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Process by which the body makes ALL blood cells. In adults this process happens primarily in the BM and is known as _______.
- medullary hematopoeisis
In utero hematopoeisis starts in the ______ and continues in the ____ & ____ as the baby develops and finally transitions primarily to the BM by the ___ month of gestation.
- yolk sac
- liver & spleen
Where does extramedullary hematopoeisis (outside BM) occur?
- mucosal associated lymph tissue (MALT)
- **percentage of blood produced this way is in the range of 3% or less**
When does extramedullary hematopoeisis usually occur? What is the hemoglobin type usually associated with extramedullary hematopoeisis?
- BM is "crowded out" by a clonal disorder involving over-proliferation of an abnl cell type
- hemoglobin F
What are the 3 distinct properties of stem cells?
- self renewal
- multiple lineages
- proliferation potential
Provide a continuously renewable "lifetime supply" of required blood cells.
hematologic stem cells
Which stem cell line proliferates into the RBCs, megakaryocytes, and granulocytes?
Is produced in the BM (and other sites) in the presencce of erythropoeitin (EPO).
Produced in the kidneys in response to a perceived decrease in O2 saturation.
- erythropoeitin (EPO)
- **kidneys are the body's natural pulse ox machine**
How long will RBCs survive in the body before being removed by the reticuloendothelian system (spleen)?
Refers to "newly released" RBCs that still contain significant amounts of ribosomal RNA which makes them excellent markers for RBC production in the BM.
What are the two pathways of the reticuloendothelial system that removes aged cells?
- extra-vascular (spleen)= 90%
- intra-vascular= 10%
Which RES pathway is described as iron being recycled to the BM via transferrin and heme is broken down to bilirubin which is returned tot he liver via albumin for additional processing (conjugation) and eventual secretion in the gut (bile to aid fat digestion)?
Which RES pathway works by directly releasing RBC contents into the plasma, followed by the free hemoglobin being bound by haptoglobin and returned to the liver?
What stimulates the BM production of granulocyte WBCs?
- G-CSF (granulocyte colony stimulating factor)
- GM-CSF (granulocyte macrophage colony stmulating factor)
What is the half life of granulocytes?
6-8 hours (complete turn around in nl individuals q24 hours)
The most common form of leukocyte, is phagocytic for infectious material (esp bacteria), and die in the line of duty (remains form bulk of pus).
neutrophils ("polys" or "PMNs")
What is the normal circulating form of neutrophils? What is an immature form?
- band (left shift)
WBC elevated in allergic reactions and parasitic infections, are drawn in great numbers to sites of foreign material absorption or injection such as an insect sting or rhusoil (poison ivy/oak/sumac).
Rarest of the circulating granulocytes, quickly exits in the circulatioin and sets up as a mast cell.
Largest of the circulating leukocytes (granulocyte) that assists others in the blood and connective tissue. They eventually migrate to the spleen, liver, lung and BM, and mature into macrophages.
Most numerous and most important of the agranulocytes with two functional types.
lymphocytes (types T & B)
Lymphocyte responsible for cell mediated immune reactions (releases cytotoxins).
Lymphocyte responsible for humoral immunity (secretes antibodies).
Where is thrombopoietin produced?
How long do platelets live?
Lab value that is the BEST measure of O2 carrying capacity.
Percentage of blood occupied by RBCs, roughly corresponds to 3 times the Hgb value but may be falsely elevated/reduced for various reasons.
- **dehydration produces high HCT, nl values vary by geography**
Gives the average size of RBCs, is the most important measurement in determining your differential for various forms of anemia, and is measured in femtoliters.
MCV (mean corpuscular volume)
Which measurement in the CBC is useful in diagnosing myeloproliferative disorders such as polycythemia vera?
RBC count (millions/microliter)
CBC measurement that estimates the RANGE of sizes of RBCs (anisocytosis).
RDW (red cell distribution width)
What is usually included in the automated differential on a CBC, and is measured in the thousands/ml (~4-11K)? (from most to least)
- neutrophils (41-73%)
- lymphocytes (18-46%)
- monocytes (0-10%)
- eosinophils (0-6%)
- basophils (0-2%)
- **manual diff will measure actual cell numbers**
What can cause leukocytosis (increased WBCs) besides an infection?
- post surgical inflammation
- medication side effects (corticosteroids)
- bone marrow disorders (leukemia)
Type of reaction characterized by leukocytosis approaching 50K/ml with a significant increase in early neutrophil precursors in the peripheral blood (myeloblasts), and is usually observed as a response to infection or a stress response in newborn infants.
In contrast to acute leukemia, this reaction shows increased proliferation and orderly maturation of all normal myeloid elements from the BM with the morphology of the myeloid elements being normal (MUST be distinguished from leukemia acutely).
What are the causes for leukemoid reactions? (there are 5)
- drugs (sulphas like dapsone/septra, glucocorticoids, G-CSF/related growth factors, all trans retinoic acids)
- infection (TB, pertussis, mono)
- trisomy 21 in infancy
- paraneoplastic phenomenon
How is the absolute neutrophil count (ANC) calculated? When is someone considered to have neutropenia?
- ANC: total WBC x % neutrophils on differential
- neutropenia: ANC <500
What is the most frequent cause of neutropenia? What are some other less frequent causes?
- MC: chemo and other meds
- others: overwhelming infx, primary BM disorders
Is it possible to have a normal white cell count and still be neutropenic/lymphopenic?
yes (if either of those cell lines are low)
What lab study is most useful in determining the severity of polycythemia (overproduction of RBCs)?
RBC mass (measures RBC mass in comparison to PLASMA volume)
What lab study measures the percentage of immature RBCs in circulation which reflects BM production in response to anemia? What is the normal range?
- reticulocyte count
- normally 0.5-1.5%
What is the reticulocyte index and when is it used to correct the reticulocyte count?
- retic index: retic % x pt HCT/nl HCT (low end)
- use: when HCT is abnormal which may cause overestimation of retics d/t fewer RBCs
What is the appropriate marrow response to anemia as reflected by the reticulocyte index?
at least 3%
Irregular fragmented RBCs in crescent and helmet shapes with a "bitten" appearance.
What conditions can cause shistocytes (crescent/helmet/bitten RBCs) to occur?
Smaller than average RBCs with a rounded shape and no area of central pallor.
What conditions can cause spherocytes (rounded RBCs) to occur?
- hereditary spherocytosis
- any process involving significant hemolysis
These neutrophils present on peripheral smear with >6 nuclear lobe septations, and are highly consistent with MEGALOBLASTIC anemia.
What are the clinical indications for examination of a blood smear? (table)
What lab study is almost never a first line consideration in evaluation of anemia and is saved as a last resort (when all else fails)?
bone marrow biopsy
What are the indications for ordering a bone marrow biopsy? (there are 4)
- unexplained anemia, leukopenia, thrombocytopenia, or pancytopenia
- assessment of BM iron stores in complicated/uncertain iron deficiency
- dx & staging of lymphomas, plasma cell tumors (multiple myeloma) and leukemias
- part of FUO workup with suspected mycobacterial infection, granulamtous disorder or infiltrative dz
Lab study that determines the types of hemoglobin (ie. A, A2, F, etc) present in a given blood sample.
hemoglobin electrophoresis (confirms sickle cell hgb)
What are values and basic classification of anemias based on the MCV (mean corpuscular volume)?
