Bleeding Disorders & Anemia Flashcards
Disorders of primary hemostasis are usually due to abnormalities in ________; they are divided into quantitative or qualitative disorders
Platelets
General clinical features seen when there is a disorder of primary hemostasis
Mucosal and skin bleeding
Symptoms of mucosal bleeding include epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.
Symptoms of skin bleeding include petechiae, purpura, ecchymoses, and easy bruising
_______ are a sign of thrombocytopenia and are not usually seen with qualitative disorders
Petechiae
Useful lab studies in a pt presenting with mucosal and/or skin bleeding (suggesting problem with primary hemostasis)
Platelet count — lets us know if quantitative problem
Blood smear — can roughly estimate platelet count and look at size
Bone marrow biopsy — check for megakaryocytes
Bleeding time (primitive test - not as commonly used; normal is 2-7 minutes)
List disorders of primary hemostasis
Immune thrombocytopenic purpura (ITP)
Microangiopathic Hemolytic Anemia (MAHA)
Thrombotic Thrombocytopenic Purpura
Hemolytic Uremic Syndrome
Bernard-Soulier syndrome
Glanzmann Thrombasthenia
Other: ASA administration, Uremia
[ITP, MAHA, TTP, HUS are quantitative disorders; BS, GT, ASA admin, and uremia are qualitative disorders]
Most common cause of thrombocytopenia in children and adults
ITP
[usually acute ITP in kids, chronic ITP in adults]
What causes ITP?
Autoimmune production of IgG against platelet antigens (e.g., GPIIb/IIIa)
Autoantibodies are produced by plasma cells in the spleen. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia
Describe acute vs. chronic ITP
Acute form arises in children — weeks after viral infection or immunization. Self-limited and usually resolves within weeks of presentation.
Chronic form arises in adults — usually women of childbearing age. May be primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in offspring; anti-platelet IgG can cross the placenta
Lab findings in ITP
[platelet count, PT, PTT, findings on bone marrow bx]
Decreased platelet count, often <50K/ul
Normal PT/PTT
Increased megakaryocytes on bone marrow bx
3 Treatment options for ITP
Initial tx is corticosteroids [children respond well to corticosteroids; adults may show early response, but often relapse]
IVIG can raise the platelet count in symptomatic bleeding but effect is short-lived (macrophages eat the IVIG instead of the pts own platelets, but only until the IVIG is all eaten up)
Splenectomy — eliminates primary source of antibody and site of destruction; only performed in refractory cases
Pathogenesis of microangiopathic hemolytic anemia (MAHA)
Pathologic formation of platelet microthrombi in small vessels
Platelets are consumed in the formation of these microthrombi. Also, RBCs are “sheared” as they cross the microthrombi, resulting in hemolytic anemia with schistocytes
Microangiopathic hemolytic anemia is associated with what 2 conditions?
Thrombotic Thrombocytopenic Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)
TTP is caused by deficiency in _______ which is required to cleave vWF multimers into smaller monomers for eventual degradation. Large, uncleaved multimers lead to abnormal platelet _______, resulting in ________
ADAMSTS13; adhesion; microthrombi
What is the most common cause of decreased ADAMSTS13 in TTP?
Acquired autoantibody; most commonly seen in adult females
Hemolytic uremic syndrome is due to endothelial damage by drugs or infection. HUS is classically seen in what setting, and how does this lead to MAHA?
Classically seen in children with E.coli O157:H7 dysentery
Results from exposure to undercooked beef
E.coli verotoxin (shiga-like toxin) damages endothelial cells, resulting in platelet microthrombi —> MAHA
Clinical findings of TTP and HUS
Skin and mucosal bleeding Microangiopathic hemolytic anemia Fever Renal insufficiency CNS abnormalities
[Note: TTP and HUS cannot be distinguished from each other based on clinical findings alone]
Lab findings in TTP and HUS
[platelet count, bleeding time, PT, PTT, peripheral smear, bone marrow bx]
Thrombocytopenia with increased bleeding time
Normal PT/PTT
Anemia with schistocytes on PB smear
Increased megakaryocytes on bone marrow bx
Treatment for TTP and HUS
Plasmapheresis and corticosteroids, particularly in TTP
[note: plasmapheresis removes auto-ab to ADAMSTS13]
What is Bernard-Soulier syndrome and how does it present on blood smear?
Genetic GPIb deficiency — platelet adhesion is impaired
Blood smear shows mild thrombocytopenia with enlarged platelets
[Bernard-Soulier = Big Suckers — refers to enlarged platelets]
What is Glanzmann thrombasthenia?
Genetic GPIIb/IIIa deficiency — platelet aggregation is impaired
How does aspirin affect primary hemostasis?
ASA irreversibly inactivates cyclooxygenase
Lack of TXA2 (usually derived from platelet cyclooxygenase) —> impairs platelet aggregation
_____ disrupts platelet function such that both adhesion and aggregation are impaired; this is due to the buildup of nitrogenous waste products
Uremia
Disorders of secondary hemostasis are usually due to factor abnormalities. What are the general clinical features of disorders of secondary hemostasis?
