Step Up to Medicine: Chapter 09 Hematologic Diseases and Neoplasms

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What is the diagnostic criteria for MM?

At least 10% abnormal plasma cells in bone marrow PLUS (1) of the below:
1. M-protein in the serum
2. M-protein in the urine
3. Lytic bone lesions (well-defined radioluencies on radiographs) - redominantly found in the skull and axial skeleton

What is NHL?

Occurs by the malignant transformation and growth of B and T cells or their precursors

Splenic sequestration crisis is?

The sudden pooling of blood into the spleen results in rapid development of splenomegaly and hypovolemic shock

- potentially fatal complication of SCD and b-thalassemia) curring more commonly in children because they have intact spleens.

Features of CLL:

1. Asymptomatic - found incidentally on CBC
2. Painless LAD
3. Splenomegaly
4. Frequent respiratoy or skin infections 2/2 immune deficiency
5. More advanced disease: fatigue, weight loss, pallor, skin rashes, easy bruising, bone tenderness and abdonminal pain.

Causes of thrombocytopenia:

1. Decreased production 2/2:
a. Bone marrow failure:
aquired aplastic anemia
congenital (Fanconis anemia)
congenital intrauterine rubella
b. Bone marrow invasion:
tumors, leukemia, fibrosis
c. Bone marrow injury: drugs (ethanol, gold, CA chemo agents, chloramphenicol), chemicals (benzene), radiation, infection

2. Increased destruction
a. Immune: infection, DI, ITP,SLE, HIT type 2, HIV-assocaited thrombocytopenia

b. Nonimmune: disseminated intravascular coagulation dIC, Thombotic thromboy=cytopenic purpura (TTP), HIT type I

3. Sequestration from splenomegaly
4. Dilutional - after transfusions or hemorrhage
5. Pregnancy - usually an incidental finding (especially third trimester) but can also occur in setting of pre-eclampsia or eclampsia (remember HELLP syndrome)

Clinical features of Hemophilia A

1. Hemarthrosis (factor VIII) - KNEES most common site
a. progressive joint destruction can occur 2/2 recurrent hemarthrosis
b. maintaining normal factorVIII levelsby prophylactiv administration of factor VIII concentrate can minimize joint dectruction
c. SYNOVECTOMY (arthroscopic) or radiosynovectoy may be needed if recurrent hemarthrosis occurs despite optimatl medical management

2. Intracranial bleeding
a. second most common cause of death (AIDS due to past history of transfusions)
3. Intramusclar hematomas
4. Retroperitoneal hematomas
5. Hematuria or hemospermia

Sickle Cell Anemia
General characteristics:

1. Autosomal recessive disorder that results when the normal hemoglobin A chain is replaced by the mutant Hb S. Sickle cell disease is caused by inheritance of two Hb S genes where as sickle cell trait is caused by the inheritance of one HbS gene (heterozygous)

What are the three major subtypes with varying severity of vWD:

1. Type 1 (most common)- decreased levels of vWF
2. Type 2 (less common)-exhibits qualitative abnormalities of vWF
3. Type 3 (least common) - absent vWF (severe dz)

Most common critically ill patients (in ICU) usually are diagnosed with >>> however it can occur in healthy patients as well

-can be acute and fatal or more gradual

DIC!

Severity of thrombocytopenia and associated risk

1. Platelet count: > 100,000
2. 20,000-70,000
3. < 20,000
4. < 5,000

1. > 100k: abnormal bleeding (even after trauma or surgery) is usual
2. 20-70K: Increased bleeding hemorrhage during surgery or trauma
3. < 20K: minor spontaneous bleeding: easy bruising, petechiae, epistxis, menorrhagia, bleeding gums
4. < 5K: Major spontaneous bleeding; intracranial bleeding, heavy GI bleeding

Protein C deficiency

-autosomeal dominant inheritence
-inhibitor of factors 5 and 8 thus deficiency leads to unregulated finbrin synthesis

ALMOST ALL PATIENTS HAVE ++++++ EITHER IN SERUM OR URINE IF MULTIPLE MYELOMA IS DIAGNOSIS

M PROTEIN

What are the clinical features of ITP:

1. Petechiae and ecchymoses on the skin
2. Bleeding of the mucous membranes
3. NO splenomegaly

Name one intermediate NHL

Diffuse Large-Cell Lymphoma:
1. B-cell origin
2. Middle-aged and elderly patients
3. Locally invasive; presents as large extranodal mass
4. 80% cure rate with CHOP

What is a MACROCYTIC anemia?

1. MCV > 100
2. Vitamin B12 is involved
a. Cofactor in coversion of homocysteine to methionine
b. cofactor in coversion of methylmalonyl CoA to succinyl CoA
3. Vitamin B12 stores in the liver are plentiful and can be sustained for 3 or more yrs
4. Vitamin B12 is bound to intrinsic factor (produced by gastric parietal cells), so it can be absorbed by the terminal ileum.

What is Sezary syndrome?

NHL involving the skin and bloodstream

What is the therapy for AML?

7 + 3

*Induction therapy
1. 7 days CYATARABINE
2 DAY1-3 WITH DAUNORUBICIN
****WAIT 7 SEVENS DAYS
3. DAY 14 BMBx

IF ANC < 1000 and or platelets <100K --> 5 + 2 which includes
1. 5 days of CYTARABINE
2. DAY 1-2 with DAUNORUBICIN
****WAIT 7 days
3. DAY 12 BMBx

IF STILL blasts after 2nd BMBx post induction and re induction with 5+2, then performthe HiAM treatment

____________

IF ANC > 1000 or PLT > 100K

1. Start CONSOLIDATION therapy which includes: HiDAC + Dasatinib for 21 days
2. Gets three cycles total

What is the prognosis of a patient with SCA? (sickle cell anemia)

Survival correlates with the frequency of vaso-occlusive crisis - the more frequent crisis are associated with a SHORTER LIFESPAN

If there are more than three crises per year, the median age of death is 35 years. Patients with fewer crises per year may live into their 50s. (<3/years = 50YO lifespan)

IN GENERAL, SICKLE CELL DISEASE REDUCES LIFE BY 25-30 YEARS.

