week 10- heme Flashcards
1
Q
What are the d/os of thrombocytopenia and platelet dysfunction?
A
o Acquired platelet dysfunction
o Hereditary intrinsic platelet d/os
o Idiopathic (Immune) Thrombocytopenic Purpura (ITP)
o Thrombocytopenia due to Splenic Sequestration
o Thrombocytopenia: Other causes: immunologic and non-immunologic
o Thrombotic Thrombocytopenic Purpura: (TTP)
o Von Willebrand’s Dz
2
Q
• What are normal platelet counts? Lifespan?
A
o 140,000-440,000/uL
o Varies according to menstrual cycle phase
o Dec in near-term pregnancy
o Increases in response to inflammatory cytokines
o Life: 7-10 days, eventually destroyed by the spleen.
3
Q
• What are the general types of platelet d/os?
A
o include increased numbers, decreased numbers, and platelet dysfunction
4
Q
• what are causes of thrombocytopenia?
A
o failure of production o inc sequestration o inc destruction or consumption o inc dilution o Combo of above o Quinine, drugs, liver dz, DIC, pregnancy, preeclampsia, ITP, HIV, more
5
Q
• When does thrombocytopenia cause increased bleeding?
A
o the lower the platelet count
o < 50,000/uL: Easy minor bleeding, major bleeding risk inc
o <10,000 mb asx
6
Q
• How is thrombocytopenia diagnosed?
A
o CBC
o coagulation studies (normal)
o smear- platelet ct
o Suspect platelet dysfunction if CBC, INR and PTT are normal
7
Q
• How can you ddx thrombocytopenia vs platelet dysfunction?
A
o penia: smear may suggest cause; Abnormalities may require BM aspiration
o dysfunction: Hereditary cause suspected if hx of easy bleeding and prolonged bleeding after surgery; VWF studies mb done
8
Q
• What is acquired platelet dysfunction?
A
o Due to aspirin, NSAIDS, other platelet inhibiting drugs, or systemic d/os (HIV, hepatitis C)
o Very common
o Suspect if single incidence of prolonged bleeding occurs, and other possible diagnoses are eliminated
9
Q
• What are hereditary intrinsic platelet d/os? 3 types? Dx?
A
o Suspect in pts with lifelong bleeding d/os but normal platelet ct and coag studies
o Three main types:
o Most common: D/os of platelet activation
o Glanzmann’s Thrombasthenia: rare AR d/o
o Bernard-Soulier Syndrome: rare AR d/o
o Dx: platelet aggregation test results will differentiate the d/os
10
Q
• What is idiopathic immune thrombocytopenic purpura (ITP)?
A
o AI d/o with inc platelet destruction
o Bimodal age distribution, children and >60yrs
o Acute and self-limited in children (often triggered by viral illness)
o Chronic in adults
11
Q
• What is cause of ITP? Ssx? Ddx?
A
o HIV; Hep C; CMV; Drugs; Idiopathic loss of peripheral tolerance
o Ssx: Petechiae on dependent areas of the body (affected by gravity, feet, etc), mucosal bleeding, conjunctival hemorrhages; mb SM
o ddx: vasculitis purpura, hemophilia, thrombocytopenia, TTP
12
Q
• how is ITP diagnosed?
A
o Suspect in pts with unexplained thrombocytopenia
o Low platelet ct, with otherwise normal CBC
o BM exam if other abnormalities are present in smear
o = normal or possibly with increased megakaryocytes
13
Q
• What is thrombocytopenia due to splenic sequestration?
A
o Platelet ct usu > 30,000
o Occurs in d/os that produce SM:
o Advanced cirrhosis
o MF or myeloid metaplasia have lower cts
14
Q
• What are 2 other causes of thrombocytopenia?
A
o Immunologic: Blood transfusion; CT and lymphoproliferative d/os; Drug-induced
o Non-immunologic: ARDS; Gram Negative sepsis; HIV
15
Q
• What is thrombotic thrombocytopenic purpura (TTP)?
