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243 Cards in this Set
- Front
- Back
|
Compensatory mechanisms when RBC mass (Hgb) decreases
|
(1) Increase cardiac output; (2) Increased extraction ratio; (3) Right-shift of oxyHb curve 2/2 increased 2,3-DPG; (4) Expansion of plasma volume
|
|
|
When is a blood transfusion recommended?
|
(1) Hb < 7g/dL or (2) Patient requires increased O2-carrying capacity [Pts with CAD or other cardiopulmonary disease]
|
|
|
Historical findings to consider in patients with anemia
|
(1) FHx of hemophilia, G6PD deficiency, thalassemia; (2) Bleeding (melena, recent trauma/surgery, hematemesis); (3) Chronic illnesses (renal failure); (4) Alcoholism (folate, B12, Iron)
|
|
|
What is pseudoanemia?
|
A decrease in Hb and Hct 2/2 acute volume infusion or overload
|
|
|
Clinical features of anemia
|
(1) Nonspecific complaints - HA, fatigue, poor concentration, diarrhea, nausea, vague abdominal discomfort; (2) Pallor - best noted in conjunctiva; (3) Hypotension and tachycardia; (4) Signs of the underlying cause - jaundice if hemolytic anemia, blood in stool if GI bleeding
|
|
|
In what subset of patients is anemia poorly tolerated?
|
In patients with impaired cardiac function; if Pt has good cardiac function and intravascular volume is adequate, low Hb and Hct levels are tolerated - even an Hb of 7-8 provides sufficient oxygen-carrying capacity for most patients
|
|
|
PRBCs
|
Contains no platelets or clotting factors. Mix with NS to infuse faster (not with LR because Ca2+ can cause coagulation within the IV line); Each unit raises Hb by 1 point, Hct by 3-4 points. Typically administered in 2 units; each unit given over 90-120 minutes. Always check CBC after transfusion completed
|
|
|
FFP
|
Contains all of the clotting factors. Contains no RBCs/WBCs/platelets. Given for high PT/PTT, coagulopathy, and deficiency of clotting factors - FFP can be given if you cannot wait for Vitamin K to take effect, or if patient has liver failure and vitamin K will not work. Follow up with PT, PTT to assess response
|
|
|
Cryoprecipitate
|
Contains factor VIII and fibrinogen. For hemophilia A, decrease fibrinogen (DIC) and vWD
|
|
|
Platelet transfusions
|
1 unit raises the platelet count by 10,000.
|
|
|
Reticulocyte index
|
Indicates whether effective erythropoiesis is occurring in the bone marrow. Effective erythropoiesis is dependent on adequate raw materials (iron, B12, folate) in bone marrow, absence of intrinsic bone marrow disease (aplastic anemia), adequate EPO from kidney, and survival of reticulocytes (no premature destruction before leaving the marrow)
|
|
|
Reticulocyte index >2%
|
Implies excessive RBC destruction or loss. Bone marrow is responding to increased RBC requirements
|
|
|
Reticulocyte index <2%
|
Implies inadequate RBC production by the bone marrow
|
|
|
Reticulocyte Index Calculation
|
Retic Count (%) x Hematocrit/Normal Hematocrit (45 is used most commonly), This number is then corrected (divide by 1.5 if Hct is 26-35 or 2 if 16-25) to get the reticulocyte index
|
|
|
Intravascular vs Extravascular hemolysis
|
Intravascular is acute hemolytic reactions from ABO-mismatch. Serioues and life threatening; occurs in the circulation. Extravascular is delayed hemolytic transfusion reaction and is less severe and in most cases self-limited. Occurs 3-4wks after a transfusion due to minor RBC antigen; occurs within RE system, primarily the spleen
|
|
|
Microcytic Anemias
|
MCV<80. (1) IDA is the MCC. (2) Anemia of chronic disease - iron is present in the body but is not available for hemoglobin synthesis (iron trapping in macrophages); (3) Thalassemias - defective globin chain synthesis; (4) Ring sideroblastic anemias (includes lead poisoning, pyridoxine deficiency, toxic effects of alcohol). This is a defective diagnosis of protoporphyrins. Iron accumulates in mitochondria
|
|
|
Macrocytic Anemias
|
MCV >100. (1) Nuclear defect (MCV increases significantly) - vitamin B12 deficiency and folate deficiency. (2) Liver disease (MCV increases up to 115) due to altered metabolism of plasma lipoproteins into their membranes, altering RBC shape (and increasing volume); (3) Stimulated erythropoiesis (MCV up to 110) - reticulocytes are larger than mature RBCs, resulting in an increase in polychromatophilic RBCs
|
|
|
DDx for normocytic anemia
|
(1) Aplastic anemia; (2) Bone marrow fibrosis; (3) Tumor; (4) Anemia of chronic disease (chronic inflammation or malignancy); (5) Renal failure (decreased EPO production)
|
|
|
Iron Deficiency Anemia
|
MCC of anemia worldwide; Causes include: (1) chronic blood loss [MCC of IDA in adults]; (2) Menstrual blood loss is the most common source. In absence of menstrual bleeding, GI blood loss is most likely
|
|
|
Dietary deficiency/increased iron requirements
|
Primarily seen in 3 age groups: (1) Infants and toddlers: esp if diet is predominantly human milk (low in iron). Children in this age group also have an increased requirement for iron because of accelerated growth. It is most common between 6mo and 3yr of age; (2) Adolescents - rapid growth increases iron requirements. Adolescent women are particularly at risk due to loss of menstrual blood; (3) Pregnant women - pregnancy increases iron requirements
|
|
|
Clinical features of IDA
|
(1) Pallor; (2) Fatigue, generalized weakness; (3) Dyspnea on exertion; (4) Orthostatic hypotension; (5) Hypotension, if acute; (6) Tachycardia
|
|
|
Diagnosis of IDA
|
(1) Decreased serum ferritin - most reliable test available; (2) Increased TIBC; (3) Elevated transferrin levels; (4) Decreased serum iron; (5) Microcytic, hypochromic RBCs on peripheral smear
|
|
|
Diagnosis of AoCD
|
(1) Normal/high serum ferritin; (2) Low serum iron; (3) Normal/low TIBC
|
|
|
Diagnosis of Thalassemia
|
(1) Normal/high serum ferritin; (2) Normal/high serum iron; (3) Normal TIBC
|
|
|
Treatment for IDA
|
Oral Iron replacement with ferrous sulfate - a trial should be given to a menstruating woman. However, if men and post-menopausal women with IDA, attempt to determine the source of blood loss
|
|
|
Side effects of Ferrous Sulfate
|
Constipation, nausea, dyspepsia
|
|
|
Parenteral iron replacement
|
(1) Iron dextran can be administered IV or IM; this is rarely necessary because most patients respond to oral therapy. It may be useful in patients with poor absorption, patients who require more iron than oral therapy can provide, or patients who cannot tolerate oral ferrous sulfate
|
|
|
Thalassemias: Beta-thalassemia
|
Beta-chain production is deficient, but synthesis of alpha chains is unaffected. Excess alpha chains bind to and damage the RBC membrane. It is most often found in people of Mediterranean, Middle Eastern, and Indian ancestry
|
|
|
Thalassemias: Alpha-thalassemia
|
Decrease in alpha-chains, which are a component of all types of Hb. The beta-globin chains form tetramers, which are abnormal hemoglobins. Severity depends on the number of gene loci that are deleted/mutated - it can range from an asymptomatic carrier state to prenatal death [hydrops fetalis]
|
|
|
Beta-Thalassemia major
|
Occurs predominantly in Mediterranean populations; Clinical Features: (1) Severe anemia (microcytic, hypochromic); (2) massive hepatosplenomegaly; (3) Expansion of marrow space-can cause distortion of bones; (4) Growth retardation and FTT; (5) If untreated with transfusions, death in first few years 2/2 progressive CHF
|
|
|
Diagnosis of beta-thalassemia major
|
Hb electrophoresis - Hb F is elevated! Peripheral smear shows microcytic, hypochromic anemia
|
|
|
Treatment of beta-thalassemia major
|
Frequent PRBC transfusions required to sustain life. NOTE: iron overload sometimes develops in patients with transfusion dependent thalassemia, and if untreated this can lead to CHF (symptoms of hemochromatosis). Therefore, patients are often treated with desferrioxamine.
|
|
|
Beta-Thalassemia minor
|
Clinical Features: (1) Patients usually asymptomatic; a mild microcyctic, hypochromic anemia is the only symptom; Diagnosis: Hb electrophoresis; Treatment: usually not necessary (patients are not transfsion-dependent)
|
|
|
What might be a reason a patient does not respond to IDA treated with oral iron?
|
Alpha- or beta-thalassemia. Obtain a Hb electrophoresis
|
|
|
Alpha-thalassemias: silent carriers
|
Mutation/deletion of only one alpha locus; Patients are asymptomatic and have normal Hb/Hct. No treatment is necessary.
