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161 Cards in this Set
- Front
- Back
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PLASMA
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the liquid portion of the blood which contains hundreds of different proteins including immunoglobulins (antibodies), clotting factors and anti-coagulant factors
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BUFFY COAT
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composed of platelets and white blood cells
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What percent of normal blood is made up of RBC?
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40-50%
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What is difference btw SERUM & Plasma?
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Serum doesn't contain clotting factors
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How do you calculate MCV?
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Hematocrit /erythrocyte count (RBC x 10^6/ul)
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How do you calculate MCH?
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hemoglobin (gm/dl)/ erythrocyte count (RBC x 10^6/ul)
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What is MCV?
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Mean corpuscular volume (MCV):the average size/volume of a red blood cell
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What is MCH?
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Mean corpuscular hemoglobin: the average amount of hemoglobin per cell
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What is RDW?
When is it high? |
Red cell distribution width (RDW): the RDW is a measurement of anisocytosis (variation in RBC size) and is calculated as a coefficient of variation of the distribution of RBC volumes divided by the MCV.
High: Iron deficiency;reflecting an increased variability in the size of red blood cells Low: |
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Where does definitive hematopoiesis begin?
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In the fetal liver; after birth in the bone marrow
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How can stem cells be identified?
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NOT in bone marrow aspirate
Can be identified by in vivo assays & in vitro assays |
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Do stem cells tend to be very mitotically active?
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No.
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Characteristic Findings:
1) "Tear drop" shaped RBC 2) Leukoerythroblasts (immature WBC & nucleated RBC) 3) extramedullary hematopoeisis WHAT IS THIS? |
Myelophthisis
When the bone marrow, is infiltrated, normal hematopoiesis may be impaired by “crowding out” of normal hematopoietic cells (inhibitory factors may play a role as well) |
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Common Causes of Myelopthisis?
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1) Metastatic cancer:
2) Hematologic malignancies: leukemia, lymphoma, myeloma 3) Fibrosis: myelofibrosis 4) Infection: granulomata (Tb), fungi (cryptococcus), parasites (toxoplasmosis) Lipid-laden macrophages in storage diseases (Gaucher disease). |
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What can renal disease cause a deficiency in?
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Inadequate production of erythropoietin (EPO)
(90% is made in the kidney) |
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What is the danger of CMV?
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CMV infection of bone marrow stroma (microenvironment) can impair production of growth factors and result in cytopenias
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What is this?
TBC: Pancytopenia; low retic Epi: peaks in 20s and >60; asia Etiology: idiopathic (75%), drugs/chemicals, chemo benzene |
APLASTIC ANEMIA
a bone marrow failure syndrome characterized by an anatomic and physiologic failure of the bone marrow resulting in the loss of hematopoietic cells from the bone marrow (aplasia) and pancytopenia (anemia, leukopenia, thrombocytopenia). |
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What is Fanconi Anemia
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increased sensitivity of DNA to physical and chemical damage secondary to defects in DNA repair mechanisms, resulting in chromosomal breaks.
Tx: stem cell transplant; however this will only cure the bone marrow failure and they are at risk for other malignancies |
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what are these symptoms of?
Pancytopenia Short stature absent or hypoplastic thumbs cafe au lait spots presents primarily in childhood |
Fanconi Anemia
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What is a megaloblast? How is that different than a macrocyte
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Megaloblast: a larger than normal cell with increased cytoplasm and an immature nucleus
Macrocyte: large RBC (from fewer cell divisions) |
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What is the pathogenesis of megaloblastosis?
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Megaloblastosis is characterized, biochemically, by defective DNA synthesis.
There is an asynchrony between the maturity of the nucleus and that of the cytoplasm. These abnormal megaloblasts are prematurely destroyed in the bone marrow (intramedullary hemolysis). This results in “ineffective erythropoiesis” and anemia. |
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What are causes of megaloblastosis?
