Hemonc Flashcards
G6PD deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- the first and rate limiting step in HMP pathway, it converts glucose-6-phosphate to 6-phosphogluconate
- NADPH is necessary to keep glutathione reduced
- Oxidizing agents (e.g. fava beans, sulfonamides, primaquine, anti-tuberculosis
- X-linked recessive disorder in some; more prevalent among blacks, may provide malarial resistance due to increased H2O2 in RBCs
-Heinz bodies – oxidized Hemoglobin precipitated within RBCs.
-Bite cells- result from the phagocytic removal of Heinz bodies
by splenic macrophages.
drugs) oxidize Hb, NADPH via GSH reduces Hb
THINK: “BITE into some HEINZ ketchup.”
Heinz Bodies- Oxidization of iron from ferrous to ferric form. Seen in G6PD deficiency or with certain drugs
Erythrocytes and precursors
Carries O2 to tissues and CO2 to lungs
- Anucleate and biconcave
- Life span of 120 days
- 90% of glucose used in glycolysis, 10% in HMP shunt
- Reticulocyte = immature erythrocyte, marker of erythroid proliferation, bluish color on Wright-Giemsa stain (ribosomes)
- Anisocytosis = varying sizes
- Poikilocytosis = varying shapes
- Erythrocytosis =polycythemia= incr. hematocrit
A 30-year-old, previously healthy man passes dark brown urine several days after starting the prophylactic antimalarial drug primaquine. On physical examination, he appears pale and is afebrile. There is no organomegaly. Laboratory studies show that his serum haptoglobin level is decreased (sign of intravascular hemolysis). Which of the following is the most likely explanation of these findings?
A. Mechanical fragmentation of RBCs
B. Increased susceptibility to lysis by complement
C. Nuclear maturation defects resulting from impaired DNA synthesis
D. Impaired globin synthesis
E. Hemolysis of antibody-coated cells
F. Oxidative injury to hemoglobin
G. Reduced deformability of the RBC membrane
- oxidative injury to hemoglobin
- this patient has glucose-6-phosphate dehydrogenase deficiency. A drug that leads to oxidative injury to the RBCs such as primaquine can induce hemolysis. Oxidant injury to hemoglobin produces inclusion of denatured hemoglobin within RBCs. The inclusions damage the cell membrane directly, giving rise to intravascular hemolysis. These cells have reduced membrane deformability and they are removed from the circulation by the spleen
A. Mechanical fragmentation of RBCs
B. Increased susceptibility to lysis by complement
C. Nuclear maturation defects resulting from impaired DNA synthesis
D. Impaired globin synthesis
E. Hemolysis of antibody-coated cells
F. Oxidative injury to hemoglobin
G. Reduced deformability of the RBC membrane
Platelet
Platelet (thrombocyte)
-Small cytoplasmic fragment derived from megakaryocytes -Contains dense granules (ADP, calcium) and α granules (vWF,
fibrinogen, fibronectin)
-Approximately 1/3 of platelet pool is stored in spleen
-Petechiae (< 3mm) if platelets low
White blood cell differentiation
Blood Cell Differentiation
-WBC differential
Neutrophils (60%)
Lymphocytes (30%) - around the size of RBCs
Monocytes (5%)
Eosinophils (2%)
Basophils (1%)
-the last three are unlikely to be seen in peripheral smear unless abnormlality.
Neutrophils Like Making Everything Better
What are normals of leukocytes: Divided into granulocytes (neutrophil, eosinophil, basophil) and mononuclear cells (monocytes, lymphocytes).
4000-11,000 cells/mm^3 or microliter
Neutrophil
- Acute inflammatory response cell. Increased in bacterial infections. Phagocytic. Multi-lobed nucleus. PMN -Small more numerous specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin,
- Larger, less numerous azurophilic granules (lysosomes) contain acid phosphatase, myeloperoxidase, and β-glucuronidase
- Hypersegmented polys (6 or more lobes) are seen in vitamin B12/folate deficiency
- Band forms seen in CML and infection
- PMN chemotactic factors: IL-8, LTB4, C5a, PAF
Respiratory burst and CGD
Respiratory Burst (Oxidative Burst) -Involves the activation of the phagocyte NADPH oxidase complex - end product is HClO radical aka bleach which is formed from myeloperoxidase converting H2o2 into bleach -the NADPH will prevent escaped H2O2 from killing the PMN by converting it into water -Note that NADPH plays a role in both the creation (O2 radical via NADPH oxidase( deficiency leads to chronic granulomatous disease) and neutralization (via GSH) of ROS Myeloperoxidase contains a blue-green heme- containing pigment that gives sputum its color.
[CGD]
Phagocytes of patients with chronic granulomatous disease (CGD) who lack NADPH oxidase can still utilize H2O2 generated by invading organisms and convert it to ROS. However CGD patients are at increased risk for infection by catalase positive species (S. aureus, Aspergillus which breakdown H2O2) - all organisms generate H2O2 to kill related organisms so they can have prominence. If you are invaded by a catalase positive species which gets rid of hydrogen peroxide by themselves and also no H2O2 are generated so these patients are more vulnerable
Eosinophils and Basophils
Eosinophil -Defends against helminthic infections (major basic protein). Bilobed nucleus.
-Produces histaminase (helps limit reaction following mast cell degranulation) (limiting basophils) and major basic protein (MBP, a helminthotoxin) which kills helminths
Loves to eat antigen-antibody complex
Causes of eosinophilia (elevated eosinophils= NAACP Neoplastic Asthma Allergic processes Chronic adrenal insufficiency Parasites (invasive)
Basophil
- Mediates allergic reaction
- basophil granules containing heparin (anticoagulant), histamine (vasodilator) and leukotrienes.
- Elevated in CML
Mast cell
- Mediates allergic reaction in local tissues. Resembles basophils with basophilic granules
- Can bind the Fc portion of IgE to membrane. IgE cross-links upon antigen binding
- **Cromolyn sodium prevents mast cell degranulation (used for asthma prophylaxis) ‘
- Degranulation leads to release of histamine, heparin, tryptase, leukotrienes and eosinophil chemotactic factors.
Basophils & Mast Cells are similar but arise from different lines
Easy- A 10-year-old male patient is diagnosed with an acute bacterial infection. His blood leukocyte count was 38,000 cells per µL (reference range: 4,000 to 11,000 per µL). The predominant cell type found in increased numbers in this patient’s blood is
A. Eosinophils B. Neutrophils C. Monocytes D. B cells E. Dendritic cells
Neutrophils - could have lots of lobes or could look like what? Bands. All band is is that sausage thing, neutrophil that is pushed out early before its lobes are formed.
VitK
Vitamin K Function: Reduced vitamin K catalyzes γ-carboxylation of glutamic acid. Necessary for the synthesis of clotting factors II, VII, IX, X and proteins C, S and Z. Warfarin – vitamin K antagonist
Deficiency: Vitamin K not found in breast milk. So neonates are given a vitamin K injection at birth to prevent hemorrhage. VitK comes from gut bacteria which babies don’t have- no food yet. Vit. K deficiency can also occur after prolonged use of broad-spectrum antibiotics because no gut bacteria are present to synthesize vitamin K.
A 63 year old man with adenocarcinoma of the colon presents with a 1 month history of widespread eccymoses. On PE he appears cachetic and pale. Laboratory studies show hemoglobin 8.5 g/dL (normal 11-15); platelet count, 15,000/ mm3 (normal 150-440K); WBC count, 9000/mm3 (normal 4-11K); prothrombin time, 30 seconds (normal 11-15); partial thromboplastin time, 55 seconds (normal 25-40); very elevated FDP and D-dimer levels; and very low fibrinogen levels. What is the best explanation for the patient’s condition?
A. Thrombocytopenia due to a bone marrow defect B. Vitamin K deficiency due to broad spectrum antibiotic use C. Disseminated intravascular coagulation caused by a mucin- containing procoagulant D. Chronic blood loss from colon cancer
DIC caused by mucin-containing procoagulant - all the clots - hemoglobic anemia.
A: Prothombin time and PTT are both off and they shouldn’t
B: he may have defect in PT and PPT: shouldn’t have problem with platelets
D: he would have anemia but not problem with platelets
Procoagulants from the adenocarcinoma activate non-specific coagulation throughout the body consuming coagulation factors and platelets. Cancers usually cause a chronic type of DIC as described here. Acute causes of DIC include sepsis, burns and obstetric complications
Which of the following is a vitamin K–dependent factor that is activated by thrombin and limits coagulation by cleaving activated factors V and VIII.
A. Protein C B. Protein S C. Antithrombin III (ATIII) D. Plasminogen E. Prekallikrein
Protein C:
thrombin activates factors 8 and 5 to enhance coagulation. Thrombin also activates protein C which in turn degrades factors VIII and V to limit coagulation. This is important feedback loop
A 5-year-old boy has had a history of easy bruising and blood in his urine since infancy. The is a bleeding history in the family. He has several ecchymoses of the skin on the lower extremities. Laboratory studies show hemoglobin, 13.1 g/dL (normal) platelet count, 287,600/mm3 (normal); WBC count, 6830/mm3 (normal); prothrombin time, 13 seconds (normal 11-15); activated partial thromboplastin time, 54 seconds (normal 25-40). If he does not receive appropriate treatment, which of the following manifestations of this illness is most likely to ensue?