- <80: microcytic anemia
- 80-100: normocytic anemia
- >100: macrocytic anemia
What are the two explanations for NEARLY ALL clinical manifestations of anemia?
- reduced O2 carrying capacity: fatigue, weakness, pallor, tachycardia, dyspnea, angina
- reduced blood volume: high output heart failure, murmurs, HoTN, organ underperfusion
What ethnicity can have minimally low WBC counts more frequently than the general population and do not warrant further evaluation in most cases?
What are the 3 questions for evaluating anemia?
- what is the mcv? (micro/macro/normo-cytic)
- what is the basic mechanism? (bleed/nutrition/hemolytic)
- what else about this patient? (travel/ethnicity/heredity/past med hx/meds)
CBC result with low H&H, MCV <80 and serum iron studies showing low iron, low TIBC, and high ferritin.
anemia of chronic disease (microcytic anemia)
CBC result with low H&H, MCV <80 and serum iron studies showing low iron, high TIBC, and low ferritin.
iron deficiency anemia (microcytic anemia)
CBC result with low H&H, MCV <80 and serum iron studies showing high iron, low TIBC, and high ferritin.
possible thalassemia (do hemoglobin electrophoresis to rule it out/in)
CBC result with low H&H, MCV <80 and serum iron studies showing high iron, normal TIBC, and high ferritin.
- sideroblastic anemias (BM iron shows >10% sideroblasts)
- **review RBC morphology and order other tests as needed to determine cause**
What is the limited differential for microcytic anemias (MCV <80)? (there are 4)
- iron deficiency anemia
- thalassemia syndromes
- early anemia of chronic disease (ACD)
- others like sideroblastic anemia (rare)
What are the basic mechanisms of iron deficiency anemia? (there are 3)
- blood loss (occult/overt ie. GI, menses)
- inadequate absorption (PPI, celiac dz, H pylori, gastritis, gastric bypass)
- inadequate intake (poverty, fad diets)
Where is iron incorporated after it is absorbed by the duodenal enterocytes, and how much is held by various locations in the body?
- most incorporated in RBCS (1800mg)
- BM (300mg)
- muscle (300mg)
- liver parenchyma (1000mg)
- spleen (600mg)
- plasma transferrin (3mg)
- **homeostasis of iron: 1-2mg in and out on a daily basis**
Directly related to the amount of iron STORED in the body, is the storage protein for iron within the cells, major repository is the liver.
Protein responsible for TRANSPORTING iron throughout the body, primarily from storage sites to the bone marrow.
Hormone produced in hepatocytes, binds with a cell wall protein called ferroportin which is responsible for ALLOWING IRON OUT OF STORAGE, and has an inverse relationship to intestinal iron absorption.
Insoluble form of iron formed when there is an excess of iron in the body.
What is the most common cause of anemia worldwide?
- iron deficiency (not genetic)
- **Note: more frequent in women (menses/pregnancy) and children (rapid growth vs nutrition)
What are the stages of development for iron deficiency anemia?
- negative iron balance leads to...
- fall in iron stores which leads to...
- fall in serum iron/transferrin saturation which leads to...
- hypochromic reticulocytes which leads to...
- Hgb drops which leads to...
- MCV drops
What are the EARLY standard anemia signs & symptoms? (there are 6)
- easily fatigued
- tachypnea on exertion
What are the SEVERE standard anemia sign & symptoms? (there are 5)
- cardiac murmurs
What are some clinical indications of iron deficiency anemia?
- mild glossitis
- glossitis & cheilosis
- koilonychia (spoon nails)
- PICA!! (eat dirt, sofas, etc)
- plummer-vinson syndrome (rare)
Triad of dysphagia, glossitis, and iron deficiency anemia, most commonly occurs in postmenopausal women.
plummer vinson syndrome
What are the serum levels that differentiate anemia of chronic disease from iron deficiency anemia? (must know this chart!!)
What lab study and result is DIAGNOSTIC of iron deficiency? What is the normal value?
- diagnostic ferritin: <30ng/ml
- nl ferritin: 40-160mcg/dl
Is low serum iron diagnostic of iron deficiency?
NO! (ferritin <30 is diagnostic)
What is the normal range for total iron binding capacity (TIBC)?
- **reflects transferrin ability to bind more iron**
What is the normal range for transferrin saturation?
How is potential GI blood loss evaluated?
- EGD & colonoscopy ("double dip")
- specialized test after endoscopy (SBFT, enterclysis, pill endoscopy)
- clinical judgement regarding workup urgency
What are the principles for iron deficiency therapy? (there are 3)
- oral iron good enough for most
- IV iron is NOT a therapy of convenience
- do NOT treat empirically with iron!
What are the complications of oral, IV and IM iron therapy?
- oral: constipation, GI upset, dark tarry stools similar to melena (give colace)
- IV: anaphylaxis risks
- IM: painful & leaves hemosiderin deposits
What is the goal of iron replacement therapy and what is the usual dosing?
- goal: deliver at least 100mg of elemental Fe daily
- usual dose: 325mg FeSO4
When will most patients show some improvement with iron replacement therapy (oral), and how long should the therapy be continued?
- 2 months
- until ferritin returns to normal
Iron replacement therapy reserved for those who are truly unable to tolerate oral iron with significant anemia, has theoretical risks for oxidative damage, and absorption may still be impaired in pts with significant chronic inflammatory states.
IV iron replacement (consult hematology at this point)
Iron replacement therapy method that is rarely used (saved for last), and usually causes extreme pain and hemosiderin deposition at the site which is often unacceptableto patients.
IM iron replacement
What is the MCV, mechanisms and extra factors associated with thalassemias?
- MCV: often <70
- mechanism: alpha thalasessemia=number of deletions of alpha hgb chains, no substitutes, is a QUANTITATIVE problem; beta thalassemia=type of point mutations, beta hgb chains subbed with γ & δ
- other info: ethnicity, geographic location (are they from malaria belt?)
Heterogeneous, hereditary disorders characterized by defects in the synthesis of one or more of the globin chain subunits of hemoglobin, is usually characterized by significant microcytosis, and may be found in any ethnic group and geographic location but is most commonly traced to Mediterranean basin and equatorial regions of Africa and Asia.
What are the keys to the the dx of thalassemia?
- microcytosis disproportionate to the degree of anemia (MCV 60; HCT 35 vs Fe deficiency MVC 60; HCT 25)
- positive fam hx/lifelong person hx of microcytic anemia
- abnl RBC morphology (microcytes, acanthocytes, target cells)
How are thalassemia trait, intermedia, and major described?
