Hemostasis 1 Flashcards
What is primary hemostasis?
the formation of a weak platelet plug
What are the general steps of primary hemostasis?
(1) transient vasoconstriction of the damaged vessel
(2) Platelet adhesion to the surface of the disrupted vessel
(3) platelet degranulation
(4) platelet aggregation
What mediates transient vasoconstriction?
(1) reflex neural stimulation
(2) endothelin release from endothelial cells
Describe platelet adhesion to a damaged vessel in primary hemostasis
vWF binds to exposed subendothelial collagen; the platelets then bind the vWF via GP1b receptor on the platelet surface
Where does vWF come from?
(1) the Weibel-Palade bodies of endothelial cells
(2) alpha-granules of the platelets
Describe platelet degranulation
The adhesion of the platelet induces a shape change in the platelets and degranulation, with the release of multiple mediators, including ADP and TXA2 (thromboxane A2)
Where is ADP released from in platelets? What does it do?
Its released from the dense core granules
It promotes exposure of the GP2b/3a receptors on platelets
Where does TXA2 come from in platelets and what does it do?
It is synthesized from platelet cyclooxygenase, and promotes platelet aggregation
Describe platelet aggregation. What is the end result
Plates aggregate using GP2b/3a receptors, and fibrinogen as a linker molecule. The result is the formation of a weak platelet plug that must be stabilized by the coagulation cascde (secondary hemostasis).
What are the general clinical features of disorders of primary hemostasis?
mucosal and skin bleeding
What is a normal platelet count? Under what value will lead to symptoms?
150-400K/uL
<50K/uL will lead to symptoms
What is a normal bleeding time?
2-7 minutes
What happens to the bleeding time with platelet disorders?
It increases (it is prolonged)
What is the most common cause of thrombocytopenia in children and adults?
Immune Thrombocytopenic Purpura (ITP)
Briefly describe Immune Thrombocytopenic Purpura (ITP)
This is a disease in which autoantibodies (IgG) are produced against platelet antigens (e.g.,GP2b/3c). These antibodies are produced by plasma cells in the spleen, and the antibody-bound platelets are consumed by splenic macrophages –> thrombocytopenia
What are the laboratory findings in ITP?
(1) decreased platelet count (often <50K/uL)
(2) normal PT/PTT (coagulation cascade is not affected)
(3) increased megakaryocytes on bone marrow biopsy
Why do we see an increase in the number of megakaryocytes in ITP?
Because platelets are being destroyed outside the bone marrow (peripheral destruction), the bone marrow will respond by trying to produce more platelets. This leads to hyperplasia of the megakaryocytes.
What is the treatment for ITP?
(1) corticosteroids (initial treatment)
(2) IVIg (intravenous immunoglobulin)
(3) splenectomy (last resprt)
Explain how IVIG works and why it is used.
IVIG is used to raise the platelet count in symptomatic patients, but the effect is short-lived. When you administer IVIG, the splenic macrophages consume the IVIG instead of the antibody that is attached to the platelets, preventing platelet destruction. But once the IVIG is consumed, splenic macrophages will once again consume the platelet-bound IgG
How does splenectomy work?
It works in two ways, by (1) removing the site of auto-antibody production (plasma cells in the spleen); and (2) the site of antibody/platelet destruction (splenic macrophages).
This is only performed as a last resort in refractory cases
What type of infections would someone with a splenectomy be pre-disposed to?
Infections by encapsulated bacteria
What autoimmune disorder is associated with ITP, especially as a secondary cause of ITP?
SLE
What is Bernard-Soulier syndrome?
It is due to a genetic GP1b deficiency, imparing platelet adhesion
How does Bernard-Soulier syndrom present?
Blood smear shows mild thrombocytopenia with enlarged platelets.
(The platelets that are produced are large because they are produced prematurely; mild thrombocytopenia because if GP1b is not functioning, platelets tend not to live as long, and get destroyed)
What is Glanzmann thrombasthenia?
It is due to a genetic GP2b/3a deficiency that results in impaired platelet aggregation.
How does aspirin work?
Aspirin irreversibly inactivates cyclooxygenase. This inhibits TXA2 production; a lack of TXA2 impairs platelet aggregation
How does uremia affect primary hemostasis?
Uremia disrupts platelet function; both adhesion and aggregation are impaired.
What is (the purpose of) secondary hemostasis?
Secondary hemostasis stabilizes the weak platelet plug that is formed in primary hemostasis, via the coagulation cascade. The coagulation cascade results in the formation of thrombin, which then converts fibrinogen to fibrin. When fibrin is cross-linked, a stable platelet-fibrin thrombus is formed.
What is required for the activation of the coagulation cascade?
(1) an activating substance
(2) phospholipid surface (of the platelets)
(3) Calcium
What are the “activating substances” of the coagulation cascade?
Subendothelial collagen (SEC) activates the intrinsic pathway (activates factor XII) Tissue thromboplastin (tissue factor, factor III) activates the extrinsic pathway (activates factor VII)
Where does the calcium come from for the coagulation cascade?
from the platelet dense core granules
What are the general clinical features of disorders of secondary hemostasis?
Deep tissue bleeding into muscles and joints (hemarthrosis), and rebleeding after surgical procedures
What factors are part of the intrinsic pathway?