A) Splenomegaly B) Petechiae C) Hemolysis D) Hemochromatosis E) Hemarthroses
E) Hemarthroses
The patient likely has hemophilia A. With low factor VIII activity, there is severe disease and joint hemorrhages are common, leading to severe joint deformity and ankylosis
There is blood in the urine, bleeding history in the family, why do you think intrinsic instead of extrinsic? APTT is abnormal, the PT is normal so it can’t be extrinsic. Deep bleeding.
Prothrombin Time (PT) measures the integrity of the extrinsic system as well as factors common to both pathways. The international normalized ratio (INR) is a derivative of PT. Activated Partial Thromboplastin Time (aPTT), which measures the integrity of the intrinsic system and the common components. Thrombin time (TT) is rarely used
A 23-year-old woman has had a history of bleeding problems all of her life, primarily heavy menstruation and bleeding gums. A sister and an uncle also have bleeding problems. Physical examination shows several bruises. Laboratory studies show hemoglobin, 9.5 g/dL (normal 11-15); platelet count, 229,300/mm3 (normal 150-440K); WBC count, 7185/mm3 (normal 4-11K); prothrombin time, 12 seconds (normal 11-15); and partial thromboplastin time, 46 seconds (normal 25-40). Ristocetin-dependent platelet aggregation in patient plasma is markedly reduced. Ristocetin acts as a denuded blood vessel wall. Which of the following responses should the physician use when advising the patient of potential consequences of this disease?
A) You might need allogeneic bone marrow transplantation B) Expect increasing difficulty with joint mobility C) Anticoagulation is needed to prevent deep venous thrombosis
D) You could experience excessive bleeding after oral surgery
E) A splenectomy might be necessary to control the disease
The answer is D. An inherited bleeding disorder with normal platelet count suggests a common bleeding disorder, von Willebrand disease. In most cases it is inherited as an autosomal dominant trait. A reduction in the quantity of vWF impairs platelet adhesion to damaged walls and hemostasis is compromised. Because vWF acts as a carrier for Factor VIII the level of this procoagulant protein is diminished and the apttt is elevated.
Why is it not B? Hemearthroses
Ristocetin is a factor that mimics a blood vessel wall and shows you if patient blood and VWF works
70-year-old male presents to his primary care physician for complaints of fatigue. The patient reports feeling tired during the day over the past 6 months. Past medical history is significant for moderately controlled type II diabetes. Family history is unremarkable. Thyroid stimulating hormone and testosterone levels are within normal limits. Complete blood cell count reveals the following: WBC 5.0K, hemoglobin 9.0, hematocrit 28%, and platelets 350K. Mean corpuscular volume is 76. Iron studies demonstrate a ferritin of 15 ng/ml (nl 30-300). Of the following, which is the next best step?
A. Bone marrow biopsy B. Blood transfusion C. Gel electrophoresis D. Coombs test E. Colonoscopy
Colonoscopy - the most likely anemia in general is iron deficiency anemia. In a patient of this age, blood loss from colorectal cancer should be suspected so a colonoscopy would be the next best step.
A 37-year-old woman presents to her primary care physician with a 6-month history of fatigue. She denies any recent history of fevers, chills or headaches. She does not smoke or drink alcohol. A complete blood count demonstrates a normocytic anemia. Iron studies are ordered and demonstrate the following: Reticulocyte production index (RPI) = 1.4 Serum iron: 41 µg/dL (normal 50–170 µg/dL) TIBC: 230 µg/dL (normal 250–370 µg/dL) Transferrin saturation: 18% (normal 15–50%) Serum ferritin: 180 µg/L (normal 15-150 µg/L)
Which of the following is a likely cause of this patient’s iron studies findings?
A. Lead poisoning B. Dysfunctional uterine bleeding C. Splenic sequestration of RBCs D. Rheumatoid arthritis E. RBC enzyme deficiency
Rheumatoid arthritis
Anemia of chronic disease
What is the WHO definition of anemia
and normal hematocrit values
The World Health Organization (WHO) defines anemia as a hemoglobin level
- < 13 g/dL in men
- <12 g/dL in non-pregnant women.
During pregnancy, women hemoglobin would be lower.
Hematocrit - if you have 100% of your blood volume, what percent is packed red blood cells
The mean hematocrit value for
adult males is 47% (normal, 40-54)
for adult females is 42% (normal, 37-47). Hematocrit is a less reliable indicator of anemia than hemoglobin due to changes in plasma volume and hemoglobin concentrations.
Anemia - hematocrit = 30%
Polycythemia - hematocrit = 70%
Dehydration - hematocrit = 70%
Hematocrit is really dependent on hydration status.
Y/N
- More reticulocytes should be found in patient with anemia?
- Young reticulocytes should last longer in the blood than old reticulocytes?
- Reticulocytes should be increased no matter the cause of anemia?
- yes
- yes
- yes
What are two corrections for reticulocyte count?
Correction #1 for Anemia: Produces the corrected reticulocyte count.
In a person whose reticulocyte count is 10%, hemoglobin 7.5 g/dL, and hematocrit 23%, the absolute reticulocyte count = 10 × (7.5/15) [or × (23/45)] = 5% (adequate response to anemia)
Correction #2 for Longer Life of Prematurely Released Reticulocytes in the Blood: Produces the Reticulocyte Production Index (RPI).
In the same person, the RPI is the corrected reticulocyte count divided by 2, which reflects the increased life expectancy of prematurely released reticulocytes RPI= 5/2= 2.5
-reticulocytes that are young will last longer, you have to divide by approximate lifespan of reticulocytes. 5% divided 2 > RPI = 2.5. That number we will use to determine if the response of the marrow is good. In the end that is the number that is the bar where we decide if marrow is good or not. 2.5 or greater regardless of degree of anemia there is GOOD production from the marrow
A healthy 19-year-old woman suffered blunt abdominal trauma in a motor vehicle accident. On admission to the hospital, her initial hematocrit was 33%, but over the next hour, it decreased to 28%. A paracentesis yielded serosanguineous fluid. She was taken to surgery, where a liver laceration was repaired, and 1 L of bloody fluid was removed from the peritoneal cavity. She remained stable. A CBC performed 5 days later is most likely to show which of the following morphologic findings in RBCs in the peripheral blood?
A) Reticulocytosis B) Basophilic stippling C) Hypochromia D) Schistocytes
The acute blood loss in this case probably intraperitoneal hemorrhage results in reticulocytosis from marrow stimulation by anemia
Schistocytes: are not sickle cells, they are little shitty cells. Here I am, I am a pudgy RBCs, if there is narrowing in vascularity, I get fragmented. Like in DIC - blood vessels lined by clots, if these cells go through them they get fragmented.
What are the size values in anemia in femptoLiters
Microcytic <80fL
Normocytic 80-100fL
Macrocytic >100fL
- Microcytes are associated with poor cytoplasmic maturation- no Hb
- Macrocytes are associated with poor nuclear maturation - form more hemoglobin during this time and grow larger
Pathologic RBC forms
Acanthocyte Basophilic Stippling Dacrocyte (tear drop cell) Bite cell Burr cell Hereditary elliptocytosis Macro-ovalocyte Ringed Sideroblast Schistocyte Spherocytosis Target Cell Heinz bodies Howell-jolly bodies
- Acanthocyte: Liver disease, cholesterol dysregulation
- Basophilic Stippling: Myelodysplastic syndromes, sideroblastic anemias, Lead poisoning (subset of sideroblastic)
- Dacrocyte: (teardrop cell) Myelofibrosis [shed a tear]
- Bite cell: G6PD deficiency - removing oxidized hemoglobin
- Burr cell: ESRD, PK deficiency Energy trouble in cells, more uniform projections versus acanthocyte
- Hereditary elliptocytosis: asymptomatic, caused by mutation in genes encoding RBC membrane proteins (spectrin)
- Macro-ovalocyte: Megaloblastic anemia (also hypersegmented PMNs), marrow failure
- Ringed Sideroblast: Sideroblastic anemia. Excess iron in mitochondria=pathologic - seen when stained for iron, incorporated in mitochondria in the last step, when iron isn’t incorporated you see it heavily staining in the mitochondria
- Schistocyte DIC, TTP/HUS, mechanical hemolysis (e.g. heart valve prosthesis)
- Spherocytosis Hereditary, autoimmune hemolytic anemia - not as flexible - loss of plasma membrane.
- Target Cell Asplenia, Liver disease, Thalassemia - looks opposite from the normal central pallor- dark middle and ring, why? Spleen should filter out crappy RBCs,
- Heinz bodies Oxidation of iron from ferrous to ferric form. Seen in G6PD deficiency. SH to S-S. Leads to bite cells
- Howell-Jolly bodies (nuclear remnants) Normally removed from RBCs by splenic macrophages. Seen in patients with functional hyposplenia or asplenia
Microcytic, hypochromic (MCV< 80 fL) anemia
Iron deficiency-most common
Decreased iron due to chronic bleeding (GI loss, menorrhagia), malnutrition, gastrectomy (acids promotes Fe2+ form which is more readily absorbed) increased demand (pregnancy), hookworm (developing world)
Findings: decreased iron and ferritin, and increased TIBC. Fatigue, conjunctival pallor, pica (consumption of nonfood substances), spoon nails (koilonychia)
May manifest as Plummer-Vinson syndrome (triad of 1. iron deficiency anemia, 2. esophageal webs, and 3. atrophic glossitis)
Central pallor > 1/3 of RBC diameter is a marker of hypochromia
How do each of these change? Serum iron TIBC Ferritin - storage form) % transferrin sat
in
Iron deficiency
ACD
Hemochromatosis
Pregnancy/Contraceptive use
Iron deficiency: Serum iron - decreases TIBC - increases Ferritin - storage form) - decreases % transferrin sat - really decreases
ACD
Serum iron - decreases
TIBC - decreases
Ferritin - storage form) - increases
% transferrin sat - normal (not iron deficiency)
-inflammation of the liver, IL stimulate the liver to make hepsiden - blocks ferroportin which means iron can’t get out of the enterocyte, sloughs and lose in the stool. You block ability of iron to get in. Hepsiden also blocks transport of liver outside. You have iron trapped in these organs. TIBC reciprocal is low
Hemochromatosis Serum iron - increases TIBC - decreases Ferritin - storage form) - increases % transferrin sat - really increases -high iron, very high ferritin, high saturation. You can set off the metal detector.