- trait: lab features w/out significant clinical impact
- intermedia: req RBC transfusion/other moderate clinical impact
- major: life threatening disorder
What are some of the features of beta thalassemia syndromes based on the genetic and clinical manifestations? (table)
Severe thalassemia syndromes are more characterized by ______ complications more than the others (trait/intermedia).
What are the 4 main things that are used to help diagnose thalassemia anemias?
- clinical suspicion after Fe deficiency is r/o
- RDW typically normal
- genetic testing (complex cases)
What is the treatment for mild thalassemia syndromes?
- avoid unnecessary iron replacement
- used caution with meds (sulfa drugs) which can induce oxidative stress and subsequent hemolysis
What is the treatment for severe thalassemia syndromes? (there are 4)
- frequent transfusions (may cause iatrogenic iron overload syndrome)
- folate supplements
- BM transplant when possible
Drugs and toxins lead this category of anemias which are secondary to the high frequency of alcohol abuse in many societies, and cause disturbed mitochondrial metabolism which is at the center of all disorders in this category in which a cause has been determined.
sideroblastic anemia (AQUIRED far exceeds hereditary varieties)
These cells show normal iron uptake, but subsequent poor incorporation into heme...mishandling of iron by mitochondria chould be the basis of the iron deposits.
What are the drugs that can cause siderblastic anemia? (there are 5)
What are the copper chelators that can cause sideroblastic anemia? (there are 3)
- triethylene tetramine
- dihydrochloride (trientene)
What are the toxins that can cause sideroblastic anemia? (there are 3)
Anemia characterized by fatigue, decreased tolerance to physical activity, and dizziness with a hx of possible toxin or drug exposures, and a blood smear that sometimes reveals basophilic stippling (esp with lead poisoning).
sideroblastic anemia (remains in ddx of pts with iron deficiency & anemia refractory to iron replacement)
How is sideroblastic anemia managed/treated?
(there are 5)
- r/o reversible causes (etoh/other drug/toxin exposure); discontinue offending agent
- largely supportive tx
- blood trans to maintain acceptable hgb level
- trial of pyridoxine 100-200mg qd PO w/ gradual escalation to 500mg qd PO
- folic acid supplement
What is the MCV, basic mechanism and extra pt info associated with macrocytic anemias?
- MCV: >100
- mechanism: mostly d/t cell formation disruption
- other info: social hx, med usage, medical conditions
What are the causes and mechanisms of macrocytosis? (table)
What could explain the increased MCV in macrocytic anemia besides B12 and folate deficiency, and there are no nutritional or drug-induced causes?
- MCV around 100: hypothyroidism, pregnancy, liver dz, etoh abuse
- >105: BM d/o (MDS, late megaloblastic anemia)
Hypersegmented neutrophils and macro-ovalocytes strongly suggest what?
Term that refers to the large atypical erythroblasts that develop in association with abnormal DNA synthesis.
Term that is often applied for anemia classification purposes since the most common causes of megaloblastic anemia (B12 & folate deficiencies) can be related to inadequate intake.
How are hypersegmented neutrophils explained with B12 deficiency?
asynchronous cellular, nuclear and cytoplasma maturation leads to excess cytoplasm and abnl nuclei
Unrecognized and untreated B12 deficiency will lead to profound systemic consequences beyond the hematologic system such as _________.
What are the causes of B12 deficiency?
Autoimmune disease w/ antibodies to gastric parietal cells as well as intrinisc factor with a strong hereditary component with Caucasian predominance. Diagnoses in confirmed by B12 deficiency w/ NORMAL folate and presence of typical autoantibodies.
Macrocytic anemia caused by folate deficiency d/t nutritional deficiencies commonly from underconsumption of plant matter.
Why will clinically significant findings in folate deficiency develop sooner than a B12 deficiency?
daily usage of folate is greater than b12
What are the main causes of folate deficiency (megaloblastic anemia)?
- nutrition: decreased intake/etoh make "dual deficiency" by interfering with initial absorption and enterohepatic circulation
- increased requirements: physiologic (preggo, infancy, etc), pathologic (hemolytic anemia, other dz with increased cell turnover)
- malabsorption: normal intestinal mucosa (congenital), abnl intestinal mucosa (sprue, IBD, etc)
What are the drugs that affect folate? (there are 10)
What are the clinical features of megaloblastic anemia? (there are 8)
- hematologic: macro anemia leading to pancytopenia w/ megaloblastic marrow
- cardiopulmonary: CHF
- GI: macroglossitis, malabsorption syndromes
- derm: melanin pigmentation & premature graying
- genital: cervical/uterine dysplasia
- reproductive: infertility/sterility
- psychiatric: depressed affect & cognitive dysfunction
- neuropsychiatric: disrupted proprioception, neuropathic pain & parasthesias (specific to B12)
What are the laboratory tests that help diagnose megaloblastic anemia?
- direct B12 & folate measurement
- homocysteine level (elevated w/ B12 & folate deficiency)
- methylmalonic acid level (elevated in B12 deficiency alone)
What is the tx for B12 deficiency?
- pernicious anemia requires parenteral replacement
- typically 1000mcg monthly unless neurologic dysfunction is suspected then daily/weekly
- otherwise oral replacement is ok
- hypersegmented neutrophils disappear around 10-14 days
What is the treatment for folate deficiency?
- oral replacement ok for nearly all pts
- typical dose is 1mg daily
How soon can macrocytosis d/t alcohol abuse resolve with abstinence if irreversible damage to the liver has not occurred yet?
within 2-4 months
Heterogenous BM disorders characterized by ineffective blood cell production that increases in prevalence with age esp after 60.
myelodysplastic syndromes (MDS)
What can cause secondary myelodysplastic syndrome (MDS)?
- radiation therapy
- toxic substances (benzene)
Clinical features of this condition include hematologic manifestations (MCV ≥105, cytopenias, monocytosis), increased risk for developing acute myelogenous leukemia, considered as "pre-leukemia" or "neoplastic anemia", and 30% of pts with it develop acute myelogenous leukemia.
How are myelodysplastic syndromes (MDS) diagnosed?
- high clinical suspicion in appropriate age groups with typical hematologic features NOT EXPLAINED BY OTHER CAUSES
- refer! get a BM biopsy with expert hematopathologist interpretation
How are myelodysplastic syndromes (MDS) treated?
- majority of pts have limited options
- transfuse RBCs & plts as required
- hematologic stimulating factors
- BM transplant
- others (chemo, immunosuppression)
This condition causes the MCV to spuriously increase due to excessive reticulocytes and their larger size than RBCs, and is usually transiently observed in pts with massive hemolysis without a coexisting microcytic process (can mimic macrocytic anemias).
This condition can cause mild macrocytic anemia which may be related to a relative erythrocyte hypoproliferation in response to a reduced metabolism...these pts should also be evaluated for pernicious anemia d/t polyglandular association.
This condition is d/t increased folate requirements and may account for mild macrocytosis rarely >100.
What are the general causes for megaloblastic (macrocytic) anemia with low vitamin B12?
- dietary deficiency
- GI disease
- **AKA pernicious anemia**
What are the general causes for megaloblastic (macrocytic) anemia with low folate?