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Folic acid deficiency (dietary)
Vit B12 deficiency (absorptive) |
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What is this:
Clinical: a sore mouth and tongue; jaundice & splenomegaly CBC: Pancytopenia Peripheral smear: RBC macrocytic; hypersegmentation of neutrophils, Elevated MCV & low retic count Bone marrow: giant metamyelocytes and giant bands Serum folate: low Homocysteine: high |
FOLATE DEFICIENCY
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Most common causes of B12 deficiency?
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Absence of intrinsic factor secondary to gastric atrophy
Pernicious anemia (autoimmune) that is anti-parietal cells & anti -IF |
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What is key difference btw folate deficiency and B12 deficiency?
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Elevated urinary (and serum) levels of METHYLMALONIC ACID!!!!
Specific and sensitive for B12 deficiency (they are not increased in folate deficiency; B12 is a cofactor for the conversion of methylmalonyl CoA to Succinyl CoA). B12 deficiency can cause neurologic complications if only treated w/ folate |
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Explain how Schilling test can determine the cause of B12 deficiency?
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Part I: Decreased urinary excretion of radioactive B12 indicates that absorption was impaired.
Part II: If due to Intrinisc Factor, B12 will be absorbed If the cause of the impaired absorption is ileal disease (Sprue, resection, Tb, etc), B12 will still not be absorbed (even if intrinsic factor is provided). |
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What causes a "false negative" in Schilling test?
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If in Part II IF is still not absorbed
This is because the gastrointestinal mucosa is also abnormal in patients with PA (B12 deficiency affects the turnover of the GI mucosa) and malabsorption will still occur. |
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Causes of folate deficiency
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1) Dietary insufficiency (most common)
2) Increased utilization (pregnancy, lactation, malignancies, hyperthyroidism) 3) Dialysis 4) Drugs & alcohol |
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Causes of B12 deficiency
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Pernicious anemia
Gastric Atrophy Proton Pump Inhibitor Gastrectomy Bacterial overgrowth Heliobacter Pylori infection Ileal disease (site of B12 absorp) Deficiency of Transcobalamin II Strict Veganism |
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What is the relationship btw IRON and Transferrin?
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Inverse;
Thus, the level of soluble transferrin receptor increases with iron deficiency. |
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What is Hepcidin?
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Hepcidin is a peptide synthesized in the liver that acts as a negative regulator of iron transport. Increased hepcidin leads to decreased absorption of iron. Decreased hepcidin leads to increased iron absorption.
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When is Hepcidin high?
When is hepcidin low? |
Hepcidin synthesis is induced by iron in the diet. Hepcidin synthesis is suppressed by anemia and hypoxemia
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In iron deficiency will plasma ferretin be high or low?
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Low; low stores of iron
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What is this?
Clinical: anemia, sore tounge, spooning of nails CBC: Decrease MCV, low Retic count, low Hgb & HCT, INCREASED RDW Peripheral smear: microcytic, hypochromatic Labs: Decreased Serum Iron, Increased TIBC, Decreased ferratin, Increased transferin |
Iron Defienct Anemia
*FIND THE BLEED!!!! |
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What is this?
Clinical: Cirrhosis, arrythmias, diabetes, end-organ damage Hepcidin deficiency |
Iron overload!
Idiopathic Hereditary Hemochromatosis Must remove iron by phlembotomy |
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What is a problem w/ chronic blood infusions? What is the tx?
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Secondary hemochromatosis (Iron overload)
Tx: Iron chelation |
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What is this?
Clinical: SOB, tired CBC: anemia, MCV usually decreased, low reticulocyte count Peripheral smear: microcytic or normocytic red cells, basophilic stippling Bone marrow: hypercellular with erythroid hyperplasia; ringed sideroblasts; increased iron Labs: serum iron, transferrin saturation and ferritin are elevated |
SIDEROBLASTIC ANEMIA
Caused by drug exposure, toxins, genetic, or pre-leukemic disease |
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What is this?
Clinical: Mild anemia Peripheral: RBC either normal or hypochromatic & microcytic Bone marrow: increased iron stores Labs: serum iron decreased, TIBC decreased, ferretin normal or increased, soluble tranferrin normal, transferrin saturation decreased, Hepcidin markedly increased |
Anemia of Chronic Disease
Tx: treat underlying disease |
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What is pathogenesis of Anemia of chronic disease?