How might Hereditary spherocytosis be diagnosed? Treated?

Diagnosed: RBC osmotic fragility to HYPOtonic saline (because it tests ability of RBCS to swell in a graded series of hypotonic solutions and because of their shape, spherocytes tolerate less swelling before they rupture, thus they are OSMOTICALLY FRAGILE and undergo lysis at a HIGHER oncotic pressure.
-INCREASED retic count with elevated MCHC
-Peripheral blood smear would reveal spherocytes
-Direct coombs test result in negative which is helpful to distinguish from AIHA in which spherocytes are also seen

When might platelet transfusions be necessary:

1 unit raises platelet count by 10,000

What is the significance of ordering a SCHILLING TEST?

gives information regarding cause of b12 deficiency
-give an IM dose of unlabeled vitamin b12 to saturte binding sites
-give an oral dose of radioactive b12; measure amount of b12 in urina and plasma to determine how much b12 was absorbed
-repeat the test (oral radioactive b12) with the addition of IF. If malabsorption is the problem then adding IF will not do anything. HOWEVER if pernicious anemia is present, then adding IF will improve the serum vitamin B 12 levels.

What is the first step to perform in an anemic patient:

Assess volume status and hemodynamic stability.
If unstable, transfuse PRBCs before attempting to find the cause of the anemia

How to readily treat CLL with chemotherapy:

No current chemotherapy that can permanently treat CLL the only one we current have "treats the grass" - will continue to grow, then "debulk" by chemo but we never get rid of all the "grass" completely. Then eventally grass grows and needs to be "cut" again.

The type of lymphocyte involved and its level of differentiation determines the course of the disease and its prognosis.

B cell lymphocytes account for __% of all cases; T cell lymphocytes acct for ___% of all causes

=disease starts in the node and then spreads to blood and bone rather than node to node as seen in Hodgkins.

85
15

Treatment of essential thrombocytosis

1. Antiplatelet agents (anagrelide and low dose ASA)
2. Hydroxyurea if severe

BMB will show increase MEGAKARYOCYTES

Staging system used for Hodgkins lymphoma?

Ann Arbor staging system

Stage I: confined to 1 node
Stage 2: involvvement of two or more lymph nodes but confied to same side of diaphragm
Stage 3: Both sides of diaphargm inovlvedl
Stage 4: dissemination of disease to to extralymphatic sites

What are the cell lines of the myeloid class?

RBC, platelets, granulocytes (neutro, eosino, baso)

Intravascular hemolysis v. Extravascular hemolysis (hemolytic transfusion rxns)

1. Intravascular - ACUTE HEMOLYTIC REACTIONS
-very serious and life threatening - caused by ABO mismatched blood transfused into patient.
-fever, chills, n/v, pain in the flanks/back, chest pain, dyspnea
-complications include hypovolemic shock (hypotension.tachycardia), DIC, RF with hemoglobinuria
-management involves stopping the transfusion immediately and aggressively replacing the fluid to avoid shock and renal FAILURE.

2. Extravascular hemolysis (also called delayed hemolytic transfusion reactions)
-extravascular hemolysis is less severe and in most cases is self-limited; it may occur withint 3-4 weeks after a transfusion
-caused by minor RBC antigen --> If patient is Kell antigen-negative and has anti-Kell IgG antibodies from a previous exposure to the antigen, reexposure of her memnory B cells to Kell antigen on RBC cells will result in synthesis of IgG anti-Kell antibodies. These AB coat all of the Kell antigen-positive donor RBCs, which will be removed extravascularly by macrophages in the spleen, liver, and bone marrow.
-FEVER, JAUNDICE, ANEMIA
-Managment - none, good prog

What are the clinical features of vWD

Cutaneous and mucosal bleeding - epistaxis, easy bruising, excessive bleeding from scratches and guts with gingival bleeding.

Menorrhagia that affects more than 50% of women with vWD

GI bleeding possible

What is lymphoma?

cancers of the lymphatic system in which there are two types:

1. Hodgkins Disease
2. NHL

lymphadenopathy is usually the first finding

Myelodysplastic disoders often lead to

ACUTE LEUKEMIA

Why might a prolonged PT in a patient with cirrhosis be a poor prognostic factor?

Because only in SEVERE LIVER DISEASE does the PT become prolonged

What is waldenstrom's macroglobulinemia?

proliferation of plasmacytoid lymphocytes that produce IgM paraprotein which is large and causes hyperviscosity in the blood.
-DIAGNOSIS WHEN IgM > 5G/DL; BENCE JOINES PREOTEINURI IN 10% of cases - but NOT ANY bone lesions so can r/o MM

What is the classification of NHL?

>20 different subtypes of NHL
-the "working classification system" is the most common and classifies accprding to histologic grade: low grade (indolent), intermediate grade, and HIGH grade

Teardrops on the peripheral smear with bone marrow aspirates showing marrow fibrosis that if severe enough causes a dry tap.

Agnogenic myeloid metaplasia with myelofibrosis

What is the clinical feature of Hodgkins disease:

1. Most common symptom is a painless LAD
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, pruritis and cough

What is the treatment for SCA?