|
|
|
Alpha-thalassemia trait (or minor)
|
Mutation/deletion of two alpha loci on chromosome 16. Characterized by mild microcytic hypochromic anemia; Common in AA patients, no treatment necessary
|
|
|
Hb H disease
|
Mutation/deletion of three alpha loci. Hemolytic anemia, splenomegaly, significant microcytic, hypochromic anemia. Treatment is same as for patients with beta-thalassemia major. Splenectomy is sometimes helpful
|
|
|
Mutation/deletion of all four alpha loci
|
Either fatal at birth (hydrops fetalis) or shortly after birth
|
|
|
Sideroblastic anemia
|
Caused by an abnormality in RBC iron metabolism; (1) Hereditary or acquired-acquired causes include drugs (chloramphenicol, INH, EtOH), exposure to lead, collagen vascular disease, and neoplastic disease (MDS); (2) Clinical findings include: increased serum iron, ferritin, normal TIBC; ringed sideroblasts in bone marrow; Treatment: remove offending agents, consider pyridoxine
|
|
|
Medications associated with aplastic anemia
|
Chloramphenicol, sulfonamides, gold, and carbamazepine
|
|
|
Infections associated with aplastic anemia
|
Human parvovirus, hepatitis B and C, Epstein-Barr virus, CMV, HZV, HIV
|
|
|
What reactions use vitamin B12 as a cofactor?
|
(1) Conversion of homocysteine to methionine; (2) Conversion of methylmalonyl CoA to succinyl CoA
|
|
|
What is the dietary source of B12? How long do B12 stores last?
|
(1) Fish and meat [animal products] are the source of B12. Vitamin B12 stores in the liver are plentiful and can sustain an individual for 3 or more years
|
|
|
Where is vitamin B12 absorbed?
|
B12 is bound to intrinsic factor (produced by gastric parietal cells) so it can be absorbed in the terminal ileum
|
|
|
Causes of Vitamin B12 Deficiency
|
(1) Pernicious anemia - MCC in Western Hemisphere; (2) Gastrectomy; (3) Poor diet - strict vegetarianism; (4) alcoholism; (5) Crohn's disease, ileal resection (terminal ileum); (6) Other organisms competing for B12 [fish tapeworm Diphyllobothrium latum], (7) Blind-loop syndrome [bacterial overgrowth]
|
|
|
Clinical features of vitamin B12 deficiency
|
(1) Anemia; (2) Sore tongue (stomatitis and glossitis); (3) Neuropathy - demyelination of posterior columbs, lateral corticospinal tracts, and spinocerebellar tracts - leading to loss of position/vibratory sensation in lower extremities, ataxia, and upper motor neuron signs [increased DTRs, spasticity, weakness, Babinski] - this is Subacute Combined Degeneration
|
|
|
Peripheal smear findings in B12 deficiency
|
(1) Megaloblastic anemia - macrocytic RBCs (MCV > 100); (2) Hypersegmented polys; (3) Low B12 level (<100pg/ml); (4) Elevated MMA and homocysteine levels-these are elevated in vitamin B12 deficiency and are useful if vitamin B12 levels are equivocal
|
|
|
Can patients with B12 deficiency have neurologic findings without anemia?
|
YES! The delay in diagnosis can lead to irreversible neurologic disease
|
|
|
Treatment of B12 deficiency
|
Parenteral therapy is preferred-cyanocobalamin (vitamin B12) IM once per month
|
|
|
What is the dietary source of folate? How long to folate stores last?
|
Folic acid stores are limited. Inadequate intake of folate over a 3-month period can lead to deficiency. Green vegetables are the main source of folate. Overcooking of vegetables can remove folate
|
|
|
Causes of folate deficiency
|
(1) Inadequate dietary intake such as old ladies on their 'tea and toast' diet; (2) Alcoholism; (3) Long-term use of oral Abx; (4) Increased demand; (5) Pregnancy; (6) Hemolysis; (7) Use of folate antagonists such as MTX; (8) Anticonvulsants (phenytoin); (9) Hemodialysis
|
|
|
Hemolytic Anemias: General characteristics
|
(1) Premature destruction of RBCs that may be due to a variety of causes; (2) Bone marrow is normal and responds appropriately by increasing erythropoiesis, leading to an elevated reticulocyte count. However, is erythropoiesis cannot keep up with the destruction of RBCs, anemia results
|
|
|
Causes of Acquired Hemolysis
|
(1) Immune hemolysis; (2) Mechanical hemolysis (prosthetic heart valves, MAHA); (3) Medications, burns, toxins (snake bite, brown recluse spider); infection (malaria, clostridium, etc)
|
|
|
Intrinsic causes of hemolysis
|
Most cases are INHERITED; (1) Hemoglobin abnormalities: sickle cell anemia, hemoglobin C disease, thalassemias; (2) Membrane defects: hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria; (3) Enzyme defects: glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency
|
|
|
Schistocytes vs Helmet Cells
|
Schistocytes suggest intravascular hemolysis ('trauma' or mechanical hemolysis); Spherocytes or helmet cells suggest extravascular hemolysis (depending on the cause)
|
|
|
Compensatory mechanisms when RBC mass (Hgb) decreases
|
(1) Increase cardiac output; (2) Increased extraction ratio; (3) Right-shift of oxyHb curve 2/2 increased 2,3-DPG; (4) Expansion of plasma volume
|
|
|
When is a blood transfusion recommended?
|
(1) Hb < 7g/dL or (2) Patient requires increased O2-carrying capacity [Pts with CAD or other cardiopulmonary disease]
|
|
|
Historical findings to consider in patients with anemia
|
(1) FHx of hemophilia, G6PD deficiency, thalassemia; (2) Bleeding (melena, recent trauma/surgery, hematemesis); (3) Chronic illnesses (renal failure); (4) Alcoholism (folate, B12, Iron)
|
|
|
What is pseudoanemia?
|
A decrease in Hb and Hct 2/2 acute volume infusion or overload
|
|
|
Clinical features of anemia
|
(1) Nonspecific complaints - HA, fatigue, poor concentration, diarrhea, nausea, vague abdominal discomfort; (2) Pallor - best noted in conjunctiva; (3) Hypotension and tachycardia; (4) Signs of the underlying cause - jaundice if hemolytic anemia, blood in stool if GI bleeding
|
|
|
In what subset of patients is anemia poorly tolerated?
|
In patients with impaired cardiac function; if Pt has good cardiac function and intravascular volume is adequate, low Hb and Hct levels are tolerated - even an Hb of 7-8 provides sufficient oxygen-carrying capacity for most patients
|
|
|
PRBCs
|
Contains no platelets or clotting factors. Mix with NS to infuse faster (not with LR because Ca2+ can cause coagulation within the IV line); Each unit raises Hb by 1 point, Hct by 3-4 points. Typically administered in 2 units; each unit given over 90-120 minutes. Always check CBC after transfusion completed
|
|
|
FFP
|
Contains all of the clotting factors. Contains no RBCs/WBCs/platelets. Given for high PT/PTT, coagulopathy, and deficiency of clotting factors - FFP can be given if you cannot wait for Vitamin K to take effect, or if patient has liver failure and vitamin K will not work. Follow up with PT, PTT to assess response
|
|
|
Cryoprecipitate
|
Contains factor VIII and fibrinogen. For hemophilia A, decrease fibrinogen (DIC) and vWD
|
|
|
Platelet transfusions
|
1 unit raises the platelet count by 10,000.