- dietary deficiency
- GI disease
What are the general causes for macrocytic anemia with normal B12 and folate levels?
- liver dz
- myelodysplastic syndromes
What are the general mechanisms of normocytic anemia (MCV 80-100)?
- acute blood loss
If the rate of change of H&H with normocytic anemia is SLOW what should you think of?
anemia of CHRONIC disease (ACD)
If the rate of change of H&H with normocytic anemia is FAST what should you think of?
With normocytic anemia, what evidence can show that it is due to hemolysis?
- increased reticulocytes
- decreased haptoglobin
- **if there IS hemolysis look for spherocytes/shistocytes on the peripheral smear**
What is the ddx for normocytic anemia?
- anemia of chronic disease (ACD)
- acute blood loss
- multifactorial anemia
- renal failure associated anemia
- aplastic anemia
- hemolysis (intrinsic/extrinsic)
AKA anemia of inflammation, is the 2nd most common form of anemia and presents more commonly as normocytic. The underlying cause of inflammation may also cause anemia via other mechanisms (ie SLE & autoimmune hemolytic anemia).
anemia of chronic disease (ACD)
The key pathophysiologic principle of this condition is the disturbance in iron homeostatsis mediated by chronic inflammation...hepcidin is released from the the liver in the presence of IL-6 leading to an inflammatory process that causes increased uptake and retention of iron within the macrophages as ferritin...interferon γ promotes iron uptake by macrophages and inhibits EPO production, TNF α increases RBC degradation, and hepcidin block ferroportin from releasing iron for re-use.
anemia of chronic disease (ACD)
What is the net result of the combined inflammatory processes involved with anemia of chronic disease (ACD)?
- decreased iron availability in BM leads to reduced RBCs
- reduced RBC survival
What are the underlying causes of anemia of chronic disease (ACD)? (table)
What are the therapeutic options for the tx of pts with ACD?
- EPO is considered in pts with CA undergoing active chemo, chronic kidney dz, and HIV/myelosuppressive SE of therapy
This reason for normocytic anemia is generally clinically evident, MAY be masked in a hospitalized pt with an atypical site of involvement, and CBCs are generally not accurate in pts who are in the midst of treatment with IV fluid and blood products.
acute blood loss
Normocytic anemia noted in most pts with prolonged renal failure d/t a slow reduction in erythropoietin production leading to decreased BM production of RBCs.
- renal failure associated anemia
- **most nephrologists advocate routine, chronic synthetic EPO agents in pts with renal failure associated anemia**
What is the goal of using routine, chronic synthetic EPO agents in the treatment of pts with renal failure associated anemia?
Normocytic anemia d/t a hypocellular BM form of pancytopenia with primary and secondary types.
What is thought to be the mechanism behind the primary and secondary forms of aplastic (normocytic) anemia?
- primary: may be immune-mediated
- secondary: inherited (Fanconi's)/ acquired (chemo/radiation, other drugs, infections, PNH)
What are the BM disorders that cause pancytopenia? (there are 6)
- aplastic anemia
- acute leukemia
- infiltrative disease (lymphoma, myeloma, carcinoma, hairy cell leukemia)
- megaloblastic anemia
What are the non BM disorders that cause pancytopenia?
- systemic lupus erythematosus (SLE)
- infection (TB, AIDs, leishmaniasis, brucellosis)
What are the characteristic physical anomalies in Fanconi's anemia from most frequent to least? (there are 10)
- skin pigment changes
- short stature
- upper limb abnormalities (thumbs, hands, radii)
- hypogonadal & genital changes (mostly male)
- other skeletal (head, face, neck, spine)
- eyes/lids/epicanthic fold abnormalities
- renal malformations
- ear abnormalities (external & internal) deafness
- hip, leg, foot, toe abnormalities
- GI and cardiopulm malformations
What are the major causes of acquired aplastic anemia? (table)
Clinical features of this normocytic anemia include bimodal distribution (15-25 and again after 60), bleeding, and infections.
How is the diagnosis of aplastic (normocytic) anemia made?
How is aplastic (normocytic) anemia treated according to age?
- ≤20 yo: BM transplant
- >45 yo: immunosuppression (given the increased problem with graft-vs-host dz)
- **overall tx is individualized**
What is the prognosis for aplastic (normocytic) anemia according to age?
- <50 yo: ~70% 5 yr survival
- >70 yo: ~50% 5 yr survival
- pts with severe unresponsive dz have a 1yr untreated mortality rate of 70%
An acquired hemolytic (normocytic) anemia d/t a mutation defect in the PIGA gene which renders RBCs susceptible to complement mediated hemolysis (unregulated complement response d/t CD55 & 59 deficiency), and manifests with episodic hemolysis.
- paroxysmal nocturnal hemoglobinuria (PNH)
- **may progress to aplastic anemia if further stem cell injury occurs beyond the PIGA mutation**
What are the helpful tips for diagnosing normocytic anemia d/t paroxysmal nocturnal hemoglobinuria (PNH)? (there are 4)
- episodic hemoglobinuria
- hemolytic anemia
- thrombosis is common (hypercoagulable state)
- acquired hemolysis
Clinical manifestations of this condition causing normocytic anemia include dark cola colored urine (mostly reported with 1st morning void), can show hemosiderin in the urine sediment (accumulates in kidneys which shows up on MRI/CT scans), hallmark manifestations of intravascular hemolysis, and being prone to thrombosis which usually occurs in unusual veins (hepatic, abdominal, cerebral, subdermal veins).
paroxysmal nocturnal hemoglobinuria (PNH)
What are the hallmarks of intravascular hemolysis from paroxsymal nocturnal hemoglobinuria (PNH)? (there are 3)
- elevated reticulocytes and serum LDH
- low serum haptoglobin
- absence of hepatosplenomegaly
What is the treatment for paroxysmal nocturnal hemoglobinuria (PNH)? (there are 6)
- eculizumab (anti-complement targeting CD5)
- life long therapy indicated since tx does not alter the underlying defect
- iron monitoring (supplement as necessary)
- BM transplant (pts who convert to MDS or leukemia)
- bottom line: REFER!!
Type of hemolytic (normocytic) anemia caused by a defect in the RBC itself (hereditary) causing membrane defects leading to conditions such as spherocytosis, PNH, or glycolytic defects, oxidation vulnerability (G6PD, methemoglobin), or hemoglobinopathies like sickle cell and severe thalassemia.
intrinsic hemolytic anemia
Type of hemolytic (normocytic) anemia caused by an external factor to the RBC from sources like the immune system (autoimmune, lymphoproliferative, drug toxicity), microangiopathic conditions (TTP, HUS, valve hemolysis, vasculitis), infection (plasmodium, clostridium, borrelia), and burns and hypersplenism.
extrinsic hemolytic anemia
What is the most common site of hemolysis causing hemolytic (normocytic) anemia?