A
o Platelets destroyed by deposited fibrin strands in small vessels
o Thrombi form in multiple organs
o High fatality rate if left untreated
16
Q
• What causes TTP?
A
o Def in plasma enzyme ADAMTS13
o Hemorrhagic colitis from E. Coli O157:H7 or certain strains of Shigella
o Pregnancy
o Drugs (quinine, cyclosporine, mitomycin C)
o AI: SLE, scleroderma, anti-phospholipid
o Many cases idiopathic
17
Q
• What are ssx of TTP?
A
o Fever, organ ischemia (with varying severity)
o Ischemia manifests as: Confusion, coma, sz, HA; Abd pain; Arrhythmias, Chest pain
18
Q
• How is TTP diagnosed?
A
o Suspect in pts with anemia, thrombocytopenia and sxs o UA o smear o Retic ct o Serum LDH o Renal function o Serum bilirubin (direct and indirect) o Coombs’ test o Dx suggested by anemia, thrombocytopenia, RBC fragments on blood smear, evidence of hemolysis (falling Hb, polychromasia, elevated retics, negative Coombs), renal abnormalities
19
Q
• What is hemolytic uremic syndrome?
A
o HUS refers to TTP in children with enterohemorrhagic infection (E. Coli O157:H7 or certain strains of Shigella)
o Usu spontaneously remits
o Untreated cases dt other causes often fatal
o Most pts have only one incidence of TTP-HUS
20
Q
• What is Von Willebrand’s dz?
A
o Hereditary (AD) bleeding d/o; impaired synthesis of VWF o prolonged bleeding time and mild to severe factor 8 def
21
Q
• What are ssx of VWD?
A
o Usu mild to moderate sxs
o Mild skin and mucosal bleeding, easy bruising
o Menorrhagia
o Prolonged bleeding after surgery
22
Q
• How is VWD diagnosed?
A
o Suspect in pts with bleeding d/os, esp if family hx
o Screening coagulation tests mb borderline normal (normal INR, normal or slightly prolonged PTT)
o Prolonged bleeding time
o Normal platelet ct
o Definitive dx: Plasma VWF antigen, VWF activity, and Factor 8; All will be depressed between 15-60% of normal; VWF antigen mb 40% below normal in healthy people with Type O blood
o ASA will seriously prolong the bleeding time
23
Q
• What is hemostasis?
A
o the arrest of bleeding from an injured blood vessel
o Requires activity of vascular, platelet, and plasma factors
o Abnormalities in any factors may result in excessive bleeding or thrombosis
24
Q
• What are vascular factors of hemostasis?
A
o Local vasoconstriction reduce blood loss from trauma
o Extravasation of blood into surrounding tissues compresses injured vessels
25
• What are platelet factors of hemostasis?
o NO and prostacyclin promote blood fluidity, dilate vessels, prevent platelet adhesion
o Production stops if endothelium is injured
o Platelets aggregate and adhere to damaged intima:
o Adhere first to VWF in endothelium
o Platelet activation: Plts release mediators including ADP, and cause COX-mediated conversion of arachidonic acid to TxA2; cause platelet aggregation
o Fibrinogen binds and helps connect platelets together
o Thrombin converts fibrinogen to fibrin to further stick platelets together and to the damaged endothelium.
26
• What are plasma factors of hemostasis?
o interact to produce Thrombin
o In vivo coagulation is predominantly through Extrinsic pathway.
o Injury -> VIIa/TF activates Factor X andIX; IXa and VIIIa combine to form more Xa.
o X activation is required for normal hemostasis, and is affected by def of XIII and IX
27
• What are the regulatory mechanisms that prevent uncontrolled coagulation?
o Inactivation of coagulation factors by protease inhibitors
o Fibrinolysis via dissolution of fibrin by the proteolytic enzyme plasmin
o Plasminogen activators (to plasmin): tPA, urokinase, streptokinase
o Regulation of Fibrinolysis by Plasminogen Activator Inhibitors (PAIs), and plasmin inhibitors
o Primary PAI: PAI-1 inactivates tPA and urokinase
o Primary plasmin inhibitor: α2-antiplasmin
28
• What are signs of a pt with a possible bleeding d/o?