Pregnancy Serum iron TIBC - increases Ferritin - storage form) - N/A % transferrin sat -decreases
Iron deficiency has low iron stores (ferritin) with a compensatory increase in TIBC
• Anemia of chronic disease (ACD) due to inflammation has ferritin trapped in cells and a low TIBC.
Alpha-thalassemia
α-thalassemia
Two genes on each chromosome 16, four genes total
α -globin gene deletions > decreased α-globin synthesis.
Cis deletion prevalent in Asian populations; trans deletion prevalent in African populations.
1 allele deletion no anemia
2 allele deletion- mild microcytic anemia
3 allele deletion – HbH disease. Very little α-globin. Excess β-globin forms β4 (HBH) - microcytic anemia
4 allele deletion- No α-globin. Excess γ-globin forms γ4 (causes fatal hydrops fetalis). More likely in Asians
beta-thalassemia
β -thalassemia
One beta gene on each chromosome 11, two total. β+ mutant, β0 absent
Prevalent in Mediterranean and AA populations
β-thalassemia minor (heterozygote): β/β+ Diagnosis confirmed by increased HbA2 (alpha2delta2)>2.5% ) and/or HbF (α2γ2, >1.0%) on Hb electrophoresis
β-thalassemia major (homozygote): β0/β0 (β chain is absent, >95% HbF); β+/β+ (>70% HbF) - means if both are mutated as opposed to both absent
Severe anemia with target cells requiring blood transfusion. Marrow expansion (crew cut on skull x-ray). Chipmunk facies. Increased risk of parvovirus B19-induced aplastic crisis - it wipes out this hyperplastic bone marrow. HbF is protective in the infant and disease only becomes symptomatic after 6 months.
(something important I realized, in alpha thal you can still make tetramers of beta and make RBCs, in beta thal major, alpha globins can’t make tetramers, you make precipitates, and its toxic killing RBC precursors. This is why you have the associated target cell (low hemoglobin), extramedullary hematopoiesis, and aplastic crisis due to PARVO
Sideroblastic anemia
Sideroblastic anemia Defect in heme synthesis: in forming the protoporphyrin ring (the first step)
most common cause alcohol (acquired), myelodysplastic syndrome, genetic X-linked defect in δ-ALA synthase, vitamin B6 deficiency, copper deficiency
Findings: high serum iron (not used), high ferritin, low TIBC, high saturation, basophilic stippling (retained rRNA)
Treatment: Pyridoxine (B6, cofactor for delta ALA synthase) - minor enzymatic defect may respond
Lead poisoning
Lead inhibits *ferrochelatase and δ-ALA dehydratase, ringed sideroblast and basophilic stippling
Symptoms: (LEAD)
Lead Lines on gingivae (Burton Lines) and long bones.
Encephalopathy and Erythrocyte basophilic stippling.
Abdominal colic and sideroblastic anemia.
Drops- wrist and foot drop.
(these are severe chronic lead poisoning and are not that useful) - usually just have suspicion and test positive for lead
Treatment: Chelation with dimercaprol and EDTA
A 73-year-old man has been healthy all his life. He takes no medications and has had no major illnesses or surgeries. For the past year, he has become increasingly tired and listless, and he appears pale. Physical examination shows no hepatosplenomegaly and no deformities. CBC shows hemoglobin, 9.7 g/dL (nl 13-17); hematocrit, 29.9% (nl 40-54); MCV, 69 mm3; platelet count, 331,000/mm3 (nl 150-400K); and WBC count, 5500/mm3 (nl 4.5-11K). Which of the following is the most likely underlying condition causing this patient’s findings?
(A) Occult malignancy (B) Autoimmune hemolytic anemia (C) β-Thalassemia major (D) Chronic alcoholism (E) Vitamin B12 deficiency (F) Hemophilia A
A) malignancy
This patient has microcytic anemia - MCV is low
first thing to think about is blood loss > occult malignancy in the colon.
this patient has microcytic anemia which is typical of iron deficiency. Iron deficiency is the most common form of anemia worldwide. The lack of iron impairs heme synthesis. The marrow response is to downsize the RBCs eventually resulting in a microcytic and hypochromic anemia. At this patient’s age, bleeding from an occult malignancy should be strongly suspected as the cause of iron deficiency.
A 32-year-old woman from Saigon, Vietnam, gives birth at 34 weeks’ gestation to a hydropic stillborn male infant. Autopsy findings include hepatosplenomegaly and cardiomegaly, serous effusions in all body cavities, and generalized hydrops. No congenital anomalies are noted. There is marked extramedullary hematopoiesis in visceral organs. Which of the following findings is most likely to be present on hemoglobin electrophoresis of the fetal RBCs?
(A) Hemoglobin A1 (B) Hemoglobin A2 (C) Hemoglobin Bart’s (D) Hemoglobin C (E) Hemoglobin E (F) Hemoglobin F (G) Hemoglobin H
C)
The infant had alpha- thalassemia major, which is most likely to occur in individuals of Southeast Asian ancestry, each of whose parents could have two abnormal alpha-globin genes on chromosome 16. A complete lack of alpha-globin chains precludes formation of hemoglobins Alpha1, Alpha 2 and F. ONly a tetramer of gamma chains (bart’s hemoglobin can be made leading to severe fetal anemia, Inheritance of three abnormal alpha globin chains leads to hemoglobin H disease with tetramers of beta chains;survival to adult hood is possible. Hemoglobin C and E produce mild hemolytic anemias
Anemia of chronic disease
Inflammation > increased hepcidin from the liver > inhibits iron transport > decreased release of iron from macrophages and decreased iron absorption from gut.
Associated with conditions such as rheumatoid arthritis, SLE, neoplastic disorders and chronic kidney disease
Decreased serum iron and TIBC; increased ferritin
Can become microcytic like iron deficiency anemia. Iron can’t reach the bone marrow where it is needed to make erythrocytes
Treatment: EPO (chronic kidney disease only)
Aplastic anemia
Aplastic Anemia Caused by destruction of myeloid stem cells due to:
- radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites),
- viruses (parvovirus B19, EBV, HIV, HCV),
- Fanconi anemia (DNA repair defect),
- idiopathic primary stem cell defect
Pancytopenia: all cell types are down, RBC, WBC, platelets. Normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap)
Symptoms: Fatigue, malaise, pallor, purpura (low platelets-bleeding), mucosal bleeding, petechiae, infection
Treatment: immunosuppressives, allogenic bone marrow transplantation, RBC and platelet transfusion, bone marrow stimulation with colony stimulating factors. You can’t transfuse WBC as they have MHC class 1.
What is the classic and other viruses that cause aplastic anemia
*Parvovirus B19, EBV, HIV, HCV
Intravascular vs extravascular hemolysis
Intravascular hemolysis Findings: decrease haptoglobin, increased LDH and some increase in unconjugated bilirubin, hemoglobinuria, and hemosiderinuria,
Causes: paroxysmal nocturnal hemoglobinuria, G6PD deficiency, micro/macro angiopathic anemia, malaria
Extravascular hemolysis Findings: macrophage in spleen clears RBCs - outside the blood circulation. Increased LDH plus large (breakdown if much more effective) increase in unconjugated bilirubin (from heme breakdown in macrophages), which causes jaundice but NO hemoglobinuria/hemosiderinuria. (most of the breakdown goes right into the blood)
Causes: RBC membrane defect, RBC enzyme defect, hemoglobinopathies (S and C), autoimmune
How do each of these differ in intravascular and extravascular hemolysis
Serum Haptoglobin urine hemoglobin urine hemosiderin Unconjugated bilirubin Serum LDH
Intravascular: Serum Haptoglobin- absent urine hemoglobin - present urine hemosiderin - present Unconjugated bilirubin - elevated Serum LDH - elevated
Extravascular: Serum Haptoglobin - mildly reduced - minimal spilling of heme urine hemoglobin - absent urine hemosiderin - absent Unconjugated bilirubin - very elevated Serum LDH - elevated
INTRINSIC hemolytic anemia
4 kinds
- Hereditary spherocytosis: Defect in proteins interacting with RBC membrane skeleton and plasma membrane causes premature removal of RBCs by spleen. - vertical posts interact with spectrin allows an RBC to be biconcave. Spherocyte exposed to macrophage chews on it, gets some cell membrane off forming a spherocyte. - spleen is taking this out, its extravascular predominantly but intrinsic defect.