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The anemia of chronic disease results from decreased production of red blood cells due to cytokines that inhibit the production of erythropoitin.
It also results from impaired transfer of storage iron from macrophages to blood cells. |
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What is hemoglobin degraded into?
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1) Amino acids (from globin)
2) Iron (which is incorporated into ferritin) 3)Biliverdin (from the porphyrin ring of heme) |
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What is high levels of conjugated bilirubin a sign of?
What is high levels of unconjugated bilirubin a sign of? |
conjugated: liver failure
Unconjugated: hemolysis |
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What is haptoglobin?
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Circulating carrier of hemoglobin that brings hemoglobin to the liver to be degraded by hepatic phagocytes
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Signs of jaundice
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Increased Bilirubin (primarily unconjugated)
Bilirubin gall stones Splenomegaly Increased RBC production, increased retic count & nucleated RBC Erythroid hyperplasia (in bone marrow) Elevated LDH - from hemolyzed cells Decreased haptoglobin levels |
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What is a key sign of intravascular hemolysis? Why?
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hemosiderinuria. (blood in urine)
There is more free hemoglobin than haptoglobin so the excess goes to the kidneys where the cells are excreted in the urine; Also, there is no splenomegaly |
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What is pathogenesis of immune mediated hemolysis?
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Antibodies and/or complement bind to red blood cells and result in their premature destruction.
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What is "cold" antibody?
what is "warm" antibody? |
Cold = IgM (max activity in extremities)
Warm = IgG (max activity in core) |
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What is a coomb's test used to identify?
What is a direct vs indirect coomb's test? |
Direct = detects presence of antibody (IgG or IgM) on RBC
Indirect = detects presence of antibody in the serum of the patient |
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What are the three mechanisms of a drug induced hemolysis
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1) Innocent bistander: drug plus antibody form immune complex that attaches to RBC and activates complement leading to intravascular hemolysis
2)Hapten mediated: drug absorbed onto RBC surface and immune response is generated to drug/RBC combo 3) Drug induces antibody formation against the RBC |
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What is a spherocyte? What causes it?
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A red cell with a little less membrane (relative to the intracellular volume) and, thus, a more spherical appearance
Cause: IgG antibodies bound to cell and small portion being bitten off after Fc macrophage binds to Fc portion of antibody |
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What disease often has spherocytes?
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Autoimmune hemolytic anemia (most common)
Also: Drug induced hemolysis Lymphoproliferative disorders |
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What is this:
Clinical: Jaundice, splenomegaly CBC: MCV increased, high reticulocytes Peripheral smear: spherocytes, polychromasia, nucleated RBC Labs: Positive direct Coombs test |
autoimmune hemolytic anemia
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When do cold antibodies arise?
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Infecitons (ex. Epstein Barr Virus and mycoplasma pneumonia)
lymphoproliferative disorders (chronic cold agglutens) Paroxysmal cold hemoglobinuria: IgG antibody that can activate complement in the cold and cause intravascular hemolysis |
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Which is intravascular hemolysis and which is extravascular hemolysis?
Cold type (IgM) Warm type (IgG) |
IgM (cold) is intravascular hemolysis
IgG (warm) is extravascular (spleen) hemolysis |
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A G6PD deficiency would cause what?
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Hemolysis
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What is a Hereditary spherocytosis?
How is it passed on genetically? How is it diagnosed |
It is the most common inherited RBC membrane disorder. Defects in the membrane cytoskeleton causes membrane loss and spherocytes as a result.
It is autosomal dominant Dx: osmotic fragility test (they will hemolyze in less hypotonic conditions than normal RBC. |
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Target cells & spur cells are the sign of what?
What is the underlying cause of this? |
Spur cell anemia
When the membrane enlarges without a change in the cell volume; this is usually the result of uptake of cholesterol by the membrane and is commonly seen in liver disease |
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What is a hereditary disorder that causes intravascular hemolysis?
