Heme/Onc 2 Flashcards
von Willebrand Factor is synthesized by what 2 cells?
endothelial cells and megakaryocytes
What are the 2 roles of von Willebrand Factor in hemostasis?
- Binds platelets to endothelium and other platelets
- Carrier of factor VIII
How does Von Willebrand Disease present?
- Usually mild, non-life threatening bleeding
- Easy bruising, skin bleeding
- Prolonged bleeding from mucosal surfaces → menorrhagia
What are normal/abnormal lab findings present in Von Willebrand Disease?
- Increased PTT and bleeding time
- Normal PT and normal platelet count
- No aggregation with Ristocetin cofactor activity assay
What is Ristocetin cofactor activity assay?
- Ristocetin is an antibiotic that binds vWF and glycoprotein GPIb
- If vWF is present → platelet aggregation
What is the most common inherited bleeding disorder? What is the inheritance pattern?
- Von Willebrand Disease
- Most cases autosomal dominant
What are 3 treatments for Von Willebrand Disease?
vWF concentrate
Desmopressin
Aminocaproic acid
What is the mechanism of Aminocaproic acid?
Inhibits plasminogen activation to plasmin (antifibrinolytic)
What is Heyde’s Syndrome? What are 2 features?
GI bleeding associated with aortic stenosis
- Angiodysplasia
- High shearing force caused by aortic stenosis uncoils vWF multimers → cleaved by ADAMST13 → vWF deficiency
What is the treatment for Heyde’s Syndrome?
aortic valve surgery
↓cAMP lead to [increased/decreased] platelet activation
increased
Aspirin inhibits the production of [2]
Thromboxane A2
Prostaglandins
What are 5 effects of PGE2?
- Redness (Vasodilation)
- Edema (Increased permeability)
- Fever (hypothalamus)
- Pain
- Afferent Renal vasodilation
What is the effect of PGE2/PGI2?
protects the GI mucosa
NSAIDS [reversibly/irreversibly] inhibit COX-1 and COX-2; Aspirin [reversibly/irreversibly] inhibits COX-1 and COX-2
reversibly, irreversibly
What is the lifespan of a platelet?
7-10 days
Naproxen and Indomethacin are
NSAIDs
What are common uses of aspirin?
- Reduce inflammation, pain, fever
- Coronary disease: Acute MI, secondary prevention
- Stroke: acute ischemic stroke, secondary prevention
What are 4 possible adverse effects of Aspirin?
- Bleeding
- Gastritis/Ulcers
- Tinnitus: caused by salicylate
- Reye’s syndrome: liver failure and encephalopathy in with aspirin use in children
Aspirin is given to children in what rare condition?
Kawasaki
What are 2 drugs classified as Thienopyridines?
Clopidogrel, Prasugrel
What is the mechanism of Thienopyridines (Clopidogrel, prasugrel)?
Irreversible P2Y12 receptor blockers
What are 2 side effects of Thienopyridines?
- Bleeding
- Thrombotic Thrombocytopenic Purpura (rare)
What is the mechanism of Ticagrelor? What is a unique side effect?
- Reversible P2Y12 receptor blocker (inhibits platelet activation)
- Dyspnea
What is the mechanism of Dipyridamole? Indications (2)?
- PDE III inhibitor and blocks adenosine uptake by cells
- Indication: stroke prevention with aspirin, chemical cardiac stress testing
Adenosine is a [vasoconstrictor/vasodilator]
Vasodilator
What is the mechanism of Cilostazol? Indication?
- PDE III inhibitor (raises cAMP in platelets and vascular smooth muscle)
- Indication: peripheral arterial disease (rarely used for anti-platelet effects)
What are 3 side effects of PDE inhibitors?
- Flushing
- Headache
- Hypotension
*due to vasodilation
What is the mechanism of Abciximab, eptifibatide, tirofiban? Indication?
- IIB/IIIA receptors blockers → prevent aggregation
- Abciximab: Fab fragment
- IV drugs used in acute coronary syndromes/stenting
What is a side effect of IIB/IIIA receptors blockers? Name 3 of the drugs
Thrombocytopenia (must monitor platelet count after administration)
Abciximab, Tirofiban, Eptifibatide
What are 2 components that form a thrombus?
fibrin and activated platelets
Heparin is found naturally in what type of cells?
mast cells
Heparin is used in what two forms?