What are the lab values that help diagnose hemolytic (normocytic) anemia? (there are 5)
- decreased haptoglobin (binds with free hgb)
- increased indirect bilirubin (intravascular hemolysis)
- hemoglobinuria (telltale sign of intravascular hemolysis)
- increased LDH (released from lysed RBCs)
- increased/normal reticulocytes
MC cause of hemolytic (normocytic) anemia d/t RBC membrane defect in spectrin, which leads to a chronic hemolytic anemia.
hereditary spherocytosis (autosomal dominant)
What are the clinical findings associated with hereditary spherocytosis? (there are 7)
- normocytic anemia (may be mild/severe)
- bilirubin gallstone formation
- HCT may be normal
- reticulocytosis (ALWAYS PRESENT)
- increased indirect (unconjugated) bilirubin
What are the diagnostic labs used to identify hereditary spherocytosis (normocytic anemia)?
- microcytosis & increased MCHC
- NEG Coombs test
- osmotic fragility test (abnl test indicates an increased presence of spherocytes; may be falsely neg in pts with milder forms if HS)
What is the treatment for hereditary spherocytosis?
- folic acid 1 mg/d
- **REFER THEM!**
The MC enzymatic disorder of RBCs causing intrinsic hemolytic anemia d/t a hereditary (x-linked) enzyme defect resulting in hemolysis with oxidative stress (cell damage that occurs from radical O2 species).
- G6PD deficiency
- **do not equate oxidative stress ONLY with hypoxemia or low O2, it is actually most frequently induced by meds and infection**
This enzyme acts to keep glutathione in a reduced state which protects hemoglobin from oxidative denaturation...deficiency can present with variable clinical manifestations since its activity declines in individual RBCs as they age (older cell populations are more likely affected) therefore making laboratory measurements falsely normal if done immediately after a hemolytic episode.
Hemolytic (normocytic) anemia caused by oxidized hemoglobin that forms bonds and precipitants which cause membrane damage in RBCs that can sometimes be seen on a peripheral smear.
Heinz body hemolytic anemia
What are the drugs that can induce oxidative stress which is a bad thing for pts with G6PD deficiency?
- antimalarials (primaquine, pamaquine, dapsone)
- sulfonamides (sulfamethoxazole)
- miscellaneous (vitamin K, doxorubicin, methylene blue, nalidixic acid, furazolidone, niridazole, phenazopyridine)
What is the best treatment for pts with G6PD deficiency?
avoid oxidative stress!
Autosomal recessive disorder characterized by a point mutation in the beta-globin chain gene resulting in the formation of Hgb S, occurs primarily in Africans but can occur in other groups as well esp in the malaria belt.
sickle cell anemia (normocytic)
What are the clinical features of sickle cell disease?
- episodic clinical course (crises)
- onset is during the first year of life
- acute chest syndrome (fever, chest pain, hypoxemia & pulm infiltrates)
What are the lab findings in a pt with sickle cell disease?
- chronic hemolytic anemia (normocyctic anemia)
- howell-jolly bodies & target cells
- chronic reticulocytes (elevates with crises)
How is sickle cell anemia (normocytic) diagnosed?
- sickled cells on peripheral smear
- howell jolly bodies/target cells (hallmark of hyposplenism)
- electrophoresis (confirmation)
What is the treatment for sickle cell anemia (normocytic)?
- supportive! (IVF, O2, analgesia)
- hydroxyurea (may increase hgb F production)
- transfusion therapy (chronic for pts at high risk for vaso-occlusive complications/exchange transfusion)
Extrinsic hemolytic anemia d/t acquired autoantibodies to an RBC membrane component with severity being determined by the amount/type of antibody, avidity of the antibody, and the antibody's ability to fix complement.
autoimmune hemolytic anemia (AIHA)-->normocytic
The most common autoimmune hemolytic anemia (normocytic) d/t IgG antibodies that react at normal body temp and usually results in extravascular hemolysis (spleen).
Type of autoimmune hemolytic anemia (normocytic) d/t IgM that only reacts at reduced body temps, is associated with increased complement activity and intravascular hemolysis (liver).
What is the etiology of WARM autoimmune hemolytic anemia (AIHA)? (there are 5)
- idiopathic in most cases
- lymphomas (esp NHL)
- SLE & other autoimmune disease
- drugs (α-methyldopa, PCN, quinidine)
- post-viral infections
What is the etiology of COLD autoimmune hemolytic anemia (AIHA)? (there are 2)
- lymphoproliferative disease (NHL)
- infections (mycoplasma pneumoniae, mono-EBV)
Clinical features of this hemolytic anemia (normocytic) include an episodic course usually associated with physiologic stress, a rapid onset of anemia that may be life threatening, pts c/o fatigue, angina, dyspnea, palpitations (some report pain with eating/drinking something cold).
autoimmune hemolytic anemia (AIHA)-->normocytic
What labs are associated with identifying autoimmune hemolytic anemia (AIHA)?
- significant spherocytosis on smear
- positive direct Coombs test +/- indirect Coombs test (pos indirect=large amounts of autoantibodies present)
What is the treatment for autoimmune hemolytic anemia (AIHA)? (there are 4)
- REFER to hematologist for confirmation/subsequent care
- immunosuppression (steroids)
- complicated transfusions
- splenectomy for WARM AIHA
Type of hemolytic anemia (normocytic) that is characterizerd by intravascular hemolysis due to RBC fragmentation (traumatic destruction), schistocytosis & thrombocytopenia.
microangiopathic hemolytic anemia (MAHA)
What are the infectious agents that often act as facilitating agents to other hemolytic processes causing hemolytic anemias?
- parvovirus in hereditary spherocytosis pt leads to "oxidative" stress
- acute strep pneumoniae in sickle cell pt sets off crisis
- mycoplasma infection triggers IgM COLD AIHA
- plasmodium spp replication also triggers hemolysis
Anemia with MCV 80-100, high serum bilirubin and LDH, low serum haptoglobin and increased osmotic fragility can be due to what conditions?
- RBC protein defects
Anemia with MCV 80-100, high serum bilirubin and LDH, low serum haptoglobin and decreased G6PD activity can be due to what condition?
Anemia with MCV 80-100, high serum bilirubin and LDH, low serum haptoglobin and positive sickle cell screen with confirmatory electrophoresis is d/t what condition?
sickle cell anemia
Anemia with MCV 80-100, high serum bilirubin and LDH, low serum haptoglobin and abnormal coagulation tests can be d/t what condition?
Anemia with MCV 80-100, high serum bilirubin and LDH, low serum haptoglobin and a positive direct antiglobulin test (DAT) can be d/t what condition?
What situations determine whether a blood transfusion has a high or low benefit for a patient?
- high: Hgb <6 g/dl
- low: Hgb >10 g/dl
What treatment is considered as a "last resort" for chronic anemia?
What is the most commonly used blood product to raise hematocrit?
How much does a unit of pRBCs increase H&H?
- HCT: increase of 3-4 % with each unit
- HGB: increase of 1 g/dl with each unit
What are the indications for using leukocyte reduced ("leukopore") filtered RBCs, which reduces leukoagglutination reactions, platelet alloimmunization, transfusion related acute lung injury, and CMV exposure? (there are 4)
- previous transfusion reactions
- undergoing cardiovascular surgery
- potential transplant
- chronically transfused pts
What is the most common utilization of autologous blood products? What are the benefits to using autologous blood? How long can it be stored?
