Anemias, Thrombotic Disorders, Bleeding Disorders Flashcards
What is the definition of anemia?
A reduction in circulating RBC mass.
Name six clinical manifestations of anemia.
- Weakness
- Fatigue
- Dyspnea
- Pale conjunctiva and skin
- Headache, lightheadedness
- Angina, especially when there is pre-existing CAD
What serum Hb value is the cutoff for anemic/not anemic in males and females, respectively?
Anemia is Hb < 13.5g/dL in males and < 12.5g/dL in females
What values correspond to normal MCV?
80-100 fL
What is the differential for macrocytic anemias?
- B12 deficiency
- Folate deficiency
- Orotic aciduria
- Alcoholism
- Liver disease
- Drugs (ex. 5-FU)
Other than measuring serum folate and B12 levels, how can you figure out which is deficient in a person with a macrocytic anemia?
Serum homocysteine and methylmalonic acid levels. If both are elevated, the patient has a B12 deficiency. If only homocysteine is elevated, the patient has a folate deficiency.
What would you see on a blood smear in a patient with megaloblastic anemia?
- Macroovalocytes
2. Hypersegmented neutrophils (>5 lobes)
What is megaloblastic anemia?
A macrocytic anemia caused by either B12 or folate deficiency.
Characterized by macroovalocytes and hypersegmented neutrophils on blood smear, as well as megaloblastic changes in rapidly-dividing cells like GI epithelial cells.
Where along the GI tract is folate absorbed?
Jejunum
In what foods are folate found?
Green vegetables, fruits
Your patient is anemic and a blood smear shows macrocytosis. On physical exam you note glossitis. What diagnosis does this exam finding support?
This supports a B12 or folate deficiency anemia (megaloblastic anemia)
Methotrexate inhibits _________ (an enzyme) and can potentially cause _______ deficiency.
inhibits DHF reductase, can cause folate deficiency
Does the body store much folate? How long does it take to develop a folate deficiency if one suddenly stops eating foods containing folate?
Folate stores are minimal; folate deficiency can develop within months
Describe the process of absorption of B12 in the GI tract.
- B12 binds to haptocorrin/R-binder/transcobalamin, which is made by salivary glands
- In the duodenum, pancreatic enzymes cause dissociation of B12-haptocorrin
- B12 attaches to intrinsic factor
- In the distal ileum, B12-IF binds to cubilin receptors on epithelial cells –> endocytosis
- B12 is released into the blood and binds to transcobalamin/haptocorrin, which is the transport protein for B12 in the blood –> liver (principal storage site for B12)
What foods are B12 found in?
Fish, meat, dairy
Does the body store much B12? How long does it take to develop a B12 deficiency if one suddenly stops eating foods containing B12?
Liver stores a lot of B12 so it takes years to develop B12 deficiency
What is pernicious anemia?
Autoimmune destruction of gastric parietal cells (that make acid and intrinsic factor) –> B12 deficiency
Your anemic patient has lower extremity weakness and hyperreflexive achilles and patellar reflexes. What is possibly going on?
Subacute combined degeneration of the spinal cord from build-up of methylmalonic acid (from B12 deficiency)
Vegans can potentially develop a _____ deficiency due to not ingesting much of it.
B12
In general, anything that disrupts synthesis of ___________ can cause a microcytic anemia.
hemoglobin
What is the differential diagnosis for microcytic anemias?
- Iron deficiency
- Anemia of chronic disease
- Sideroblastic anemia
- Thalassemias
In the early stages of iron deficiency, which lab value would most likely be low: serum iron, TIBC, % saturation, or serum ferritin?
Serum ferritin, because this measures intracellular iron stores, and this is what decreases first
Your anemic patient has mildly low serum iron levels and % iron saturation, but has normal-sized RBCs on blood smear. What is an explanation for this?
