Other Disorders of Hemostasis Flashcards
A disorder of platelet destruction that is secondary to heparin therapy…
Heparin-induced thrombocytopenia
With heparin-induced thrombocytopenia, how can the development of thrombosis occur?
Fragments of destroyed platelets may activate the remaining platelets causing a thrombosis
What does heparin form a complex with in heparin-induced thrombocytopenia and what does this cause the formation of?
Forms a complex with PF4 causing the formation of IgG antibodies against the platelets
A pathological activation of the coagulation cascade with widespread microthrombi that results in ischemia and infarction…
Disseminated intravascular coagulation (DIC)
What is the mechanism of excessive bleeding from IV sites and mucosal surfaces observed in disseminated intravascular coagulation?
With DIC there is a rapid consumption of platelets and coagulation factors which lead to the excessive bleeding
Disseminated intravascular coagulation is almost always secondary to another disease. What are the 5 most common diseases that can cause DIC?
1) Obstetric complications
2) Sepsis
3) Adenocarcinoma
4) Acute promyelocytic leukemia
5) Rattlesnake bite
What is the mechanism of disseminated intravascular coagulation formation an obstetrical patient?
Tissue thromboplastin within the amniotic fluid activates the coagulation cascade
Sepsis can cause disseminated intravascular coagulation. What is the mechanism of action?
Endotoxins from bacterial wall (E. coli or N meningitides) and cytokines induce endothelial cells to make tissue factor.
What activates the coagulation cascade when disseminated intravascular coagulation occurs secondary to adenocarcinoma?
Mucin
Patients with acute promyeloctic leukemia can develop disseminated intravascular coagulation. What causes the activation of the coagulation cascade?
Primary granules
A bite can cause disseminated intravascular coagulation. What animal can cause this and what is produced by the animal to cause DIC?
Rattlesnake bite—venom causes activation of coagulation cascade→ DIC
What are the laboratory findings with disseminated intravascular coagulation with respect to PT, PTT, Platelet count, and Fibrinogen?
PT: elevated
PTT: elevated
Platelet count: decreased
Fibrinogen: decreased
What type of anemia is seen with disseminated intravascular coagulation?
Microangiopathic hemolytic anemia
What is the best screening test for disseminated intravascular coagulation?
Elevated D-dimer
Derived from splitting of cross-linking fibrin
What is the treatment for disseminated intravascular coagulation?
Treatment of underlying cause and blood transfusion and cryoprecipitate.
What is the purpose of fibrinolysis?
Removal of thrombus after damaged vessel has healed.
What are the 3 steps of fibrinolysis?
1) tPA conversion of plasminogen to plasmin
2) Plasmin cleaves fibrin and serum fibrinogen—destroying the coagulation factors and blocks platelet aggregation
3) A2-antiplasmin inactivates plasmin
What is responsible for the conversion of plasminogen to plasmin during fibrinolysis?
tPA-(tissue plasminogen activator)
After fibrinolysis has occured, what inactivates the plasmin to stop its function?
A2-antiplasmin
Disorders of fibrinolysis usually involve over activity of what substance?
Plasmin
Over activity of plasmin seen in disorders of fibrinolysis causes what to occur?
Excessive cleavage of serum fibrinogen
What are the 2 most common causes of disorders to fibrinolysis?
Radical prostatectomy
Cirrhosis of the liver
What is release during a radical prostatectomy that causes a disorder of fibrinolysis?
Urokinase
When urokinase is released during a radical prostatectomy, what occurs to allow for the disorder of fibrinolysis?
Urokinase activates plasmin
Why does cirrhosis of the liver cause disorders in fibrinolysis?
There is a reduction in the production of a2-antiplasmin, which allows plasmin to remain activated.
What are the typical laboratory findings seen with disorders of fibrinolysis with respect to PT/PTT, bleeding time, Platelet count, and fibrinogen levels?
PT/PTT: elevated
Bleeding time: elevated
Platelet count: normal
Fibrinogen: decreased (without D-dimers)
How can a disorder of fibrinolysis be differentiated from disseminated intravascular coagulation?
DIC will have D-dimers with the splitting of fibrinogen and DIC will also have a decreased platelet count. Disorder of fibrinolysis will have normal platelet count
A disorder of fibrinolysis will have ABSENCE of D-dimer because fibrin thrombi are absent
What is the treatment for a disorder of fibrinolysis?
Aminocaproic acid—this blocks the activation of plasminogen
Where is the most common location for thrombosis formation?
Deep veins (DVT) of the leg below the knee
What are the two characteristics of a thrombosis and why are these important findings on autopsy?