- Unfractionated: widely varying polymer chain lengths
- Low molecular weight: smaller polymers only
What is the mechanism of Unfractionated Heparin?
Activates Antithrombin III
Antithrombin III inhibits what 5 coagulation factors?
XII, XI, IX, Xa, and Thrombin
*12, 11, 9, 10a
Heparin will increase which coagulation assays?
- Increases PTT and Thrombin time
- Can increase PT at high dosages
Dosing of Unfractionated Heparin
Response is highly variable from patient to patient due to binding to plasma proteins and cells
- Dose must be adjusted
What is the mechanism of Protamine? What is it used for?
- Binds heparin → neutralizes drug
- Reversal agent for heparin overdose (most effective against unfractionated heparin) i.e. in cardiac surgery
Why is protamine used in cardiac surgery?
High dose heparin is administered for heart-lung bypass → quick reversal at completion of case
What are 2 uses for Unfractionated Heparin?
- Acute management: DVT/PE, MI, Stroke
- Prophylaxis for DVT in hospitalized patients
What are 3 side effects of Unfractionated Heparin?
- Mainly bleeding and thrombocytopenia
- Osteoporosis (long term use)
Direct suppressive effect of platelet production with heparin is called
“Non-immune” thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is what type of hypersensitivity reaction?
Type II
(Immune complexes bind platelet factor 4-heparin)
What is the mechanism of Heparin-induced thrombocytopenia (HIT)?
IgG-Hep-PF4 Complexes → bind to platelet surface → 1) removal by splenic macrophage 2) Platelet aggregation/activation
*lead to diffuse arterial/venous thrombosis and thrombocytopenia
When does Heparin-induced thrombocytopenia (HIT) occur?
5-10 days after heparin exposure
How to definitively diagnose Heparin-induced thrombocytopenia?
HIT antibody testing
What is the mechanism of Enoxaparin?
Activates ATIII to a less degree → only inhibits Xa
Dosing of Low Molecular Weight Heparin
Dosed based on weight (reduced plasma proteins and cells)
- Usually no monitoring required
What are 2 benefits to using Low Molecular Weight Heparin vs UF Heparin?
- Do not need to adjust dose or monitor PTT
- Lower incidence of HIT
Unlike UF heparin, LMWH only effects _____. How does this affect coagulation assays?
- Factor X
- Thrombin test will not change
- PTT is NOT sensitive to LMWH
Low Molecular Weight Heparin use should be monitored in what 2 conditions? What test is used?
- Obesity, Renal failure
- Anti Xa level test
How is Anti Xa Level measured? What is it used for?
- Pt sample is added to Xa substrate + cromophore (illuminates when Xa substrate is split)
- High Xa activity = high illumination
- Used to monitor LMWH effect in patients with obesity or renal failure
What is the mechanism of Rivaroxaban and Apixaban?
Factor Xa inhibitors
Rivaroxaban and Apixaban are used in
- Used in A Fib as alternatives to warfarin (do not require monitoring)
What are the effects of Rivaroxaban and Apixaban on PT and PTT?
Increase (Xa in both pathways)
What is the mechanism of Lepirudin, Bivalirudin, and Desirudin?
Direct Thrombin Inhibitors
What is the mechanism of Argatroban?
Direct Thrombin Inhibitor
What is the mechanism of Dabigatran?
Direct Thrombin Inhibitor
How do Direct Thrombin Inhibitors affect coagulation assays?
- Prolong PT, PTT, and thrombin time
Which 2 Anticoagulants prolong thrombin time?
Direct Thrombin Inhibitors
UF Heparin
(inhibit thrombin function)
Patients with HIT should be initiated on which drug?
Direct Thrombin Inhibitors
Bivalirudin is used in
Acute coronary syndromes
Dabigatran is used to treat
- A fib, as an alternative to warfarin
- does not require monitoring
What is the mechanism of Warfarin?
Inhibits Vitamin K epoxide reductase → ↓ vitamin K dependent factors (II, VII, IX, X)
What is the role of Vitamin K in activating clotting factors?
Forms γ-carboxyglutamate(Gla) residues in the clotting factors
What are the 2 forms of vitamin K? Where are they found?
K1: found in green leafy vegetables
K2: synthesized by GI bacteria
Why does Warfarin take days to achieve its effect?