Early iron deficiency anemia can cause a normocytic anemia. This is when the bone marrow is simply making fewer RBCs, but they’re normal in morphology.
Other than the six general clinical manifestations of anemia, name two more findings that would be suggestive of iron-deficiency anemia.
- Koilonychia
2. Pica
Describe the pathophysiology of anemia of chronic disease.
Inflammation –> IL-6 upregulation –> upregulation of hepcidin –> endocytosis and degradation of ferroportin –> iron is locked in cells –> microcytic, hypochromic anemia
Hepcidin also suppresses EPO production
What is the treatment for iron-deficiency anemia?
Supplemental iron (oral ferrous sulfate)
What is the most common mutation responsible for hereditary hemochromatosis?
HFE gene mutation
Describe the pathophysiology of hereditary hemochromatosis.
Mutated hepcidin –> uncontrolled uptake and release of iron –> iron overload
You see a patient with a chief complaint of impotence. It is in the middle of winter and the patient is very tan. He also has a laterally displaced cardiac apex and a systolic murmur radiating to the back. What is the treatment for the likely disease this person has?
Hereditary hemochromatosis –> iron overload –> hemosiderin deposition in skin (tan skin) and in myocardium –> congestive HF
Treatment is regular phlebotomies
What syndrome is characterized by the triad of iron-deficiency anemia, dysphagia from esophageal web, and glossitis?
Plummer-Vinson syndrome
Ring sideroblasts are erythroblasts with excess iron inside ________ (an organelle) that stain strongly with prussian blue stain. What is the congenital (inherited) defect that can cause this? How can one acquire this?
This is sideroblastic anemia, a problem with protoporphyrin synthesis.
Iron builds up inside mitochondria in erythroblasts.
Congenital cause: ALA-synthase mutation (1st, rate-limiting step in porphyrin synthesis)
Acquired: toxins: lead poisoning (denatures ALA-DH and ferrochetalase), ethanol, chloramphenicol, isoniazid, B6 deficiency (ALA-S needs it)
Describe the expected lab values one would see in sideroblastic anemia.
It is an iron-overloaded state…
increased ferritin, decreased TIBC, increased serum iron, increased % saturation
What is the differential Dx for normocytic anemias w/ fragments and/or schistocytes on a blood smear?
- Paroxysmal nocturnal dyspnea
- G6PD deficiency
- Immune hemolytic anemia
- TTP
- HUS
- DIC
- Prosthetic heart valves/aortic stenosis
- Malaria
Describe the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH).
Acquired defect of the GPI in the myeloid stem cell –> DAF (CD55) and MIRL (CD59) can’t attach to RBC surface –> CD55 can’t degrade C3b and CD59 can’t prevent MAC formation –> red cell lysis at night when there is respiratory acidosis (which increases complement activity) from hypoventilation –> hemoglobinuria
What is the main cause of death in patients with PNH?
Thrombosis of hepatic, portal, or cerebral veins (cell fragments activate coagulation cascade in vessels)
Your patient presents with back pain and hemoglobinuria, and you see Heinz bodies and bite cells on peripheral blood smear. What is your Dx?
G6PD deficiency
What are Heinz bodies?
Precipitates of hemoglobin that occur in RBCs of G6PD deficiency patients after oxidative stress insult
What does a positive Coombs test tell you? What is the difference between an indirect and direct Coombs test?
Positive test = immune hemolytic anemia
Direct test looks for IgG already on the patient’s RBCs, indirect tests looks for antibodies in serum and uses a known sample of good RBCs (after they are mixed, clumping means antibodies were in the serum)
What is the treatment for immune hemolytic anemia? What about ITP?
Treatment is the same for both.
Corticosteroids and IVIG to overwhelm splenic macrophages. Rituximab is may be used in patients with warm (IgG) autoantibodies. Splenectomy is last resort
What Ig subtype is involved in warm immune hemolytic anemia? What about cold immune hemolytic anemia? Which one results in an intravascular hemolysis and which one results in an extravascular hemolysis?