Deep tissue bleeding into muscles and joints
Rebleeding after surgical procedures
2 most useful lab studies to evaluate secondary disorders of hemostasis, and what they measure
PT — measures extrinsic and common pathways
PTT — measures intrinsic and common pathways
Etiology of hemophilia A
Genetic factor 8 deficiency
X-linked recessive inheritance — predominantly affects males
Can arise from a new mutation without any family history
Clinical presentation of hemophilia A
Deep tissue, joint, and postsurgical bleeding
Clinical severity depends on degree of deficiency
Lab findings in hemophilia A
[PTT, PT, coag factors, platelet count, bleeding time]
Prolonged PTT; normal PT
Decreased factor VIII levels
Normal platelet count and bleeding time
Treatment for hemophilia A
Recombinant factor VIII
What causes hemophilia B
Genetic factor IX deficiency
Resembles hemophilia A, except factor 9 levels are decreased instead of factor 8
[Note: Hemophilia B is also called Christmas disease]
A coagulation factor inhibitor is an acquired antibody against coagulation factor resulting in impaired factor function. The most common acquired antibody is _____
Anti-factor VIII
An anti-factor VIII coagulation factor inhibitor will present the same as hemophilia A in terms of most clinical and lab findings. What test can be used to differentiate the two?
Mixing study
With anti-factor VIII, PTT does not correct upon mixing normal plasma with pts plasma since inhibitor is present.
PTT does correct in hemophilia A, which is simply a deficiency of one of the factors
Most common inherited coagulation disorder and the most common type
Von Willebrand Disease; most common subtype is Autosomal Dominant with decreased vWF levels (quantitative problem resulting in defective adhesion and presenting with mucosal and skin bleeding)
[VWD is a genetic vWF deficiency — multiple subtypes exist etiology can be quantitative or qualitative defects in vWF]
Lab findings associated with von willebrands disease
[bleeding time, PTT, PT, other tests]
Increased bleeding time
Prolonged PTT, normal PT
Abnormal ristocetin test — no aggregation occurs on addition of ristocetin
[Note: PTT is prolonged because vWF normally stabilizes factor VIII, but PTT is not usually prolonged enough to alter secondary hemostasis]
Treatment for von willebrands disease
Desmopressin — increases vWF release from Weibel-Palade bodies of endothelial cells
What nutritional deficiency disrupts function of factors 2, 7, 9, protein C and protein S?
Vitamin K (required for gamma carboxylation of factors 2, 7, 9, C, and S)
Vitamin K deficiency disrupts the function of what coagulation factors?
Factor II Factor VII Factor IX Protein C Protein S
What are 3 conditions in which vitamin K deficiency is common?
Newborns — gut is not yet colonized; all newborns are given vitamin K
Long-term antibiotic therapy — gut flora is killed off
Malabsorption (especially fat malabsorption)
What are the 2 reasons why liver failure causes problems of secondary hemostasis?
Decreased production of coagulation factors
Decreased activation of vitamin K by epoxide reductase
The effect of liver failure on coagulation is followed using what lab test?
PT
How do large-volume transfusions affect hemostasis?
Large-volume transfusions may cause disorder of secondary hemostasis by diluting coagulation factors, resulting in relative deficiency
What is Heparin-induced Thrombocytopenia (HIT)?
Platelet destruction that arises secondary to heparin therapy
Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis
[caused by IgG antibodies to platelet factor 4 (PF4); Also note it is a thrombocytopenia that results in THROMBOSIS, not bleeding. Treatment is to stop heparin and begin another anticoagulant, but coumadin/warfarin cannot be used because there is increased risk of skin necrosis in these pts]
What is DIC?
Pathologic activation of the coagulation cascade —> widespread microthrombi resulting in ischemia and infarction
Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces
DIC is almost always secondary to another disease process. What are some examples of common preceding conditions?
Obstetric complication Sepsis Adenocarcinoma Acute promyelocytic leukemia Rattlesnake bite
Lab findings in DIC
[platelet count, PT, PTT, fibrinogen, peripheral blood, d-dimer]
Decreased platelet count Prolonged PT and PTT Decreased fibrinogen Microangiopathic hemolytic anemia Elevated fibrin split products (D-Dimer)
[Note: elevated D-dimer is best screening test for DIC]
Treatment for DIC
Address underlying cause!
Transfuse blood products and cryoprecipitate as needed
Disorders of fibrinolysis are due to ______ overactivity resuling in excessive cleavage of fibrinogen. These disorders present with increased bleeding and often resemble ____
Plasmin; DIC
[tPA is what allows for conversion of plasminogen to plasmin. Plasmin cleaves fibrin and serum fibrinogen — thus lysing the clot that exists, and preventing further clotting from occurring]
Examples of disorders of fibrinolysis include radical prostatectomy, in which release of ______ activates plasmin; and cirrhosis of the liver, in which there is reduced production of ________
Urokinase; alpha2-antiplasmin
Lab findings of disorders of fibrinolysis
[PT, PTT, bleeding time, platelet count, d-dimer]
Prolonged PT and PTT
Increased bleeding time with normal platelet count
Increased fibrinogen split products WITHOUT D-dimer
[distinguish from DIC based on normal platelet count and lack of d-dimer]
Treatment for disorders of fibrinolysis
Aminocaproic acid — blocks activation of plasminogen
Thrombosis is pathologic formation of intravascular blood clot. This can occur in an artery or vein. What is the most common location?