1. Advise the patient to avoid high altitudes (low o2 tension can precipitate crisis)
2. Maintian fluid intake (dehydration can precipitate crisis)
3. Treat infecions PROMPTLY (infection/fever precipitates crisis)

1. Early vaccination for S. pneumo; H. influ; Pneumovax, Neisseria meningitis
2. Prophylactic penicillin for children until 6YO-start at 4 months
3. Folic acid supplements (due to chronic hemolysis)
5. Management of painful crisis
-hydrations
-morphine for pain
-keep patient warm
-supplemental O2
6. HYDROXYUREA-enhanves HbF levels which interferes witht he sickling processing and results in reduced incidence of painful crisis and accelerates healing of leg ulcers and may reduce recurrence.
7. Blood transfusion - NOT USED UNLESS NECESSARY!! Based on clinical condition and NOT the Hb levels.
-acute chest syndrome
-stroke
-priapism
8. BMT-this has been performed successfully to treat SCA but is not routinely performed due to matched donor avilablilty and risk of copmlications. It may be more cost-effective in the long run that conservative therapy.

Signs of aplastic anemia

1. Fatigue and SOB
2. signs and symptos of thombocytopenia (petechieac, easy bruising
3. Inreased incidence of infections due to neutropenia
4 Can transform into acute leukemia

Causes of spherocytosis include:

1. Hereditary spherocytosis
2. G6PD deficiency
3. ABO incompatibility (but not Rh incompatibility)
4. Hyperthemia
5. AIHA (autoIMMUNE hemolytic anemia)

How is heparin administered?

Two ways:
1. Standard heparin
2. LMWH

What makes HbS differ from HbA?

The substiution of an uncharged (neutral) valine for a negatively charged glutamic acid at the 6th position of the B chain yeilds a newly POLAR molecule that has a changed structure after the initial binding and release of O2.

Clinical features of Vitamin k deficient coagulopathy:

1. First finding is a prologed PT
2. PTT will begin to diminish as other clotting factors decrease

Fresh frozen plasma (FFP) is used for?

1. Contains all of the clotting factors
2. Contains no RBCs/WBC/platelets
3. Given in patients for high PT/PTT, coagulopathy, and deficiency of clotting factors - FFP can be administered if you cannot wait for Vitamin K to take effect, or if pateint has liver failure (in which cause VK will not work)
4. Follow up PT and PTT to assess response

Warfarin

a. MOA
b. Indication for use
c. Administration

a. MOA- a vitamin K antagonist - leads to a decrease in vitamin K -dependent clotting factors 2, 7, 9, 10 and protein C and S. Causes prolongation of PT (and increases INR).

** it takes 4-5 days for the anticoagulant effect to begin therefore start heparin as well if the goal is acute anticoagulation because heparin has an immediate effect. Once warfarin is therapeuic by checling INR, then stop the heparin and continue warfarin for as long as necessary.

b. same as heparin but used for LT anticoagulation
c. administered orally - must give heparin first as soon as pTT is therapeutic, inititate warfarin. Continue heparin for at least 4 days after starting warfarin. Once INR becomes therapeutic, stop heparin. THe level of INR in most causes is therapeutic from 2-3

Hemophilia A

XLINKED RECESSIVE
-affects male patients primarily
-caused by deficiency or defect of factor 8 coag protein
-bleeding tendency is related to factor VIII activity

If rapid reversal of acute bleeding from warfarin is indicated, administer?

FFP

What are the clinical features associated with thrombocytopenia?

1. Cutaneous bleeding; petechiae (most common in dependent areas), eccymoses 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. ICH and heavy GI bleeding can be life threatening and occur when platelets are SEVERELY LOW
5. Unlike coagulation disorder (eg hemophilia) heavy bleeding into tissues and joints (hemarthrosis, hematomas) is not seen in thrombocytopenia!!

How can hemolytic anemias be classified?

1. Hemolytic anemia due to external factors to RBC defects (aquired)
-immune hemolysis
-mechanical hemolysis
-medications, burns, toxins
2. Hemolysis due to intrinsic RBC defects - most cases are inherited
-hemoglobin abnormality (SCA), hemoglobin C disease, thalassemia
-membrane defects: hereditary spherocytosis; paroxysmal ND (PND)
-enzyme defects: G6PD, PK deficiency
3. Hemolytic anemia INTRAVASCULAR -- within circulation
4. Hemolytic anemia EXTRAVASCULAR--within the RES, primarily the spleen but can include the lymph notes, bone marrow

What is the treatment regimen for ACUTE LEUKS

AML v. ALL?

1. Treatment of emergenies
a. Blood cultures and AB if infectious
b. Blood transusions for anemia anad platelet transfusion for bleeding. If needed
2. Aggressive combo chemo in HIGH doses for several weeks to obtain remission (absent leukemic cells in bone marrow). One remission occurs, maintenance therapy is used for months to years to prevent recurrance

3. ALL - more than 75% children with it achieve complete remission. WHen occur (relapse) usually response to treatment with aggressive therapy adding 15 years to life. Up to 50% of all ALL patients are cured

4. AML: more difficult to treat and doesnt response well to chemotherapy Survival rates are considerably lower dspite intenive treatment. Bone marrow transplant gives the best chance of remission

5. BMT

B-Thalassemia v. A-Thalassemia

B-thal: B production is deficient but synthesis of alpha is unaffected. Excess a-chain bind to and DAMAGE the RBC membrane. Severity depends upon quantitiative amt of mutation

A-thal: there is a decrease in alpha chains which are a component of ALL tpyes of hemoglobin. The b-globin chains form tetramers which are abnormal hemoglobins. The severity depends on th number of gene loci that are deleted/mutated - it ranges from an aymptomatic carrier state to prenatal death

Causes of DIC:

1. Infection (gram neg sepsis most common like N. Meningitis)
2. Obstetrial complication
a. placenta and uterus have increased TFactor
b. amniotic fluid emboli
c. retained dead fetus
d. abruptio placenta
3. Major tissue injury - trauma , major surgery, burns, fractures
4. Malignancy - lungs, pancreas, prostate, GI tract, acute promeylocytic leukemia
5. Shock, circulatory collapse
6. Snake venum (rattlesnakes

Leukemoid reaction versus CML leukemoid reaction:

1. Usually no hepatosplenomegaly
2. Increased leukocyte alkaline phosphatase
3. History of a precipitating event (eg infection - CML
-opposite to the above findings

WHy might coag failure occur in liver?