|
|
|
Reticulocyte index
|
Indicates whether effective erythropoiesis is occurring in the bone marrow. Effective erythropoiesis is dependent on adequate raw materials (iron, B12, folate) in bone marrow, absence of intrinsic bone marrow disease (aplastic anemia), adequate EPO from kidney, and survival of reticulocytes (no premature destruction before leaving the marrow)
|
|
|
Reticulocyte index >2%
|
Implies excessive RBC destruction or loss. Bone marrow is responding to increased RBC requirements
|
|
|
Reticulocyte index <2%
|
Implies inadequate RBC production by the bone marrow
|
|
|
Reticulocyte Index Calculation
|
Retic Count (%) x Hematocrit/Normal Hematocrit (45 is used most commonly), This number is then corrected (divide by 1.5 if Hct is 26-35 or 2 if 16-25) to get the reticulocyte index
|
|
|
Intravascular vs Extravascular hemolysis
|
Intravascular is acute hemolytic reactions from ABO-mismatch. Serioues and life threatening; occurs in the circulation. Extravascular is delayed hemolytic transfusion reaction and is less severe and in most cases self-limited. Occurs 3-4wks after a transfusion due to minor RBC antigen; occurs within RE system, primarily the spleen
|
|
|
Microcytic Anemias
|
MCV<80. (1) IDA is the MCC. (2) Anemia of chronic disease - iron is present in the body but is not available for hemoglobin synthesis (iron trapping in macrophages); (3) Thalassemias - defective globin chain synthesis; (4) Ring sideroblastic anemias (includes lead poisoning, pyridoxine deficiency, toxic effects of alcohol). This is a defective diagnosis of protoporphyrins. Iron accumulates in mitochondria
|
|
|
Macrocytic Anemias
|
MCV >100. (1) Nuclear defect (MCV increases significantly) - vitamin B12 deficiency and folate deficiency. (2) Liver disease (MCV increases up to 115) due to altered metabolism of plasma lipoproteins into their membranes, altering RBC shape (and increasing volume); (3) Stimulated erythropoiesis (MCV up to 110) - reticulocytes are larger than mature RBCs, resulting in an increase in polychromatophilic RBCs
|
|
|
DDx for normocytic anemia
|
(1) Aplastic anemia; (2) Bone marrow fibrosis; (3) Tumor; (4) Anemia of chronic disease (chronic inflammation or malignancy); (5) Renal failure (decreased EPO production)
|
|
|
Iron Deficiency Anemia
|
MCC of anemia worldwide; Causes include: (1) chronic blood loss [MCC of IDA in adults]; (2) Menstrual blood loss is the most common source. In absence of menstrual bleeding, GI blood loss is most likely
|
|
|
Dietary deficiency/increased iron requirements
|
Primarily seen in 3 age groups: (1) Infants and toddlers: esp if diet is predominantly human milk (low in iron). Children in this age group also have an increased requirement for iron because of accelerated growth. It is most common between 6mo and 3yr of age; (2) Adolescents - rapid growth increases iron requirements. Adolescent women are particularly at risk due to loss of menstrual blood; (3) Pregnant women - pregnancy increases iron requirements
|
|
|
Clinical features of IDA
|
(1) Pallor; (2) Fatigue, generalized weakness; (3) Dyspnea on exertion; (4) Orthostatic hypotension; (5) Hypotension, if acute; (6) Tachycardia
|
|
|
Diagnosis of IDA
|
(1) Decreased serum ferritin - most reliable test available; (2) Increased TIBC; (3) Elevated transferrin levels; (4) Decreased serum iron; (5) Microcytic, hypochromic RBCs on peripheral smear
|
|
|
Diagnosis of AoCD
|
(1) Normal/high serum ferritin; (2) Low serum iron; (3) Normal/low TIBC
|
|
|
Diagnosis of Thalassemia
|
(1) Normal/high serum ferritin; (2) Normal/high serum iron; (3) Normal TIBC
|
|
|
Treatment for IDA
|
Oral Iron replacement with ferrous sulfate - a trial should be given to a menstruating woman. However, if men and post-menopausal women with IDA, attempt to determine the source of blood loss
|
|
|
Side effects of Ferrous Sulfate
|
Constipation, nausea, dyspepsia
|
|
|
Parenteral iron replacement
|
(1) Iron dextran can be administered IV or IM; this is rarely necessary because most patients respond to oral therapy. It may be useful in patients with poor absorption, patients who require more iron than oral therapy can provide, or patients who cannot tolerate oral ferrous sulfate
|
|
|
Thalassemias: Beta-thalassemia
|
Beta-chain production is deficient, but synthesis of alpha chains is unaffected. Excess alpha chains bind to and damage the RBC membrane. It is most often found in people of Mediterranean, Middle Eastern, and Indian ancestry
|
|
|
Thalassemias: Alpha-thalassemia
|
Decrease in alpha-chains, which are a component of all types of Hb. The beta-globin chains form tetramers, which are abnormal hemoglobins. Severity depends on the number of gene loci that are deleted/mutated - it can range from an asymptomatic carrier state to prenatal death [hydrops fetalis]
|
|
|
Beta-Thalassemia major
|
Occurs predominantly in Mediterranean populations; Clinical Features: (1) Severe anemia (microcytic, hypochromic); (2) massive hepatosplenomegaly; (3) Expansion of marrow space-can cause distortion of bones; (4) Growth retardation and FTT; (5) If untreated with transfusions, death in first few years 2/2 progressive CHF
|
|
|
Diagnosis of beta-thalassemia major
|
Hb electrophoresis - Hb F is elevated! Peripheral smear shows microcytic, hypochromic anemia
|
|
|
Treatment of beta-thalassemia major
|
Frequent PRBC transfusions required to sustain life. NOTE: iron overload sometimes develops in patients with transfusion dependent thalassemia, and if untreated this can lead to CHF (symptoms of hemochromatosis). Therefore, patients are often treated with desferrioxamine.
|
|
|
Beta-Thalassemia minor
|
Clinical Features: (1) Patients usually asymptomatic; a mild microcyctic, hypochromic anemia is the only symptom; Diagnosis: Hb electrophoresis; Treatment: usually not necessary (patients are not transfsion-dependent)
|
|
|
What might be a reason a patient does not respond to IDA treated with oral iron?
|
Alpha- or beta-thalassemia. Obtain a Hb electrophoresis
|
|
|
Alpha-thalassemias: silent carriers
|
Mutation/deletion of only one alpha locus; Patients are asymptomatic and have normal Hb/Hct. No treatment is necessary.
|
|
|
Alpha-thalassemia trait (or minor)
|
Mutation/deletion of two alpha loci on chromosome 16. Characterized by mild microcytic hypochromic anemia; Common in AA patients, no treatment necessary
|
|
|
Hb H disease
|
Mutation/deletion of three alpha loci. Hemolytic anemia, splenomegaly, significant microcytic, hypochromic anemia. Treatment is same as for patients with beta-thalassemia major. Splenectomy is sometimes helpful
|
|
|
Mutation/deletion of all four alpha loci
|
Either fatal at birth (hydrops fetalis) or shortly after birth
|
|
|
Sideroblastic anemia
|
Caused by an abnormality in RBC iron metabolism; (1) Hereditary or acquired-acquired causes include drugs (chloramphenicol, INH, EtOH), exposure to lead, collagen vascular disease, and neoplastic disease (MDS); (2) Clinical findings include: increased serum iron, ferritin, normal TIBC; ringed sideroblasts in bone marrow; Treatment: remove offending agents, consider pyridoxine
|
|
|
Medications associated with aplastic anemia
|
Chloramphenicol, sulfonamides, gold, and carbamazepine
|
|
|
Infections associated with aplastic anemia
|
Human parvovirus, hepatitis B and C, Epstein-Barr virus, CMV, HZV, HIV
|
|
|
What reactions use vitamin B12 as a cofactor?
|
(1) Conversion of homocysteine to methionine; (2) Conversion of methylmalonyl CoA to succinyl CoA
|
|
|
What is the dietary source of B12? How long do B12 stores last?
|
(1) Fish and meat [animal products] are the source of B12. Vitamin B12 stores in the liver are plentiful and can sustain an individual for 3 or more years
|
|
|
Where is vitamin B12 absorbed?
|
B12 is bound to intrinsic factor (produced by gastric parietal cells) so it can be absorbed in the terminal ileum
|
|
|
Causes of Vitamin B12 Deficiency
|
(1) Pernicious anemia - MCC in Western Hemisphere; (2) Gastrectomy; (3) Poor diet - strict vegetarianism; (4) alcoholism; (5) Crohn's disease, ileal resection (terminal ileum); (6) Other organisms competing for B12 [fish tapeworm Diphyllobothrium latum], (7) Blind-loop syndrome [bacterial overgrowth]
|
|
|
Clinical features of vitamin B12 deficiency
|
(1) Anemia; (2) Sore tongue (stomatitis and glossitis); (3) Neuropathy - demyelination of posterior columbs, lateral corticospinal tracts, and spinocerebellar tracts - leading to loss of position/vibratory sensation in lower extremities, ataxia, and upper motor neuron signs [increased DTRs, spasticity, weakness, Babinski] - this is Subacute Combined Degeneration
|
|
|
Peripheal smear findings in B12 deficiency
|
(1) Megaloblastic anemia - macrocytic RBCs (MCV > 100); (2) Hypersegmented polys; (3) Low B12 level (<100pg/ml); (4) Elevated MMA and homocysteine levels-these are elevated in vitamin B12 deficiency and are useful if vitamin B12 levels are equivocal
|
|
|
Can patients with B12 deficiency have neurologic findings without anemia?
|
YES! The delay in diagnosis can lead to irreversible neurologic disease
|
|
|
Treatment of B12 deficiency
|
Parenteral therapy is preferred-cyanocobalamin (vitamin B12) IM once per month
|
|
|
What is the dietary source of folate? How long to folate stores last?