Deep vein of the leg below the knee (DVT)
What 2 morphologic features are characteristic of a thrombus, and distinguish it from a postmortem clot?
- Lines of Zahn
2. Attachment to vessel wall
3 major risk factors for thrombosis (virchows triad)
- Disruption in blood flow (stasis or turbulence)
- Endothelial cell damage
- Hypercoagulable state (excess procoagulant or defective anticoagulant proteins)
[Examples of disruptions in flow include immobilization, cardiac wall dysfunction, and aneurysm. Examples of endothelial damage include atherosclerosis, vasculitis, and high levels of homocysteine. Diseases resulting in hypercoagulable state can be inherited or acquired]
Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis. One way in which the endothelial cells are protective is by formation of a physical barrier, thus blocking exposure of subendothelial collagen. Another way in which it is protective is by production of various mediators. What are 5 mediators secreted by endothelial cells that protect against clot formation?
Prostaglandin I2 (PGI2) — blocks platelet aggregation
Nitric oxide — causes vasodilation
Heparin-like molecules — activate anti-thrombin III (inactivates thrombin and production of coagulation factors)
tPA — converts plasminogen to plasmin (cleaves fibrin, fibrinogen, destroys coagulation factors, blocks platelet aggregation)
Thrombomodulin — modulates thrombin activity so that it activates protein C, which inactivates factors V and VIII
One important cause of endothelial damage leading to thrombosis is high levels of homocysteine. What are some ways in which homocysteine levels become elevated thus leading to increased risk of thrombosis?
Vitamin B12 or folate deficiency — because pts can no longer convert homocysteine to methionine
Cystathionine beta synthase (CBS) deficiency — enzyme necessary for converting homocysteine to cystathionine
Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels with homocystinuria. What are the 4 characteristic clinical features of this disease?
Vessel thrombosis (d/t elevated homocysteine)
Mental retardation
Lens dislocation
Long slender fingers
The classic presentation of pts with a hypercoagulable state is recurrent DVTs or a DVT at a young age, usually occurring in the deep veins of the legs. Other sites include hepatic and cerebral veins.
One example of a hypercoagulable state is a deficiency in proteins C or S. How does this deficiency lead to a hypercoagulable state?
Decreases negative feedback on coagulation cascade
[Proteins C and S normally inactivate factors V and VIII]
When considering pharmacologic therapy in a pt with protein C or S deficiency, what is one important adverse effect to be aware of concerning a commonly used anti-coagulant?
Pts with protein C or S deficiency are at increased risk for warfarin skin necrosis
[Warfarin blocks epoxide reductase in the liver, that blocks activation of vitamin K, leading to reduced production of factors 2, 7, 9, 10, protein C, and protein S — and C and S are typically the first factors that get degraded. Thus these will be degraded extremely quickly pts that already do not have much protein C or S, leading to a higher overall percentage of clotting factors being present in the blood and an increased risk of thrombosis and warfarin skin necrosis]
Describe the most common inherited cause of hypercoagulable state
Factor V Leiden — mutated form of factor V that lacks cleavage site for deactivation by proteins C and S
What is prothrombin 20210A?
Inherited point mutation in prothrombin resulting in increased gene expression —> promotes thrombus formation
______ deficiency decreases the protective effect of heparin-like molecules produced by endothelium, increasing the risk for thrombus
Anti-thrombin III
Important pharmacologic consideration in utilizing heparin in pts with anti-thrombin III deficiency
In ATIII deficiency, PTT does not rise with standard heparin dosing
High doses of heparin activate limited ATIII; coumadin is then given to maintain anticoagulated state
Why are oral contraceptives associated with hypercoagulable state?
Estrogen induces increased production of coagulation factors, thus increasing risk for thrombosis
An embolism is defined as an intravascular mass that travels and occludes downstream vessels; symptoms depend on the vessel involved. What is the most common type of embolus (>95%)?
Thromboembolus — aka a thrombus that dislodges
An atherosclerotic embolus is due to a plaque that dislodges. These are characterized by the presence of ____ ____ in the embolus.
Cholesterol clefts
A fat embolus is associated with bone fractures, particularly long bones, and soft tissue trauma. This type of emboli typically develops while fracture is still present or shortly after repair. What are the characteristic clinical features of a fat embolus?
Dyspnea
Petechiae on the skin overlying the chest
In what situation are gas emboli typically seen? What are the presenting signs/symptoms?
Decompression sickness; presents with joint and muscle pain (bends) + respiratory symptoms (chokes)
Caisson disease
Chronic gas emboli, characterized by multifocal ischemic necrosis of bone
_____ embolus may occur during laparascopic surgery as air is pumped into the abdomen
Gas
Amniotic fluid emboli enter maternal circulation during labor or delivery. What is the classic clinical presentation and associated histologic features?