Findings: Splenomegaly, aplastic crisis (parvovirus B19) Labs: Osmotic fragility test Treatment: Splenectomy which resolves hemolysis but Howell-Jolly bodies appear - G6PD deficiency: Most common enzymatic disorder of RBCs. X-linked recessive so disease of males. Increased RBC susceptibility to oxidant stress (no reduced glutathione) when exposed to sulfa drugs, anti-malarials, infections, fava beans. Heinz bodies and bite cells - from splenic macrophages .
- Pyruvate kinase deficiency: Defect in pyruvate kinase > decreased ATP > rigid RBCs > extravascular hemolysis. Newborn hemolytic anemia - it only uses glycolysis - terminal enzyme is pyruvate kinase. RBC can’t form the biconcave shape, taken out vascularly.
- HbC:Glutamic acid-to-lysine mutation in β-globin. Patients with HbSC (1 of each mutant gene) have milder disease than have HbSS patients Labs (homozygotes) target cells
- valine is uncharged allowing hemoglobin to stick together. glutamic acid is negative charge but this is why hemoglobin sickles when sticking together .IN contrast, glutamic acid is negative, lysine is positive. You’ve changed a negative to positive. You get target cells with HbC.
Sickle Cell anemia
Sickle Cells Anemia: HbS point mutation (substitution of glutamic acid with valine) at position 6. 8% of African Americans carry the HbS trait. Low O2, dehydration or acidosis precipitates sickling > anemia, and vaso-occlusive disease. This gives the Hb a new ability to polymerase when deoxygenated
HbS/β-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of β-globin - sickle trait has one normal beta and one sickle. Sickle beta thal would have even less beta. More likely to sickle.
Findings: Newborns are initially asymptomatic because of increased HbF and decreased HbS. “Crew Cut” on skull x-ray due to marrow expansion from increased erythropoiesis (also in thalassemias). Sickle cells on smear. Crew cut: Bone marrow expansion in the calvara. Anytime bone marrow is hyperactive is going to produce an aplastic crisis by effecting the stem cells.
Complications:
-Aplastic crisis
(Parvovirus B19),
-Autosplenectomy (Howell-Jolly bodies)> increased risk of infection with encapsulated organisms (common cause of death in children),
-Salmonella osteomyelitis,
-Extramedullary hematopoiesis,
-Dactylitism (swollen fingers from vaso- occlusion),
-Acute chest syndrome (common cause of death in adults),
-Renal papillary necrosis (due to low O2 in papilla.
Treatment: hydroxyurea (increased HbF) and hydration
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal Nocturnal Hemoglobinuria
Acquired mutation in a hematopoietic stem cells. Increased complement- mediated RBC lysis (impaired synthesis of GPI anchor for decay accelerating factor that protects RBC membrane from complement). Mild respiratory acidosis at night triggers hemolysis. 10% of patients > acute leukemia.
Triad: Coombs (-) hemolytic anemia, pancytopenia, and venous thrombosis (cause of death)
Labs: CD55/59 (-) RBCs on flow cytometry, low or no haptoglobulin.
Treatment: Eculizumab (complement pathway inhibitor)
Only pure cause of intravascular hemolysis due to an intrinsic RBC defect.
4 kinds of extrinsic hemolytic normocytic anemia
Autoimmune hemolytic anemia (AIHA)
Warm agglutinin (IgG)- chronic anemia seen in SLE (most common), CLL, α-methyldopa, pencillin.
Cold agglutinin (IgM)- acute anemia triggered by cold; seen in CLL, Mycoplasma and Mononucleosis. RBCs agglutinate and may cause painful, blue fingers and toes with cold exposure.
Many warm and cold AIHA are idiopathic but most are Coombs (+)
Microangiopathic anemia: RBCs are damaged when passing through obstructed or narrowed vessel lumina. DIC, TTP-HUS, SLE, and malignant hypertension. Schistocytes (helmet cells) due to mechanical destruction of RBCs
Macroangiopathic anemia: Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia secondary to mechanical destruction. Schistocytes on peripheral blood smear
Infections:
Malaria, Babesia invade RBCs and cause lysis
A 17-year-old boy reports passage of dark urine to his physician. He has a history of multiple bacterial infections and venous thromboses for the past 10 years, including portal vein thrombosis in the previous year. On physical examination, his right leg is swollen and tender. CBC shows hemoglobin, 9.8 g/dL; hematocrit, 29.9%; MCV, 92 µm3; platelet count, 150,000/mm3; and WBC count, 3800/mm3 with 24% segmented neutrophils, 1% bands, 64% lymphocytes, 10% monocytes, and 1% eosinophils. He has a reticulocytosis, and his serum haptoglobin level is very low. A mutation affecting which of the following gene products is most likely to give rise to this clinical condition?
(A) Spectrin (B) Glucose-6-phosphate dehydrogenase (C) Phosphatidylinositol glycan A (PIGA) (D) β-Globin chain (E) Factor V (F) Prothrombin G20210A
C)
portal vein thromboses is odd.
WBC count: low
Paroxysmal nocturnal hemoglobinuria is an acquired disorder in the myeloid stem cell membrane produced by a mutation in the PIGA gene. Mutation in this gene prevents the membrane expression of certain proteins that require a glycolipid anchor. These include proteins that protect cells from lysis by spontaneously activated complement. As a result, RBCs, granulocytes, and platelets are exquisitely sensitive to the lytic activity of complement. The RBC lysis is intravascular, patients can have hemoglobinuria (dark urine. Defects in platelet function are believed to be responsible for venous thrombosis
Cause of megaloblastic anemia - vitB12/B9
Function: Cofactor for methionine synthase (transfers CH3 groups) and methylmalonyl-CoA mutase (metabolizes methylmalonyl-CoA). Found in animal products and only synthesized by microorganisms. Folate works with B12 to form methionine from homocysteine. Folate (THF) required for many synthetic pathways including nucleotide synthesis.
B12 deficiency- Methylmalonyl CoA accumulates and causes CNS damage
- to make B12 you must have animal byproducts
- folate comes from greens.
THF (folate) + B12 + homocysteine= methionine. If they don’t make methionine you have increase of homocysteine. Elevated homocysteine leads to damage to blood vessels, thrombosis. If you dont have B12, all of the folate is trapped as methyl tetrahydrofolate but you need THF in other areas to make DNA. Nucleus sitting there that can’t replicate its DNA< nucleus is immature.
B12 also converts methymalonyl coA > succinyl-coA - leads to CNS damage dorsal and lateral corticospinal columns (differs it from folate). Even chain fatty acids are broken down to acetyl coA, odd chain fatty acids is the only time you have methylmalonyl coA- without B12 you can’t further metabolize it. Its the one example where fatty acids can be converted into glucose via succinyl coA. (ONE EXCEPTION)
Causes of megaloblastic anemia
Megaloblastic Anemia Impaired DNA synthesis> delayed maturation of nucleus of precursor cells in bone marrow is delayed relative to cytoplasm. Macrocytosis, hypersegmented neutrophils, glossitis
Folate Deficiency- takes months to develop
Causes: malnutrition (alcoholics), malabsorption, antifolates (methotrexate, trimethoprim, phenytoin), increased requirement (hemolytic anemia, pregnancy).
B12 deficiency- takes years to develop Causes: insufficient intake (strict vegans), malabsorption (Crohn disease), pernicious anemia (no intrinsic factor), Diphyllobothrium latum (fish tapeworm), gastrectomy. Pancreatic disease (need enzymes to release B12 so it can bind to IF)
Neurologic symptoms: subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis. spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction. Accumulated methymalonic acid - Subacute combined degeneration
Diagnosed with Schilling test: Schilling Test- Give oral radioactive B12 without (Part 1) and then with intrinsic factor (IF, Part 2). Measure radioactive B12 in urine - ileum - chrons disease (folate is absorbed, duodenum and jejunum. B12 and IF together are used for absorption. Say you don’t have B12 in urine, then you add IF and you do, then you know you have pernicious anemia
Orotic aciduria:
Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathways). AR. **megaloblastic anemia that cannot be cured by folate or B12. Treatment: UMP to bypass mutated enzyme
A 62-year-old man goes to the emergency department in an obvious state of inebriation. On physical examination, he is afebrile. The spleen tip is palpable, and the liver edge is firm. Laboratory studies show hemoglobin of 8.2 g/dL, hematocrit of 25.1%, MCV of 107 µm3, platelet count of 135,000/mm3, and WBC count of 3900/mm3. The peripheral blood smear shows prominent macrocytosis. A few of the neutrophils show six to seven nuclear lobes. Which of the following is the most likely explanation of these findings?
(A) Mechanical fragmentation of RBCs (B) Increased susceptibility to lysis by complement (C) Nuclear maturation defects resulting from impaired DNA synthesis (D) Hemolysis of antibody-coated cells (E) Reduced deformability of the RBC membrane (F) Production of abnormal hemoglobin
C)
Non-megaloblastic macrocytic anemia
Non-megaloblastic macrocytic anemias:
Macrocytic anemia in which DNA synthesis unimpaired. Caused by liver disease, alcoholism.
RBC Macrocytosis w/o hypersegmented neutrophils
These conditions are likely precursors to megaloblastic.
I noticed that there are a few disorders including (Bernard-Soulier syndrome) that results in enlarged platelet size. Is there a pathological basis for this change in morphology?
As a follow-up, regarding Bernard-Soulier, is there reason for why thrombocytopenia occurs?