|
Folic acid stores are limited. Inadequate intake of folate over a 3-month period can lead to deficiency. Green vegetables are the main source of folate. Overcooking of vegetables can remove folate
|
|
|
Causes of folate deficiency
|
(1) Inadequate dietary intake such as old ladies on their 'tea and toast' diet; (2) Alcoholism; (3) Long-term use of oral Abx; (4) Increased demand; (5) Pregnancy; (6) Hemolysis; (7) Use of folate antagonists such as MTX; (8) Anticonvulsants (phenytoin); (9) Hemodialysis
|
|
|
Hemolytic Anemias: General characteristics
|
(1) Premature destruction of RBCs that may be due to a variety of causes; (2) Bone marrow is normal and responds appropriately by increasing erythropoiesis, leading to an elevated reticulocyte count. However, is erythropoiesis cannot keep up with the destruction of RBCs, anemia results
|
|
|
Causes of Acquired Hemolysis
|
(1) Immune hemolysis; (2) Mechanical hemolysis (prosthetic heart valves, MAHA); (3) Medications, burns, toxins (snake bite, brown recluse spider); infection (malaria, clostridium, etc)
|
|
|
Intrinsic causes of hemolysis
|
Most cases are INHERITED; (1) Hemoglobin abnormalities: sickle cell anemia, hemoglobin C disease, thalassemias; (2) Membrane defects: hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria; (3) Enzyme defects: glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency
|
|
|
Schistocytes vs Helmet Cells
|
Schistocytes suggest intravascular hemolysis ('trauma' or mechanical hemolysis); Spherocytes or helmet cells suggest extravascular hemolysis (depending on the cause)
|
|
|
Heinz bodies are seen in what disease?
|
Heinz bodies are seen in G6PD. They represent inclusions within red blood cells composed of denatured hemoglobin. NOTE: can also be seen in alpha-thalassemias --> represent beta-globin tetramers
|
|
|
Lab findings with hemolytic anemia
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(1) Increased LDH - released when RBCs destroyed; (2) Decreased haptoglobin (especially intravascular hemolysis). Haptoglobin binds to Hemoblobin, so its absence means that hemoglobin was destroyed; (3) Elevated indirect (unconjugated bilirubin) due to degradation fo heme 2/2 RBC destruction; (4) Direct Coombs Test - detects antibody or complement on RBC membrane; positive in AIHA
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Treatment of AIHA
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(1) Treat underlying cause!; (2) Transfuse PRBCs if severe anemia is present or patient is hemodynamically compromised; (3) Folate supplements (folate is quickly depleted in hemolysis)
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Organ Involvement in Sickle Cell Anemia
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(1) BLOOD: chronic hemolytic anemia; (2) HEART: high-output CHF 2/2 anemia; (3) CNS: stroke; (4) GI TRACT - gallbladder disease (stones), splenic infarctions, abdominal crises; (5) BONES - painful crises, osteomyelitis, avascular necrosis; (6) LUNGS - infections, acute chest syndrome; (7) KIDNEYS: hematuria, papillary necrosis, renal failure; (8) EYES: proliferative retinopathy, retinal infarcts; (9) GENITALIA: priaprism
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Sickle Cell Anemia: cause
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AUTOSOMAL RECESSIVE disorder 2/2 substitution of uncharged valine in place of negatively charge glutamic acid in hemoglobin BETA chain. This produces Hb S instead of Hb A. Sickle cell disease is caused by inheritance of two Hb S genes and is diagnosed with Hb electrophoresis.
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Sickle Cell crises
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Under reduced oxygen conditions (acidosis, hypoxia, changes in temperature, dehydration, and infection), the Hb molecules polymerize, causing the RBCs to sickle. Sickled RBCs obstruct small vessels, leading to ischemia
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Sickle Cell prognosis
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Survival correlates with frequency of vaso-occlusive crises-more frequent crises are associated with a shorter lifespan. If there are more than 3 crises/yr, the median age of death is 35 years. Patients with fewer crises per year may live into their 50s. In general, sickle cell anemia reduces life expectancy by 25-30 years
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Clinical Features of Sickle Cell Disease
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(1) SEVERE, LIFELONG HEMOLYTIC ANEMIA: jaundice, pallor, gallstone disease (very common) w/ pigmented gallstones; the anemia itself is well compensated and is rarely transfusion dependent; (2) HIGH-OUTPUT HEART FAILURE over time 2/2 anemia; many adults usually die of CHF!; (3) APLASTIC CRISES: usually provoked by viral infection such as parvovirus B19, which reduces ability of bone marrow to compensate. Treatment is blood transfusion - the patient usually recovers in 7-10 days; (4) PAINFUL BONE CRISES: bone infarction causes severe pain. This is the most common clinical manifestation; pain is usually self-limiting and lasts 2-7 days; (5) HAND-FOOT SYNDROME: dactylitis with painful swelling or dorsa of hands and feet seen in infancy and early childhood (4-6 months) and often the FIRST manifestation of SCD caused by avascular necrosis of MC and MT bones. (6) REPEATED SPLENIC INFARCTS leading to autosplenectomy; spleen is large in childhood, no longer palpable by 4 years of age; (7) AVASCULAR NECROSIS OF JOINTS - hips and shoulders; (8) PRIAPRISM 2/2 vasoocclusion; (9) CVA 2/2 cerebral thrombosis; (10) OPHTHALMOLOGIC COMPLICATIONS - retinal infarcts, vitreous hemorrhage, proliferative retinopathy; (11) RENAL PAPILLARY NECROSIS with hematuria; (12) CHRONIC LEG ULCERS - typically over lateral malleoli; (13) INFECTIOUS COMPLICATIONS: functional asplenia therefore predisposition to capsulated bacteria such as H. flu, S. pneumoniae; predisposition to Salmonella osteomyelitis
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Treatment of Sickle Cell Disease
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(1) Early vaccination for S. pneumoniae, H. influenzae, and N. meningitidis; (2) Prophylactic PCN for children until 6yo - start at 4mo; (3) Folic acid supplements due to chronic hemolysis; (4) Management of painful crises with morphine, supplemental oxygen; (5) Hydroxyurea: enhances HbF levels, interfering with sickling; (6) Transfusions- not unless absolutely necessary like in acute chest syndrome, stroke, priaprism, cardiac decompensation; (7) Bone Marrow Transplantation
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Splenic Sequestration Crisis
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Sudden pooling of blood into the spleen results in rapid development of splenomegaly and hypovolemic shock. A potentially fatal complication of sickle cell disease (and beta-thalassemia) occurring more in children (because they have intact spleens)
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Hereditary Spherocytosis
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Autosomal Dominant inheritance of a defect in the gene coding for spectrin and other RBC proteins. Spectrin content is decreased but is not totally absent. There is a loss of RBC membrane surface area without a reduction in RBC volume, necessitating a spherical shape. The spherical RBCs become trapped and destroyed in the spleen (by macrophages)-hence the term extravascular hemolysis
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Diagnosis of Hereditary Spherocytosis
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(1) RBC osmotic fragility to hypotonic saline - spherocytes tolerate les swelling before rupture; thus, they are osmotically fragile. The RBCs undergo lysis are a higher (thus earlier) oncotic pressure
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Treatment of Hereditary Spherocytosis
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Splenectomy is the treatment of choice
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G6PD Deficiency
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X-linked recessive disorder that primarily affects men; known precipitants include sulfonamides, nitrofurantoin, primaquine, dimercaprol, fava beans, and infection
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Types of G6PD Deficiency
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(1) Mild form, present in 10% of AAM (A-variant) with self-limited episodes that mainly involve only the older RBCs and spare the younger RBCs that have sufficienct G6PD to prevent RBC destruction; (2) A more severe form is present in people of Mediterranean descent. In this form, young as well as old RBCs are G6PD -deficient. This causes severe hemolytic anemia when exposed to fava beans and may require transfusions until the drug is eliminated from the body.
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Diagnosis of G6PD
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(1) PBS: shows 'bite cells' RBCs after the removal of Heinz bodies look as if they have 'bites' taken out of them 2/2 phagocytosis of Heinz bodies by splenic macrophages; (2) Heinz bodies (abnormal Hb precipitates within RBCs) are visible with special stains; (3) Deficient NADPH formation on G6PD assay; (4) Measurement of G6PD levels is diagnostic, but levels may be normal during hemolytic episode because RBCs that are most deficient have already been destroyed. Repeating the test 2-3 months later facilitates the diagnosis.