Presents with shortness of breath, neurologic symptoms, and DIC
Characterized by squamous cells and keratin debris from fetal skin in embolus
Pulmonary emboli are usually due to a thromboembolus. What is the most common source of thromboembolus leading to a PE?
DVT of lower extremity, usually involving femoral, iliac, or popliteal veins
T/F: most often, pulmonary emboli are clinically silent
True — lungs have dual blood supply, embolus is usually small and self-resolves
Only about 10% of pulmonary emboli cause pulmonary infarction. What are some risk factors for this complication?
Obstruction of large- or medium-sized artery with pre-existing cardiopulmonary compromise
Clinical features of pulmonary infarction, including results on V/Q scan, CT, US, and d-dimer
SOB, hemoptysis, pleuritic chest pain, and pleural effusion
V/Q scan shows mismatch; perfusion is abnormal
Spiral CT shows a vascular filling defect in the lung
LE Doppler US is useful to detect DVT
D-dimer is elevated (due to lysis of DVT and PE)
Gross exam findings of lung that has undergone pulmonary infarct
Hemorrhagic, wedge-shaped infarct
[Hemorrhagic due to dual blood supply — while one is blocked, the other continues to bring blood to the loose, damaged tissue, filling it with blood]
When is PE associated with sudden death?
Large saddle embolus or significant occlusion of a large pulmonary artery
Death is due to electromechanical dissociation
Chronic pulmonary emboli that reorganize over a period of time are associated with development of _____ _____
Pulmonary HTN
Systemic embolism is usually due to thromboembolus, most commonly arising in _____ ______. The embolus then travels through systemic circulation to occlude flow to organs, most commonly the _____ _____
Left heart; lower extremities
What are some presenting signs/symptoms of anemia?
Weakness, fatigue, and dyspnea
Pale conjunctiva and skin
Headaches and lightheadedness
Angina, especially with preexisting CAD
[aka signs and symptoms of HYPOXIA]
Anemia is a reduction in RBC mass, which is difficult to measure. What 3 lab tests are used as surrogates for RBC mass?
Hb
Hct
RBC count
[these are only surrogates because they are dependent on concentration]
Classification of anemia based on MCV
Microcytic (MCV < 80)
Normocytic (MCV 80-100)
Macrocytic (MCV > 100)
Microcytic anemias occur due to a decreased production of _____, and the microcytosis is due to an “extra” division during RBC development.
Hb
[if cells are smaller, they are able to cope with lower levels of hemoglobin]
Hemoglobin is made up of heme and globin. Heme is composed of ______ and _______. A decrease in any of these components leads to a _______ anemia
Iron; protoporphyrin; microcytic
What are the 4 microcytic anemias?
Iron-deficiency anemia
Anemia of chronic disease
Sideroblastic anemia
Thalassemia
Most common type of anemia
Iron deficiency anemia
[Lack of iron is most common nutritional deficiency in the world]
Iron is consumed in heme (meat-derived) and non-heme (vegetable-derived) forms. The ____ form is more readily absorbed. Absorption occurs in the _______, where enterocytes transport iron into blood via _________.
_______ then transports iron and delivers it to liver and bone marrow macrophages for storage. Stored intracellular iron is bound to _______
Heme; duodenum; ferroportin
Transferrin; ferritin
Lab measurements of iron status
Serum iron
Total iron binding capacity (TIBC) — tells you how much transferrin you have in the serum (whether bound or not)
% saturation — tells you how much transferrin is bound by iron
Serum ferritin — tells you how much iron is in storage sites
Iron deficiency is typically caused by dietary lack or blood loss. What are the most common causes in infants, children, adults, and elderly?
Infants — breastfeeding
Children — poor diet
Adults — peptic ulcer disease (males); menorrhagia or pregnancy (females)
Elderly — colon polyps/carcinoma (Western world); hookworm (developing world)
[other causes include malnutrition, malabsorption (celiac), and gastrectomy]
Why does gastrectomy decrease iron absorption?
The body more readily absorbs Fe2+ (as opposed to Fe3+)
Gastric acid keeps more of the iron in Fe2+ making it more readily absorbable. Following a gastrectomy, there is less acid present so there is less readily absorbable iron.
Stages of iron deficiency include depletion of storage iron, depletion of serum iron, normocytic anemia, and then eventually microcytic hypochromic anemia.
How is iron deficiency reflected on PB smear, ferritin, TIBC, serum iron, % saturation, and free erythrocyte protoporphyrin (FEP)?
Microcytic hypochromic anemia with increased RDW
Decreased ferritin, increased TIBC
Decreased serum iron, decreased % saturation
Increased FEP
Clinical features of iron deficiency
Anemia
Koilonychia (spoon-nails)
Pica (chewing dirt, ice, etc.)