1. Decreased synthesis of clotting factors
2. Chlestasis leads to decreased vitamin K absorption, which leads to vitamin K deficiency
3. hypersplenism (splenomegaly due to portal hypertension causing thrombocytopenia)

Name 5 causes of Normocytic (MCV 80-99) anemia with a normal to LO reticulocyte index:

1. Bone marrow fibrosis
2. Aplastic anemia
3. Tumor
4. Anemia of chronic disease
5. Renal failure

Name three types of a-thalassemia related disorders

1. Silent carriers
2. A-thalassemia trait (or minor) - mutation/deletion of two alpha loci that is common to african americans
3. HB H disease - mutation/deletion of three alpha loci
-hemolytic anemia, splenomegaly
-significant microcytic, hypochromic anemia
-hemoglobin electrophoresis shows HbH
-treatment is same as for paitnes with B thal major (continuous transfusions)
or possible splenectomy
4. Mutatoin/deletion of all found alpha loci-this is either fatal at birth (*HYDROPS FETALIS) or shortly after

Which lab studies should be ordered if suspected hemolytic anemia?

1. LDH
2. Haptoglobin
3. Bilirubin

Sideroblastic anemia usually manifests as a ______/_______ anemia simulating iron-def anemia. Only different is that iron studies will show high serum iron levels and low TIBC. In patients with an identifiably cause of vitamin b6 deficiency like _____ or _____, the administration of pyridoxine can easily correct the problem.

hypochromic, normocytic
drugs or alcohol (isonized)

What makes factor 8 unit (clotting factor)

Has two portions:
1. The coagulant portion (factor 8 coagulant protein) and an antigenic portion (factor VIII antigenic protein). The latter is synonymous with vWF

Under decreased O2 conditions, (acidosis, hypoxia, changes in termparture, dehydration and infection) the Hb molecules polymerize, causing the RBCs to sickle. How do sickled cells affect the vessels?

They cause obstruction leading to ischemia of the small vessels

Diagnosis of Hodgkins lymphoma

1. Lymph node biopsy: REED STERNBERG CELLS is required to make a diagnosis
a. Neoplastic, large cell with two or more nuclei "owl eyes"
b. B-cell phenotype
c. reed sternburg cells seen in other neoplasma

2. INflammatory cell infiltrates which distinguishes it from NHL because these cells present are reactive to the RS cells. These include plasma cells, eosinophils, fibroblasts and T and B cells

3. CXR and CT scan of the chest and abdomen to detect lymph node involvment
4. Bone marrow biopsy - to evaluate bone marrow involvement
5. Laboratory findings - leukocytosis, eosinophilia; level of ESR elevation sometimes corresponds with disease activity

In elderly patients with iron deficiency anemia (normocytic with low reticulocyte) - what must be RULED OUT

Colon cancer

What is the treatment for DIC

1. management of condition that caused DIC (infection or obstetrictic or trauma or shock or snake venom)
2. supportive: FFP replaces clotting factors; platelet transfusions; cryo replaces clotting factors and fibrinogen; low dose heparin (IV or SC) inhibits clotting and can prevent consumption of clotting factors.
3. admin O@ and IV fluids, maintain BP and renal perfusion

How is PNH diagnosed?

Ham's test: the patients cells are incubated in acidified serum, triggering the alternative complement pathway,, resulting in lysis of PNH cells but not normal cells

Sugar water test: patients serum mixed in sucrose. In PNH, hemolysis ensues

FLOW cytometry: anchored surface protens CD55 and CD59 are much more sensitive and specific for PNH

Chronic Lymphocytic Leukemia

Most common leukemia that occurs after age 50
-most patients are > 60YO
-most common in Western world
-unknown cause
-Monoclonal proliferation of lymphocytes that are morphologically mature but functionally defective - they do not act as functional plasma cells and produce NO antibodies

What is essential thrombocytosis?

Platelets > 600,000
-reactive (due to infection/inflammation, bleeding) and other myeloproliferative dsordes MUST BE EXCLUDED
-manifested by THROMBOSIS (CVA) or by bleeding due to defective platelet function
-LOW MORTALITY but high morbidity

What is sickle cell trait?

1 out of 12 people of african decent carry the sickle cell trait; they are heterogenous. This also appears in ITALIANS, GREEKS, SAUDI ARABIANS

-patients with SCTrait are not anemic and have a NORMAL LIFE EXPECTANCY!

Aspiraginase adminstrations should always be followed with a check for?

FIBRINOGEN and AMYLASE

How does sickle cell disease affect the organs below:
1. Blood
2. Heart
3. CNS
4. GI
5. Bones
6. Lungs
7. Kidneys
8. Eyes
9. Genitalia

1. Blood - chronic HA, aplastic crisis
2. high output CF due to anemia
3. stroke
4. gallbladder disease (stones), splenic infarctions, abdominal crisis
5. painful crisis, osteomylitis, ascascular necrosis
6. Infections, acute chest syndrome
7. hematuria, papillary necrosis, renal failure
8. proliferative retinopathy, retinal infarcts
9. priapism

Protein S deficiency

1. Cofactor to protein C so a def leads to decreased protein C activity

OTHER lab tests indicative of MMyeloms

-Hypercalcemia
-elevated total protein in the serum due to paraproteins in blood *hyperglobulinemia
-Peripheral blood smear shows reuloux formation which resembles a stack of poker chips
-hyperglobulinemia causes the RBCs to stick together
-Urine will be elevated with BENCE JONES PROTEINS

What is the diagnosis of ITP? How do you make it? How is it treated?