There are two important points I think- about platelet size. Some disorders associated with thrombocytopenia, like ITP, are caused by platelet destruction. In all other ways, however, we can presume the bone marrow and the platelets themselves are normal. The bone marrow will ramp up to make new platelets (as free circulating TPO will increase) and newly formed “young” platelets will come into the blood stream- immature platelets are larger sized. You would expect the mean platelet volume (an indicator of platelet size) to be higher. This is analogous to what happens with immune-mediated destruction of RBCs (as well as other causes of anemia when the bone marrow is capable of responding) when young, immature RBCs (reticulocytes) enter the blood stream in larger numbers and these are also LARGER than normal RBCs. Bottom line: platelets are larger than expected-they are normally 1/5th the size of an RBC so maybe some will be 2X normal .
This is distinct from Bernard-Soulier Syndrome (BSS). With BSS- the platelet receptor that is absent or decreased in expression (GPIb/IX/V) mediates platelet adhesion to vWF- so basically- the platelets can’t adhere when and where they need to (e.g. at sites of vascular injury).
HOWEVER, because the GPIb/IX/V complex is located in the platelet cytoskeleton, it is also essential to the production of platelets from the megakaryocytes in the bone marrow. The altered receptor expression directly affects how the platelets are made- leading to the large size and decreased numbers of platelets in this syndrome.
With regard to size- we are talking GIANT platelets !!! these platelets can be the size of RBCs so this is 5X the normal size- WAYYYYY bigger than normal. Another congenital platelet disorders that does this-is a deficiency of platelet alpha granules (eg, gray platelet syndrome). Inherited platelet disorders with giant platelets are quite rare…….so you know- stick it on your bulletin board for step 1
I am a bit confused about First Aid’s NH Lymphoma chart versus the idea from lecture that Follicular Lymphomas are the most common type of NH lymphomas (see attached lecture slide versus FA chart)”.
First Aid is right- but in the lecture - I specified that Follicular Lymphoma was the most common INDOLENT (slow growing) lymphoma- not most common overall- Overall, most common is DLBCL- but the behavior of this tumor is different, it is faster growing and thus more aggressive- so I separate the diseases out in terms of their behaviors so you can think about this for the vignettes.
What about molecules?
FA also lists BCL2 as being important to DLBCL- this is also correct but I do not think it is as important to know as the association with BCL6
Important summary points:
Follicular lymphoma : 85-90% have t(14;18) and remember that this is necessary (but not sufficient) for transformation.
DLBCL: I emphasized the BCL6 translocation [t(3;14)] but also pointed out that when all DLBCL patients are considered, 30-40% have the BCL6 translocation- and the rest have mutations causing BCL6 to be overexpressed via another mechanism. In other words- BCL6 is the BIGGER problem.
BCL2 translocation typical of follicular lymphoma can also be found in 20-30% of DLBCL patients- some people think that part of this population represents people with follicular lymphoma that has transformed and become more aggressive.
Translocation (8;14)
Burkitt lymphoma (c-myc activation)
t (9;22) philadelphia chromosome)
CML (BCR-ABL hybrid) ALL (less common with poor prognostic factor)
- Philadelphia CreaML cheese. The Ig heavy chain genes on chromosome14
are constitutively expressed. When other genes (eg, c-myc and BCL-2) are translocated next to this heavy chain gene region, they are overexpressed.
t (11;14)
Mantle cell lymphoma (cyclin D1 activation)
t(15;17)
APL (M3 type of AML)
responds to all-trans retinoic acid
t(14;18)
Follicular lymphoma (BCL-2 activation)
Langerhans cell histiocytosis
Collective group of proliferative disorders of
dendritic (Langerhans) cells. Presents in a
child as lytic bone lesions and skin rash or as recurrent otitis media with a mass involving the mastoid bone. Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentation.
Cells express S-100 (mesodermal origin) and CD1a. Birbeck granules (“tennis rackets” or rodshaped on EM) are characteristic
Burkitt lymphoma
Burkitt lymphoma
Adolescents or young
adults
t(8;14)—translocation of c-myc (8) and
heavy-chain Ig (14)
“STARRY 🤩sky” appearance: “lymphoid cells with numerous mitotic figures”, sheets of lymphocytes with interspersed “tingible body” macrophages
Associated with EBV. Jaw lesion in endemic form in Africa; pelvis or abdomen in sporadic form.
*HIGHLY aggressive B cell non-Hodgkin lymphoma, rapidly growing tumor with VERY SHORT doubling time (25 hrs)
Diffuse large B-cell lymphoma
Usually older adults but 20% in children
Alterations in Bcl-2, 6
Most common type of non-Hodgkin lymphoma in adults
BcL-6 association is more important to know: zinc finger transcriptional repressor
This mutation: prevents cells from undergoing apoptosis in response to DNA damage, suppresses normal DNA damage response, damaged cells progress through the cell cycle, encourages somatic hypermutation
Follicular lymphoma
Adults
t(14;18) - heavy chain ig (14) and BCL-2 (18)
Indolent course; Bcl-2 inhibits apoptosis.
Presents with painless “waxing and waning” lymphadenopathy.
Follicular architecture:
small cleaved cells (grade 1), large cells (grade 3), or mixture (grade 2).
Arises from germinal center B cells
BCL2 is an antiapoptotic protein. Mature lymphocyte population expands!
Mantle cell lymphoma
adult males
t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14),
CD 5+
Very aggressive, patients typically present with late-stage disease
Promotes G1-to-S phase transition
Marginal zone lymphoma
adults
t(11,18)
Associated with chronic inlammation (eg, Sjögren syndrome, chronic gastritis [MALT lymphoma]).
Primary central nervous system lymphoma
Adults
Most commonly associated with HIV/AIDs; pathogenesis involves EBV infection
Considered an AIDS-deining illness. Variable presentation: confusion, memory loss, seizures. Mass lesion(s) on MRI needs to be distinguished from toxoplasmosis via CSF analysis or other lab tests.
Adult T-cell lymphoma
Adults
Caused by HTLV (associated with IV drug abuse)
Adults present with cutaneous lesions; common in Japan, West Africa, and the Caribbean. Lytic bone lesions, hypercalcemia.
Mycosis fungoides/Sezary syndrome
Adults
Mycosis fungoides: skin patches/plaques (cutaneous T-cell lymphoma), characterized by atypical CD4+ cells with cerebriform nuclei and intraepidermal neoplastic cell aggregates. (Pautrier microabscess). May progress to Sézary
syndrome (T-cell leukemia).
Hodgekin vs non-Hodgekin lymphoma
Both Hodgkin and non-Hodgkin lymphoma are malignancies of a family of white blood cells known as lymphocytes, which help the body fight off infections and other diseases. Hodgkin lymphoma is marked by the presence of Reed-Sternberg cells, which are mature B cells that have become malignant, are unusually large, and carry more than one nucleus. The first sign of the disease is often the appearance of enlarged lymph nodes. Non-Hodgkin lymphoma, by contrast, can be derived from mature B cells or T cells and can arise in the lymph nodes as well as other organs. (B cells and T cells play different roles in the body’s immune response to disease.)
Both diseases are relatively rare, but non-Hodgkin lymphoma is more common in the United States, with more than 70,000 new cases diagnosed each year, compared to about 8,000 for Hodgkin lymphoma. The median age of patients with non-Hodgkin lymphoma is 60, but it occurs in all age groups. Hodgkin lymphoma most often occurs in people ages 15 to 24 and in people over 60. There are more than 60 distinct types of non-Hodgkin lymphoma, whereas Hodgkin lymphoma is a more homogeneous disease.
The two forms of lymphoma are marked by a painless swelling of the lymph nodes. Hodgkin lymphomas are more likely to arise in the upper portion of the body (the neck, underarms, or chest). Non-Hodgkin lymphoma can arise in lymph nodes throughout the body, but can also arise in normal organs. Patients with either type can have symptoms such as weight loss, fevers, and night sweats.
The diseases often follow different courses of progression. Hodgkin lymphoma tends to progress in an orderly fashion, moving from one group of lymph nodes to the next, and is often diagnosed before it reaches an advanced stage. Most patients with non-Hodgkin lymphoma are diagnosed at a more advanced stage.
Treatments for lymphoma vary depending on the type of disease, its aggressiveness, and location, along with the age and general health of the patient. As a general rule, however, Hodgkin lymphoma is considered one of the most treatable cancers, with more than 90 percent of patients surviving more than five years. Survival rates for patients with non-Hodgkin lymphoma tend to be lower, but for certain types of the disease, the survival rates are similar to those of patients with Hodgkin lymphoma. New treatment approaches, including the use of therapies that spur the immune system to attack cancerous lymphocytes, are showing considerable promise.
vWF
Endothelial cells constitutively synthesise and release von Willebrand factor (vWF) into blood, which serves two functions (at least). Firstly, vWF stabilises coagulation factor VIII and protects it from proteolytic degradation in plasma. Secondly, vWF binds avidly to collagen and activates platelets when it does so. Now, blood and collagen don’t usually come into contact with each other unless the endothelium is damaged. When the endothelium is disrupted – say by a cut through a vessel – vWF immediately binds to collagen ready to activate the first platelet that comes along.
Bax, Bak, Bcl-2, Bid,Bad, PUMA
Bax and Bak promote pore formation; release of cytochrome c and APAF1 initiates apoptosis
Bcl-2 binds Bax/Bak and prevents pore formation; anti-apoptotic
Bid, Bad, and PUMA promote apoptosis: tie up Bcl-2 and free Bax/Bak.