IgG = warm --> extravascular hemolysis (IgG opsonizes RBCs --> eaten by splenic macrophages) IgM = cold --> intravascular hemolysis (IgM fixes complement --> MAC --> RBC lysis)
What infections are associated with IgM-mediated immune hemolytic anemia?
Mycoplasma pneumoniae and EBV
Name two diseases that are associated with IgG-mediated immune hemolytic anemia.
- SLE
2. Chronic lymphocytic leukemia (CLL)
What finding would one expect to see on a peripheral blood smear from a patient with microangiopathic hemolytic anemia?
Schistocytes/fragments
What is the differential for microangiopathic hemolytic anemia?
TTP, HUS, DIC
How can one distinguish TTP from HUS with regards to clinical symptoms/presentation?
The predominant symptom in TTP is CNS/neurologic abnormalities, while the predominant symptom in HUS is renal insufficiency.
HUS usually occurs in kids following a diarrheal illness. TTP often occurs following a viral illness.
Classic patient in TTP is an adult female w/ another autoimmune condition
What is the mnemonic for clinical symptoms of HUS/TTP?
FAT RN: Fever Anemia Thrombocytopenia Renal insufficiency Neurologic abnormalities
Describe the pathogenesis of TTP.
Can be congenital or acquired.
Mutation or autoimmune attack (following illness) on ADAMTS13 –> no cleavage of vWF multimers –> platelet aggregation in microvessels –> RBCs are sheared as they pass by
Describe the pathogenesis of HUS.
E. coli O157:H7 shiga-like toxin damages endothelium –> platelet aggregation in microvessels –> RBCs are sheared
What would you expect PT and PTT to be (normal, prolonged) in patients with microangiopathic hemolytic anemia?
Normal! It is not a problem with secondary hemostasis.
Name four qualitative platelet disorders.
- Bernard-Soulier
- Glanzmann thrombasthenia
- Aspirin overdosase
- Uremia
Describe the pathogenesis of Bernard-Soulier syndrome.
Genetic GPIb deficiency (the GP that platelets use to attach to vWF) —> impaired platelet adhesion
Describe the pathogenesis of Glanzmann thrombasthenia.
Genetic GPIIb/IIIa deficiency or autoimmune (antibody) attack on GPIIb/IIIa (the GP that platelets use to attach to fibrinogen for aggregation) —> impaired platelet aggregation
Describe the pathogenesis of heparin induced thrombocytopenia.
Heparin forms a complex with platelet factor 4 on the surface of platelets –> IgG antibodies are made against this complex –> platelet activation and consumption –> thrombocytopenia
What is the treatment for heparin induced thrombocytopenia?
Stop heparin and give a direct thrombin inhibitor like dabigatran instead.
What is the treatment for DIC? Should you transfuse patients?
Treat underlying cause. Only transfuse w/ blood or CCP if the patient is bleeding.
Briefly describe what primary and secondary hemostasis are.
Primary hemostasis is formation of a platelet plug, and secondary hemostasis is stabilization of the plug via the coagulation cascade.
Which glycoprotein on platelets binds to vWF during primary hemostasis?
GPIb
After platelet aggregation, what mediators do they release to recruit more platelets? What mediator stimulates the expression of GPIIb/IIIa?
TXA2 is released, which recruits more platelets. ADP induces platelets to express GPIIb/IIIa.
What clinical features are typically seen in disorders of primary hemostasis? What about secondary hemostasis?
Primary hemostasis disorders: Epistaxis, mucosal bleeding, menorrhagia, easy bruising, petechiae, purpura.
Secondary hemostasis: deep tissue bleeding, joint bleeding, post-op bleeding.
What is the most common cause of thrombocytopenia?
Idiopathic thrombocytopenic purpura (ITP)
Describe the pathogenesis of ITP.
