Neoplasia/Hematology - Mechanisms of Disease - Hemostasis Flashcards
What are the main components of primary hemostasis?
Platelet adhesion and aggregation
What are the main components of secondary hemostasis?
Plasma clotting factors leading to fibrin formation
What are the main components of tertiary hemostasis?
Fibrin cross-linking and eventual fibrinolysis
Platelet activity is mostly part of _________ hemostasis.
Platelet activity is mostly part of primary hemostasis.
The clotting cascade is mostly part of _________ hemostasis.
The clotting cascade is mostly part of secondary hemostasis.
What do platelet dense granules contain?
Ca2+;
ADP;
ATP;
serotonin
What do platelet alpha granules contain?
Many factors:
vWF
Fibrinogen
Thromboglobulin
Thrombospondin
PDGF
PF4
P-selectin
Which platelet granules contain PDGF, PF4, and P-selectin?
(The āPās)
Alpha granules
Where is PF3 when the platelet is inactivated?
And when it is activated?
The inner membrane layer;
the outer membrane layer
PF3 is expressed by activated platelets to induce what process?
Thrombin formation
(uniting primary and secondary hemostasis)
What is the full name of the glycoprotein that connects platelets to vWF?
gpIb/V/IX
gp______ connects platelets to vWF on exposed collagen.
gpIb/V/IX connects platelets to vWF on exposed collagen.
gp______ connects platelets together on fibrinogen chains.
gpIIb/IIIa connects platelets together on fibrinogen chains.
Why do platelets and clotting factors normally not interact with undamaged endothelium?
Negative charge repulsion
What substance is expressed on endothelial cell surfaces to reduce coagulation?
Thrombomodulin
What substances are secreted by endothelial cell surfaces to reduce coagulation?
Nitric oxide;
serotonin;
prostacyclin;
heparin-like molecules
True/False.
In low shear stress conditions, platelets can bind directly to collagen without vWF as an intermediary.
True.
Via gpIa/IIa.
vWF is produced by what cell type(s)?
Megakaryocytes;
endothelial cells
What role does vWF play in secondary hemostasis?
Factor VIII stabilization
True/False.
vWF is produced as very large multimers that require cleavage for proper function.
True.
Where is vWF stored after synthesis?
Weibel-Palade bodies
What enzyme cleaves the ultra-high molecular weight vWF multimers into smaller multimers?
ADAMTS13
True/False.
Only small or intermediate vWF multimers (cleaved) have significant hemostatic function.
False.
Only large vWF multimers have significant hemostatic function.
Binding of platelet gpIb/V/IX to vWF leads to secretion of what in particular?
ADP and serotonin
(causing platelet activation and vasoconstriction, respectively)
What does ADP-activation in platelets cause to occur?
Expression of gpIIb/IIIa
Platelet gpIIb/IIIa can bind what substances in particular?
Fibrinogen;
vWF
What are the steps of platelet activity in clot formation?
- Plug/adhere wound
- Aggregate together
- Initiate clotting cascade
What is the normal blood count range for platelets?
150,000 - 450,000
Which have a higher MPV, young or mature platelets?
Young
(younger platelets are larger)
What two tests allow for assessment of platelet function?
Bleeding time;
PFA-100
What types of bleeding are typically seen in disorders of primary hemostasis?
Mucosal bleeds;
petechiae;
purpura;
immediate intra-operative (within minutes);
post-operative
Glanzmann thrombasthenia is an inherited deficiency of what?
Platelet gpIIb/IIIa
Bernard-Soulier syndrome is an inherited deficiency of what?
Platelet gpIb/V/IX
What inherited platelet disorder does not typically result in thrombocytopenia?
Glanzmann thrombasthenia
What is the generic name for Plavix?
Clopidogrel
Name a few conditions in the following categories that can cause thrombocytopenia:
Immune reactions
Organ dysfunctions
Thrombotic conditions
ITP;
splenomegaly, aplastic anemia, MDS, etc.;
DIC, TTP, HIT
True/False.