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Treatment of G6PD
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(1) Avoid drugs that precipitate hemolysis; (2) Maintain hydration; (3) Perform RBC transfusion when necessary
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Warm AIHA
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(1) Autoantibody is IgG, which binds optimally to RBC membranes best at 37C, hence 'warm'; (2) Results in extravascular hemolysis - the primary site of RBC sequestration is the spleen. Splenomegaly is a common feature
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Causes of Warm AIHA
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(1) Primary (idiopathic); (2) Secondary to lymphomas, leukemias (CLL), other malignancies, collagen vascular diseases (especially SLE), drugs such as alpha-methyldopa
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Cold AIHA
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(1) Autoantibody is IgM, which binds optimally to RBC membrane at cold temperatures (0-5C); (2) Produces complement activation and INTRAVASCULAR hemolysis, primary site of RBC sequestration is the liver
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Causes of Cold AIHA
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(1) Idiopathic (elderly) or (2) Due to infection (Mycoplasma pneumoniae or infectious mononucleosis)
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Diagnosis of AIHA
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(1) Direct Coombs Test - if RBCs are coated with IgG (positive direct Coombs test) then the diagnosis is warm AIHA; (2) If RBCs are coated with complement alone, then the diagnosis is cold AIHA; (2) If there is a positive cold agglutinin titer, then the diagnosis is cold AIHA; (3) Spherocytes may be present in warm AIHA
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Treatment of Warm AIHA
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Generally, none needed because hemolysis is mild; however, (1) glucocorticoids are the mainstay of therapy, and (2) splenectomy is used in patients whose condition does not respond to glucocorticoids; (3) immunosuppression with azathioprine or cyclophosphamide may be beneficial; (4) RBC transfusion - if absolutely necessary; (5) Folate supplementation
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Treatment of Cold AIHA
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(1) Avoid cold! (2) RBC transfusions if absolutely necessary; (3) Various chemotherapeutic agents; (4) Steroids are NOT beneficial
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Paroxysmal Nocturnal Hemoglobinuria: General Characteristics
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(1) Acquired disorder that affects hematopoietic stem cells and cells of all blood lineages; (2) Caused by deficiency of anchor proteins CD55 and CD59 that link complement-inactivating proteins to blood cell membranes. The deficiency of this anchoring mechanism results in an unusual susceptibility to complement mediated lysis of RBCs, WBCs, and platelets
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PNH: Clinical Features
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(1) Chronic intravascular hemolysis causing chronic paroxysmal hemoglobinuria, elevated LDH; (2) Normochromic, normocytic anemia (unless IDA is also present); (3) Pancytopenia; (4) Thrombosis of venous systems can occur - eg. of the hepatic veins (Budd-Chiari syndrome); (5) May evolve into aplastic anemia, myelodysplasia, myelofibrosis, and acute leukemia; (6) Abdominal, back, and musculoskeletal pain
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Diagnosis of PNH
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(1) Ham's test: patients cells are incubated in acidified serum, triggerin the alternative complement pathway, resulting in lysis of PNH cells but not normal cells; (2) Sugar water test: patient's serum mixed in sucrose. In PNH, hemolysis ensues; (3) Flow cytometry of anchored cell surface proteins (CD55, CD59) - much more sensitive and specific for PNH.
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Treatment of PNH
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(1) Glucocorticoids (prednisone) are the usual initial therapy, but many patients do not respond; (2) Bone marrow transplantation; (3) Eculizumab - a monoclonal antibody directed against complement protein C5 blocking cleavage of C5 and inhibiting cell-mediated cell destruction
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HIT Type 1
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Heparin directly causes platelet aggregation; seen <48hrs after initiating heparin; no treatment is needed;
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HIT Type 2
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Heparin induces antibody-mediated injury to platelet; seen 3-12 days after initiating heparin; herparin should be discontinued immediately
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Causes of Thrombocytopenia
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(1) Increased destruction - Immune: ITP, SLE, HIT type 2, HIV & Non-Immune: DIC, TTP, HIT type 1; (2) Decreased production - aplastic anemia, bone marrow invasion/injury; (3) Sequestration from splenomegaly
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Clinical Features of Thrombocytopenia
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(1) Cutaneous bleeding: petechiae (MC in dependent areas), ecchymoses at sites of minor trauma; (2) Mucosal bleeding: epistaxis, menorrhagia, hemoptysis, bleeding in GI and genitourinary tracts; (3) Excessive bleeding after procedures or surgery; (4) Intracranial hemorrhage and heavy GI bleeding can be life-threatening and occur when platelet levels are severely low; (5) Unlike coagulation disorders (hemophilia), heavy bleeding into tissues and joints (hemarthroses, hematomas) are not seen in thrombocytopenias
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ITP
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Autoimmune antibody formation against host platelets. These antiplatelet IgG antibodies coat and damage platelets, which are then removed by splenic macrophages (reticuloendothelial system binds self-immunoglobulins attached to the platelet). Occurs in two forms: (1) Acute form - seen in children, preceded by a viral infection in most cases, and usually self-limited with 80% resolving spontaneously; (2) Chronic form - usually seen in adults, women 20-40 is MC; spontaneous remissions are rare.
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Would you expect splenomegaly in ITP?
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NO! Petechiae and ecchymoses are common, and bleeding of mucous membranes (Wet purpura) but no splenomegaly!
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Treatment of ITP
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(1) Prednisone; (2) IVIG - saturates RE system binding sites for platelet-bound self-immunoglobulin, so there is less platelet uptake and destruction by the spleen; (3) Splenectomy - induces remission in 70-80% of cases of chronic ITP; (4) Platelet transfusions - for life-threatening and serioues hemorrhagic episodes
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Thrombotic Thrombocytopenic Purpura (TTP)
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(1) Rare disorder of platelet consumption; (2) Hyaline microthrombi (mostly platelet bound thrombi) occlude small vessels - any organ may be involved. They cause mechanical damage to RBCs (schistocytes on PBS); (3) This is a life-threatening emergency that is responsive to therapy. If untreated, death occurs within a few months. (4) Caused by antibody to ADAMTS-13, vWF-cleaving metalloproteinase
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Clinical Pentad of TTP
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(1) Hemolytic anemia (MAHA); (2) Thrombocytopenia; (3) Acute renal failure; (4) Fever; (5) Fluctuating, transient neurologic signs - can range from mental status change to hemiplegia
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Treatment of TTP
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(1) Plasmapheresis (large volume) as soon as diagnosis is established; (2) Response is usually good (monitor platelet count, which should increase); (3) Corticosteroids and splenectomy - may be of benefit in some cases; (4) Platelet transfusions are contraindicated
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Bernard-Soulier Syndrome
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(1) Autosomal recessive disease of platelet adhesion due to deficiency of GPIb-IX; (2) On PBS, platelets are abnormally large; (3) Platelet count Is mildly low
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Glanzmann's Thrombasthenia
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(1) Autosomal recessive disease of platelet aggregation due to deficiency in platelet GPIIb-IIIa; (2) Platelet count is normal
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Disorders of Coagulation: von Willebrand's Disease (vWD)
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(1) Autosomal dominant disorder characterized by deficiency or defect of factor VIII-related antigen (vWF); (2) vWF enhances platelet aggregation and adhesion (the first steps in clot formation). It also acts as a carrier of factor VIII in blood; (3) THE MOST COMMON INHERITED BLEEDING DISORDER - 1-3% of population!)
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Function of vWF (aka factor VIII-related antigenic protein)
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(1) Platelet adhesion-mediates the adhesion of platelets to the injured vessel walls (i.e. it reacts with platelet Ib/IX and subendothelium); (2) Binds to factor VIII coagulant protein and protects it from degradation
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Site of vWF synthesis
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Endothelial cells and megakaryocytes
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Acquired causes of platelet function abnormalities
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(1) Drugs [ASA, NSAIDs, antibiotics, PCN], (2) Uremia - uremic toxins affect F. XIII biochemistry; (3) Liver disease; (4) Bone marrow disorders (leukemias, myeloproliferative disorders; (5) Dysproteinemias [Multiple Myeloma]; (6) Antiplatelet antibodies; (7) Cardiopulmonary bypass [partial degradation of platelets]
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Reactive causes of thrombocytosis
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(1) Iron deficiency; (2) Splenectomy; (3) Rebound thrombocytosis; (4) Inflammatory diseases [IBD]; (5) Malignancy [GI, lung]
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Why is there thrombocytosis in iron deficiency?
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Erythroid precursors and megakaryocytes derive from a common precursor, and erythropoietin has a lot of homology with thrombopoeitin. It is speculated that the reason we see thrombocytosis in some cases of iron deficiency is because the high levels of erythropoietin are able to cross react and stimulate the thrombopoietin receptor.
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Types of vWD
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TYPE 1 [most common form]: decreased levels of vWF; TYPE 2 [less common]: exhibits qualitative abnormalities of vWF; TYPE 3 [least common form]: absent vWF (very severe disease)
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What are the two components of Factor VIII?
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(1) The coagulant portion (factor VIII coagulant protein) and (2) The antigenic portion (factor VIII antigenic protein). The latter is synonymous with vWF
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What is Heyde's syndrome?