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Paroxysmal Nocturnal Hemoglobinuria:
PNH is a clonal, stem cell disorder that is associated with the production of red cells that are missing a membrane anchor needed to bind complement regulating proteins. As a result, PNH red blood cells are very sensitive to lysis by complement. |
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What are Henize bodies? When are they seen?
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Heinz bodies are damaged hemoglobin that precipitates in RBC (looks like little spots in a RBC).
They are the sign of G6PD Deficiency This occurs when red cells are exposed to oxidant stress: infections, acidosis, and certain drugs |
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When are schistocytes often seen?
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In mechanical destruction. Either damaged blood vessels or prosthetic heart valves cause the fracture of Red cells this is called microangiopathic
Two major causes: 1) Disseminated intravascular coagulation (DIC) 2)Thrombotic thrombocytopenic purpura (TTP) |
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What chromosome is the alpha family globin located on?
What chromosome is the beta family globin located on? |
Alpha = 16
Beta = 11 |
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What is fetal hemoglobin comprised of?
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2 alpha
2 gamma |
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What is adult hemoglobin A comprised of?
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2 alpha
2 beta |
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What is adult hemoglobin A2 comprised of?
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2 alpha
2 delta |
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Where does 2,3 DPG bind? What does it do?
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2,3 DPG binds at the N termini of the beta chain and when it is bound it leads to decreased affinity of hemoglobin for oxygen and thus, oxygen unloading.
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Does a decrease in pH increase or decrease hemoglobin's affinity for oxygen
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Decrease
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Do 2,3,DPG levels rise or fall during anemia
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Rise --> promoting O2 unloading in the tissues
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Are patients w/ low affinity hemoglobin hypoxic?
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No! Despite their bluish coloration
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What is Methemoglobinemia?
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Methemoglobinemia is a condition characterized by the abnormal accumulation of methemoglobin within the red cell. Methemoglobin is a hemoglobin molecule in which the iron molecule has been oxidized to the ferric (Fe+3) state and is unable to reversibly bind oxygen (becomes high affinity and cannot transport oxygen).
Patients have cyanosis |
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What is an aplastic crisis?
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Failure of the marrow to adequately increase erythropoiesis to compensate for the chronic ongoing hemolysis may lead to progressive, severe anemia and aplastic crisis.
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What is splenic sequestrian syndrome?
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in this complication (which only occurs in children who still have functional spleens) sudden massive intrasplenic sickling leads to acute severe left upper quadrant pain, a rapid increase in spleen size (secondary to sequestration of blood) an abrupt fall in the hematocrit and shock.
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What is Beta Thalasemmia pathogenesis?
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In beta thalassemia, beta globin chain synthesis is decreased or absent.
Overall less production of hemoglobin A This results in a hypochromic, microcytic anemia. |
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How does the body compensate in Beta Thalasemmia
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Makes Hemoglobin F (alpha 2, gammma 2) and Hemoglobin A2 (alpha2, delta 2)
Also Hematopoiesis occurring outside the marrow is known as extramedullary hematopoiesis (generally this occurs in the liver and spleen resulting in hepatosplenomegaly) |
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What is Cooley's Anemia?
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Thalasemmia major (homozygous beta thalasemmia)
Presents in early childhood when fetal hemoglobin stops being produced |
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What are some of the complications of Thalasemmia major?
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Chronic anemia
Splenomegaly & hepatomegally (extramedullary erythropoiesis) High output cardiac failure Iron overload!!! --> from chronic tranfusions, excess iron deposits in the hearts leading to arrythmias (most common cause of death) |
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What is this?
Clinical: skeletal abnormalities (chipmunk faces), growth retardation, splenomegaly Peripheral smear: microcytic, hypochromatic RBC, target cells, polychromasia CBC: decreased MCV &MCH; slightly elevated retic count, decreased hemoglobin & hematocrit Bone marrow: hypercellular with erythroid hyperplasia Labs: increased indirect bilirubin & LDH |
Thalasemmia Major!
Dx: Hemoglobin electrophoresis -->will reveal a marked decrease or complete absence of hemoglobin A and an increase in hemoglobin A2 and Hemoglobin F. |
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How many alpha globin genes are there are chromosome 16?