Inhibits formation of clotting factors, no effect on already circulating clotting factors
[PT/PTT] is more sensitive to the effects of Warfarin
PT (extrinsic pathway)
Dosing of Warfarin? Why?
- Dose monitored and adjusted to reach target PT/INR
- Drug effect varies with amount of Vitamin K in the body
Which coagulation factor is the first to fall with Warfarin use? Why?
Factor VII (shortest half life)
Thrombin time with Warfarin use?
Normal
What is the underlying mechanism of the prothrombotic effects of Warfarin?
- Warfarin also inhibits production of Vitamin K dependent Protein C (anti-clotting factor with short half life)
- Initial Warfarin Rx → Protein C deficient
Warfarin is often started without heparin in what condition?
A Fib
What are adverse effects of Warfarin?
- Crosses placenta → fetal warfarin syndrome
- Bleeding
- Skin necrosis
[Unfractionated heparin/Warfarin] is often used in pregnancy. Why?
UF heparin, does not cross placenta
Who is at risk for Warfarin Skin Necrosis? What symptoms does this cause?
- Patients with protein C deficiency
- Thrombosis of skin tissues → large purple skin lesions
What are 3 uses for Warfarin?
- Stroke prevention atrial fibrillation
- Mechanical heart valves
- DVT/PE
What is a downside of Warfarin use?
requires INR checks (monthly blood draw)
What are Novel Oral Anticoagulants? Examples?
- Alternative to Warfarin
Factor Xa inhibitors: Rivaroxaban, Apixaban
Direct Thrombin inhibitors: Dabigatran
What is the upside to using Novel Oral Anticoagulants vs Warfarin? Downside?
- No INR checks, consistent dose
- Expensive, no reversal agent (except for Dabigatran)
What is the reversal agent for Dabigatran?
Idarucizumab
What are 3 thrombolytics drugs? What is a side effect?
- tPA, Urokinase, Streptokinase
- MAJOR bleeding risk
What are the reversal agent for Anticoagulants?
Fresh frozen plasma: corrects deficiencies of any clotting factor
What are 2 reversal agents for Warfarin? When are they used?
- Fresh frozen plasma (used with severe bleeding + ↑INR)
- Vitamin K (used with ↑ INR in absence of serious bleeding)
What is the target INR for most patients on Warfarin?
3-Feb
Increasing INR levels and Warfarin use
INR 3-5: Hold warfarin
INR 5-9: Hold warfarin, Oral vitamin K
INR >9: Consider IV vitamin K, FFP
Normocytic anemia may result from what 2 mechanisms?
Non-hemolytic (low production)
Hemolytic (increased destruction)
What are 3 extrinsic causes of Hemolysis?
- Antibodies
- Mechanical trauma (narrow vessels)
- RBC infection
What are intrinsic causes of Hemolysis? What are examples?
Failure of membrane, hemoglobin, or enzymes
- Membrane: Hereditary spherocytosis
- Enzyme: G6PD deficiency
- Hemoglobin: Sickle cell anemia (Abnormal Hgb)
What are 6 hallmarks of Hemolysis?
- Normocytic anemia
- Elevated plasma LDH (Converts pyruvate to lactate, spills out of RBC)
- Increased reticulocyte count (hemolysis → increase EPO → increase reticulocyte)
- Elevated indirect bilirubin → jaundice
- Increased risk of pigment stones
- Decreased Haptoglobin (lower in intravascular)
- Urine Hgb and hemosiderin (intravascular)
What is a key blood test in normocytic anemias? What does this differentiate?
Corrected Reticulocyte Count (corrected for degree of anemia)
- Low: underproduction
- High: increased destruction (hemolysis)
How do you calculate the Corrected Reticulocyte Count? What does <2% mean?
<2% = inadequate bone marrow response, underproduction
reticulocyte % × (patient Hct/normal Hct)
What is the purpose of Reticulocyte Production Index (RPI)? How to calculate?
Corrects longer life of reticulocytes
What does a low corrected reticulocyte count indicate?
Underproduction of reticulocytes.
What does a high corrected reticulocyte count indicate?
Increased destruction (hemolysis) of red blood cells.
How do you calculate the Corrected Reticulocyte Count?
Reticulocyte % × (patient Hct/normal Hct).
What does a corrected reticulocyte count of <2% mean?