Hepatic and renal dysfunction can both lead to platelet dysfunction.
True.
How can myeloproliferative diseases lead to platelet dysfunction?
Bone marrow crowding
(can produce ineffective and/or decreased platelets)
_______________ is an inherited deficiency of platelet gpIIb/IIIa.
Glanzmann thrombasthenia is an inherited deficiency of platelet gpIIb/IIIa.
_______________ is an inherited deficiency of platelet gpIb/V/IX.
Bernard-Soulier syndrome is an inherited deficiency of platelet gpIb/V/IX.
True/False.
Bernard-Soulier syndrome and Glanzmann thrombasthenia are typically characterized by thrombocytopenia.
False.
Bernard-Soulier syndrome is typically characterized by thrombocytopenia; Glanzmann thrombasthenia is typically characterized by a normal CBC.
Gray platelet disorder is an inherited deficiency of _________ platelet granules.
Gray platelet disorder is an inherited deficiency of alpha platelet granules.
All the following disorders are characterized (in part) by deficiencies of _________ platelet granules:
- Hermansky-Pudlak syndrome*
- Chediak-Higashi syndrome*
- TAR syndrome*
- Wiscott-Aldrich syndrome*
All the following disorders are characterized (in part) by deficiencies of dense platelet granules:
- Hermansky-Pudlak syndrome*
- Chediak-Higashi syndrome*
- TAR syndrome*
- Wiscott-Aldrich syndrome*
How do the platelets appear if alpha granules are deficient?
Enlarged, gray
(gray platelet syndrome ā thrombocytopenia may be present)
Name an inherited disorder of primary hemostasis that is the most common inherited bleeding disorder and does not directly involve platelet alterations.
vWF disease
How does vWF deficiency typically present?
Similar to platelet disorders
(mucosal bleeding, petechiae, etc. ā severe cases may also result in factor VIII dysfunction)
What is the inheritance pattern for the most common form of vWF disease?
Autosomal dominant
Type 3 vWF disease involves a complete absence of vWF.
How does this uncommon form present?
What is its inheritance pattern?
Similar to hemophilia (factor VIII dysfunction);
autosomal recessive
What substance is a cofactor for vWF and can be used to evaluate vWF function and concentration?
Ristocetin
What is the vWF multimers test used to assess?
The size of vWF multimers
(small, medium, large)
A patient with vWF disease has ristocetin added to a sample of their blood.
What will happen?
No coagulation
vWF is an acute phase reactant, and so a workup for vWF disease should not be done in what scenarios?
Pregnancy (2nd or 3rd trimester);
strenuous exercise;
stressful situations
What is the main treatment for vWF disease that increases vWF release from endothelial cells?
Desmopressin
What is it called when an individual develops a lack of vWF secondary to other disease processes (e.g. SLE, myeloma, Waldenstromās, hypothyroidism, aortic stenosis, etc.)?
Acquired vWF disease
What is the underlying cause of thrombotic thrombocytopenic purpura (TTP)?
ADAMTS13 deficiency
Describe thrombotic thrombocytopenic purpura (TTP) in terms of the following:
PT
PTT
TT
Fibrinogen
D-dimers
Typically all normal
(distinguishes it from DIC)
What is the pentad of symptoms usually seen in thrombotic thrombocytopenic purpura (TTP)?
Fever;
thrombocytopenia;
hemolysis (microangiopathic);
confusion;
renal failure
How can thrombotic thrombocytopenic purpura (TTP) be treated?
Exchange transfusion
(replaces ADAMTS13)
What microangiopathy is typically seen in younger patients due to verotoxin or shigellosis?
Hemolytic uremic syndrome
How are the presentations of HUS and TTP different?
Less altered mental status and more renal involvement in HUS
What is the effect of the antibodies in antiphospholipid syndrome?