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A syndrome of aortic valve stenosis associated with GI bleeding from colonic angiodysplasia. It is due to the induction of vWD type IIa by valvular stenosis
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Clinical Features of vWD
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(1) Cutaneous and mucosal bleeding - epistaxis, easy bruising, excessive bleeding from scratches and cuts, gingival bleeding; (2) Menorrhagia (affects >50% of women with vWD); (3) GI bleeding is possible
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Diagnosis of vWD
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(1) Prolonged bleeding time (but normal platelet count) - PTT may be prolonged (but a normal PTT does not exclude this diagnosis); (2) Decreased plasma vWF, decreased factor VIII activity; (3) Reduced ristocetin-induced platelet aggregation
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Treatment of vWD
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(1) DDAVP (desmopressin) - induced endothelial cells to secrete vWF [helpful in types I and II vWD; not at all in type III]; (2) Factor VIII concentrates (containing high-MW vWF) for patients with vWD after trauma or during surgery and type 3 vWD patients; (3) Cryoprecipitate is not recommended as treatment for vWD because it carries the risk of viral transmission; (4) Avoid aspirin/NSAIDs as these exacerbate bleeding tendency
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Hemophilia A
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X-linked recessive disorder that affects male patients primarily; caused by deficiency or defect of factor VIII coagulant protein; Bleeding tendency is related to factor VIII activity
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Clinical features of Hemophilia A
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(1) Hemarthroses - knees MC site. Maintaining normal factor VIII levels with recombinant protein can minimize the progressive joint destruction that often occurs; (2) Intracranial bleeding - second most common cause of death (AIDS 2/2 transfusion before screening is actually the most common)
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Diagnosis of Hemophilia A
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(1) Prolonged PTT; (2) Low factor VIII level and normal levels of vWF
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Detection of factor VIII inhibitor
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(1) Normal plasma + plasma from a hemophiliac patient = normal PTT; BUT…with an inhibitor the PTT will NOT normalize in a mixing study, thus confirming the presence of a factor VIII inhibitor
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Treatment of acute hemarthrosis in Hemophilia A patient
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(1) Analgesia with codiene +/- acetaminophen - AVOID ASA and NSAIDs!; (2) Immobilization of joint, ice packs, non-weight bearing
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Clotting factor replacement in Hemophilia A
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(1) Factor VIII concentrate is the mainstay of therapy (both plasma-derived and recombinant factor VIII are available) for acute bleeding episodes and before surgery or dental work; (2) Cryoprecipitate and FFP are not recommended because of the risk of viral transmission
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Use of DDAVP in Factor VIII deficiency
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May be helpful in patients with mild disease (5-10% of normal factor VIII); It can increase the levels of factor VIII up to fourfold
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Hemophilia B
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(1) Caused by deficiency of factor IX; (2) X-linked recessive disorder, much less common than hemophilia A. (3) Clinical features are identical to those of hemophilia A; (4) Treatment involves administration of factor IX concentrates; DDAVP does not play a role in treatment
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Disseminated Intravascular Coagulation: general characteristics
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(1) DIC is characterized by abnormal activation fo the coagulation sequence, leading to formation fo microthrombi throughout the microcirculation. This causes consumption of platelets, fibrin, and coagulation factors. Fibrinolytic mechanisms are activated, leading to hemorrhage. Therefore, bleeding and thrombosis occur simultaneously; (2) Most common in critically ill patients in the ICU, but can occur in healthy patients as well
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Causes of DIC
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(1) Infection - MCC; especially gram-negative sepsis; (2) Obstetric complications (placenta and uterus have increased levels of tissue factor) - amniotic fluid emboli (often acute and fatal); retained dead fetus (often chronic); abruptio placentae; (3) Major tissue injury - trauma, major surgery, burns, fractures; (4) Malignancy - lungs, pancreas, prostate, GI tract, APL; (5) Shock, circulatory collapse; (6) Snake venom (rattlesnakes)
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Clinical Features of DIC
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(1) Bleeding tendency (esp. in acute cases) with superficial hemorrhages [petechiae, purpura, ecchymoses]; (2) Bleeding from GI tract, urinary tract, gingival, or oral mucosa; (3) Oozing from sites of procedures, incisions, and so on; (4) Thrombosis - occurs most often in chronic cases. End-organ infarction may develop; all tissues are at risk, esp. the CNS and kidney
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Diagnosis of DIC
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(1) Increased PT, PTT, bleeding time, Thrombin Time, Fibrin split products, and D-dimer; (2) Decreased fibrinogen level, platelet count (thrombocytopenia); (3) Peripheral smear reveals schistocytes from damage of RBCs as they go through the microcirculation with microthrombi
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Complications of DIC
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(1) Hemorrhage - intracranial bleeding is a common cause of death; (2) Thromboembolism - stroke, pulmonary embolism, bowel infarction, acute renal failure, arterial occlusion
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Treatment of DIC
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(1) Management of the condition that precipitated DIC; (2) Supportive measures may be indicated if severe hemorrhage is present (these are only temporizing measures); (3) FFP to replace clotting factors, platelet transfusions, cryoprecipitate replaces clotting factors and fibrinogen, low doses of heparin inhibits clotting and can prevent consumption of clotting factors. The use of heparin is controversial; give only in rare cases in which thrombosis dominates the clinical picture
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Vitamin K deficiency
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(1) Several clotting factors depend on vitamin K as a cofactor in their synthesis by the liver (Factors II, VII, IX, X, Protein C and S). The process is posttranslational modification (gamma-carboxylation); (2) Sources of vitamin K include diet (green leafy vegetables) and synthesis by intestinal bacterial flora
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Causes of Vitamin K deficiency
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(1) Broad-spectrum antibiotics (suppression of gut flora) in patients who are NPO [inadequate dietary intake]; (2) Patients on TPN [unless vitamin K is added]; (3) Malabsorption of fat-soluble vitamins (small-bowel disease, IBD, obstructive jaundice); (4) Warfarin - a vitamin K antagonist (causes production of inactive clotting factors
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Clinical features of Vitamin K deficiency
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(1) Hemorrhage - serious bleeding can develop; (2) PT is initially prolonged (factor VII has shortest half-life). PTT prolongation follows as other factors diminish
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Treatment of Vitamin K deficiency
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(1) Vitamin K replacement; it may take a few days for PT to normalize; (2) If bleeding is severe and emergency treatment is necessary, FFP should be transfused
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Coagulopathy of Liver disease
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(1) All clotting factors are produced by the liver except for vWF; the liver disease must be severe for coagulopathy to develop, therefore if coagulopathy is 2/2 liver failure, the overall prognosis is very POOR
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Why does coagulopathy develop in liver failure?
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(1) Decreased synthesis of clotting factors; (2) Cholestasis leads to decreased vitamin K absorption, which leads to vitamin K deficiency; (3) Hypersplenism (splenomegaly 2/2 portal HTN) causes thrombocytopenia
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Clinical Features of Coagulopathy of liver disease
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(1) Abnormal bleeding - GI bleeding is the most common, primarily due to varices secondary to portal HTN, but exacerbated by the coagulopathy; (2) Prolonged PT and PTT (especially the PT)
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Treatment of Coagulopathy of Liver disease
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(1) FFP (contains all clotting factors) if PT or PTT prolonged or if bleeding is present; (2) vitamin K in certain cases (cholestasis); (3) Platelet transfusion - if thrombocytopenia is present; (4) Cryoprecipitate - if there is a deficiency of fibrinogen
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Why is a prolonged PT a poor prognostic indicator in cirrhosis?
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Because synthesis of clotting factors is not significantly impaired until liver disease is advanced
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Causes of Inherited Hypercoagulable States
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(1) Antithrombin III deficiency [ATIII is an inhibitor of thrombin, so a deficiency leads to thrombosis]; (2) Antiphospholipid antibody syndrome; (3) Protein C deficiency [Protein C is an inhibitor of factors V and VIII, so a deficiency leads to unregulated fibrin synthesis]; (4) Protein S deficiency [Protein S is a cofactor of Protein C, so a deficiency leads to decreased protein C activity]; (5) Factor V Leiden (activated protein C resistance) [A mutation in factor V gene so that protein C can no longer inactivate factor V, leading to unregulated prothrombin activation, and thus an increase in thrombotic events; (6) Prothromin 20210 gene mutation; (7) Hyperhomocysteinemia
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Causes of Acquired Hypercoagulable States
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(1) Malignancy (especially pancreas, GI, lung, and ovaries); (2) Antiphospholipid antibody syndrome - the lupus anticoagulant, beta-2 glycoprotein antibodies, and anticardiolipin antibody; (3) Pregnancy - and up to 2 months postpartum; (4) Immobilization, causing stasis of blood; (5) Myeloproliferative disorders; (6) OCPs; (7) Post-operative state [esp. after orthopedic procedures]; (8) Trauma; (9) Nephrotic Syndrome; (10) Heparin-induced thrombocytopenia or DIC; (11) Paroxysmal Nocturnal Hemoglobinuria; (12) Heart failure - causes stasis of blood
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Clinical Features of Hypercoagulable States
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(1) Venous thromboembolism (DVT and PE are the most common sequelae). Such hypercoagulable disorders are usually not diagnosed until the patient has had several episodes of DVT or PE
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When should a hypercoagulable state be suspected?