1. Platelet count < 20K; remainder of the blood count is normal (unless significant bleeding has occurred in which case the HB/Hct is decreated and the reticulocyte count is increased
2. Peripheral smear shows decreased platelets
3. Bone marrow aspiration shows INCREASED MEGAKARYOCYTES
4. There is an increased amount of platelet associated IgG

Treatment: Adrenal corticosteroids (cortisol) +IVIg that saturates the reticuloendothelial system binding sites for platelet bound self immunoglobulin so thre is less platelet uptake and destruction by the spleen + splenectomy + platelet transfusions for life-threatening and serious hemorrhagic episodes.

Aplastic anemia

1. Bone marrow failure leading to pancytopenia (anemia, neutropenia, thrombocytopenia)
a. Causes: IDOPATHIC - marjoity of cases
-radiation exposure
-viral infections (Human parvovirus, hepatitis C, hepatitis B, Epsetin Barr Virus (EBV), CMV, herpes zoster, HIV
-Chemicals - benzene/insectisides

Standard v. LMWH

1. STD Heparin
-therapeutic dose is usually given IV, intiated with a bolus of 70 to 80 U'kg and followed by continuous IV infusion (15-18 U/kg/hr infusion). Theraputic PTT is usually between 60-90 seconds. But this varies dependng on situation
-prophylactive dose is given subcutaneously-low dose hepatin (5000U SC every 12 hours). PTT monitoringis not necessary for SC dosing

2. LMWH
-theraputic dose (give as a weight adjusted dose)
-prophylactic dose (varies dependingon type of produce)

What are the clinical findings in someone with a coagulopathy 2/2 severe LIVER disease?

-abnormal bleeding- GI is the most common primarily due to varices 2/2 portal hypertension but exacerbated by coagulopathy.
-prolonged PT and pTT especially PT

Reticulocyte index is important because:

1. Initial test to evaluate anemia - indicates whether effective erythropoiesis is occuring in the bone marrow. Effective erythropoiesis is dependent on adequate raw materials (iron, vitamin B12, folate) in bone marrow, absense of intrinsic bone marrow disease (eg asplastic anemia), adequate EPO from kidney, and survival of reticulocytes (no premature destruction before leaving the bone marrow)

Clinical features of inherited hypercoag states

1. Venous thromboembolism (DVT, and PE) are teh most comon. Hypercoaguabile stats are not fiagnosed until the patient has had sever episodes.
2. Suspect an inherited hypercoag state if one or more of the following:
a. The patient has a family history of DVT, PE, thrombotic events
b. the patient has recurrent episodes of DVT, PE or thrombotic events
c. frist thrombotic even efore age 40
d. patient experiences thombosis in usual sites (mesentary, inferior VC, renal veins, verebral veins

What are the phases of MYELOID CELL GROWTH

1. Myeloblast
2. Promyelocyte
3. Myelocyte
4. Metamyelocyte
5. Bands
6. Segmented neutrophils

How does leukemia differ from lymphoma?

Leukemia is characterized by neoplastic proliferation of abnormal WBCS in which accumulate and interfere with the production of normal WBCs as well as the production of RBC and plts resulting in both anemia and thrombocytopenia.

Two classes:
1. The type of WBC affected:
a. Granulocytes/monocytes are affected, myelogenous leukemia present
b. Lymphocytes are affected, then lymphocytic leukemia is present
2. Maturity of cells affected and the rapidity of disease progression
a. acute is rapid and affects immature cells and so immature cells proliferate before having matured.
b. chronic leuk progresses slow and affects mature cells

What are the two varients of G6PD deficiency

Mild form is present in 10% of african american men (a-variant)
-in this form, HA are self-limited beacuse they maintly involve only the OLDER RBCs and spares the younger RBCs (the younger RBCs have sufficient G6PD to prevent RBC destruction) and thus the hemolytic episodes are usually trigger by infection or by drugs like (ANTIMALARIALs, SULFUR CONTAINING AB like TMP-SMX)

MORE SEVERE form is present in people of mediterranean descent. In this form, young as well as old RBCs are G6PD deficiencyt and thus severe HA occurs when exposed to FAVA beans
-Rx requires blood transfusions until drug is elimianted from the body

General characteristics of Thalassemia:

1. Inherited microcytic disorder of the RBC
2. Mutated production of alpha OR beta-globin chain
3. Classified according to chain deficiency (B thal lacks B, a-thal lacks A)

What are the clinical features of G6PD deficiency?

accumulation of unneurtalized H2O2 which denatures Hb precipitating Heinz body formation within RBCs
-HEINZ bodies attach to RBC membranes, reducing their flexibility and making them prone to sequestration by the spleen
-OFTEN DRUG induced and reports with DARK URINE and JAUNDICE on physical exam!

What is the formula for converting Hb into Hct?

Hb x 3 = Hct (IU PRBCS increased Hb level by 1 point and Hct by 3)

What is the treatment for NHL:
1. Indolent:
2. Intermediate
3. High grade

1. Indolent forms of NHL are not curable but have a 5 year survival rate of 75% thus OBSERVE, chemotherapy and radiation therapy are good options
2. Intermediate and high grade MAY be curable with aggressive treatmanets but if complete remission is not achieved, survival is less than 2 years. Aggressive treatments include: CHOP and radiation therapy
3. Very high dose chemotherapy with bone marrow transplantation is LAST resort

When might it be appropriate to be put on LT therapy of warfarin?

If two or more thromboembolic events have occured

Essential thrombocytosis on peripheral smear:

hypogranular, abnormally shaped platelets

What is polycythemia vera?