Platelet activation
(due to binding to platelet lipids)
What substance is used in making the diagnosis of antiphospholipid syndrome?
Dilute Russell viper venom
True/False.
Antiphospholipid syndrome is a bleeding disorder characterized by an increased aPTT and increased likelihood of thrombosis and miscarriage.
False.
Antiphospholipid syndrome is not a bleeding disorder. It is an autoimmune coagulative disorder characterized by an increased aPTT and increased likelihood of thrombosis and miscarriage.
What is the typical mediator for heparin-induced thrombocytopenia?
Antiplatelet antibodies
(that increase platelet activation)
Where is tissue factor typically found?
Subendothelial surfaces
Describe the intrinsic pathway of coagulation.
12 ā> 11 ā> 9 + 8 ā> common pathway
Describe the extrinsic pathway of coagulation.
Tissue factor ā> VII ā> common pathway
Where do the intrinsic and extrinsic pathways of coagulation meet to begin the common pathway?
Factor X (+ V)
Which is more efficient at producing thrombin, the extrinsic pathway or the intrinsic pathway?
Intrinsic
Factor X cleaves __________ to form thrombin, which then cleaves __________ to form fibrin.
Factor X cleaves prothrombin to form thrombin, which then cleaves fibrinogen to form fibrin.
Megakaryocytes are responsible for synthesis of what clotting factor(s)?
vWF;
fibrinogen
Endothelial cells are responsible for synthesis of what clotting factor(s)?
vWF;
factor VIII
The liver is responsible for synthesis of virtually all clotting factors except which?
vWF
Name a few of the contact factors that facilitate the clotting cascade in vitro.
Factor XII;
HMWK;
prekallikrein
Name the most important contact factor that facilitates the clotting cascade in vivo.
Tissue factor
In vivo, the factor VIIa / tissue factor complex also activates factor ___ in addition to factor X (thus, initiating the extrinsic and intrinsic pathways).
In vivo, the factor VIIa / tissue factor complex also activates factor IX in addition to factor X (thus, initiating the extrinsic and intrinsic pathways).
(Crossover pathway)
True/False.
The extrinsic pathway of the clotting cascade is activated via vessel wall damage, and the intrinsic pathway is activiated via events not related to vessel wall damage.
False.
In vivo, the factor VIIa / tissue factor complex also activates factor IX in addition to factor X (thus, the extrinsic and intrinsic pathways are typically activated together for full, strong clot formation).
How do platelets contribute to secondary hemostasis (the clotting cascade)?
PF3 (a surface phospholipid in activated platelets) activates factor VII (leading to activation of IX, X, and II).
Why might you prepare a blood sample with added citrate?
To chelate the calcium and prevent clotting
Name all the factors activated by thrombin (factor II).
Factors:
I (fibrin)
V
VIII
XI
XIII (clot stabilization)
What factor is especially important in cross-linking / stabilizing the fibrin mesh after it has been formed?
Factor XIII
If tissue factor pathway inhibitor (TFPI) binds tissue factor once the intrinsic and extrinsic clotting cascades have already been initiated, what will happen next?
The extrinsic pathway is stopped, but the intrinsic will continue through a thrombin positive-feedback loop.
If tissue factor activates factor VII, what will factor VII do?
Activate factors X (common pathway) and IX (intrinsic pathway)
(Crossover pathway)
True/False.
Thrombin has a positive-feedback loop that induces more thrombin formation.
True.
Name two endogenous factors that inhibit tissue plasminogen activator.
Plasminogen activator inhibitor (PAI);
alpha2-antiplasmin
Increased TPA activity leads to increased levels of serum what?
D-dimers
(fibrin split/degradation products)
____________ directs thrombin to activate protein C, thus inactivating factors ____________.
Thrombomodulin directs thrombin to activate protein C, thus inactivating factors VIIIa and Va.