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(1) Family history of DVT, PE, or thrombotic events; (2) Recurrent episodes of DVT, PE, or thrombotic events; (3) Patient's first thrombotic event before age 40; (4) Patient experiences thrombosis in unusual sites, e.g., in mesenteric veins, IVC, renal veins, or cerebral veins
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Heparin MOA
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(1) Potentiates the action of antithrombin to primarily inhibit clotting factors IIa and Xa; (2) Prolongs PTT; (3) Half-life of standard heparin is 1hr; it is longer for LMWH (3-24h)
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Indications for Heparin use
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(1) VTE - DVT or PE; (2) Acute coronary syndromes: unstable angina, myocardial infarction; (3) low dose for DVT prophylaxis; (4) Atrial fibrillation in acute setting; (5) After vascular bypass grafting
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Administration of Standard Heparin
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(1) A therapeutic dose is usually given IV, initiated at a bolus of 70 to 80U/kg and followed by continuous IV infusion (15 to 18U/kg/hr). Therapeutic PTT is ~60-90 seconds; (2) A prophylactic dose is given subcutaneously, low-dose heparin (5,000U SC q12h). PTT monitoring is not necessary with SC dosing
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Adverse effects of Heparin
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(1) Bleeding; (2) HIT - lower incidence with LMWH; (3) Possible osteoporosis - lower incidence with LMWH; (4) Transient alopecia; (5) Rebound hypercoagulability after removal due to depression of ATIII
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Contraindictions to Heparin
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(1) Previous HIT; (2) Active bleeding, GI bleeding, intracranial bleeding; (3) Hemophilia, thrombophilia; (4) Severe HTN; (5) Recent surgery on eyes, spine, brain
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How are the effects of heparin and LMWH reversed?
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(1)The t1/2 of standard heparin is short, so it will cease to have an effect within 4 hours of its cessation; (2) One can give protamine sulfate to reverse the effects of heparin if necessary (effectiveness is not proven, but it is the only potential antidote that exists in the case of severe bleeding); (3) LMWH has a longer half-life than standard heparin, so it takes longer for the effects to fade
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LMWH MOA
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(1) LMWHs mostly inhibit factor Xa (equivalent inhibition of factor Xa as standard heparin) but have less inhibition of factor IIa (thrombin) and platelet aggregation; (2) They cannot be monitored by PT or PTT because they do not effect either
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Indications for LMWH use
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(1) LMWHs are being used more now because of their greater convenience compared with standard heparin, as well as a decreased risk for side effects (HIT, osteoporosis).
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Administration of LMWH
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(1) They are given SubQ (no IV administration); (2) PTT monitoring is not necessary; (3) They are easier to use as an outpatient - the patient may be discharged if stable, and the patient can continue LMWH until the level of long-term anticoagulation with coumadin is therapeutic
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Warfarin MOA
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(1) A vitamin K antagonist - leads to a decrease in vitamin K-dependent clotting factors (II, VII, IX, X) and protein C and S; (2) Causes prolongation of PT (and increase in the INR); (3) Takes 4-5 days for the anticoagulation to begin. Therefore, start heparin as well if the goal is acute anticoagulation because heparin has an immediate effect. Once warfarin is therapeutic (Checking by INR, usually 2-3), then stop the heparin and continue warfarin for as long as necessary
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Adverse effects of Warfarin
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(1) Hemorrhage; (2) Skin necrosis - rare but serious complication. Caused by a rapid decrease in protein C (a vitamin K-dependent inhibitor of factors Va and VIIIa); (3) Teratogenic - avoid during pregnancy!; (4) Should not be given to alcoholics or to any patient who is prone to frequent falls because of an intracranial bleed in a patient on warfarin can be catastrophic
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Reversing the effects of Warfarin
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(1) Discontinue warfarin and administer vitamin K; (2) t1/2 of warfarin is much longer than that of heparin - it takes 5 days to correct the effects of warfarin on stopping the medication. Vitamin K infusion corrects an abnormal PT within 4-10 hours if the patient has normal liver function; (3) Giving vitamin K makes it difficult to return the patient to therapeutic INR levels if anticoagulation is to be continued
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What should be used in rapid reversal of warfarin?
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Fresh Frozen Plasma (FFP)
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Multiple Myeloma
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Neoplastic proliferation of a single plasma cell line producing monoclonal immunoglobulin (usually IgG or IgA); Incidence is increased >age 50, 2x as common in AA as in Caucasians
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What features suggest multiple myeloma?
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(1) Low Hgb; (2) High Ca2+; (3) High serum protein; (4) Poor renal function
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Clinical features of multiple myeloma
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(1) Bone pain 2/2 osteolytic lesions, fractures, and vertebral collapse - especially in the low back or chest (ribs) and jaw (mandible); (2) Normochromic, normocytic anemia 2/2 marrow infiltration, renal failure; (3) Renal failure 2/2 myeloma nephrosis with Ig precipitation in renal tubules causing tubular casts of Bence-Jones protein and hypercalcemia; (4) Recurrent infections - 2/2 deprivation of normal IgGs, therefore humoral immunity is affected. MOST COMMON CAUSE OF DEATH! up to 70% of patients die of lung or urinary tract infections; (5) Amyloidosis develops in 10% of patients (usually clinically insignificant)
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Diagnostic Criteria for Multiple Myeloma
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At least 10% abnormal plasma cells in bone marrow PLUS one of the following: (1) M-protein in serum [85% of patients]; (2) M-protein in urine [75% of patients]; (3) Lytic bone lesions (well-defined radiolucencies on radiographs - predominantly in skull and axial skeleton)
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Treatment of Multiple Myeloma
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(1) Treatment usually reserved for patients with symptoms or advanced disease. Indications for treatment include hypercalcemia, bone pain, and spinal cord compression. (2) Systemic chemotherapy - preferred initial treatment (alkylating agents); (3) Radiation therapy (if no response to chemotherapy and if disabling pain is present); (4) Autologous peripheral SCT preferred over Bone Marrow Transplant
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What causes osteolytic lesions in multiple myeloma?
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The release of osteoclast-activating factor by neoplastic plasma cells
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What is the prognosis of Multiple Myeloma?