```
o Evaluate pts with ssx of unusual bleeding or if lab abnormality suggests a bleeding d/o (usu found incidentally)
o Unexplained epistaxis
o Menorrhagia
o Prolonged bleeding after minor cuts
o Easy bruising or petechiae
o Unexplained gingival bleeding
```
29
• What Q’s should you ask about hx of bleeding d/os?
o Systemic dzs associated with defects in coagulation or platelets
o Ingestion of drugs, including NSAIDS
o Excessive unusual prior bleeding (including prolonged bleeding time, menorrhagia, epistaxis, hematuria, GI bleeding, hemoptysis); Suggests thrombocytopenia
o FHx of bleeding d/os; Absence does not preclude a genetic d/o
30
• What PE should be done for bleeding d/os?
o Exam skin and mucosal surfaces for signs of bleeding
o Look for joint tenderness or swelling
o If severe, may see signs of hypovolemia or shock
o Signs of anemia
31
• What 2 tests should be done for bleeding d/os?
o Platelet count (PT/INR, PTT )
| o bleeding time
32
• What mb seen on platelet count for bleeding d/os? Factors?
```
o PT (normal 10-13 sec): extrinsic and common pathways: VII, X, V, prothrombin (II), fibrinogen (I)
o PTT (normal 28-34 sec): intrinsic and common: XII, XI, IX, VIII, X, V, prothrombin and fibrinogen
o Heparin prolongs PTT
o Auto-abs to Factor VIII prolong PTT (Hemophilia)
o Prolongation of PT or PTT may indicate a Factor def or presence of an inhibitor
o Factors must be at least 70% def to see a prolongation of PT/PTT
o Abnormalities of either should lead to testing of specific factors to narrow down ddx
```
33
• How are bleeding time results interpreted?
o controversial due to many factors that can compromise reliability, including use of aspirin or NSAIDs
34
• what are the thrombotic d/os/ thrombophilias?
o Factor V Leiden mutation (APC Resistance)
o Proteins C and S Def
o Antithrombin Def
o Prothrombin 20210 Gene Mutation (Factor II Mutation)
o Antiphospholipid Ab Syndrome (Lupus Anticoagulant)
o Hyperhomocysteinemia
35
• what are the genetic causes of increased propensity for venous thromboembolism?
o Factor V Leiden mutation
o Prothrombin 20210 gene mutation
o Def of protein C, S, Z or antithrombin
o Hyperhomocysteinemia
36
• What are the acquired causes of increased propensity of venous/arterial thrombosis?
o Heparin-induced thrombocytopenia/thrombosis
o Anti-phospholipid abs
o Hyperhomocystinemia (dt B12, folate, or B6 def)
o D/os/Environmental/Lifestyle factors:
o Post-surgical stasis or prolonged immobilization
o Heart failure
o Pregnancy
o Obesity
o Tissue injury from trauma or surgery
o Neoplasms
o Sepsis or severe infection
o Oral Contraceptives containing estrogen
o Atherosclerosis
o Cigarette Smoking (not in Merck)
37
• What is Factor V Leiden mutation (APC resistance)?
o Factor V Leiden is most common Factor V mutation and increases the tendency to thrombosis.
o Homo riskier for thrombosis than hetero
o 5% prevalence in European populations. Rarely in Asians or Africans.
o DVT and/or PE with no provocation
o Present in 20-60% of pts with spontaneous venous thrombosis
38
• How is Leiden diagnosed?
o Screening with PTT
o Functional plasma coagulation assay
o Molecular analysis of Factor V gene
39
• What are protein C and protein S def?
o promote venous thrombosis
o Het def is prevalent in 0.2-0.5%; 75% get venous thromboembolism
o Homo def is obvious neo-natally (neonatal purpura fulminans).
o C Sx: Venous thromboembolism, warfarin induced skin necrosis
o S Sx: Venous and arterial thrombosis.