Myeloproliferative disorder in which malignant clonal proliferation of hematopoeitc stem cells leads to an excess erythrocyte production

-inc RBC mass occurs independentally of EPO
-median survival with treatment is ~ 9-14 years

What are myelodysplastic syndromes?

class of aquired clonal blood disorders that are characterized by ineffective hematopoiesis with apoptosis of myeloid precursors. This results in pancytopenia despite a normal or hypercellular bone marrow

-occurs more commonly in elderly patients are slightly more commen in men than in women

Heparin

1. Platelet count
2. Bleeding time
3. PT
4. PTT

1. NL or dec
2. normal
3. normla
4. increased

Treatment for ITP

adrenal corticosteroids
IvIg to force out binding sites in spleen (competitive)
splenectomy
platelet transfusion

What are the epidemiological associations with NHL

Burkitts lymphoma in regions of africa
Patients with HIV and HIV associated lymphomas
Adult T cell lymphoma in japan and the carribean

Two types of ACUTE LEUKEMIAS

1. Acute myelogenous leukemia (AML)
-neoplasm of myelogenous progenitor cells
-AML occurs mostly in adults (80% of adult acute leuks)
-risk factors include exposure to radiation, myeloproliferative syndrome, Down's syndrome, and chemotherapy (alkylating agents)

2. Acute lymphocytic leukemia (ALL)
-ALL is a neoplasm of early lymphocytic precursors with histology revealing predomiance of lymphosblasts; MOST COMMON IN CHILDREN UNDER 15 YO IN THE US
-most responsive to therapy
-poor prognostics: age <2YO or >9YO; WBC 10^5/mm^3 and/or CNS involvement
-if bcell phenotpye, LDH increase, or rapid leukemic cell proliferation - increased risk for CNS involvement.

Adverse effects of heparin?

bleeding
heparin-induced thrombocytopenia *HIT-lower incidence with LMWHs
possile osteoporosis - lower incidence with LMWH
-transient alopecia
-rebound hypercoag after removal due to depression of AT3

Thrombotic thrombocytopenic purpura: ((TTP))
Characteristics:
PNEUMONIC:

-disorder of platelet consumption - unknown cause
-hyaline microthombi occluse small vessels and any organ may be involved and cause mechanical damage to RBCs (schistocytes on peripheral smear)
-life threatening emergency that is responsive to therapy - if untreated - death occurs in months.

Pneumonic: FATRN
1-fever
2-anemia (hemolytic) microangiopathic
3-thrombocytopenia (<150K)
4-acute renal failure (mild)
5-neurological changes *AMS

In which platelet disorder are platelets abnormally large on peripheral smears?

Bernard souliers syndrome- d/o off adhesion to subendothelium due to platelets glycoprotein GPIb-IX; low platelets but large

When is heparin indicated for use?

Venous thromboembolism: DVT, PE
Acute coronary syndromes: USA, MI
Low dose standard heparin or LMWH for DVT prophylaxis
Atrial fibrillation in acute setting
After vascular bypass grafting (CABG)

B-thalassemia MINOR diagnosis? Treament?

Dx: Hemoglobin electrophoresis
Rx: Not necessary as patients are not transfusion-depending like BthalMAJOR)

What is autoimmune hemolytic anemia? (AIHA)

Production of autoantibodies to RBC resulting in destruction of RBCs - this type of AB produced is either IgG or IgM and determines the prognosis, site of RBC destruction and response to treatment.

How might hemophilia A be diagnosed?

1. Prolonged PTT
2. Low factor VIII coagulant level and normal levels of vWF
3. Detection of factor VIII inhibitor
a. If normal plasma is mixed with plasma from a hemophilliac patient, PTT will becme normal.
a. IF the PTT fails to normalize, this is diagnostic of the presnese of a factor VIII inhibitor

What is Bernard-Soulier Syndrome?

Autosomal recessive disease
-disorder of the platelets adhesion (to subendothelium)due to deficiency of platelet glycoprotein GPIb-IX
-on peripheral blood smear, platelets are abnormally large
-platelet transfusions are contraindicated

vWD
1. Platelet count
2. Bleeding time
3. PT
4. PTT

1. normal
2. increased
3. normal
4. increased

What is the MOA of Heparin?

1. Potentiates the action of antithrombin to inhibit clotting factors IIa and Xa
2. Prolongs the PTT
3. Half-life of standard heparin is 1 hour. It is longer for low moleculr weight heparins (LMWH) - longer than 2 hours and up to 24 hours depending on the product

Patient: Male with unsuspected hemorrhaging that occurs with a positive family history

Hemophilia A

How is NHL diagnosed?

Lymph node biopsy for definitive diagnosis - any lymph node > 1cm for a period > 4 weeks that cannot be attributed to infection should be biopsied

-CXR
-CT scan (chest abdomen and pelvis) to dettermin the extent of disease spread and patients response to treatment
-serum LDH and B2 microglobulin are indirect indcators of tumor burden
-if ALKphos is elevated, bone or liver involvement is liekly
-if LFTs or bilirubin is elevated, liver invovlvement is likely
-CBC
-Serum electrolytes, RFT
-Bone marrow biopsy

If patient is neutropenic WITH a fever, what is the goal for PLT count? What is the goal for Hb?

Plt goal is >20
Hb > 8

What is the most common type of thalassemia?

B-thalassemia minor (b-thal) is more common than alpha minor but both are mistaken with thalassemia.

TTP
1. Platelet count
2. Bleeding time
3. PT
4. PTT

1. Decreased
2. Increased
3. normal
4. normal

What are the clinical features of DIC?

Bleeding tendency (more common in acute cases)
-superficial hemorrhages
-bleeding from GI tract, urinary tract, gingival or oral mucosa
-oozing from sites of procedures
-incisions

Thrombosis
-occurs most often in chronic cases. ENd organ infarction may develop, all tissues at risk esp CNS and KIDNEY

Low molecule weight heparin (LMWH)

LMWH mostly inhibit factor Xa (equivalent inhibiton of factor Xa as STD heparin)
=less inhibition of factor IIa (thrombin) and platelet aggregation
=they cannot be monitored by PT or PTT because they do not affect either

Fevers, night sweats, anorexia, weight loss, recurrent infections, easy bruising/bleeding, symptoms of anemia, splenomegaly, hepatomegaly, lymphadenopathy

CML

How is iron deficiency anemia treated?