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Very poor; with median survival of 2-4 years with treatment, and only a few months without treatment. 5-yr survival is about 10%
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Waldenstrom's Macroglobulinemia
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(1) Malignant proliferation of plasmycytoid lymphocytes. These cells produce IgM para-protein, which is very large and causes hyperviscosity of the blood; (2) Diagnosis: IgM >5g/dL; Bence-Jones protein in 10% of cases. Absence of bone lesions; (3) Clinical Features: LAD, splenomegaly, anemia, abnormal bleeding, and hyperviscosity syndrome (due to elevated IgM)
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Treatment of Waldenstrom's Macroglobulinemia
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No definitive cure; use chemotherapy and plasmapheresis for hyperviscosity
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Monoclonal Gammopathy of Undetermined Significance
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(1) Common in the elderly - up to 10% of patients >75 years of age; (2) Usually asymptomatic; (3) Diagnosis: IgG spike < 3.5g; less than 10% plasma cells in bone marrow; Bence-Jones proteinuria <1g/24h; (4) Fewer than 20% develop multiple myeloma in 10-15 years; (5) No specific treatment is necessary, just close observation
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Hodgkin's Disease: General Characteristics
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(1) Bimodal age distribution - 15-30y and >50y; (2) Four subtypes: [a] lymphocyte predominance (10-20%) - few Reed Sternberg cells and many B cells; [b] Nodular sclerosing (40-60%) occurs more frequently in women; bands of collagen envelope pools of Reed Sternberg cells; [c] Mixed cellularity (20-40%) - large numbers of Reed Sternberg cells in a pleomorphic background; [d] Lymphocyte depletion (1-10%) lacking in mix of reactive cells; associated with the worst prognosis
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Staging of Hodgkin's Disease
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Stage I: single lymph node; Stage II: involvement of two or more lymph nodes but confined to the same side of diaphragm; Stage III: both sides of diaphragm involved; Stage IV: dissemination of disease to extralymphatic sites. Suffixes: A: No symptoms, B: Fever, weight loss, night sweats. Presence of these constitutional symptoms worsens the prognosis
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Clinical Features of Hodgkin's Disease
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(1) MC symptom is a painless lymphadenopathy; (2) Supraclavicular, cervical, axillary, mediastinal lymph nodes; (3) Spreads by continuity from one lymph node to adjacent lymph nodes; (4) Other presentations may or may not be present, including B symptoms (fever, NS, chills, weight loss), pruritus, and cough (secondary to mediastinal lymph node involvement)
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Diagnosis of Hodgkin's Disease
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(1) Lymph node biopsy - presence of REED STERNBERG cells is required to make the diagnosis, usually of B-cell phenotype CD15+, CD30+; (2) Presence of inflammatory cell infiltrates - this distinguishes Hodgkin's lymphoma from NHL. The inflammatory cells present are reactive to the Reed Sternberg cells. These include plasma cells, eosinophils, fibroblasts, and T and B lymphocytes; (3) CXR and CT scan to detect lymph node involvement; (4) BM Bx
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Treatment of Hodgkin's Disease
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Stages I, II, IIIA can be treated with radiotherapy alone. However, some physicians advocate use of chemotherapy as well; Stages IIIB and IV require chemotherapy (ABVD = Adriamycin, Bleomycin, Vinblastine, and Dacarbazine)
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Non-Hodgkin's Lymphoma
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Malignant transformation and growth of B (85%) or T (15%) cells; usually starts in the lymph nodes and may spread to blood and bone marrow. NHL is 2x as common as Hodgkin's Lymphoma. At presentation, patients with NHL have more advanced disease than patients with Hodgkin's Disease
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Clinical Features of NHL
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(1) LAD - sometimes the only manifestation of disease - lymph nodes are usually painless, firm, and mobile and enlargement is often rapid with supraclavicular, cervical, and axillary odes involved most often; (2) B symptoms - less common than in Hodgkin's Lymphoma; (3) Hepatosplenomegaly, abdominal pain, fullness; (4) Recurrent infections, symptoms of anemia or thrombocytopenia due to bone marrow involvement; (5) Various other findings are possible - SVC syndrome, respiratory involvement, bone pain
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Diagnosis of NHL
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(1) Lymph node biopsy for definitive diagnosis; ANY NODE >1cm PRESENT FOR >4WKS THAT CANNOT BE ATTRIBUTED TO INFECTION SHOULD BE BIOPSIED; (2) Other tests - CXR with hilar/mediastinal LAD; (3) CT to determine extent of diseas spread and patient's response to treatment; (4) Serum LDH and Beta-2 microglobulin are indirect indicators of tumor burden; (4) Elevated Alk Phos indicates bone, liver involvement
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Treatment of NHL
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Varies depending on stage and subtype of NHL; INDOLENT FORMS are NOT CURABLE, but have 5-year survival rate of 75%; INTERMEDIATE AND HIGH-GRADE forms are curable with aggressive treatments, but if complete remission is not achieved, survival is < 2 years. Usually R-CHOP is used (Rituxan, Cyclophosphamide, Hydroxdaunomycin (doxorubicin), Oncovin (vincristine), and Prednisone
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Acute Myelogenous Leukemia
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Occurs mostly in adults (80% of adult acute leukemias); Risk factors include radiation exposure, myeloproliferative syndromes.
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Acute Lymphoblastic Leukemia
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Most common malignancy in children <15 years of age in the United States; It is the leukemia most responsive to therapy. Poor prognostic indicators are: age <2 years of age or >9 years of age;WBC >100,000; and/or CNS involvement
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Clinical Features of Acute Leukemias
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(1) Anemia and associated symptoms; (2) Increased risk of bacterial infections 2/2 neutropenia; (3) Abnormal mucosal or cutaneous bleeding 2/2 thrombocytopenia; (4) Splenomegaly, hepatomegaly, LAD; (5) Bone and joint pain [invasion of periosteum]; (6) CNS involvement; (7) Testicular involvement (ALL); (8) Anterior mediastinal mass (T-cell ALL); (9) Skin nodules (AML)
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Tumor Lysis Syndrome
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Rapid cell death with release of intracellular ions causing hyperkalemia, hyperuricemia, and hyperphosphatemia. Treat as a medical emergency and prevent with allopurinol and fluids
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CLL
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Most common leukemia that occurs after age 50; Most patients >60 years of age. MOST COMMON LEUKEMIA IN WESTERN WORLD! Monoclonal proliferation of lymphocytes that are morphologically mature but functionally defective (do not differentiate into antibody-manufacturing plasma cells); Least aggressive type of leukemia, prolonged indolent course
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Diagnosis of CLL
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(1) WBC 50k-500k+; (2) Absolute lymphocytosis on PBS with SMUDGE CELLS; (3) Bone marrow biopsy shows presence of infiltrating leukemic cells in bone marrow
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Treatment of CLL
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(1) Chemotherapy has little effect on overall survival, but is given for symptomatic relief and reduction of infection. Fludarabine and chlorambucil have been shown to be of some benefit
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CML
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Neoplastic, clonal proliferation of myeloid stem cells that usually occurs in patients >40yrs. Follows an indolent course until it transforms into acute leukemia [BLAST CRISIS] which is an accelerated phase of blast and promyelocyte production. Associated with translocation t(9;22), the Philadelphia chromosome
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Diagnosis of CML
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Marked leukocytosis with left shift towards granulocytes. Few blasts, but eosinophilia and myelocytes, metamyelocytes, bands, and segs are present. Decreased leukocyte alkaline phosphatase activity; Thrombocytosis
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Treatment of CML
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Gleevec / Imatinib is first line. Nilotinib or Dasatinib are TK inhibitors that were developed to combat resistance to Imatinib
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Blast crisis
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Final phase of evolution of CML, behaves like an acute leukemia, with rapid progression and short survival. Blast crisis has (1) >20% myeloblasts or lymphoblasts in blood/bone marrow; (2) Large clusters of blasts in the bone marrow on biopsy; (3) Development of a chloroma (solid focus of leukemia outside the bone marrow)
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Diagnosis of P. vera
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All 3 major or 2 major + 1 minor: MAJOR CRITERIA = (1) Elevated RBC mass (men >36L/kg, women >32L/kg); (2) Arterial O2 sat >92%; (3) Splenomegaly. MINOR CRITERIA: (1) Thrombocytosis (>400k); (2) Leukocytosis (>12k); (3) Leukocyte alkaline phosphatase >100 without fever/infection; (4) B12 >900pg/ml
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Polycythemia vera
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Excessive erythrocyte production 2/2 malignant clonal proliferation. The increase in RBC mass occurs INDEPENDENT of erythropoietin
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Clinical features of PV
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(1) Symptoms 2/2 hyperviscosity - HA, dizziness, weakness, pruritus, visual impairment, dyspnea; (2) Thrombotic phenomena - DVT, CVA, MI, portal vein thrombosis; (3) Bleeding - GI or GU bleeding, ecchymoses, epistaxis
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Diagnosis of PV
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(1) rule out causes of secondary polycythemia (e.g. hypoxemia, CO exposure); (2) elevated RBC, Hb, Hct; (3) reduced EPO levels; (4) elevated B12 level; (5) hyperuricemia is commom; (6) BM bx confirms diagnosis
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Treatment of PV
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(1) Repeated phlebotomy to lower hematocrit; (2) Myelosuppression with hydrea or recombinant INF-alpha
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Myelodysplastic Syndromes
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(1) Class of clonal blood disorders characterized by ineffective hematopoiesis, with apoptosis of myeloid precursors resulting in pancytopenia despite a normal or hypercellular bone marrow; (2) More commonly in elderly patients; (3) Idiopathic most often, but exposure to radiation, immunosuppressive agents, and certain toxins like benzene are known to be risk factors
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Clinical Features of MDS
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Often asymptomatic in early stages, Pancytopenia may be an incidental finding on a routine blood test; May present with manifestations of anemia, thrombocytopenia, or neutropenia
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Treatment of MDS
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(1) Mainly supportive - RBC/platelet transfusions are mainstays of treatment; (2) EPO; (3) G-CSF; (4) vitamin supplementation, particularly with B6, B12, and folate important given the large turnover of marrow cells; (5) Pharmacologic therapy includes immunosuppressive agents, chemotherapy, and androgenic steroids; (6) BM transplant is only potential cure
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Essential Thrombocytosis
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Defined as platelet count >600k - must EXCLUDE reactive thrombocytosis due to infection/inflammation; Primarily manifested by thrombosis (CVA) or paradoxically (and less often) by bleeding 2/2 defective platelet function. It is a disease with high morbidity, but low mortality
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Treatment of ET
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Antiplatelet agents such as anagrelide and low-dose aspirin; sometimes hydrea is used
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Agnogenic Myeloid Metaplasia with Myelofibrosis
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This condition refers to fibrosis of the bone marrow resulting in pancytopenia and extramedullary hematopoiesis. (1) Massive splenomegaly, fatigue, bleeding, infection are common; (2) Teardrop cells on PBS are a HALLMARK FEATURE, as are large abnormal patelets and immature myeloid cells; (3) Bone marrow aspirate shows marrow fibrosis - if severe enough, may be a 'dry tap'. Prognosis is poor, patients often progress to AML or may die of bleeding/infection. Treatment is supportive with blodo transfusions, EPO, and sometimes splenectomy for palliative relief of painful splenomegaly. BM transplantation is sometimes appropriate
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