o Mb acquired, with liver dz, chemo, DIC, warfarin therapy
o Dx: functional plasma coagulation assays
40
• What is antithrombin def?
o Antithrombin inhibits thrombin, factors Xa, IXa, and XIa.
o Het def prevalence 0.2-0.4% (1/2 get venous thrombosis)
o Homo: fatal to fetus
o Acquired def in DIC, liver dz, nephrotic syndrome, heparin therapy
o Dx: Plasma inhibition of thrombin in the presence of heparin
41
• What is Prothrombin 20210 Gene Mutation (Factor II Mutation)?
o inc plasma prothrombin levels, inc risk of thrombosis.
o Het def has 2% prevalence in whites, 0.5% in African Americans, rare in Asians.
o Dx: DNA test for Factor II mutation
42
• What is Antiphospholipid Ab Syndrome (Lupus Anticoagulant)?
o Predisposed to AV thrombosis, stroke, DVT and PE
o Only a minority of pts have recurrent thrombotic problems
o Dx: Prolonged PTT (paradoxical response); Blood test for presence of Lupus Anticoagulant/APA
43
• What is Hyperhomocysteinemia?
o May predispose to AV thromboembolism
o hi homocysteine contributes to endothelial cell injury
o Homo cystathionine β-synthase def results in increase in plasma homocysteine levels > 10 fold
44
• What are the coagulation d/os?
o Disseminated Intravascular Coagulation (DIC)
| o Hemophilias
45
• What are causes of abnormal bleeding?
```
o D/os of coagulation system:
o Acquired causes
o Hereditary causes
o D/os of platelets
o D/os of blood vessels
```
46
• What are acquired causes of bleeding d/os?
o Vit K def
o Liver dz: Impaired clotting factor synthesis; PT/INR and PTT will be elevated; May see excessive fibrinolysis; Dt increased synthesis of α2 antiplasmin
o DIC
o Circulating anti-coagulants
47
• What are hereditary most common causes of bleeding d/os?
o Hemostasis: VWD
| o Coagulation: hemophilia
48
• What are the circulating anticoagulants?
o Autoabs that neutralize clotting factors or inhibit protein-bound phospholipid
o Factor VIII anticoagulants:
o 15-35% of Hemophilia A pts; Complication of therapy
o May occur in other AI dzs
o May results in life-threatening hemorrhage
49
• What is Disseminated Intravascular Coagulation (DIC)?
o Widespread activation of the clotting system and consumption of all the clotting factors resulting in bleeding
o excess generation of thrombin and fibrin deposition, then factor depletion
50
• what causes DIC?
o Obstetrical complications: Therapeutic abortion; Retained dead fetus or other conception products
o Infx: Activated by bacterial toxins or tissue products in circulation
o Malignancy: Usu adenocarcinomas of pancreas, prostate
o Shock from any cause
o Common in severe dzs and terminal states, also after large bone fractures and surgery
51
• What are ssx of DIC?
o Mb rapid, or slow-evolving
o Slow evolving: possible sxs of venous thrombosis and PE
o Severe, rapidly evolving:
o Caused by thrombocytopenia and clotting factor depletion
o Persistent bleeding at skin puncture sites
o Ecchymoses at injection sites
o Serious GI bleeding may occur
o May see intravascular hemolysis
52
• How is DIC diagnosed? Slow? Rapid?
o Suspect in pts with unexplained bleeding or venous TE (esp. with predisposing condition)
o Platelet count, PT/INR, PTT, Fibrinogen and D-dimer must be done
o Slow: mild thrombocytopenia, normal to prolonged PT/PTT, normal or reduced fibrinogen, increased D-dimer; 2 consecutive measurements showing evolution of values will help with the Dx.
o Rapid DIC: severe thrombocytopenia, more prolonged PT/PTT, rapidly declining fibrinogen, high D-dimer; Use Factor VIII level to differentiate b/w massive hepatic necrosis (elevated) and DIC (reduced)
53
• What are hemophilias?