Chronic myelogenous
leukemia
Occurs across the age spectrum with peak incidence 45–85 years, median age at diagnosis 64 years.
Deined by the Philadelphia chromosome (t[9;22], BCR-ABL) and myeloid stem cell proliferation. c-Abl is a tyrosine kinase that promotes proliferation and survival- gains a domain from BCR that facilitates dimerization - constitutively active and trapped in cytoplasm.
Presents with dysregulated production of mature and maturing granulocytes (eg, neutrophils, metamyelocytes, myelocytes, basophils) and splenomegaly.
May accelerate and transform to
AML or ALL (“blast crisis”).
Very low LAP as a result of low activity in malignant neutrophils (vs benign neutrophilia [leukemoid reaction], in which LAP is increased). Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib).
Acute myelogenous leukemia
Median onset 65 years. Auer rod, myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in
APL (formerly M3 AML); SUPER INCREASE in circulating myeloblasts on peripheral smear; adults.
-FTL3 (receptor tyrosine kinase) mutation: expressed by immature hematopoietic cells, poor prognosis, found in 30% of AML
Risk factors: prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders,
Down syndrome.
APL: t(15;17), responds to all-trans retinoic acid (vitamin A), inducing
differentiation of promyelocytes; DIC is a common presentation.
PML-RAR alpha fusion protein accumulates - activates transcription. So what happens is that RA usually binds to RAR and relieves repression allowing transcription to activate. This leads to proliferation of immature myeloid cells because self-renewal activity is enhanced. If you give pharmacologic doses of RA, you can bypass and force the cells to mature
Anaplastic Large Cell Lymphoma
ALK (anaplastic lymphoma kinase) - nonreceptor tyrosine kinase located on chromosome 2
t (2;5) translocation is most common.
T cell lymphoma
ALK fusion is constitutively active
RUNX1 (AML)
RUNX1 (ALL)
both are hematopoietic transcription factors
RUNX1 (AML)
-t(8;21) RUNX-RUNXT1 - AML-ETO
blocks RUNX function
RUNX1 (ALL)
-t(12;21) ETV6-RUNX - TEL-AML
Activation of transcrption
*both good prognosis
Mixed lineage leukemia
MLL
(KMT2A - histone methyltransferase)
associated with both ALL and AML
most common cytogenetic abnormality in infants with acute leukemia)
ALL vs AML
lymphocytic vs other blood cell types found in bone marrow
poor prognosis
What is leukemia
Unregulated growth and differentiation of WBCs in bone marrow > marrow failure > anemia
(decreased RBCs), infections (decrease mature WBCs), and hemorrhage (decrease platelets). Usually presents with
increasecirculating WBCs (malignant leukocytes in blood); rare cases present with normal/decrease WBCs. Leukemic cell iniltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.
Acute lymphoblastic leukemia/lymphoma
Most frequently occurs in children; less common in adults (worse prognosis). T-cell ALL can present as mediastinal mass (presenting as SVC-like syndrome).
Associated with Down syndrome. Peripheral blood and bone marrow have SUPER INCREASEDlymphoblasts. TdT+ (marker of pre-T and pre-B cells), CD10+ (marker of pre-B cells). Most responsive to therapy.
May spread to CNS and testes. t(12;21)> better prognosis.
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Age: > 60 years. Most common adult leukemia.
CD20+, CD23+, CD5+ B-cell neoplasm. Often asymptomatic, progresses slowly; smudge cells in peripheral blood smear; autoimmune
hemolytic anemia.
CLL = Crushed Little Lymphocytes (smudge cells).
*Richter transformation—CLL/SLL transformation into an aggressive lymphoma, most commonly
diffuse large B-cell lymphoma (DLBCL).
Hairy Cell leukemia
Age: Adult males. Mature B-cell tumor. Cells have filamentous, hair-like projections (fuzzy appearing on LM). Peripheral lymphadenopathy is uncommon. Causes marrow fibrosis > drytap on aspiration.
*even though hair cell leukemia affects the white cells, the lymph nodes usually don’t enlarge and they tend to accumulate in bone marrow, liver and spleen.
100% have a BRAF mutation
Patients usually present with massive splenomegaly and pancytopenia. Stains TRAP (tartrate-resistant acid phosphatase)⊕. TRAP stain largely replaced with low cytometry. Treatment: cladribine, pentostatin.
Polycythemia vera
Primary polycythemia. Disorder of increased RBCs. May present as intense itching after hot shower. Rare
but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities
*JAKV617F mutation - nonreceptor tyrosine kinase which leads to constitutive activation
Decreased EPO (vs 2° polycythemia, which presents with endogenous or artiicially increasedEPO). Treatment: phlebotomy, hydroxyurea, ruxolitinib (JAK1/2 inhibitor).
Essential thrombocythemia
Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include
bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may
be large or otherwise abnormally formed. Erythromelalgia may occur.
Myelofibrosis
Obliteration of bone marrow with fibrosis due to increasedfibroblast activity.
Often associated with
massive splenomegaly and “teardrop” RBCs. “Bone marrow is crying because it’s fibrosed and
is a dry tap.”
Agonists used for platelet aggregation studies
• Arachidonic acid: used to assess the viability of the thromboxane
pathway.
• Thrombin: Most potent physiologic agonist of platelets. Reacts
with several membrane sites to induce full aggregation and secretion of organelle contents independent of the prostaglandin or ADP pathways.
• Collagen: Important for platelet adhesion and activation of the
ECM of the endothelium. Depends on intact membrane receptors,
membrane phospholipase pathway integrity and normal
cyclooxygenase and thromboxane pathway function.
• ADP: Mild platelet agonist. Binds to a specific platelet membrane receptor and causes platelet activation and release of dense granule stored ADP.
• Epinephrine: Mild platelet agonist. Binds to specific receptor and
causes ADP secretion.
• Ristocetin: requires vWF and intact surface membrane including a
functional vWF receptor site (GPIb).
Increased destruction
Immune thrombocytopenic purpura (ITP)
• Immune thrombocytopenic purpura (ITP)
• Acquired thrombocytopenia secondary to autoantibodies against platelet antigens: usually it is an IgG made by patient that acts on glycoprotein receptors in platelets
• Primary: Autoimmune platelet destruction
• Secondary: Associated with underlying condition
component of impaired production)
Pathogenesis:
• Reduced platelet lifespan secondary to antibody-mediated destruction (also • Triggers
• Infection (more often viral): viral like symptoms, all of a sudden the yhave massive bruising
• Immune alteration: lupus, RA
Manifestations - Petechiae, purpura, epistaxis, severe bleeding (<1% of patients)
Diagnosis:
• Thrombocytopenia
• Mild (>100,000/ul) to severe (>10-20,000/ul)
• Increased MPV/giant platelets
• Absence of other abnormal findings
(Rest of CBC normal, normal coags) • Bone marrow exam: Normal cellularity, normal or increased number of megakaryocytes, normal hematopoiesis
Treatment • Immunosuppression • Steroids • Rituxan • Splenectomy • TPO agonists
Keywords - thrombocytopenia, large platelets, Hb is normal, WBC is normal, normal CoAgs , normal PT, PTt, fibrinogen.