Treatment of iron deficiency anemia
Supplemental iron (ferrous sulfate)
[also determine underlying cause and treat that as well]
Triad of Plummer-Vinson Syndrome
Iron deficiency anemia
Esophageal webs
Atrophic glossitis
[Clinically presents with anemia, dysphagia, and beefy-red tongue]
Most common type of anemia in hospitalized patients
Anemia of chronic disease
— typically associated with chronic inflammation or cancer
Chronic disease results in acute phase reactants, one of which is _______, which sequesters iron in storage sites. This limits iron transfer from macrophages to erythroid precursors and suppresses _____ production. Decreased availability of iron makes it a _______ anemia
Hepcidin; EPO; microcytic
Lab findings with anemia of chronic disease
[ferritin, TIBC, serum iron, %sat, FEP]
Increased ferritin, decreased TIBC
Decreased serum iron, decreased %sat
Increased FEP
Treatment of anemia of chronic disease
Address underlying cause
Exogenous EPO is useful in a subset of patients, especially those with cancer
What causes sideroblastic anemia?
Defective protoporphyrin synthesis
[decreased protoporphyrin leads to a microcytic anemia]
Protoporphyrin is synthesized via a series of reactions. The first step is conversion of _______ to aminolavulinic acid (ALA) by ______ which is the rate limiting step in production of protoporphyrin and requires ____ as a cofactor. ALA is then converted to porphobilinogen by ALA dehydrogenase.
Eventually portoporphyrin is generated and the final reaction attaches protoporphyrin to iron to make heme using the enzyme ________, which occurs in the ________
Succinyl CoA; aminolavulinic acid synthase (ALAS); vitamin B6
Ferrochelatase; Mitochondria
What effect does sideroblastic anemia have on iron processing?
While this protoporphyrin is being synthesized, iron is transferred to erythroid precursor and enters mitochondria to form heme.
If protoporphyrin is deficient, iron remains trapped in MITOCHONDRIA. Iron-laden mitochondria form a ring around the nucleus of erythroid precursors — these cells are called ringed sideroblasts (found in bone marrow)
Sideroblastic anemia can be congenital or acquired. Congenital defect most commonly involves __________
ALAS (rate limiting enzyme in production of protoporphyrin)
3 primary causes of acquired sideroblastic anemia
- Alcoholism — damages mitochondria and thus production of protoporphyrin
- Lead poisoning — denatures enzymes (often ALAD and ferrochelatase) necessary for production of protoporphyin
- Vitamin B6 deficiency — necessary cofactor in RL step (ALAS) in production of protoporphyrin [think isoniazid therapy]
Vitamin B6 deficiency often occurs in the setting of what pharmacologic therapy?
Isoniazid —> sideroblastic anemia
Lab findings in sideroblastic anemia
[ferritin, TIBC, serum iron, %sat]
Increased ferritin, decreased TIBC
Increased serum iron, increased %sat
[resembles hemochromatosis]
Thalassemia is divided into alpha- and beta-thalassemia based on which chain of Hb is affected. What causes thalassemia (in general)?
Decreased synthesis of globin chains of Hb; usually due to an inherited mutation
[decreased globin leads to decreased Hb, resulting in a microcytic anemia]
Carriers of the inherited mutation that causes thalassemia are protected against _________
Plasmodium falciparum malaria
What are the 3 normal types of hemoglobin?
HbF (alpha 2, gamma 2) = fetal Hb
HbA (alpha 2, beta 2)
HbA2 (alpha 2, delta 2)
Describe the normal gene associated with alpha component of Hb. How do changes in this gene cause alpha thalassemia?
Normally, 4 alpha alleles are present on Chr 16
Alpha-thalassemia is usually due a gene deletion, and how many deletions are present will determine severity of disease
When 2 alpha genes are deleted in alpha-thalassemia, the deletion can be cis or trans. What is the difference between these types of deletion, and which one is worse?
Cis = both genes deleted off same chromosome (more common in Asia)
Trans = one gene lost off of each chromosome (more common in Africa)
Cis deletion is worse — associated with increased risk of severe thalassemia in offspring
Describe the normal gene associated with beta component of Hb. How do changes in this gene cause beta thalassemia?
2 beta genes are present on Chr 11
Beta-thalassemia is due to gene mutations resulting in absent (B0) or diminished (B+) production of B-globin chain
[Note: contrast with alpha thalassemia which is caused by DELETIONS]
Alpha-thalassemia is usually due a gene deletion, and how many deletions are present will determine severity of disease. How would one, two, three, and four-deletions of the alpha gene be characterized?
1 gene deleted = asymptomatic
2 genes deleted = mild anemia with slightly increased RBC count
3 genes deleted = severe anemia; beta chains form tetramers (HbH) that damage RBCs. HbH is seen on electrophoresis.