o Inherited bleeding d/os with clotting factor def
o Most commonly Factor VIII (hemophilia A) or IX (hemophilia B) is involved
o 80% Hemophilia A
o A and B are identical clinically
o Inherited sex linked recessive trait with bleeding seen only in males
o Hemophilia pts have < 5% of normal Factor VIII and IX levels
o Normal hemostasis requires > 30%
54
• What are ssx of hemophilias?
o begins in early childhood and persists
o Variable severity
o Serious hemorrhage from minor injuries
o Hemarthrosis is virtually diagnostic, pain occurs with bleeding
o Hematuria and easy bruising very common
55
• How is hemophilia diagnosed?
o Suspect in pts with recurrent bleeding, unexplained hemarthroses, or prolonged PTT
o Must do: PT/PTT, platelet ct, factor VIII and IX assays.
o PTT will be prolonged, PT and platelet ct normal.
o Factor 8 and 9 determine type and severity of Hemophilia:
o less than 1% of normal: severe bleeding throughout life
o 1-5% of normal: Moderate, bleeding after minimal trauma
o 5-25% of normal: Mild, excessive bleeding after surgery, dental extraction
o around 50% seldom have spontaneous bleeds (carriers)
o Factor VIII may also be reduced in von Willebrand’s dz.
o Run VWF assays in pts with hemophilia A
56
• How can you prevent complications with hemophilia?
o Avoidance of aspirin and NSAIDS
o Regular dental care to avoid extractions
o Use of oral or IV drugs rather than IM, which causes hematomas
o Counseling about importance of injury prevention where possible
57
• What are the bleeding d/os due to abnormal blood vessels?
o Dysproteinemias
o Hereditary Hemorrhagic Telangiectasia (HHT)
o Purpura Simplex (easy bruising)
o Senile Purpura
58
• What are effects of vascular d/os dt vessel defects?
o produce petechiae, purpura, and bruising.
o Seldom cause serious bleeding.
o Mb seen in vascular collagen def syndromes (Ehlers-Danlos or other rare CT d/os)
o Hemorrhage mb feature of scurvy or Henoch-Schönlein purpura
o Hemostatic testing is normal, so dxs are clinical
59
• What are the dysproteinemias?
o Amyloidosis: amyloid deposition in vessels, increasing vascular fragility; Suggested by periorbital purpura or purpuric rash after gentle stroking in non-thrombocytopenic pt.
o Cryoglobulinemia: small vessel vasculitis and purpura
o Hypergammaglobulinemic Purpura: mostly women; Vascular purpura, small crops of purpura on lower legs; Residual brown spots; Usu accompanied by immunologic d/o like SLE
o Hyperviscosity Syndrome: From markedly elevated plasma IgM levels; Usu seen in Waldenström’s Macroglobulinemia
60
• What is Hereditary Hemorrhagic Telangiectasia (HHT)?
o Arteriovenous malformations (AVMs), affects 1 in 5,000 people
o small red-to-violet telangiectasias on face, lips, oral and nasal mucosa, tips of fingers and toes
o Mb present in GI tracts, resulting in bleeding
o Nosebleeds
o Pulmonary AV fistulas: Dyspnea, fatigue, cyanosis, Polycythemia
o Thrombi may cause stroke
o Dx: characteristic lesions, malformations seen on angiography or endoscopy
61
• What is Purpura Simplex (easy bruising)
o Very common
o Bleeding into skin dt vascular fragility
o More common in women
o Easy bruising without significant blood loss generally
o Mb transient from drugs, fever, infx, hypothyroidism
o Dx:
o Normal labs: platelet ct, PT/PTT, fibrinogen
o Hx: no other abnormal bleeding, easy bruising mb in family members
62
• What is senile purpura?
o Persisent dark purple ecchymoses in elderly pts
o Usu confined to forearms and hands
o Lesions appear without known trauma
o May resolve after several days , leaving brownish discoloration dt hemosiderin
o Skin appears thinned and atrophic
63
• What are the spleen d/os?
o Splenomegaly
| o Hypersplenism
64
• What are the functions of the spleen?