1. Oral iron supplementation (watch for constipation, nausea, dyspepsia)
2. Parenteral iron replacement
a. Iron dextran (IV or IM)
b. Useful in patients with poor absorption or require > O2 than iron oral therapy can provide
3. Blood transfusion is unstable and Hb concentration is < 7

What is the diagnosis of vWD?

-clinical findings and lab information
-prolonged bleed time but normal platelet count (PTT may be prolonged)
-decreased plasma vWF, decreased factor VIII activity
-reduced ristocetin-induced platelet aggregation

While most HIV patients are prohibited from LIVE vaccinations, which vaccination should be administered to HIV + patients with CD4 count > than 200

MMR because is fatal if otherwise untreated

What are AUER RODS and when might these be present?

granules and eosinophilis rods inside malignant cells and are seen in AML but not ALL

Describe how hemolytic anemia presents in a SCA patient?

-jaundice, pallor
-gallstone disease (very common) - pigmented gallstones
-the anemia itself is well compensated and is rarely transfusion dependent
-high-output heart failure may ovver over time (secondary to anemia)-many adults eventually die of CHF
-aplastic crisis: these are provoked by viral infection such as human parvovirus B19, which reduces the ability of the bone marow to compensate. Rx: blood transfusion - the patient recovers in 7-10 days

What is the treatment of HODGKINS lymphoma?

Chemotherapy + radiation therapy to the involved field.

Stage I, II, IIIA can be treated by radiation along
-some will use chemo adjuvant therapy

Stage IIIB or IV require chemo

***chemo+radiation therapy in combination achieve cure rates of over 70% in hodgkins disease

If anemia develops rapidly, what symptoms develop?

If anemia develops gradually?

Rapidly: then symptoms are much more likely to be present bc little time for compensation

Gradually: compensatory mechanisms are able to maintain oxygen delivery and symptoms may be minimal or ABSENT

What is the treatment for PNH?

Glucocorticoids (prendnisone) are the usual initial therapy, but many patients do not respond thus will administer...

BMT!

Diagnosis of myelodysplastic syndrome:

BONE MARROW BIOPSY
-dysplastic marrow cells
-blasts/ringed sideroblasts

CBC WITH PERIPHERAL SMEAR
-normal or elevated MCV
-low retics
-HOWELL JOLLY BODIES with BASOPHILIC STIPPLING and NUCLEATED RBC and HYPOLOBULATED NEUTROPHILIC NUCLEI and LARGE PLATLETS

What is the least aggressive type of leukemia with the highest rate of survivial?

CLL; and most survive longer than those with acute leuks or those with CML. The course is variable but typically follows a prolonged indolent course.

Presense of "smudge cells" in peripheral smear is diagnostic for?

CLL

More than 75% of patients with hemophilia A and 50% of patients with hemophilia B are _____-positive. These values should be decreasing with time 2/2 modern screening of donor blood. (>1985)

HIV-positive

Only instance in which WHOLE BLOOD is used

massive blood loss

What is monoclonal gammopathy of undetermined significance (MGUS)? How does this differ from MM?

Common in the elderly (up to 10% in patients > 75 Yrs of age)
-asymptomatic
-diagnosis: IgG spike < 3.5g; less than 10% plasma cellsin bone marrow; bence jones proteinuria < 1g/24 hours.
-fewer than 20% develops MM in 10-15 years
-no treatment necessary; close observation is suggested

Diagnosis of iron deficiency anemia:

1. Decreased serum ferritin - most reliable test available
2. Increased TOTAL IRON BINDING CAPACITY
3. Elevated transferrin levels
4. Decreased serum IRON
5. Microcytic, hypochromic RBCs on peripheral smear
6. Bone marrow biopsy-GOLD STD
7. Guaiac stool test - if GI bleed is suspected

What are the two forms of ITP?

1. Acute form: seen in children, preceded by a viral infection (in most cases); usually self-limited - 90% resolve spontaneously within 6 months

2. Chronic form: seeen in adults most commonl women between 20-40 YO; spontaneous remissions are rare

Antiphosphoslipid AB syndrome

1. Aquired
2. Presents with arterial or venous thrombi

What is the prognosis of multiple myeloma with treatment? WIthout treatment? 5 year survival rate?

With treatment = 2-4years
Without treatment = 6 months
5 year survival = 10%

What are the clinical features of MM?

1. Bone pain due to osteolytic lesions in the low back or chest (ribs) and jaw (mandible)
2. Pathological fractures
3. Loss of height 2/2 collapse of vertebrae

Anemia (normocytic normochromic)-present in most patients due to bone marrow infiltration adn renal failure

Renal failure - mainly due to:
1. Myeloma nephrosis = immunoglobulin precipitation in renal tubules leads to tubular casts of Bence Johnees protein and hypercalcemia also plays a role in renal dcompensation

Recurrent infections - 2/2 deprivation of normal Ig; therfore hemoral immunity is affected
-MOST COMMON CAUSE OF DEATH - UP TO 70% OF PATIENTS DIE OF INFECTION (LUNG OR URINARY TRACT IS THE MOST COMMON)

What is the treatment of AIHA?