Lines of Zahn and attachment to vessel wall
If found on autopsy—indicates that thrombosis occur prior to death
What are the 3 major risk factors contributing to thrombosis formation also known as Virchow triad?
1) Disruption in blood flow
2) Endothelial cell damage
3) Hypercoagulable state
What are the 3 common disruptions in normal blood flow that can lead to the formation of thrombosis?
1) immobilization—increased risk of DVT
2) Cardiac wall dysfunction—(a-fib, MI)
3) Aneurysm
What are the 5 ways in which endothelial cells prevent the formation of thrombosis?
1) Blockage of exposure to subendothelial collagen and underlying tissue factor
2) Production of PGI2 and NO—vasodilatation and inhibition of platelet aggregation
3) Secretion of heparin-like molecules—ATIII augmentation causing inactivation of thrombin and coagulation factors
4) Secretion of tPA
5) Scretion of thrombomodulin
The production of PGI2 and NO to prevent thrombosis formation works through what mechanism(s)?
Cause vasodilation and inhibition of platelet aggregation
How does the secretion of heparin-like molecules prevent the formation of thrombosis?
Causes augmentation of antithrombin III (ATIII), which in turn inactivates throbin and coagulation factors
The secretion of tPA stops the formation of thrombosis through what mechanism?
Converts plasminogen to plasmin—this does 3 things
1) cleaves fibrin and serum fibrinogen
2) destroys coagulation factors
3) blocks platelet aggregation
The secretion of thrombomodulin prevents the formation of thrombosis through activation of what?
Causes redirection of the thrombin to activate protein C—this in turn inactivates factor V and VIII
What are the 3 most common causes of endothelial cell damage?
Atherosclerosis
Vasculitis
High levels of homocysteine
What 2 deficiencies cause a mild elevation of homocysteine levels, which increase the risk of thrombosis formation?
Vitamin B12 deficiency
Folate deficiency
What is the mechanism for increased homocysteine levels with a vitamin B12 or folate deficiency?
Lack of Vitamin B12 or folate leads to the decreased conversion of homocysteine to methionine due to the inability to transfer a methyl group. This leads to a build up of homocysteine
A deficiency in cystathionine beta synthase (CBS) causes a high level of what substance?
Homocysteine
What is the enzymatic function of cystathionine beta synthase (CBS)?
Conversion of homocysteine to cystathionine
What are the 4 characteristic findings seen in patients who present with a cystathionine beta synthase (CBS) deficiency?
1) Vessel Thrombosis
2) Mental retardation
3) Lens dislocation
4) Long slender fingers
What is the classic presentation of a patient who presents with a hypercoagulable state?
Reccurent DVTs or DVT at a young age
What are the most common sites for DVTs to occur?
Deep veins of the leg
Hepatic and cerebral veins
What deficiency is typically found with patients who have a hypercoagulable state?
Protein C and S deficiency
What does a protein C and S deficiency cause within the coagulation cascade?
Deficiency decreases the negative feedback on the coagulation cascade
What is the normal function of protein C and S within the coagulation cascade?
Inactivate factors V and VIII
Patients who present with a protein C and S deficiency are at an increased risk of developing what type of necrosis?
Warfarin skin necrosis
A disease involving a mutated form of factor V that results in the factor V without a cleavage site for deactivation by protein C and S…
Factor V Leiden
What is the most common inherited cause of a hypercoagulable state?
Factor V Leiden
A disease involving an inherited point mutation in prothrombin resulting in an increased gene expression of prothrombin…
Prothrombin 20210A
How does prothrombin 20210A promote the production of thrombus?
Increased prothrombin→ increased thrombin→ thrombus formation
This deficiency decreases the protective effect of heparin-like molecules produced by the endothelium, which increases the risk of thrombus formation…
ATIII deficiency
What do heparin-like molecules normally activate and what role does this play in the coagulation pathway?
Activates ATIII, which inactivates thrombin and coagulation factors
What laboratory measurement is used to monitor heparin therapy?
PTT
A patient presents with ATIII deficiency and is given heparin. What laboratory value will be different when comparing it to a patient WITHOUT ATIII deficiency who was given heparin?
The PTT level does not rise with standard heparin dosing in the patient with the ATIII deficiency
What is given to overcome an ATIII deficiency and maintain an anticoagulated state?
A high dose of heparin is given to activate the limited number of ATIII and then Coumadin is given to maintain an anticoagulated state
What is the mechanism by which oral contraceptives increase the risk of developing a hypercoagulable state?
Estrogen within the oral contraceptive will increase the production of the coagulation factors—this increases the risk of thrombosis