Unknown insult triggers the production of IgG against platelet antigens like GPIIb/IIIa
Describe the two types of ITP with respect to their typical clinical presentations.
Acute ITP: seen in kids usually after a viral infection or immunization; self-limited
Chronic ITP: seen in adults, often seen in people with other autoimmune conditions, relapse is common
What would a bone marrow biopsy in a patient with ITP show?
Hyperplasia of megakaryocytes
What is the treatment for ITP?
IVIG to overwhelm splenic macrophages
If you suspect a patient has a disorder of primary hemostasis but has normal platelet counts, what diseases might you consider?
Qualitative platelet disorders: Aspirin overdosage, uremia, Glanzmann thrombasthenia, Bernard-Soulier syndrome
What are the molecular defects involved in Bernard-Soulier and Glanzmann thrombasthenia, respectively?
Bernard-Soulier: mutated GPIb –> no binding to vWF
Glanzmann: mutated GPIIb/IIIa –> no platelet aggregation (can’t bind to each other via fibrinogen)
Would a ristocetin assay cause clumping in a patient with Bernard-Soulier syndrome? What about von Willebrand disease?
No, no
What is the most common inherited clotting disorder amongst caucasians? What is the pathophysiology of this disease?
Factor V leiden. Mutated form of factor V that lacks a cleavage site for protein C (and S as a cofactor for the cleavage rxn) –> increased thrombosis risk
What the hell is prothrombin 20210A?
Inherited point mutation of prothrombin —> excess production of prothrombin —> more fibrinogen —> fibrin
How do oral contraceptives cause increased risk of thrombosis?
Estrogen induces production of coagulation factors
The effects of heparin administration are measured by _____. This measures the ______ pathway.
PTT - intrinsic pathway
The effects of warfarin administration are measured by _____. This measures the ______ pathway.
PT/INR - extrinsic pathway
Which coagulation factor is NOT made by the liver?
factor VIII
Hemophilia A is due to a factor _____ deficiency, so patients have a prolonged _____ time.
factor VIII deficiency –> PTT time is prolonged
What is the treatment for the hemophilias?
Recombinant factor replacement
What test can you use to determine if a patient has a simple factor deficiency or if they have an inhibitor?
Mixing study - mix patient’s blood with a known sample of normal blood. If the clotting times do NOT correct there is an inhibitor present.
Which clotting factors are vitamin K dependent?
factors II, VII, IX, X, proteins C and S
How does liver failure cause a disorder of secondary hemostasis?
Most factors are made there; vitamin K is also activated in the liver
How do you treat anemia of renal insufficiency and what should your target Hb levels be?
Recombinant EPO. Target Hb level should be 12g/dL
What red cell morphology is typical of anemia due to chronic liver disease?
Normocytic or mildly macrocytic w/ target cells
What causes Fanconi anemia? Name four clinical manifestations.
Due to a defect in DNA repair.
Clinical:
- Aplastic anemia/marrow failure
- Cafe-au-lait spots
- Short stature
- Gonadal, renal, skeletal defects (lacking a thumb is common)
What diseases/factors are associated with acquired factor XIII deficiency?
- Major surgery (it is consumed)
2. Development of autoantibodies: SLE, leukemia, liver disease, DIC, inflammatory bowel disease, meds
What is the treatment for factor XIII deficiency?
Replacement w/ FFP, CCP, or factor XIII concentrates
Describe the pathogenesis of the two diseases that may cause acquired disorder of fibrinolysis.
End-stage liver disease: reduced levels of alpha-2 antiplasmin –> plasmin degrades clots
Acute promyelocytic leukemia: overexpresion of tPA-cofactor –> lots of tPA activity –> fibrinolysis
Name two tests that help you evaluate platelet function.
PFA-100 (platelet function analyzer) and platelet aggregometry
How does antithrombin work?
It inhibits factors in the coagulation cascade, most notably factors Xa and thrombin