- ELECTIVE surgical procedures
- ONLY way to almost completely eliminate infectious risks
- can be stored up to 35 days
What PRBC product is reserved for rare blood types who may be unable to find suitable blood for transfusion, is expensive and cannot be stored indefinitely (up to 3 yrs), and has all WBCs and plasma components removed?
What PRBC product is reserved for immunocompromised pts at risk for transfusion associated graft vs host disease (GVHD) or for pts who may be transplant candidates in the future?
CMV negative & irradiated PRBCs
What are the indications for using whole blood for a transfusion?
- cardiac surgery
- massive hemorrhage needing more than 10 units in 24 hours
- **must have EXACT blood type match**
Blood product that is usually obtained from a donated unit of whole blood and concentrated to a volume of 50ml, usually cannot be crossmatched (except when collected from a single donor with a specific HLA type).
- platelets (apheresis)
- **1 unit of apheresis platelets="6 pack"/6 units of whole blood derived platelets**
How much does the average platelet transfusion of one "6 pack" increase the platelet count? What should be suspected if the platelet count fails to rise appropriately after transfusion?
- increases by 15,000 to 30,000 in one hour
What are the causes for refractoriness to platelet transfusion? (there are 8)
- sepsis and/or infection
- active bleeding
- ABO mismatch
- hematopoietic cell transplant (autologous/allogenic)
Transfusion product prepared from whole blood by separating and freezing plasma withing 6 hours of phlebotomy, it contains all coag factors with decreased amounts of V and VIII d/t storage, and is primarily indicated to replace depleted coagulation factors in patients with active bleeding or high risk status for bleeding.
fresh frozen plasma (FFP)
Blood product that can be separated and refrozen from thawed FFP, contains nearly all of factor VIII, XIII, vWF, fibrinogen, and fibronectin, and is indicated for the replacement of depleted coag factors, esp in pts with von Willebrand's dz or severe hypofibrinogenemia (ie, DIC).
What testing is part of a type and screen?
- ABO & Rh type of pts RBCs
- antibody screen of pts serum
- negative antibody screen needs no further testing beyond ABO/Rh
What testing is part of a type and cross?
- pts serum is matched with donor RBCs (46-60 mins)
- cross matched for a specific pt and is not useable for any other pt
What blood type is the universal donor and universal recipient for RBCs?
- donor: O neg
- recipient: AB pos
What blood type is the universal donor and universal recipient for plasma products?
Name the "other" RBC antigens that present an increased concern in pts who have had multiple transfusions and are frequently implicated in delayed hemolytic transfusion reactions. (there are 4)
Transfusion reaction that occurs when mismatched ABO/Rh blood is given and most commonly occurs d/t a clerical error...severity depends on the amount transfused with most severe episodes occurring during surgery under general anesthesia.
hemolytic transfusion reaction
What are the classic signs of a hemolytic transfusion reaction? (there are 6)
- subjective pain at infusion site
- **pts under gen anesthesia won't manifest these signs, first sign for them may be oliguria and/or generalized bleeding**
Transfusion reaction that is similar to hemolytic transfusion reaction (HTR) only it is delayed d/t less antigen-antibody burden which results in less of a hemolytic response that may not occur for up to several days after the transfusion ("amnestic response"), after which hemolysis occurs extravascularly (spleen).
delayed hemolytic transfusion reaction
Transfusion reaction induced by the small amount of transfused donor WBCs and cytokines found in PRBC units (most commonly occurs in up to 1% of all PRBC transfusions), usually causes mild fever and chills within 12 hours of transfusion, and in severe cases presents with dyspnea, cough and pulmonary infiltrates...decision to halt transfusion in pts with hematologic malignancy may be complicated since they receive blood nearly everyday.
leukoagglutination reaction (AKA febrile non-hemolytic transfusion reaction)
What are the drugs that leukoagglutination transfusion reaction (febrile non-hemolytic transfusion reaction) may respond to?
What are the transfusion associated infections?
- Hep B
- Hep C
- HTLV (human T-lymphotropic virus)=antibody to human T cell lymphotropic/leukemia virus
What is the most well documented infectious agent that can cause bacterial contamination in a unit of platelets which can in turn cause septic shock, acute DIC, acute kidney injury and/or death from the transfused endotoxin?
yersinia enterocolitica (gram negative)
Complication from blood transfusion that causes noncardiogenic pulmonary edema in susceptible patients (surgical, critically ill)...bad signs include hypoxemia and pulmonary edema which is often following by ARDS within hours of transfusion, treatment is supportive.
transfusion associated lung injury (TRALI)
Type of transfusion that replaces >50% of the pts blood volume in 12-24 hours/ >10 units of PRBCs in 24 hours, and usually requires plasma replacement as well with FFP.
What are the hematologic and metabolic complications that can occur with a massive transfusion? (there are 6)
- dilutional thrombocytopenia
- metabolic acidosis
What are the recommendations for massive transfusion as described by the US Army Institute of Surgical Research data?
- FFP:PRBC ratio of 1:4 or less has mortality of 65%
- FFP:PRBC ratio of 1:1 has mortality of 20%
Which patients in Leukopoor (WBC filtered) blood reserved for in particular?
heme malignant pts
Anuclear cytoplasmic fragments derived from BM megakaryocytes which are produced through stimulation of thrombopoietin.
What is the job of the platelet granules?
- promote plt aggregation & adherence to areas of endothelial damage
- physiological processes beyond our understanding
What is the general mechanism of action of platelet granules?
- ADP is stored in platelets and released on activation
- this ADP reacts with receptors found on plts which causes further activation
- ADP in blood is then converted to adenosine which inhibits further plt activation
How does Plavix (clopidogrel) inhibit platelet activation?
by inhibiting the P2Y12 (ADP) receptor on the platelets
Substance in platelet granules that stimulates activation of new platelets and increases platelet aggregation.
Substance in platelet granules that plays a significant role in blood vessel formation (angiogenesis).
PDGF (platelet derived growth factor)
Fibrinogen receptor considered the final common location for platelet to platelet aggregation...blocking this receptor in the setting of acute coronary syndromes provides an anticoagulant effect.
GP IIB/IIIA receptor
What are the GP IIB/IIIA receptor inhibitors used as anticoagulation therapy for pts with acuste coronary syndromes?
- abciximab (reopro)
- tirofibran (aggrastat)
- eptifibatide (integrilin)
What are the vitamin K dependent factors?
II, VII, IX, X
Naturally occurring coagulation inhibitors produced in the liver.
- Protein C & S
- **transient hypercoagulability occurs with initiation of coumadin in protein C & S deficiency pts so they need "overlap" with heparin**
What are the 3 main stages of coagulation?
- 1: extrinsic/intrinsic pathways form prothrombinase (V)
- 2: prothrombinase (V) converted prothrombin (X) into thrombin (III)
- 3: thrombin converts fibrinogen (soluble) into fibrin (insoluble), forming the threads of the clot
What are the coagulation factors that make up the intrinsic pathway of the coagulation cascade and what lab study screens these?