How many beta globin genes are there on chromosome 11? |
4 alpha globin genes
2 beta globin genes |
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What on average tends to be more mild? Alpha or Beta Thalasemmia?
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Alpha because imbalance only occurs if 3 or 4 of the chains are affected.
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On peripheral smear, what is the main difference between Thalasemmia and Iron deficiency?
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In thalasemmia, all the RBC are small and hypochromatic and there is not much variance, whereas in Iron deficiency there is a much greater variance in size of the cells
Thalasemmia = small RDW Iron deficiency = high RDW |
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What is the cause of Hyrdrops Fetalis?
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all 4 alpha globin genes are deleted
This condition is incompatible w/ life |
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What is Hemoglobin H disease?
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3 alpha globin genes are deleted resulting in the accumulation of hemoglobin H (beta4) in the red cells.
Patients have mild to moderate hypochromic, microcytic anemia and splenomegaly (not as severe as beta thalasemmia major) Splenomegaly |
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What are 5 components of the hemostasis system?
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1) Platelets (“cell-mediated” hemostasis)
2) Fibrin-forming system 3) Fibrinolytic system 4) Endogenous anticoagulant system. 5) Vessel wall |
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What is the endogenous anticoagulant system?
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a number of proteins that INACTVATE activated clotting factors and thus REGULATE the generation of clots and inhibit thrombus formation in sites distant from the site of injury.
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What thromboregulatory molecules to endothelial cells release?
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1) Nitric oxide: induces vasodilatation, inhibits platelet aggregation
2) Prostacyclin: induces vasodilatation, inhibits platelet aggregation 3)Thrombomodulin: receptor for thrombin; when thrombin binds to thrombomodulin, it can no longer cleave fibrinogen to form fibrin, or activate coagulation factors; the thrombin-thrombodmodulin complex enhances activation of protein C (which inactivates Va and VIIIa) 4) Tissue factor pathway inhibitor (TFPI): inactivates VIIa and Xa |
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What is the action of Thrombin?
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Converts fibrinogen to Fibrin
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Where are coagulation factors synthesized?
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the Liver!
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Which of the coagulation factors are proenzymes?
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(XII, XI, X, IX, VII, prekallikrein)
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What level of coagulation factors are necessary to prevent spontaneous hemorrhage?
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20-40%
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What coagulation factors are Vitamin K dependent?
What anticoagulant proteins are Vitamin K dependent |
II (prothrombin), VII, IX, X
Protein C & S = anticoagulation protiens |
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Why do certain factors need Vitamin K
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It is required for the gamma-carboxylation of specific glutamic acid residues ---> able to bind Ca++ --> conformational change --> allow them to bind PHOPSHOLIPIDS!
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How does warafin exert its anti-coagulant effect?
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by inhibiting the vitamin K epoxide reductase, preventing the regeneration of reduced vitamin K
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What are the two main functions of Von Willebrand Factor
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1. Mediating platelet adhesion to subendothelial collagen via the platelet glycoprotein receptor Ib (GPIb) ... i.e vwf is the glue btw platelets & subendothelium
2. Carrier for factor VIII: |
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What makes VWF? Where is it stored?
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It is produced and secreted by megakaryocytes (and stored in platelet alpha granules) and endothelial cells
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What is the initiation of coagulation?
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When Tissue Factor is exposed to blood following Vessel injury
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What does TF bind to? What does this complex do?
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TF binds to factor VII turning it to VIIa which then:
1) Activates X to Xa (initiation phase) 2)Activates IX to XIa (amplification) |
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What does factor Xa do?
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Interacts w/ factor V to form prothrombinase complex which converts prothrombin (factor II) to thrombin (IIa).
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What does TFPI do?
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tissue factor pathway inhibitor (TFPI) inhibits any factor Xa that diffuses off the surface of endothelial cells
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What does thrombin do?
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Activates platelets and
Activates factors V, VIII, XI, XIII (Factors V and VIII are cofactors needed for the amplification phase) |
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Describe the "amplification phase" of the coagulation pathway
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Factor IXa binds to activated platelets and interacts w/ cofactor VIIIa to convert X to Xa
Xa & cofactor Va convert prothrombin to thrombin (lots, hence, amplification) Ca++ & phospholipids are required |
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How does factor XI get activated to XIa?