<2% indicates inadequate bone marrow response, underproduction.
What is the purpose of the Reticulocyte Production Index (RPI)?
It corrects for the longer life of reticulocytes in anemia.
What does an RPI of <2% suggest?
<2% suggests bone marrow failure.
Where does extravascular hemolysis occur?
In the liver and spleen.
What type of anemia is caused by increased hemolysis?
Normocytic anemia.
What are the Cords of Billroth?
Vascular channels in the spleen that end blindly, where old/damaged RBCs are phagocytosed.
What is a main cause of intravascular hemolysis?
Narrowed vessels leading to mechanical trauma, such as thrombus in small vessels.
What is haptoglobin and how does its level change with hemolysis?
Haptoglobin is a plasma protein that binds free hemoglobin and is removed by the liver. Its levels decrease with hemolysis.
What are haptoglobin levels in intravascular vs extravascular hemolysis?
Intravascular: low or indetectable; Extravascular: low or normal.
What organ produces haptoglobin?
The liver.
What is haptoglobin classified as?
An acute phase reactant that increases with inflammation.
What are three urine findings seen in hemolysis?
No bilirubin, hemoglobinuria when haptoglobin is saturated, and hemosiderinuria.
What can cause urine to turn red/brown?
Hemolysis (Hgb) and rhabdomyolysis (myoglobin).
What does a urine dipstick with no red cells plus + Hgb suggest?
Hemolysis or rhabdomyolysis.
What type of cells does Parvovirus B19 replicate in?
RBC progenitor cells.
What does Parvovirus B19 infection lead to in patients with chronic hemolysis?
Severe anemia (‘Aplastic crisis’).
What are two reasons for back/abdominal pain in some hemolytic disorders?
Splenomegaly and decreased nitric oxide leading to smooth muscle spasm.
What are two hemolytic disorders that commonly present with back/abdominal pain?
G6PD deficiency and paroxysmal nocturnal hemoglobinuria (PNH).
What is Autoimmune Hemolytic Anemia?
RBC destruction from autoantibodies, resulting in extravascular hemolysis.
What are the two types of Autoimmune Hemolytic Anemia?
Warm and Cold; warm is more common.
What characterizes Warm Autoimmune Hemolytic Anemia?
IgG antibodies against RBC surface antigens that bind at body temperature (37C).
What symptoms are seen in Warm Autoimmune Hemolytic Anemia?
Anemia, jaundice, splenomegaly, pallor, fatigue, tachycardia, dyspnea.
What are two diagnostic findings of Warm AIHA?
Spherocytes on blood smear and positive Direct Antiglobulin Test (DAT).
How is a direct Coombs test performed?
Patient RBCs plus anti-IgG antiserum; positive if agglutination occurs.
What does the Indirect Antiglobulin Test/Indirect Coombs test for?
It tests for antibodies in the patient’s serum.
What does the Direct/Indirect Coombs test test for?
Direct tests for antibodies bound to RBC; Indirect tests for antibodies in the serum.
Which Coombs test is commonly used in hemolytic anemia?
Direct Coombs test.
What conditions is Warm AIHA associated with?
Lupus, Non-Hodgkin lymphoma, Chronic lymphocytic leukemia (CLL), Methyldopa use.
What is the mechanism of action of Methyldopa?
CNS α2 receptor agonist; antihypertensive drug of choice in pregnancy.
Why is Methyldopa associated with Warm Autoimmune Hemolytic Anemia?
It triggers production of RBC antibodies and may alter Rh antigen on red cells.
What adverse effect can high doses of penicillin lead to?
Hemolytic anemia.
What is the underlying mechanism of hemolytic anemia with high dose penicillin use?
Penicillin binds to RBC, forming a haptan that elicits an immune response.
What are two drugs that can lead to a positive direct Coombs test?
Penicillin and Methyldopa.
What are three treatments for Warm Autoimmune Hemolytic Anemia?
Glucocorticoids, immunosuppressants, splenectomy.
What is Cold Autoimmune Hemolytic Anemia?
Large IgM antibodies bind at <30C, leading to complement fixation and RBC agglutination.
Where does Cold Autoimmune Hemolytic Anemia occur in the body?
In limbs, fingertips, toes, nose, and ears.
What unique symptoms are seen in Cold Autoimmune Hemolytic Anemia?