- I, II, V, VIII, IX, X, XI, XII
What are the coagulation factors that make up the extrinsic pathway of the coagulation cascade and what lab study screens these?
View of the coagulation cascade that states it is a combination of intrinsic and extrinsic pathways that converges into the "common pathway" with factor X activation. The ultimate result is fibrin formation..."intrinsic" pathway is invalidated in vivo by lack of clinically significant bleeding in pts deficient in factor XII. Thrombin is physiologically active and considered to be as vital as the formation of fibrin during clotting since it converts fibrinogen to an active form that assembles into fibrin. Factor XIII (stabilizes fibrin within a clot) is external to this view.
View of the coagulation cascade that involves tissue factor (thromboplastin), a transmembrane glycoprotein on most cells including vascular endothelial cells, being released at the site of injury. TF then activates factor X directly and indirectly (through factor IX) leading to fibrin formation. Both direct and indirect stimulation of factor X are needed due to counter-regulatory mechanisms (activated factor X releases tissue factor pathway inhibitor (TFPI) which inhibits TF-VIIa complex; indirect pathway appears to continue to stimulate clotting via thrombin and factor XI).
What is the modified view of the coagulation cascade as it relates to hemophilia?
indirect pathway accounts for why hemophiliacs bleed since they can't "fine tune" the coagulation response to vascular injury
What is the deficiency involved in hemophilia A?
factor VIII (fibrin stabilizing factor) deficiency
What is the deficiency involved in hemophilia B?
factor IX (christmas factor/disease) deficiency
Coagulation factor that is activated to form fibrin (factor I), is sometimes considered independently given the strong association with severe bleeding complications when depleted, esp in the context of DIC.
Provides the surface to which clot adheres, and produces the majority of von Willebrand's factor (binds to and stabilizes factor VIII & mediates plt adhesion).
blood vessel endothelium
Deficiency of vWF can be both a _____ and _____ disorder.
- functional platelet
What must be present for normal function of most coagulation factors?
adequate calcium (factor IV)
Normal circulating plasma protease inhibitor of mild potency, inhibits thrombin and factor Xa to prevent excessive thrombosis, heparin binds to it causing conformational change and subsequent increased inhibition of thrombin and factor Xa.
Measure of the "extrinsic" pathway by adding commercial thromboplastin to plasma and waiting for fibrin formation, primarily detects deficiencies in factors II, V, VII, X.
prothrombin time (PT)
What is the the normal value for PT?
Measure of the intrinsic pathway by artificial stimulation of factor XII and XI, primarily detects deficiencies in XII, XI, IX, VIII, and X.
partial thromboplastin time (PTT)
What is the normal value for PTT?
What is the calculation that allows accurate comparison of PT between labs that may have different thromboplastin and/or other variables? What is the normal value?
What can cause a falsely low platelet count result? What is the normal value for platelets?
- "clumping" mediated by EDTA sensitivity
- nl value=100K to 450K
This test is performed to determine a possible coagulation factor deficiency or the presence of an inhibitor (antibody) by adding abnl pt serum to know nl plasma.
mixing study (1:1)
If the PT/PTT "corrects" during a mixing study there is a ______. If the PT/PTT does not "correct" there is likely an ______.
- factor deficiency
- inhibitor (lupus anticoagulant is the "classic" inhibitor)
Considered a measure of platelet function by literally determining the time it takes for a pt to stop bleeding after a "standardized" cut, which is difficult to perform consistently and reliably.
Bleeding disorder usually associated with small vessel (capillary) bleeding, causing "oozing" as opposed to "gushing" with bleeding typically occuring on the mucous membranes of the nose, mouth, and GI tract, and is typically not severe.
- platelet ("plug") problem
- **not severe until plt count is <10K**
Bleeding disorder more commonly associated with large vessel bleeding with typical manifestations of hemarthrosis, large hematomas, extensive ecchymosis, and excessive bleeding with trauma.
coagulation factor ("reinforcement") problem
What is the ddx for a bleeding disorder based on an elevated PTT result? (there are 5)
- von Willebrand's disease
- hemophilia A & B
- drug effects (heparin)
- factor deficiency other than hemophilia
What is the ddx for a bleeding disorder based on an elevated PT (result)? (there are 4)
- drug effects (coumadin)
- nutritional vitamin K deficiency
- liver disease
What is the ddx for a bleeding disorder based on an elevated PT & PTT result? (there are 3)
- excessive heparin
- severe liver disease
What are the QUANTITATIVE ddx for thrombocytopenia (reduced platelets) as identified on a CBC?
- reduced survival: immune thrombocytopenia, heparin induced, TTP/HUS, hypersplenism
- reduced production: BM disorders, infection (sepsis), drugs (chemo)
What are the QUALITATIVE ddx for thrombocytopenia (reduced platelets) as identified on a CBC?
- congenital: von Willebrand's dz (deficiency of factor VIII), bernard-soulier dz (deficiency in platelet glycoproteins Ib, V, and IX), glanzmann's thrombasthenia (plts lack glycoprotein IIb/IIIa)
- acquired: drugs, end-stage renal failure (uremia), myeloproliferative disorders
Most surgeries will be cancelled if the platelet count is ______. Spontaneous or clinical bleeding does not occur until the platelet count is ______.
- **most individuals don't need as many platelets as they have**
What is the most common cause of primary immune thrombocytopenia that usually presents as a chronic problem (>6 months) and is a dx of exclusion?
- idiopathic thrombocytopenic purpura (ITP)
- **acute is mostly seen in children 2-10 yo, chronic mostly seen in adults**
What are the causes for secondary immune thrombocytopenia (can be acute/chronic)?
- autoimmune dz (SLE)
- lymphoproliferative disorders (chronic lymphocytic leukemia)
- other viral infections (Hep C)
- **chronic refers to >6 months**
What are the ONLY 2 criteria required to make a diagnosis of idiopathic thrombocytopenic purpura (ITP)?
- isolated thrombocytopenia
- no clinically apparent associated conditions that may cause it based on hx/PE
What are the clinical features of ITP?
- mild mucosal bleeding (epistaxis, gingival bleed, menorrhagia, easy bruising)
- more severe bleeding in older pts d/t comorbities/HTN
- splenomegaly (uncommon)
- significant isolated thrombocytopenia (plt <50K)
- anemia if bleeding has occurred
What is the order of bleeding as platelet count falls? What can indicate a LOW likelihood of intracranial hemorrhage?
- skin>mucous membranes>viscera
- absence of cutaneous petechia means low likelihood of ICH
When would a BM biopsy be needed for the evaluation of possible idiopathic thrombocytopenic purpura (ITP)?
- older pts (>50-60) to exclude myelodysplastic syndrome (MDS)
- pts who fail to respond to initial therapy
- prior to splenectomy for dx confirmation
How is idiopathic thrombocytopenic purpura treated?