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By thrombin!
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What role do phosphlipids play in coagulation pathway?
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Phospholipids from the platelet membrane help mediate binding of cofactors Va and VIIIa to the platelet surface.
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Where is fibrinogen produced?
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the liver
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How does thrombin convert firbinogen to fibrin?
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Splits fibrinogen into fibrinopeptide A and fibrinopeptide B (each a monomer)
Each polymeryze with eachother weakly (fibrin I) Thrombin activates XIII --> XIIIa which, w/ Ca++ causes cross linking and STRONG FIBRIN POLYMER (fibrin II) |
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What is stronger? Fibrin 1 or Fibrin II?
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Fibrin II
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What is the Extrinsic Pathway & what starts it?
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Extrinsic Pathway: something causes break in endothelium
TF + VIIa converts X-->Xa +V --> converts II (prothrombin) --> IIa (thrombin) --> converts profibrin --> Fibrin Additionally Thrombin converts V to Va +Xa --> MUCH MORE THROMBIN PRODUCED! (amplification) |
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Intrinsic Pathway?
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Factor XII (activated to XIIa by contact with the anionic activated platelet surface) converts XI to XIa and prekallikrein to kallikrein. Factor XIa activates factor IX to IXa. Factor IXa, in the presence of factor VIIIa, calcium and phospholipid (platelet membrane) will activate factor X to Xa.
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What pathway do the extrinsic and intrinsic have in common?
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Common Pathway:
Xa + Va --> activate II (prothrombin) to IIa (thrombin) --> cleaves fibrin into fibrinogen ***MUST BE IN PRESENCE OF Ca++ & phospholipid! |
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What sort of bleeding disorder does a deficiency in factor XII produce?
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NONE!
Nor does prekallikrein and high molecular weight kininogen --> Contact factors do not cause bleeding disorders! |
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Does deficiency in factor XI produce a bleeding disorder?
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It may... Thrombin activates XI to XIa giving the system a "boost" w/out this, blood can still clot, but perhaps not as easily?
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What sample are clotting tests performed on?
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PLASMA!!;
Plasma, unlike serum, contains all the clotting factors |
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What does PT measure?
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Prothrombin time (PT):
measures the components of the extrinsic (tissue factor) and common pathways: VII, X, V, II, fibrinogen. Measures the time it takes for plasma to clot after addition of tissue factor |
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What is Thrombin Time & what does it measure?
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In the thrombin time assay, thrombin is added to plasma. The test measures the action of thrombin on fibrinogen to form a fibrin clot.
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What does a PTT measure?
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Activated Partial Thromboplastin Time (aPTT): measures the components of the intrinsic (XII, prekallikrein, high molecular weight kininogen, XI, IX, VIII) and the common pathways (X, V, II, fibrinogen).
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When is thrombin time prolonged?
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1) Too little fibrinogen
2) Abnormal fibrinogen 3) Heparin present (heparin potentiates the action of anti-thrombin III) 4) Fibrin degradation products present (FDPs interfere with fibrin polymerization) 5) Paraproteins present (interfere with polymerization of fibrin e.g. multiple myeloma) |
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When would you use a Reptilase test?
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To determine if prolonged Thrombin time is because of heparin... in which case thrombin time prolonged but Reptilase is normal
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In what scenario do you do a mixing study?
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To determine if prolonged clotting test is the result of factor deficiency or b/c of inhibitors of clotting factors
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What does bleeding time indicate?
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Bleeding time:measures the platelet- vessel wall interaction and will be abnormally prolonged if there is a quantitative (thrombocytopenia) or qualitative (dysfunctional platelets: uremia, aspirin or non-steroidal anti-inflammatory drug effects on platelets; inherited platelet function disorders) defect of platelets OR if there is an abnormality in the vessel wall (e.g. vasculitis, strucutural problem);
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What is hemophilia A?