1. No treatment necessary in either type of AIHA because the hemolysis is MILD. If it is more severe, the erapeutic approach depends upon the typ of autoantibody causing it.
-WARM AIHA: glucocorticoids are the mainstay of therapy.
-splenectomy - use for patienst whose condition does not responds to glucocorticoids
-immunosuppression (AZA/cyclophosphamide.
-RBC transfusions
-folic acid supplementation
-COLD AIHA: avoiding cold exposure prevents hemolysis and anemia
-RBC transfusions if absolutely necessary
-various chemotherapeutic agents
-steroids are NOT beneficial

Treatment of aplastic anemia

Bone marrow transplant
Transfusion of PRBCs and platelets, if necessary *use judiciously
Immunosuppresion

Thrombocytopenia can result in clinical features that includes:

ecchymosis, nasal bleeding, mouth ulceration/gum bleeding, GI tract, ICH

Lo reticulocye (<2%) with macrocytic anemia (>100)

1. Check B12 and folate levels
2. Abnormal B12/folate --> diagnostic
3. Normal - then suspect LIVER DISEASE

What is the diagnosis of Hb and Hct:

1. Formula to convert Hb to Hct: Hb x 3 = Hct (1 unit of packed RBCs [PRBCs]) increases Hb level by 1 point and Hct by 3 points

2. If patient has good cardiac function and intravascular volume is adequate, low Hb and Hct levels are tolderated even an Hb of 7 or 8 provides sufficient O2 carryng capacity for most patients however anemia is not tolerated as well in patients with impaired cardiac function

How is SCA diagnosed?

1. Anemia is the most common finding.
2. Peripheral smear - sickle shaped RBCs
3. Hemoglobin electrophoresis is REQUIRED for diangosis in most casis, diagnosis is made from newborn screening tests!

Diagnosis of CLL

CLL: a cancer of B-lymphocytes
-to diagnose CLL - there is NOT ONE PARTICULAR GENETIC ABNORMALITY THAT IS PATHOPNEUMONIC (unlike that of CML in which has the t(9; 22) genetic abnormality)
-We do not have a molecular-marker, instead look at pattern (Look @ CD19, 20, 23
-Find B cells that have abnormal expression of CD5 (t cell marker) in normal cells - shouldn't have both CD20 and cd5 positive B cells because abnormal to express a T CELL marker CD5
-Thus can make diagnosis by FLOW cytometry of the peripheral blood.
-Look for population of cells that has the t cell markers 50% of the time gets diagnosed incidentally asymptomatic usually but if they do -- will have the origniation of b cells in bone marrow then go to lymph nodes and cause to swell
-if too many CLL cells in marrow, can cause some pancytopenias due to proliferation

A reticulocyte index of < 2% implies?

Inadequate RBC production produced by the bone marrow

What is the difference between HIT type I versus type II?

HIT type I = heparin directly causes platelet aggregation seen < 48 hours after initiating heparin; no treatment needed (NONIMMUNE)

HIT type II = heparin induces antibody-mediated injury to paltelet; seen 3-12 days after intiiating heparin; discontinue HEPARIN IMMEDIATELY!

How is hemoglobin S distinguished from Hb A?

By electrophoresis

What are the clinical features of irondeficiency anemia:

pallor
fatigue
dyspnea on exertion
orthostatis lightheadedness
hypotension, if acute, tachycardia

Disorders of blood coagulation:

1. von Willebrands Disease (vWD)
-autosomal dominant d/o with deficiency or defec of factor VIII-related antigen (vWF)
-vWF enhances platelet adhesion and aggregation (first two steps in platlet flot formation)
-carrier of factor VIII (8) in blood

****MOST COMMON INHERITED BLEEDING D/O (1-3% OF US)

PT v. PTT v. Thrombin time v. Bleeding time

PT: reflects extrinsic pathway (prolonged by warfarin)
PTT: reflects the intrinsic pathway (prolonged by heparin - factor X)
thrombin time: measures fibrinoen concentratoin
bleeding time: reflects platelet function

What is the treatment of/for CLL

Chemotherapy has little effect on survival but good for symptoms.

1. FLUDARABINE AND CHLORAMBUCIL have been shown to be of some benefit.

Major clinical features associated with SCA?

1. Severe lifelong hemolytic anemia
2. Findings secondary to vasal occlusion
a. Painful crisis
b. Hand-foot syndrome (dactylitis)
c. Acute chest syndrome
d. repeated episodes of splenic infarctions
e. avascular necrosis of joints
f. priapism
g. CVAs
h. Opthalmologic complications
i. Renal papillary necrosis with hematuria *painless
j. Chronic leg ulcers
k. abdominal crisis
3. infectious complications
a. functional asplenia results in increased susceptibility to infections of encap
bacteria that includes (S. pneumo, H. Influ)
b. predisposition to that of salmonella osteomyelitis (also due to splenic malfunction)
4. Delayed growth and sexual maturation, especially in boys.

Hyperviscosity, headache, dizziness, weakness, pruritis, visual impairment, dyspnea
with thrombotic phenomena (DVT, PE, VIA, MI, portal vein thrombosis) or BLEEDING -GI or GU bleeding with HTN

Polycythemia vera

High-grade NHL (name 2)

1. Lymphoblastic lymphoma: T-cell lymphoma; more common to children, can progress to T-ALL in which 50% have B symptoms; aggressive with rapid dissemination

2. Burkitts (small non-cleaved cell) lymphome: T cell lymphoma common to children. Two types (one in AA involving face and jaw and the other that is american with hepatomegaly and abdominal masses with LAD). AA linked with EBV infection and assicated with t(8; 14)

MGUS v. MM

MGUS:
1. IgG spike < 3.5g
2. Less than 10% plasma cellsin bone marrow
3. Bence jones proteinuria < 1g/24 hours.

-fewer than 20% develops MM in 10-15 years
-no treatment necessary; close observation is suggested

MM:
1. >10% abnormal plasma cells in marrow
2. Mprotein in serum, urine
3. lytic bone lesions

Causes of myelodysplastic syndromes:

1. idiopathic
2. radiation
3. immunosuppressive agents
4. Toxins

Warfarin
1. Platelet count
2. Bleeding time
3. PT
4. PTT

1. NL
2. NL
3. Increased
4. NL

HIV-associated lymphomas include:

Not a discrete entity; usually Burkitts high grade, or diffuse large t cell intermediate grade

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