- clinical F/U to watch for bleeding sxs in pts without sxs but with a platelet count <30K
- platelet count <30K with active/significant bleeding: corticosteroids with/without IVIG/anti-Rh (WinRho)
- **response generally observed in 3-5 days**
How are refractory cases of idiopathic thrombocytopenic purpura (ITP) treated?
- monoclonal antibodies (rituximab)
- splenectomy (no response to initial therapy, relapsed dz, or those requiring high doses of steroids; 60% have complete/partial remission after splenectomy)
When is platelet transfused reserved for in treating idiopathic thrombocytopenic purpura?
life threatening hemorrhages
A complication of heparin therapy that usually occurs 5-10 days after heparin exposure, is NOT dose related (can occur with hep-locks, line flushes, heparin coated catheters).
heparin induced thrombocytopenia
What is the pathophysiology for heparin induced thrombocytopenia?
- antibody response to platelet factor 4 (released from plt upon activation) and heparin complex
- heparin-PF4 complex is recognized by IgG which binds to it forming an immune complex
- immune complex binds to platelets
- platelet-immune complex is removed by the RES (spleen)
- positive feedback loop is created when immune complex triggers release of PF4 when it binds platelets (takes out more and more platelets!)
Type of heparin induced thrombocytopenia (HIT) that has no clinical consequence, causes modest thrombocytopenia (~100K), and usually starts within 1-2 days of heparin therapy (count usually returns to normal), and appears to be d/t a direct effect heparin on platelet activation.
mild (type 1) HIT
Type of heparin induced thrombocytopenia (HIT) that occurs 5-10 days after initiation of heparin therapy, is immune mediated (forms antibodies against heparin-PF4 complex) which enhances thrombin generation and subsequent paradoxical thrombosis as well as thrombocytopenia leading to "white clot syndrome" (plt rich arterial thrombosis). Pts with this type are also at risk for both DVT/PE and arterial thrombosis which persists for weeks to months after heparin stimulus is discontinued.
severe (type 2) HIT
What are the indications for suspicion of heparin induced thrombocytopenia that occur within 5-10 days of starting heparin OR in pts on prolonged LMWH therapy? (there are 5)
- onset of otherwise UNEXPLAINED thrombocytopenia
- venous/arterial thrombosis with thrombocytopenia
- PLT count has fallen 50% or more from baseline/prior value
- necrotic skin lesion at heparin injection site
- acute anaphylactoid reaction after IV heparin bolus (fever/chills, HTN, tachycardia, dyspnea, cardiopulmonary arrest)
Although heparin induced thrombocytopenia is usually a CLINICAL diagnosis, what specific tests may be used to identify the condition?
- positive serotonin release assay
- heparin induced platelet aggregation
- ELISA test for PF4 antibody complex
- **very slow turnaround time, may not always be available**
What is the treatment for heparin induced thrombocytopenia?
- STOP THE HEPARIN! (don't forget heparin bonded catheters and heparin flushes, LMWH)
- use alternate anticoagulation like...
- bivalirudin (angiomax)
- fondaparinux (arixtra)
- **do NOT use warfarin as initial tx since it has potential to transiently worsen hypercoagulability, instead use it once the patient has STABILIZED & plt count is ≥150K**
How long should pts with heparin induced thrombocytopenia be anticoagulated for?
- in absence of thrombotic event: 2-3 months
- thrombotic event has occurred: 3-6 months
What is the prognosis for heparin induced thrombocytpenia?
- IgG antibodies generally don't persist so pts may be started on heparin again later (around 100 days later)
- risk for recurrence with short term re exposure (<100 days) is high
- generally its best for these pts to avoid heparin unless absolutely necessary (ie, life saving cardiac surgery)
Acute complex syndromes with vascular endothelial injury leading to widespread thrombi formation in the microvasculature, are closely related to each other but are NOT the same, and dx requires presence of primary features to both microangiopathic hemolytic anemia (MAHA) and thrombocytopenia.
- thrombotic thrombocytopenic purpura (TTP)
- hemolytic uremic syndrome (HUS)
How are TTP and HUS pathophysiologically distinguished from one another?
based on differing response to plasmapheresis
Condition which presents with petechial rash, mucosal bleeding, fever, altered mental status, renal failure and is associated with HIV. Most cases are related to an acquired inhibitor of von Willebrand factor cleaving protease, but it may also occur secondary to drugs, chemo or cancer.
thrombotic thrombocytopenic purpura (TTP)
Plasma enzyme that attaches to endothelial cells when vWF cleaving is required...acquired reduction in vWF cleaving enzyme may be d/t inhibition from IgG antibodies. This reduction can lead to thrombotic thrombocytopenic purpura (TTP).
Condition that presents with petechial rash, HTN, renal failure (MC) that is preceded by gastroenteritis from campylobacter or E coli O157:H7 (children), medication use (cyclosporine, chemo), can only really be treated with supportive care, and is more common in children than adults.
hemolytic uremic syndrome (HUS)
What is the "classic" pentad of symptoms associated with TTP & HUS?
- microangiopathic hemolytic anemia
- renal failure
What 2 symptoms alone should be considered for the diagnosis of TTP & HUS?
- microangiopathic hemolytic anemia (MAHA)
What specific findings are more associated with TTP as compared to HUS? Why?
- neurologic findings
- d/t scattered thrombi formation in the brain and impaired blood flow & O2 delivery OR acute CNS bleeding
What specific findings are more associated with HUS as compared to TTP? Why?
- renal findings
- microvasculature thrombus formation and hemoglobinuria from intravascular hemolysis cause the renal failure
What are the labs used to help identify TTP & HUS? (there are 6)
- thrombocytopenia & MAHA (CBC)
- increased LDH
- reduced haptoglobin
- increased indirect bilirubin
- negative DAT (direct Coombs)
- ADAMTS 13 level
What is the treatment for TTP?
- plasmapheresis (removes vWF and antibodies to ADAMTS 13)
- plasma exchange therapy (continued till plt count normalizes, restores ADAMTS 13 activity)
- immunosuppression (corticosteroids, and/or rituximab/cyclosporine for refractory cases)
What is the treatment for HUS based on pt age?
- children: supportive, no antimotility drugs/abx for known E coli O157:H7 infection
- adults: stop potentially offending drugs, consider plasmapheresis
Acquired qualitative platelet disorder likely related to circulating "toxins" from severe renal failure prior to dialysis initiation.
Qualitative platelet disorder that presents with paradoxical bleeding risk with essential thrombocytosis and polycythemia vera. Adequate number of platelets are present but abnormalities from clonal proliferation leads to abnormal function.
Drug that causes a qualitative platelet disorder by irreversibly binding cyclooxygenase (COX-1) leading to reduced prostaglandin and reduced platelet aggregation.
What are the anti-platelet agents that can cause a qualitative platelet disorder besides aspirin?
- GP IIb/IIIa inhibitors: abciximab (reopro), eptifibatide (integrilin), tirofiban (aggrastat)
- adenosine diphosphate inhibitors: clopidogrel (plavix), ticlodipine (ticlid)