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an X-linked disorder resulting in decreased or absent factor VIII coagulant activity
--> usually males impacted |
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Where does hemophilia bleeding usually occur?
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Bleeding typically occurs in joints and muscles. Other sites: urinary, gastrointestinal; central nervous system; post-dental extractions.
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What labs would you expect to see in someone w/ Hemophilia A?
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Prolonged PTT
Mixing studies: complete correction with normal plasma (normal plasma supplies the deficient VIII). If an inhibitor is present, the PTT will not correct. Normal PT Normal thrombin time Normal bleeding time (Bc measures platelets not clotting factors) Decreased factor VIII coagulant activity (measure factor VIII) |
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Treatment for hemophilia A?
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Factor VIII concentrate infusion (recombinant) (every 12 hours; FVIII T1/2 is 8-12 hours)
Desmopressin (vasopressin)--> stimulates VWf & thus increases factor VIII levels |
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How much annually does it cost to treat someone w/ severe hemophilia?
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about 300,000 / year
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What are labs you'd expect from hemophilia B?
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Prolonged PTT
Normal PT Normal bleeding time Normal thrombin time Mixing studies show complete correction with normal plasma (if no inhibitor) Decreased factor IX coagulant activity. (measure factor IX) |
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What is the treatment for Hemophilia B?
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Factor IX concentrate infusion
can be complicated by the development of thrombosis (deep vein thrombosis, pulmonary embolism, DIC |
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Clinically, how does hemophilia A & B differ?
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they don't, both present the same (interjoint bleeding)
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What population tends to get Hemophilia C and what does it effect?
Treatment? |
Ashkenazi Jews; It is a Factor XI deficiency
Will often see DELAYED BLEEDING! Treatment: fresh-frozen plasma or factor XI concentrate. |
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What should you immediately think of if you hear of a girl w/ a "heavy period"
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Von Willebrand Factor Deficiency!
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What do you think of if you see Delayed bleeding (i.e bleeding a few days later)?
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Factor XIII deficiency --> makes a weak clot w/out the cross linking
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What are some risk factors for Vitamin K deficiency?
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Poor diets
Antibiotics (loss of gut bacteria) Biliary tract problems (necessary for absorbing Vit K) malabsorption syndromes |
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What do you expect the PT & PTT to look like for Vitamin K deficiency?
What about Thrombin time? |
Both will be prolonged
Thrombin time normal |
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What coagulation factors are impacted by Vitamin K?
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II, VII, IX, X
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What is the one factor that will not be decreased in liver disease
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VIII (which is also produced by megakaryocytes)
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What would you expect in a liver disease patient?
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Factor deficiencies
Dysfibrinogenemia (abnormal fibrinogen ergo prolonged Thrombin Time) Consumption of clotting factors --> DIC! Thrombocytopenia (2ndary to splenomegaly, DIC, folate deficiency) Increased fibrinolytics: decreased synthesis of alpha-2-antiplasmin (the main inhibitor of fibrinolysis) and decreased clearance of tissue plasminogen activator (the main stimulator of fibrinolysis) |
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What is the first test likely to be prolonged in patient w/ liver disease
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PT time (though both are prolonged) b/c Factor VII has shortest half life
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What is this:
Clinical: Bleeding in skin, venipuncture sites, mucous membranes, GI, GU; grangrene at fingers/nose Labs:Prolonged PT, aPTT, prolonged thrombin time, Decreased fibrinogen, thrombocytopenia, elevated fibrin degradation products Smear: |
schistocytes;
platelets will be decreased; may see increased neutrophils and bands (if infection is present); nucleated red blood cells can be seen |
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Why are their schisocytes & low RBC in DIC?
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Similar to hemolytic anemia b/c disseminated fibrin clots & RBC trying to pass through get sheared into schistocytes
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What is the most common factor to which antibodies form?
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factor VIII
Main Diagnostic Test: Mixing Studies |
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What molecules to endothelial cells produce to help control thrombis formation?
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Nitric Oxide -vasodilation & platelet inhibition
Prostacyclin vasodilation & platelet inhibition Thrombomodulin - thrombin receptor Tissue Factor Pathway Inhibitor (TFPI) - Inactivates VIIa & Xa |
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What are two GENERAL ways in which clotting is controlled?