Purple discoloration and pain in fingers/toes, symptoms associated with cold exposure.
What protein is Cold Autoimmune Hemolytic Anemia Direct Coombs positive for?
C3, because IgM is lost in warm central organs.
What antibodies are added in Direct Coombs for Cold Autoimmune Hemolytic Anemia?
Anti-C3.
What type of hemolysis does Cold Autoimmune Hemolytic Anemia cause?
Extravascular hemolysis.
Why does Cold Autoimmune Hemolytic Anemia rarely cause intravascular hemolysis?
RBC has complement inhibitory molecules (CD55/CD59).
What conditions is Cold Autoimmune Hemolytic Anemia associated with?
Chronic lymphocytic leukemia (CLL), Mycoplasma pneumonia, Epstein-Barr virus.
What is the treatment for Cold Autoimmune Hemolytic Anemia?
Avoid the cold and immunosuppressants.
What causes Microangiopathic hemolytic anemia?
Thrombi in microvasculature cause narrowing and shearing of RBCs.
What is a characteristic finding of Microangiopathic hemolytic anemia on blood smear?
Schistocytes.
What conditions is Microangiopathic hemolytic anemia seen in?
TTP, HUS, DIC, Malignant Hypertension.
What is Mechanical hemolysis?
Shear forces destroy RBCs in large blood vessels.
What conditions is Mechanical hemolysis seen in?
Aortic stenosis, mechanical heart valves, left ventricular assist devices.
What are two classic infectious agents that cause Red Blood Cell Infections?
Malaria and Babesia.
What is Paroxysmal Nocturnal Hemoglobinuria?
RBC destruction via the complement system due to a genetic mutation.
What is the mechanism of disease in Paroxysmal Nocturnal Hemoglobinuria?
Loss of GPI anchor leads to loss of DAF/CD55 and CD59 on RBC membranes.
What type of hemolysis does Paroxysmal Nocturnal Hemoglobinuria predominantly cause?
Intravascular hemolysis.
What is the clinical presentation of Paroxysmal Nocturnal Hemoglobinuria?
Sudden hemolysis at night, fatigue, dyspnea, abdominal pain, thrombosis.
What deficiency is common in Paroxysmal Nocturnal Hemoglobinuria?
Iron deficiency.
What is the leading cause of death in Paroxysmal Nocturnal Hemoglobinuria?
Thrombosis.
What diagnostic test confirms Paroxysmal Nocturnal Hemoglobinuria?
Flow cytometry.
What are four lab findings seen in Paroxysmal Nocturnal Hemoglobinuria?
Elevated LDH, low haptoglobin, hemoglobinuria/hemosiderinuria, negative direct Coombs test.
What is the mechanism of Eculizumab?
It binds complement component C5, blocking formation of the membrane attack complex.
What type of hemolysis does Eculizumab protect against?
Intravascular hemolysis.
What are the results of treating Paroxysmal Nocturnal Hemoglobinuria with Eculizumab?
Stable Hgb levels and fewer transfusions.
What cells are most affected by Pyruvate Kinase Deficiency?
RBCs, as they require PK for anabolic metabolism.
What does membrane failure with RBC commonly lead to?
Phagocytosis in the spleen.
What is the inheritance pattern of Pyruvate Kinase Deficiency?
Autosomal recessive.
When does Pyruvate Kinase Deficiency usually present?
In newborns.
What type of hemolysis does Pyruvate Kinase Deficiency cause?
Extravascular hemolysis.
What physical finding is commonly associated with Pyruvate Kinase Deficiency?
Splenomegaly.
What is Glucose-6-Phosphate Dehydrogenase’s role?
It is a key enzyme in the HMP shunt.
What is the HMP shunt necessary for?
The generation of NADPH.
What does NADPH protect RBCs from?
Oxidative stress.
What is the inheritance pattern of G6PD Deficiency?
X-linked recessive.
What does G6PD Deficiency present with?
Recurrent hemolysis after exposure to triggers.
What type of hemolysis is seen in G6PD Deficiency?
Mostly extravascular, with some intravascular.
What are three triggers for G6PD Deficiency?
Infection, fava beans, and certain drugs.
Where is G6PD deficiency highly prevalent?
Africa and the Mediterranean.
What are two classic findings on blood smear in G6PD deficiency?
Heinz bodies and bite cells.
