased cytokines
What are clinical consequences of disseminated intravascular coagulation (DIC)?
Prolonged PT and PTT

Thrombocytopenia

Excessive fibrinolysis and fibrin degradation products (FDP)

Vascular damage

Schistocytes

Bleeding

Oozing
Why do thrombocytopenia and factor deficiencies result from disseminated intravascular coagulation (DIC)?
Consumption of coagulation factors, RBCs, and platelets from secondary fibrinolysis initiated by the pathological activation of the coagulation cascade
How is disseminated intravascular coagulation (DIC) diagnosed?
Prolonged PT and PTT

Decreased fibrinogen

Decreased platelets

Increased fibrin degradation products (FDP)
How is disseminated intravascular coagulation (DIC) treated?
Treat underlying disorder!

FFP: replace factors and platelets

Cryoprecipitate (considered)
How could a massive blood replacement adversely affect the coagulation cascade and how would you correct this?
Dilutional deficiencies of factors and platelets

Treat with 1 unit fresh frozen plasma (FFP) / 5-10 units transfused blood
What can cause acquired factor VIII inhibition?
Acquiring auto-antibody against F VIII when factors infused in patient (i.e. hemophiliacs)
What is the inhibitor of importance in acquired factor VIII inhibition?
Anti-F VIII IgG antibody
How are PT, PTT and mixing studies affected in the case of acquired factor VIII inhibition?
Normal PT

Prolonged PTT

Non-corrective with mixing studies
How is acquired factor VIII inhibition diagnosed?
F VIII levels

Titer of anti-F VIII IgG antibody
What are symptoms of acquired factor VIII inhibition?
Bleeding!
How are hematological symptoms of acquired factor VIII inhibition treated?
High-dose F VIII (when hemorrhage)

Immunosuppression

Plasmapheresis (to remove antibody)