Microangiopatic hemolytic anemia (increased destruction) - DIC
(as with all MAHA), RBC is down (excludes ITP), you see schistocytes
Dissemintated intravascular coagulation (DIC)
• Activation of the coagulation cascade unnecessarily leading to
excessive fibrin in vessels, combines with platelets, making thrombi
• Consumption of platelets and coagulation factors
• Manifests as bleeding and clotting; multi-organ disease
Causes:
• Obstetric (relating to childbirth) complications, adenocarcinomas, APL (acute promyelocytic leukemia), snake bites
• Sepsis, trauma, thermal burns, vasculitis
• Acute or chronic
DIC Diagnosis: • Prolonged PT/INR, PTT, and TT • Decreased fibrinogen, increased FDPs and dd-dimer • Thrombocytopenia • Smear: schistocytes
Treatment:
• Treat underlying disorder • Transfusion support
Keywords: overactive coagulation cascade, multi-organ disease, thrombocytopenia, decreased fibrinogen, prolonged PT/INR, PTT, and TT, anemia
you have thrombocytopenia with clots going on everywhere (which is why all clotting factors are going down)
Microangiopatic hemolytic anemia (increased destruction) - HUS
Simultaneous occurrence of microangiopathic hemolytic anemia,
thrombocytopenia, and ACUTE SEVERE kidney injury
Classification
• Primary: Complement dysregulation: Mutations in complement gene, antibodies against complement factor H
Secondary: • Infection: Shiga toxin producing E.Coli, Strep pneumo, HIV • Drug toxicity • Pregnancy • Autoimmune disorders
Diagnosis
• Microangiopathic hemolytic anemia, thrombocytopenia
• Schistocytes on smear
• Normal coags, Coombs negative
• Acute kidney injury: range from hematuria/proteinuria to severe renal
failure
• Cultures, viral studies, complement studies
Treatment
• Supportive care, transfusions, dialysis
• Plasmapheresis
• Eculizumab: inhibits complement
Microangiopatic hemolytic anemia (increased destruction) - TTP
Mechanism
• Deficiency of ADAMTS13
• ADAMTS13 cleaves ultra large VWF multimers
• Increases large multimers in circulation, adhere to platelets,
thrombocytopenia and primary thrombi formation (but NOT coagulation) - Acquired or inherited
Presentation
• Thrombocytopenia and hemolytic anemia in previous healthy pt
• PENTAD: Fevers, Anemia, Thrombocytopenia, Renal, Neuro
Diagnosis • Evidence of MAHA on smear/labs • Coombs negative • Normal coags • ADAMTS13 activity <5-10%: Reflex to inhibitor
Treatment-Medical Emergency
• Plasmapheresis - FFP: fresh frozen plasma
Immunosuppression
• Steroids +/- Rituxan • Avoid transfusion - if you just give more platelets it will just bind to the multimers and cause more clotting
Keywords - sudden onset low platelet and anemia, NORMAL PTT, NORMAL Fibrinogen, NORMAL COAGS (differs from DIC)
Heparin induced thrombocytopenia
*ironic
Occurs in 5% of exposed patients
• Autoantibody against endogenous platelet factor 4 (PF4) - the protein in alpha granules - in complex with heparin
• Activates platelets
• Catastrophic arterial and venous thrombosis
Risk factors:
• Unfractionated heparin > LMWH, increased dose of heparin, female sex,
surgery, age
Presentation
• Thrombocytopenia
• Timing of drop 5-10 days after heparin exposure
• Thrombosis: arterial or venous, thrombotic sequelae
• Anaphylaxis
Treatment • Discontinuation of all heparin products • Evaluation for thrombosis • Alternative anticoagulation Long term • Transition to coumadin • Lifetime avoidance of heparin
*if someone on heparin develops a clot you should go “hmmmmmm”
Splenic sequestration
Splenic sequestration
• 1/3 of platelet mass is sequestered in spleen
• Can increase to 90% with severe splenomegaly
- Total platelet mass is normal
- Rarely with clinical bleeding
• Cirrhosis, portal hypertension, splenomegaly
Qualitative platelet disorder
-normal platelet number but these platelets aren’t working
Medications
• ASA • NSAIDS • Dipyridamole • P2Y12 receptor antagonists • Miscellaneous:
Antibiotics, SSRIS, antiepileptics, fish oils
Uremia
• Associated with chronic renal failure • Increased clinical bleeding: ecchymoses, epistaxis, GI/GU bleeding • Mechanism: intrinsic platelet metabolic defects, deficiencies in platelet
endothelial interaction, associated anemia
• Severity of renal failure does not correlate with bleeding
- Liver disease
- Cardiopulmonary bypass
- Dysproteinemia
Congential
• Bernard-Soulier
• Glanzmanns thombasthenia
• Storage pool disorders
Bernard-Soulier Syndrome
Bernard-Soulier Syndrome
Glycoprotein Ib/IX/V Deficiency
• Plays a major role in platelet adhesion to the subendothelium.
• Mediates the binding of VWF to platelets
• Characterized by prolonged bleeding time, large platelets, and thrombocytopenia
Extremely rare:
• Autosomal recessive - Often associated with consanguinity
• Populations of Europe, North America, and Japan
Clinical Manifestations
• Evident from early childhood.- Symptom severity may vary through life
• Frequent episodes of epistaxis
• Gingival and cutaneous bleeding
• Spontaneous ecchymoses
• Hemorrhage associated with trauma/surgery/dental extractions
• Menorrhagia and pregnancy manifestation may be variable
Diagnosis
• Prolonged bleeding time
• Morphologically Enlarged platelets
• Thrombocytopenia (?)
• Platelet aggregation: an isolated defect in **ristocetin-induced
aggregation - which is vWF used as an agonist
Confirmation:
• Flow cytometry: assessment of platelet surface glycoprotein
expression
• Immunoblotting of platelet lysates with specific antiplatelet glycoprotein
antibodies.
• Genotype
Management
• General measures:
• Avoiding even relatively minor trauma • Advise against the use of antiplatelet medications
• Adequate dental hygiene-to prevent gingival disease and minimize
procedures
• Iron supplementation as needed
• Hormonal control of menses
Bleeding episodes or prophylaxis:
• *Transfusion of blood and/or platelets
• Use of antifibrinolytic drugs may or may not be beneficial
• DDAVP may shorten the bleeding time in some (this drug increases the amount of platelets you have)
• Novo-7
• Hematopoeitic stem cell transplant
Glanzmann Thrombasthenia
GPIIb/IIIa Deficiency (the protein that binds to fibrinogen and links platelets)
• Characterized by a prolonged bleeding time, normal platelet count,
absent macroscopic platelet aggregation
• Relatively more severe mucocutaneous bleeding manifestation than most platelet function disorders
• Autosomal recessive
Presentation:
• Mucocutaneous bleeding during neonatal period or
infancy (ex. Circumcision)
• Spontaneous petechiae uncommon
• Epistaxis
• Gingival bleeding
• Menorrhagia
• GI/GU bleeding
• Severity of hemorrhage unpredictable, even within
families, does not correlate with deficiency
Diagnosis
• **Platelet counts and morphology normal
• Bleeding time: markedly prolonged
• Platelet aggregation: absent agonist-stimulated platelet aggregation: only ristocetin works so the complete opposite of Bernard-Soulier
• Platelet secretion by strong agonist normal
• (Weak agonists ADP/epinephrine absent)
• Flow cytometry: decreased platelet expression of GPIIb/IIIA
complex
Treatment • General measures:
• Avoiding even relatively minor trauma
• Advise against the use of antiplatelet medications
• Adequate dental hygiene-to prevent gingival disease and minimize
procedures
• Iron supplementation as needed
• Hormonal control of menses
Bleeding episodes or prophylaxis:
• Transfusion of platelets
• Use of antifibrinolytic drugs, such as ε-aminocaproic acid or tranexamic
acid • DDAVP may shorten the bleeding Novo-7 • Hematopoeitic stem cell transplant
Thrombin Time
Thrombin Time (TT) • Measures final step of coagulation, conversion of fibrinogen to fibrin
• Prolonged if fibrinogen levels are low or inhibiting anticoagulant is
present
- Used if:
- Prolonged PT/aPTT
- Evaluation of inherited fibrinogen disorder
- Detection of heparin
How to distinguish between an abnormal prolonged clotting time is due to a factor deficiency versus a factor inhibitor
abnromal pTT and PT- take patients plasma, give them additional plasma and do test again.
If they have factor deficiency, it should correct, because the plasma would contain all the factors.
Give them back the factors and if it doesn’t work, there is an inhibitor
If an inhibitor is present, mixing studies can also be used to determine the titer of the inhibitor
• Serial dilutions of patient plasma are mixed with normal plasma until the
proportion of patient plasma is reduced to the point that the mixing study does correct
• Reported in Bethesda units (BU)
Hemophilia A and B
X-linked recessive diseases that present in male children of carrier females
• Hemophilia A (factor 8)- Occurs 1:5000 live male births, 2/3 will have severe disease
• Hemophilia B (factor 9)- Occurs in 1:30,000 live male births, ½ will have severe disease
• Severe hemophilia is almost exclusively a disease of males
Initial presentation
Severe disease:
• Present within the first year to one and a half years of life
• Average age of diagnosis is 8-36 months • Majority undergo delivery without significant bleeding
• Easy bruising, hemarthrosis, bleeding due to oral injury, invasive
procedures
• Majority present with a known family history* : Although there will be some that present with a de novo gene mutation transmitted from the mother
• Mild disease
• May go undetected for significant period of time until significant
hemostatic challenge • Average age of diagnosis 14-62 years • 1/3 have minimal bleeding
Initial site of bleeding
Infants
• CNS
• Sites of medical interventions
Children
• Bruising, joint bleeds, and other sites of musculoskeletal bleeding
• More common once children begin walking
Older children and adults
• Joints and muscles
Laboratory findings
• Prolonged PTT (because factors 9 and 8 are intrinsic)
• May be normal in mild disease (factor activity >15%)
• Normal PT and platelet count
• Measurement of the factor activity
• Normal VWF antigen- Should be checked with all decreased FVIII
A: Confirmation FVIII activity <40% or identification of a known a
pathogenic factor VIII gene mutation
• Documented normal VWF antigen
B: Confirmation FIX activity <40% or identification of a pathogenic
factor IX gene mutation
• Newborns have a lower normal range of factor IX activity
Clinical severity correlates well with assayed factor levels.
• <1% factor activity defined as severe disease
• 1 to 5% defined as moderate disease
• >5% of normal defined as mild disease
• Prophylactic treatment over “on demand” treatment
• The goal to maintain the factor VIII above 1 percent
Factor XI Deficiency
Factor XI Deficiency
• Incidence is 1 in 1,000,000
• Autosomal bleeding disorder common among Ashkenazi Jews
• Heterogeneous phenotype, with a poor correlation between plasma
FXI levels and bleeding
• Most do not suffer from spontaneous bleeding
• Do not need prophylaxis for routine daily activity
• At risk of bleeding following trauma or surgery
• Higher, variable risk for menorrhagia and postpartum hemorrhage
Management
• Do not need prophylaxis for routine daily activity
• Treatment indicated for dental extraction, major surgery, trauma,
childbirth
• Surgery or injury involving tissues with high fibrinolytic activity
associated with higher bleeding risk
• Antiplatelet agents, aspirin, and other NSAIDs are absolutely
contraindicated before surgery, as their presence may increase the
risk of bleeding.
• At other times, these agents are relatively contraindicated.
Acquired Coag Factor inhibitors
Spontaneously acquired inhibitors of blood coagulation
• Antibodies that either inhibit the activity or increase the clearance
of a clotting factor.