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1) Elimination of activated clotting factors
2) Destruction of fibrin clot |
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In what way are activated clotting factors eliminated?
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1. Removal from the circulation, by the liver
2. Inactivation in the plasma by three anticoagulant systems a) Serine protease inhibition by Antithrombin (AT). b)Protein C and Protein S Activation c)Tissue factor pathway inhibitor (TFPI) |
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What is Serine Protease Inhibition?
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Antithrombin complexes with "serine proteases" XIIa, XIa, Xa, IXa and especially IIa and INACTIVATES THEM
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How does Heparin work?
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It alters the shape of Antithrombin so that it is 100x more effective
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Where is antithrombin produced?
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The liver
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How do Protein C & S operate?
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When thrombin binds to thrombomodulin --> it becomes able to activate Protein C
Protein C along with phospholipid, Ca++, and Protein S INACTIVATE factors Va & VIIIa |
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How does Warafin impact Protein C & S
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It decreases their levels b/c they are both Vitamin K dependent
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What does Tissue factor pathway inhibitor (TFPI) do?
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TFPI inactivates Xa directly and also complexes with Xa to inhibit the tissue factor/VIIa complex.
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How is fibrinolysis carried out?
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Plasminogen converted to Plasmin by activators which digests the covalently linked fibrin polymers of the fibrin clot releasing "fibring split products" that are known POTENT INHIBITORS OF CLOTTING
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What regulates fibrinolysis?
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Alpha2 plasmin inhibitor (=alpha2anti-plasmin) rapidly inactivates plasmin
Plasminogen activator inhibitor-1 (PAI-1) is produced by endothelial cells, but stored in platelets; it acts to inhibit tissue plasminogen activator |
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What is Virchow's triad?
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Thrombogenic Factors:
1)-vessel wall damage 2) static (or high shear) blood flow 3) coagulable state of blood (activation of platelets; activation of clotting) |
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What are the 4 mechanisms of anti-coagulative system?
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1) Anti-thrombin (AT)
2) Protein C, Protein S 3) Fibrinolysis 4)Normal anti-coagulant properties of intact endothelium |
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What is the result of a Factor V Leiden mutation?
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Makes Va RESISTANT to inactivation by activated Protein C (APC)
--> Inactivation becomes much slower --> Prone to thrombis |
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What is most common cause of hypercoagubility?
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APC resistance (Factor V leiden) is the most common cause of inherited hypercoagulability, existing in 20-65% of patients who present with a venous thrombosis
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What is result of Prothrombin gene mutation (Prothrombin G20210A)?
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15-30% increase in the amount of prothrombin in the blood
second most common cause of thrombophilia |
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What are signs of Protein C deficiency?
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Homozygous protein C deficiency causes neonatal thrombosis (“purpura fulminans”—an often fatal, disseminated thrombosis associated with hemorrhagic necrosis of the skin);
3x higher rate of venous thrombosis |
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Is Protein S deficiency associated w/ venous or arteriole thrombosis?
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Arteriole thrombosis
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How is antithrombin deficiency inherited?
Is it a quantitative or qualitative disease |
Autosomal dominant
It is both qualitative & quantitative defects in Antithrombin |
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What causes Hyperhomocysteinemia?
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B12, folate and B6 deficiencies result in elevated homocysteine levels.
Also inherited enzyme defiencies that is associated with an increased risk of arterial and venous thromboembolism |
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Can you give pregnant women warafin?
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NO! Its teratogenic!
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What is HIT?
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Heparin induced thrombocytopenia (HIT): “paradoxical” arterial and venous thrombosis may occur in patients who develop HIT.
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Explain antiphospholipid syndrome?
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Antiphospholipid antibodies (IgG or IgM) that bind bind phospholipid binding proteins
Labs: a prolongation of the aPTT (which does not correct in a mixing study). |
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Is Lupus anticoagulant associated with increase risk in thrombosis or bleeding?
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Thrombosis
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What are multiple miscarriages a sign of?
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Increased thrombosis
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