4 genes deleted = lethal in utero (hydrops fetalis); gamma chains form tetramers (Hb Barts) that damage RBCs. Hb Barts is seen on electrophoresis
Variations of beta-thalassemia include beta-thalassemia minor (B/B+) and beta-thalassemia major. Describe beta-thalassemia minor in terms of clinical presentation and lab findings
Mildest form of disease; usually asymptomatic with increased RBC count
Microcytic hypochromic RBCs and TARGET CELLS on PB smear
Variations of beta-thalassemia include beta-thalassemia minor (B/B+) and beta-thalassemia major (B0/B0). Describe beta-thalassemia major in terms of severity and when it presents
Most severe form of disease; presents with severe anemia a few months after birth
Fetal Hb does not require beta-chain so HbF (alpha2/gamma2) at birth is temporarily protective
Beta-thalassemia minor findings on electrophoresis
Slightly decreased HbA
Increased HbA2 to 5% (normal 2.5%)
Increased HbF to 2% (normal 1%)
Beta-thalassemia major findings on blood smear and electrophoresis
Microcytic, hypochromic TARGET cells and nucleated RBCs
Electrophoresis shows little or no HbA, increased HbA2 (alpha2/delta2) and HbF (alpha2/gamma2)
With beta-thalassemia major, alpha tetramers aggregate and damage RBCs, resulting in ineffective erythropoiesis and ________ hemolysis
Extravascular
Because beta-thalassemia major causes such severe anemia, there is concurrent massive erythroid hyperplasia. How does this present clinically?
Expansion of hematopoiesis into marrow of skull and facial bones — “Crew cut” appearance on Xray and “Chipmunk-like face”
Extramedullary hematopoeisis — Hepatosplenomegaly
Risk of aplastic crisis with parvovirus B19 (parvovirus B19 infects erythroid precursors)
Chronic _________ are often necessary to treat beta-thalassemia major, which leads to risk of secondary _________
Transfusions; hemochromatosis
Macrocytic anemia is defined as anemia with MCV > 100 and is most commonly due to ____ or ____ deficiency (megaloblastic anemia)
Folate; B12
Folate enters the body as THF and is quickly methylated. In order to participate in DNA precursor synthesis, it needs to pass off the methyl group to Vitamin B12. Vit B12 then gets rid of the methyl group by giving it to _________, which then becomes ________.
Homocysteine; methionine
Vit B12 or folate deficiency is associated with _______ neutrophils on peripheral smear
Hypersegmented
3 causes of macrocytic anemia other than Vit B12 or folate deficiency
Alcoholism
Liver disease
Drugs (e.g., 5-FU)
Folate is obtained from green vegetables and fruits. It is absorbed in the ______. Deficiency develops within ______ because body stores are minimal. Causes of deficiency include poor diet (e.g., alcoholics, elderly), increased demand (pregnancy, cancer, hemolytic anemia), or folate antagonists (e.g., methotrexate)
Jejunum; months
Clinical and lab findings of folate deficiency include macrocytic RBCs and hypersegmented neutrophils. A possible HEENT exam finding is _______. Lab findings include decreased serum folate, ______ serum homocysteine, and ______ methylmalonic acid
Glossitis; increased; normal
Dietary vitamin B12 is complexed to animal-derived proteins (e.g., meat, eggs). When it enters the body, it is complexed to _______ which is later removed by proteases produced by the pancreas. In the small intestine, vitamin B12 binds ______ _____ produced by parietal cells in the body of the stomach
R binder; Intrinsic factor
T/F: vitamin B12 is less common than folate deficiency
True — deficiency in B12 takes years to develop due to large hepatic stores
Most common cause of vitamin B12 deficiency
Pernicious anemia
______ ______ = autoimmune destruction of parietal cells in the body of the stomach, leading to intrinsic factor deficiency
Pernicious anemia
Other causes of Vitamin B12 deficiency include ______ insufficiency (because these enzymes are needed to cleave R binder from Vitamin B12), or damage to the terminal ileum due to ______ disease or ______ ______ infection.
Dietary deficiency is rare, except in _______
Pancreatic; Crohn; Diphyllobothrium latum
Vegans
Clinical and lab findings of B12 deficiency include macrocytic anemia with hypersegmented neutrophils, glossitis, and _____________________ of the spinal cord.
Lab findings include decreased serum B12, _______ serum homocysteine, and ________ methylmalonic acid
Subacute combined degeneration of the spinal cord
Increased; increased
Normocytic anemia is defined as normal-sized RBCs, meaning an MCV of 80-100. Normocytic anemia may be due to increased peripheral destruction OR underproduction of RBCs. What lab value helps distinguish between these two etiologies?
Reticulocyte count
Properly functioning bone marrow responds to anemia by increasing the reticulocyte count to _______%, a value that would indicate peripheral destruction as the cause.
However, the reticulocyte count is falsely elevated with anemia because it is measured as a percentage of total RBCs, thus the decrease in total RBCs falsely elevates the percentage of reticulocytes. The reticulocyte count can be corrected by multiplying by _____
> 3%
Hct/45
Peripheral RBC destruction (hemolysis) can be divided into intravascular and extravascular. Both result in anemia with good marrow response.