XII, XI, IX, VIII
What factor(s) are part of the extrinsic pathway?
VII
What factors are part of the common pathway?
X, V, II
Factor II
Thrombin
Factor I
Fibrinogen
Factor III
tissue factor, tissue thromboplastin
What does the PTT measure (and what does it stand for)?
PTT = the partial thromboplastin time, it measures the intrinsic and common pathways of the coagulation cascade
What does the PT measure (and what does it stand for)?
PT = Prothrombin time; it measures the extrinsic and common pathways of the coagulation cascade
What is hemophilia A
A genetic factor VIII deficiency
- X-linked recessive
- Can arise de novo (from a new mutation), without any family history, but is also hereditary
How does hemophilia A present?
with deep tissue, joint, and post-surgical bleeding
What would lab findings for hemophilia A include?
(1) increased PTT; normal PT
(2) decreased factor VIII
(3) normal platelet count and bleeding time
What is the treatment for hemophilia A?
you give the patient recombinant factor VIII
What is hemophilia B?
a genetic factor IX deficiency
it resembles hemophilia A, except Factor IX levels are decreased instead of Factor VIII
What is coagulation factor inhibitor? Which is most common?
This is an acquired antibody against a coagulation factor, resulting in impaired factor function.
The most common is anti-factor VIII.
How can a factor inhibitor, for example, anti-FVIII, be differentiated from hemophilia A?
With a mixing study. This is where you mix the patient’s plasma with normal plasma. For the patient with hemophilia A, you give back some normal FVIII, and the PTT will correct. For a patient with factor inhibitor, the antibody against the factor present in the patient’s serum will bind the FVIII, and the PTT will not correct
Where is vitamin K produced, and how is it activated?
Vitamin K is produced by bacteria in the gut and absorbed in the gut; it is then activated in the liver by epoxide reductase.
What does activated vitamin K do?
It gamma-carboxylates factors II, VII, IX, X, and protein C and S, which is necessary for their function
When do we see vitamin K deficiency?
(1) in newborns
(2) Long antibiotic therapy (kills K-producing gut bacteria)
(3) Malabsorption (especially fat-malabsorption)
Why do we give vitamin K prophylactically to all newborns?
due to lack of GI colonization by bacteria that normally synthesize vitamin K.
This prevents hemorrhagic disease of the newborn
What is von Willebrand Disease?
genetic vWF deficiency; the most common type is autosomal dominant with decreased vWF levels
How does vW Disease present clinically?
Mild mucosal and skin bleeding
the low vWF levels impairs platelet adhesion = primary hemostasis
What would the laboratory findings be in vW Disease?
(1) increased bleeding time
(2) normal platelet count
(3) increased PTT; normal PT
(4) abnormal ristocetin test
Why do we see an increased PTT with vW disease, even though vWF is involved in primary hemostasis?
The increased PTT is due to a decreased FVIII half-life. Normally, vWF stabilizes FVIII.
However, we usually still do not see the deep tissue, joint and post-surgical bleeding that is typical of disorders of secondary hemostasis.
What is the ristocetin test?
Ristocetin induces platelet aggregation by causing vWF to bind platelet GP1b.
Lack of vWF –> impaired aggregation –> abnormal test
What is the treatment for vW Disease?
Desmopressin, which is an ADH analog.
This stimulates the release of vWF from the Weibel-Palade bodies of endothelial cells
In what diseases do we see microangiopathic hemolytic anemia?
TTP (thrombotic thrombocytopenic purpura) HUS (hemolytic uremic syndrome) DIC SLE malignant hypertension
What is microangiopathic hemolytic anemia?
- -It is pathologic formation of platelet microthrombi in small vessels.
- -Platelets are consumed in the formation of the microthrombi, leading to thrombocytopenia
- -RBCs are sheared as they cross the microthrombi, resulting in a hemolytic anemia and the creation of schistocytes.
What is the cause of TTP?
It is due to a decrease in ADAMTS13, an enzyme that normally cleaves vWF multimers into monomers for eventual degradation.
The uncleaved vWF multimers leads to abnormal platelet adhesion, resulting in the formation of microthrombi
Why do we see a decrease in ADAMTS13?
it is usually do to an acquired auto-antibody that leads to the destruction of ADAMTS13.
It is most commonly seen in females
What is the cause of HUS?
HUS is due to endothelial damage by drugs or infection.
classically seen in children with E Coli O157:H7 dysentery, which results from exposure to under-cooked beef.
The E coli verotoxin damages endothelial cells resulting in platelet microthrombi.
What are the clinical findings of TTP and HUS?
(1) skin and mucosal bleeding
(2) microangiopathic hemolytic anemia
(3) fever
(4) renal insufficiency (more common in HUS) - thrombi involve vessels of kidney
(5) CNS abnormalities (more common in TTP) - thrombi involve vessels of CNS
What are the lab findings in TTP and HUS?
(1) thrombocytopenia
(2) increased bleeding time
(3) normal PT/PTT (coag cascade not affected)
(4) Anemia with schistocytes
(5) increased megakaryocytes on bone marrow biopsy
How do you treat TTP or HUS?
Particularly for TTP:
(1) corticosteroids to reduce production of auto-antibody
(2) plasmaphersis to remove auto-antibody from blood.