Thrombomodulin directs __________ to activate __________, thus inactivating factors VIIIa and Va.
Thrombomodulin directs thrombin to activate protein C, thus inactivating factors VIIIa and Va.
True/False.
Antithrombin III inactivates factors II and X (among others).
True.
Generally speaking, if you suspect a disorder of secondary hemostasis, what test(s) will you order first?
PT and PTT
(TT and fibrinogen can come later)
On working up a patientās bleeding, you note that PT and PTT are both elevated. You order a thrombin time. What does this measure?
Functionality/amount of fibrin produced
Thrombin time is usually elevated in disorders involving deficient or damaged what?
Fibrinogen
You mix blood of a patient with elevated PTT and PT with the blood of a patient with no elevation together.
You test the mixture and find an elevated PTT and PT.
Why?
The patient with the elevated PT and PTT has something in their blood (e.g. an antibody) that is inhibiting proper coagulation
You mix blood of a patient with elevated PTT and PT with the blood of a patient with no elevation together.
You test the mixture and find a normal PTT and PT.
Why?
The patient with the elevated PTT and PT must be deficient in a factor that was replaced with the healthy patientās blood.
You mix blood of a patient with elevated PTT and PT with the blood of a patient with no elevation together.
If the sick patient has a clotting inhibitor in their blood (e.g. some antibody), what will happen when you test the PTT and PT in the mixed blood?
Elevated PT and PTT
(the inhibitor blocks clotting in the normal patientās blood as well)
You mix blood of a patient with elevated PTT and PT with the blood of a patient with no elevation together.
If the sick patient has a clotting factor deficiency in their blood, what will happen when you test the PTT and PT in the mixed blood?
The PTT and PT will be normal
(the missing factor was contributed by the healthy patient)
How do disorders of secondary hemostasis (clotting factors) most commonly present?
Hemarthroses
(may also be soft tissue bleeds, large bruises, and post-operative/trauma bleeds)
What are the two most common hereditary bleeding disorders?
- vWF disease
- Hemophilia A
What is the inheritance pattern for hemophilia A?
X-linked recessive
True/False.
Most cases of hemophilia A are relatively mild.
False.
70% of cases are severe and 15% are moderate.
Hemophilia A classification:
Factor VIII > ___% of normal = mild.
Factor VIII = ___-___% of normal = moderate.
Factor VIII < ___% of normal = severe (most common).
Hemophilia A classification:
Factor VIII > 5% of normal = mild.
Factor VIII at 1 - 5% of normal = moderate.
Factor VIII < 1% of normal = severe (most common).
Describe the instigating factor typically required for each of the following hemophilia A phenotypes to bleed:
Mild
Moderate
Severe (most common)
Mild - trauma or surgery
Moderate - very mild trauma
Severe - no trauma
List the results of the following tests for an individual with hemophilia A:
PTT
PT
Mixing study
Elevated
Normal
PTT corrected
What is the inheritance pattern for hemophilia B?
X-linked recessive
What factor is deficient in hemophilia A?
Factor VIII
What factor is deficient in hemophilia B?
Factor IX
List the results of the following tests for an individual with hemophilia B:
PTT
PT
Mixing study
Elevated
Normal
PTT corrected
How do you treat a patient with an aquired clotting inhibitor (e.g. an antiphospholipid or anti-factor-VIII antibody)?
Anticoagulants
Name three inherited disorders that lead to a thrombotic predisposition due to a missing endogenous anticoagulant.
Antithrombin III deficiency;
protein C deficiency;
protein S deficiency
Factor V Leiden mutation results in a ______coagulable state because ____________ is less effective.
Factor V Leiden mutation results in a hypercoagulable state because protein C is less effective.
Protein C normally inactivates which clotting factors?
Va and VIIIa
___________ levels of prothrombin or homocysteine (seen in some inherited disorders) can lead to a hypercoagulable state.