________ hemolysis involves RBC destruction by the reticuloendothelial system, including macrophages of the spleen, liver, and LNs. This destruction involves breakdown of globin into ______ _____, breakdown of heme into _____ and _______, and breakdown of protoporphyrin into ______ ______
Extravascular; amino acids; iron and protoporphyrin; unconjugated bilirubin
Clinical and lab findings of extravascular hemolysis include anemia with splenomegaly, jaundice due to _______ bilirubin, increased risk for _______ gallstones, and marrow hyperplasia with corrected reticulocyte count >3%
Unconjugated; bilirubin
______ hemolysis is associated with clinical and laboratory findings including hemoglobinemia, hemoglobinuria, hemosiderinuria, and decreased serum haptoglobin
Intravascular
List the normocytic anemias with predominant extravascular hemolysis
Hereditary spherocytosis
Sickle cell anemia
Hemoglobin C
______ _____ is a cause of normocytic anemia with predominantly extravascular hemolysis due to inherited defect of RBC cytoskeleton membrane tethering proteins, most commonly _____, _____, or ______
Hereditary spherocytosis; spectrin, ankyrin, band 3.1
With hereditary spherocytosis, spherocytes are less able to maneuver through splenic sinusoids, so they are consumed by splenic macrophages resulting in anemia.
Clinical and lab features include spherocytes with loss of central pallor, _______ RDW and _____ MCHC, splenomegaly, jaundice with unconjugated bilirubin, and increased risk of bilirubin gallstones. There is also increased risk for aplastic crisis with _______ infection of erythroid precursors
Increased; increased; parvovirus B19
Diagnosis of hereditary spherocytosis is by the ______ _____ test
Osmotic fragility
[increased fragility in hypotonic solution = positive]
Treatment for hereditary spherocytosis is _______. Note that spherocytes persist, and ____________ will appear on blood smear
Splenectomy; Howell-Jolly bodies
Sickle cell anemia causes a normocytic anemia with predominantly ________ hemolysis. It is caused by a ______ _____ mutation in ____________, so that normal glutamic acid (hydrophilic) is replaced with valine (hydrophobic)
Extravascular; autosomal recessive; beta chain of Hb
The gene for sickle cell anemia is carried by 10% of individuals of African descent, likely due to protective role against _____________
Falciparum malaria
Sickle cell disease vs. Sickle cell trait
SCD = 2 abnormal beta genes — results in >90% HbS in RBCs
SCT = 1 abnormal beta gene, 1 normal beta gene — results in <50% HbS in RBCs. These pts are generally asymptomatic with no anemia
What causes sickling of cells in Sickle cell anemia?
HbS polymerizes when deoxygenated (hypoxemia, dehydration, acidosis, etc); polymers aggregate into needle-like structures resulting in sickle cells
_____ is a type of hemoglobin that protects against sickling and is protective for the first few months of life. Treatment with ______ increases the levels of this type of hemoglobin
HbF; hydroxyurea
With sickle cell anemia, cells continuously sickle and de-sickle while passing through microcirculation. This results in complications related to RBC membrane damage and subsequent extravascular hemolysis. There is also some associated intravascular hemolysis, leading to _____ haptoglobin and __________ on blood smear
Decreased; Target cells
Sickle cell anemia is associated with massive erythroid hyperplasia, resulting in expansion of hematopoiesis into the ____ and _____ bones. There is also extramedullary hematopoiesis with ________. Risk of aplastic crisis remains with parvovirus B19 infection of erythroid precursors
Skull; facial; hepatomegaly
One complication of sickle cell disease is irreversible sickling, which leads to complications of vasoocclusion. One manifestation of this is ______, which is swelling of hands and feet due to vaso-occlusive infarcts of bones and is the common presenting sign of this disease in infants
Dactylitis
Vasoocclusive crises in the spleen in sickle cell disease may lead to autosplenectomy, characterized by a shrunken fibrotic spleen. These pts are at increased risk of infection with _________ organisms, which is the most common cause of death in children. They also have increased risk of ______ ______ osteomyelitis. ___________ bodies will be seen on blood smear.
Encapsulated; Salmonella paratyphi; howell-jolly
What is the most common cause of death in adults with sickle cell disease?
Acute chest syndrome
[Vaso-occlusion in pulmonary microcirculation; presents with chest pain, SOB, and lung infiltrates; often precipitated by PNA]
What pathology is associated with vaso-occlusive crisis in the kidney in the setting of sickle cell disease?
Renal papillary necrosis (results in gross hematuria and proteinuria)
Pts with sickle cell trait are generally asymptomatic with no anemia. RBCs with <50% HbS do not sickle in vivo, except in the ______ ______, due to extreme hypoxia and hypertonicity resulting in microinfarctions
Renal medulla
[Leads to microscopic hematuria and eventual decreased ability to concentrate urine]
In terms of lab findings, sickle cells and target cells are seen on blood smear in sickle cell disease, but not in sickle cell trait.
A __________ _______ causes cells with any amount of HbS to sickle, and will thus be positive in both disease and trait
Metabisulfite screen
What test can be used to confirm the presence and amount of HbS in a suspected case of sickle cell disease or trait?