• May be secondary to transfusion of plasma or recombinant factor infusion, or arise de novo in previously
normal patients
• Most common against FVIII
Clinical Setting
• Alloantibodies in congenital hemophilia
• Postpartum
• Associated with immunologic disorders (SLE, RA)
• Associated with malignancies (solid tumors or lymphoproliferative)
• Drug Reactions (PCN)
• Spontaneous development (50%)
Demographics
• Gender: equal
• Age: >50 yo
Course
• Mortality 22%
• Spontaneous remission 38%
Presentation
• Severe bleeding diathesis
• Skin, mucous membrane, soft tissue bleeding
• Sudden large hematomas or hemarthroses
• Fatal GI, retroperitoneal, or intracranial bleeding
Ex. SEVERE bruising, Hb of 4, happens rapidly, they are in their 80’s and never had bleeding before, prolonged PTT, bleeding everywhere
Evaluation
• Repeat all tests
• Exclude heparin affect with dilute thrombin time and reptilase time
• Inhibitor screen (mixing test), with incubation studies
• Correction of the prolonged aPTT suggests a deficiency, while persistent prolongation of the aPTT indicates the presence of an inhibitor.
• Phospholipid: Adding source of phospholipid to the mixed plasma. Correction of the aPTT suggests the presence of antiphospholipid
antibodies.
• Factor activity assay and inhibitor screen - Establishes diagnosis and quantifies inhibitor
Management • Acute bleeding - Careful nursing care • No IM injections, fall precautions • Transfusion support • Bypassing agents: First line therapy - Recombinant FVIIa - aPCC • Factor replacement - Potential option if antibody titer is low (<5BU)
Elimination of the autoantibody
Immunosuppression
• Prednisone plus cyclophosphamide (CR 70%)
• Rituximab
• Single agent prednisone, cyclophosphamide, azathrioprine
• Some resolve spontaneously (postpartum, drug induced)
ê
• Plasmapheresis has also been studies in combination with
immunosuppression
Von Willebrand disease
Von Willebrand factor (VWF)
• Binds both platelets and endothelial components, forming bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets
• Carrier protein for FVIII
• Synthesized by megakaryocytes and endothelial cells
• Require extensive post-synthetic processing
• VWF is sufficiently decreased in the plasma or when a qualitative defect in VWF bleeding occurs
• Affect platelet plug formation during the primary hemostatic response.
*#**no enlarged platelets because no decreased platelet count either! (seen in Bernard Soulier)
Clinical Manifestations • Easy bruising • Skin bleeding • Prolonged bleeding from mucosal surfaces (eg, oropharyngeal, gastrointestinal, uterine • Bleeding more serious and earlier in life in patients with VWD variant (type 2N) or type 3 VWD • Type 3 patients often have symptoms in infancy (eg, with circumcision) or when they begin to be mobile
Types 1 and 3 are quantitative, Type 2 is qualitative, you make enough but activity is very low.
Desmopressin (DDAVP) • Overview of DDAVP administration
• Can be administered intravenously or by intranasal spray
• Increase secretion of intrinsic VW factor
• 3-5X increase in baseline levels of VWF and FVIII expected 30-60
minutes after infusion • Response lasts 6-12 hours • Limited by tachyphylaxis and hyponatremia
• Intranasal administration favored choice for minor bleeding not
requiring a hospital visit or prior to planned minor invasive
procedure
Treatment Options
- Antifibrinolytic therapy — Aminocaproic acid and tranexamic acid
- Especially good for mucosal bleeding (dental, menorrhagia)
- Can be given orally or intravenously
- Prolonged use carries a risk of thrombosis if underlying hypercoagulable state
- Contraindicated if gross hematuria •
Topical agents — Topical thrombin
• Nasal or oral bleeding
• Gelfoam or Surgicel are soaked in topical thrombin and applied to areas of bleeding
- Estrogen
- Increases synthesis of VWF •
Recombinant factor VIIa
• Can be used in patients with Type 3 disease who develop antibodies to replacement therapy
• Bypasses need for FVIII in coagulation pathway, binds activated platelets, initiates the extrinsic
clotting cascade
VW factor replacement • Plasma derived • Contain VWF and Factor VIII • Dosed based on ristocetin cofactor activity • Examples • Wilate • Humate P • Recombinant • Vonvendi • Does not contain factor VIII
Complete diagnosis of VWD performed
• DDAVP can be used in patients with Type I and mild Type 2A/M but
not Type 2B or Type 3
• Response trial should be documented
• Avoid in young patients, pregnant, history of cardiovascular disease
• Von Willebrand factor concentrate is given to patients with major
bleeding or major surgery
• Ex. involving vital organs not accessible to direct observation, requiring
more tissue dissection or for which greater-than-expected bleeding
would adversely affect the outcome
• Risk of delayed bleeding in certain circumstances
HFE gene
Conversely, when hepcidin levels are low (as occurs in hemochromatosis), basolateral transport of iron is increased, eventually leading to systemic iron overload.
The HFE gene, which is defective in hemochromatosis, regulates hepcidin production in the liver (HFE mutated leads to low hepcidin)
Hairy cell leukemia buzzwords
- Pancytopenia
- tartrate-resistant acid phosphatase (TRAP)
- massive splenomegaly (red pulp infiltration)
- hairy cells
- treatment is 2-chlorodeoxyadenosine, cladribine
- dry tap
- middle aged, caucasian men, indolent course.
WHat are conditions associated with DIC? (6)
- gram negative sepsis (ex klebsiella in alcoholics)
- trauma
- pregnancy complications
- malignancy
- pancreatitis
- kidney complications
What are four key findings (lab) of DIC
- decreased fibrinogen levels
- elevated fibrin degradation products (plasmin mediated degradation of circulating fibrinogen or fibrin)
- D dimers (only from fibrin within blood clots)
- prolonged bleeding time (from the thrombocytopenia, consumption of platelets)
What cell marker to look for in infectious mononucleosis
CD8+ T cells (reactive atypical) - viruses naturally activate cytotoxic CD8 cells
P. vivax
P.ovale
P.falciparum
P. malariae
symptoms of high grade fever and delirium
Vivax or ovale
- Schuffner dots
- oval body
- capable of causing relapse
- both leave dormant forms in liver called hypnozoites
Vivax:
Western hemisphere
P. falciparum, malariae
-do not possess dormant forms and can’t cause relapses
What is the pentad of TTP
“FaT NuRSe”
fever thrombocytopenia neurologic alterations (microthrombi) Renal dysfunction (microthrombi) Schistocytes
PT, pTT normal
-thrombocytopenia causes petechiae, ecchymoses, purpura, and prolonged bleeding time.
Treatment is plasmapharesis
frequently seen in women.
also see elevated indirect bilirubin and lactate dehydrogenase characteristic of microangiopathic hemolytic anemia.’
Similar presentation to HUS except no mental status change, commonly in children, following E.coli O157:H7 infection.
ESR (what increases and decreases)
Erythrocyte sedimentation rate - rate what which red cells settle in blood
Decreased (slow rate)
- sickle cell anemia (altered shape)
- Polycythemia vera (many cells)
- CHF (unknown)
Increased (fast)
- inflammation
- increased antibodies, make RBCs stick better to each other
(CRP is another marker of inflammation, rises more rapidly in inflammatory conditions and is not as affected by other shit so its better, ESR is just cheap and easily performed.
60 yr old, fatigue and night sweats. Generalized lymphadenopathy and hepatosplenomegaly. Numerous small mature lymphocytes, some cells are fragile and ruptured.
CLL -small round lymphocytes and smudge cells, neoplastic B cells, CD19, 20, CD5 (anomaly) -hypogammaglobulinemia -autoimmune hemolytic anemai 0transformation to DLBL (richter)
Defective platelet aggregation with ADP, epinephrine and collagen
Defective platelet aggregation with ristocetin
Glanzmann thrombasthenia - defective or decreased levels of CPiib/iiia
Von Willebrand disease, Bernard Soulier (GPIb)
Lymphogranuloma venereum
Ex 35 yr old with painful palpable masses in the groin. Multiple enlarged abscessed lymph nodes draining through the skin through indolent sinuses.
- primary lesion is a self-healing papule or shallow ulcer
- painful enlarged abscessed lymph nodes termed “buboes” with stellate abscesses
- causative organism is C.trachomatis
- granuloma inguinale caused by Klebsiella is PINLESS.
WHat is the etiology of these diseases
ITP G6PDH deficiency TTP HIT Bernard Soulier Glanzmann THromboasthenia Von Willebrand disease Hemophilias PNH
ITP - acquired autoantibody
G6PDH deficiency - X linked recessive
TTP - acquired or inherited deficiency in ADAMTS13
HIT - autoantibody against PF4
Bernard Soulier - autosomal recessive, extremely rare
Glanzmann Thromboasthenia- GPIIb/IIIa deficiency - autosomal recessive
Von Willebrand - autosomal dominant
Hemophilias - X linked recessive (usually in males) - PTT
PNH -acquired
Hemophilias - X linked recessive
For testing purposes which drug alleves pain as first line
Acetaminophen - especially if its lack of gastric distress and cardiovascular risk matter.
It has no effect on reducing inflammation
Poisoning: hepatotoxicity - asymptomatic for the first 24-48 hrs, end organ toxicity manifests. N-acetylcysteine is antidote for acetaminophen toxicity .