Elevated levels of prothrombin or homocysteine (seen in some inherited disorders) can lead to a hypercoagulable state.
What effect do fibrin split/degradation products have on thrombin activity?
Decreased
Disseminated intravascular coagulation is characterized by excessive ________ and ________.
Disseminated intravascular coagulation is characterized by excessive clotting and fibrinolysis.
True/False.
DIC can manifest with bleeding and/or thrombosis.
True.
What is the mnemonic to remember some of the causes of DIC?
STOP Making New Thrombi
Sepsis
Trauma
Obstetric complications
Pancreatitis
Malignancy
Nephrotic syndrome
Transfusion
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
S_____
T_____
O______ complications
Pancreatitis
Malignancy
Nephrotic syndrome
Transfusion
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
Sepsis**
Trauma**
Obstetric** complications
Pancreatitis
Malignancy
Nephrotic syndrome
Transfusion
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
Sepsis
Trauma
Obstetric complications
P________
M________
Nephrotic syndrome
Transfusion
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
Sepsis
Trauma
Obstetric complications
Pancreatitis**
Malignancy**
Nephrotic syndrome
Transfusion
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
Sepsis
Trauma
Obstetric complications
Pancreatitis
Malignancy
N________ syndrome
T________
Fill in the mnemonic for some of the causes of DIC:
STOP Making New Thrombi
Sepsis
Trauma
Obstetric complications
Pancreatitis
Malignancy
Nephrotic** syndrome
Transfusion**
What lab results are consistent with DIC?
Clotting tests
??????????????
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
Schistocytes + thrombocytopenia
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
Schistocytes + thrombocytopenia
Clotting tests
Increased PT, PTT, and TT
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
Schistocytes + thrombocytopenia
What lab results are consistent with DIC?
Clotting tests
Increased PT, PTT, and TT
Elevated/decreased serum substances
??????????????
Peripheral smear
Schistocytes + thrombocytopenia
Clotting tests
Increased PT, PTT, and TT
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
Schistocytes + thrombocytopenia
What lab results are consistent with DIC?
Clotting tests
Increased PT, PTT, and TT
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
?????????????
Clotting tests
Increased PT, PTT, and TT
Elevated/decreased serum substances
Decreased fibrinogen and platelets;
Increased fibrin-split products (e.g. D-dimers)
Peripheral smear
Schistocytes + thrombocytopenia
Does iron deficiency anemia have any obvious effects on white blood cells or platelets?
Thrombocytosis
Why would you check creatinine and BUN on a patient with an apparent anemia?
To check for renal failure
(decreased erythropoeitin)
How do you screen for colorectal cancer in older patients with iron deficiency anemia?
Colonoscopy
A 53 year old female presents with exertional shortness of breath and progressing fatigue over the past 5 weeks. She has no orthopnea, edema, or other signs of heart failure. She reports no changes in frequency or consistency of her bowel movements; she reports no tenesmus or straining. Further workup reveals the attached findings.
What is the next step in management?
Colonoscopy
How will a right-sided colon cancer affect stool consistency and/or frequency of bowel movement and/or muscle tone?
It will not!
(Right-sided colon cancers are often asymptomatic until perforation or blockage. The fecal material is still fluid in the right bowl and simply slides throigh the narrowed opening.)
True/False.
Iron deficiency anemia often follows a fairly gradual, progressive increase in symptoms.
True.
Right-sided colon cancer is often asymptomatic until what?
Perforation or complete obstruction or severe blood loss
etc.
A 74 year old man presents with bleeding gums and bruised extremities. He also reports a feeling of weakness and general malaise over the past few weeks, as well as some mild hair loss. Upon physical exam, you notice small red spots on his extremities.
His lab values are attached.
What is the diagnosis?
Scurvy
(Note: peripheral smear attached)
True/False.
Severe B12 deficiency is associated with pancytopenia and hemolysis.
True.