Hb electrophoresis
[Disease: 90% HbS, 8% HbF, 2% HbA2; Trait: 55% HbA, 43% HbS, 2% HbA2]
Hemoglobinopathy characterized by AR mutation in beta chain of hemoglobin in which normal glutamic acid is replaced by lysine; presents with mild anemia due to extravascular hemolysis
Hemoglobin C
[Characteristic HbC crystals are seen in RBCs]
List normocytic anemias with predominately intravascular hemolysis
Paroxysmal Nocturnal Hemoglobinuria (PNH) G6PD deficiency Immune hemolytic anemia Microangiopathic hemolytic anemia Malaria
Cause of normocytic anemia with predominantly intravascular hemolysis characterized by acquired defect in myeloid stem cells resulting in absent GPI (anchoring protein responsible for MIRL and DAF responsible for inactivating complement), rendering the cells susceptible to complement
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Why does PNH result in increased intravascular hemolysis at night?
Mild respiratory acidosis develops with shallow breathing during sleep and activates complement
[RBCs, WBCs, and platelets will all be lysed]
The ________ test is used to screen for paroxysmal nocturnal hemoglobinuria, and the confirmatory test is the acidified serum test or flow cytometry to detect lack of _______
Sucrose; CD55 (DAF)
Main cause of death in pts with paroxysmal nocturnal hemoglobinuria
Thrombosis of hepatic, portal, or cerebral veins
[destroyed platelets release cytoplasmic contents into circulation inducing thrombosis]
2 major complications of paroxysmal hemoglobinuria
Iron deficiency anemia (loss of iron in urine with hemoglobinuria)
AML (develops in 10% of pts)
Cause of normocytic anemia with predominantly intravascular hemolysis characterized by X-linked recessive disorder resulting in reduced half-life of an enzyme, rendering the cells susceptible to oxidative stress
G6PD deficiency
2 major variants of G6PD deficiency
African variant — mildly reduced half-life of G6PD
Mediterranean variant — markedly reduced half-life of G6PD
[High frequency in both these populations is likely due to protective effect from falciparem malaria]
In pts with G6PD deficiency, oxidative stress precipitates Hb as _______ _______, which are later removed by splenic macrophages resulting in ______ cells. Causes of oxidative stress include infections, drugs (primaquine, sulfa drugs, dapsone), and ______ beans.
Heinz bodies; bite; fava
A ____ preparation is used to screen for G6PD deficiency, while enzyme studies are used to confirm (but only AFTER acute episode has resolved)
Heinz
Cause of normocytic anemia with predominantly intravascular hemolysis characterized by antibody-mediated (IgG or IgM) destruction of RBCs
Immune hemolytic anemia
____-mediated immune hemolytic anemia usually involves extravascular hemolysis. This antibody binds RBCs in the relatively warm central body (warm agluttinin). The membrane of Ab-coated RBC is consumed by splenic macrophages resulting in _______
IgG; spherocytes
IgG mediated immune hemolytic anemia is associated with _____, _____ and certain drugs (e.g., penicillin, methyldopa, etc)
SLE; CLL
Treatment for IgG mediated immune hemolytic anemia
Cessation of offending drug
Steroids
IVIG (buys time)
Splenectomy
____-mediated immune hemolytic anemia usually involves intravascular hemolysis. This antibody binds RBCs and fixes complement in the relatively cold temperature of extremities (cold agluttinin). It is associated with ________ _________ infection, and infectious ________
IgM; mycoplasma pneumoniae; mononucleosis
What test is used to diagnose immune hemolytic anemia?
Coombs test
[can be direct or indirect]
The _____ Coombs test confirms the presence of antibody-coated RBCs. Anti-IgG is added to pt’s RBCs and agglutination occurs if RBCs are already coated with IgG antibody. This is the MOST important test for immune hemolytic anemia
Direct
The ______ Coombs test confirms the presence of antibodies in the pts serum. Anti-IgG and test RBCs are mixed with patient serum. Agglutination occurs if serum antibodies are present
Indirect
Cause of normocytic anemia with predominantly intravascular hemolysis resulting from vascular pathology in which RBCs are destroyed as they pass through small blood vessels; hallmark finding is schistocytes
Microangiopathic hemolytic anemia
Conditions associated with microangiopathic hemolytic anemia
Microthrombi (e.g., TTP-HUS, DIC, HELLP)
Prosthetic heart valves
Aortic stenosis
Malaria results in infection of RBCs and liver with _________; transmission is via ________
Plasmodium; female anopheles mosquito
In malaria, RBCs rupture as part of the Plasmodium life cycle, resulting in intravascular hemolysis and cyclical fever. How does fever help differentiate between Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale infection?
Plasmodium falciparum = daily fever
Plasmodium vivax and ovale = fever every other day
Treatment for Parvovirus B19 infection
Supportive
[self-limited, resolves in 5-10 days]
Anemia of underproduction characterized by damage to hematopoeitic stem cell, resulting in pancytopenia with low reticulocyte count; etiologies include drugs or chemicals, viral infections, autoimmune damage. Biopsy will show empty, fatty marrow
Aplastic anemia
Treatment of aplastic anemia
Cessation of any causative drugs
Transfusions
Marrow-stimulating factors (EPO, GM-CSF, G-CSF)
Immunosuppression
BMT (last resort)
_________ _______= pathologic process that replaces bone marrow; hematopoiesis is impaired, resulting in pancytopenia
Myelophthisic process