o White pulp: immune organ; Production and maturation of B cells
o Red pulp: phagocytic organ; Removes ab-coated bacteria and cells, senescent or defective RBCs; Reservoir for blood elements, esp WBCs and plts
o Hematopoiesis may occur in spleen (red) if injury to marrow occurs
65
• What is splenomegaly? Causes?
o When enlargement of the spleen occurs, it increases function and it sequesters blood cells.
o Almost always 2nd to another dz
o Most common causes in temperate climates: Liver cirrhosis, MPD, LPD, Storage dzs, CT dzs
o Most common causes in tropical climates: Infectious dz (malaria)
66
• What are ssx of splenomegaly?
o Easy satiety, LUQ pain and fullness (severe pain could be infarction)
o Recurrent infections, sxs of anemia, bleeding manifestations
o Palpable/percussible spleen
o Possible splenic friction rub (infarction)
o Splenic bruit (congenital splenomegaly)
o Generalized adenopathy (MPD, LPD, infectious, or AI d/o)
67
• What is work-up for splenomegaly?
o U/S is test of choice
o MRI (detection of thrombosis)/CT may provide more detail
o If no cause is identified, search for occult infection
68
• What is hypersplenism?
o SM dt cytopenia
o Spleen will extend 2 cm below costal margin for every gram decrease in Hb
o Suspect in pts with splenomegaly and anemia or cytopenia
69
• What are the eosinophilic d/os?
o Eosinophilia
| o Idiopathic Hypereosinophilic Syndrome
70
• What are eosinophils?
o Granulocytes
o Phagocytic cells, less efficient than neutrophils
o Accompany helminthic infections
o Modify immediate hypersensitivity reactions
o Normal count is < 350/µL
71
• What is eosinophilia?
o Eosinophil count > 450/µL
o Usual cause is allergic reaction (most common) or parasitic infection
o Certain neoplastic dzs may cause: Hodgkin’s Lymphoma, Ovarian Cancer
o Drugs may cause
o Dx: Elevated eosinophils on CBC
o Medical hx, travel hx, allergies, meds, PE
72
• What is Idiopathic Hypereosinophilic Syndrome?
o Peripheral ct > 1500 persisting > 6 mos
o Organ involvement: Heart, lungs, spleen, skin, and nervous system
o Absence of parasitic or allergic cause
73
• What are ssx of IHS?
o Depend on organ involved
o Usu 1 of 2 patterns
o Pattern 1: MPD with SM, thrombocytopenia, hi B12, hypogranular or vacuolated eosinophils; Pts develop endomyocardial fibrosis or leukemia
o Pattern 2: Hypersensitivity illness with angioedema, hypergammaglobulinemia, elevated IgE, circulating immune complexes; Rare heart dz; Most respond to corticosteroids
74
• How is IHS diagnosed?
o Suspect in pts with eosinophilia with no obvious cause, and sxs of organ dysfunction
o CBC, smear, B12 levels, IgG, IgE
o Echocardiography to detect myocardial involvement
o Moderate to poor px depending on access to tx
75
• What are hystiocytic d/os?
o abn proliferation of monocyte-macrophages or dendritic cells.
o Langerhans’ Cell Histiocytosis (LCH)
76
• What is Langerhans’ Cell Histiocytosis (LCH)?
o Dendritic cell d/o
o Prevalence of 1 in 50,000, most infants and children
o May affect adults, male prominence
o Abnormally proliferating dendritic cells invade one or more organs, causing dysfunction. 50% of pts have multiple organ involvement.
77
• What are ssx of LCH?
o Vary according to organ involved
o 60-80% have Eosinophilic Granuloma: Bone pain, swelling; Older children, young adults
o 15-40% have Hand-Schuller-Christian dz: Flat bone involvement, COM, COE; Exophthalmos, vision loss; Diabetes insipidus
o 10% have Letterer-Siwe dz: Severe form, children < 2 yo; Scaly, seborrheic, eczematoid rash; LAD, hepatosplenomegaly, anorexia, failure to thrive, pulmonary sxs; If thrombocytopenic, px is poor
78
• How is LCH diagnosed?
o Suspect in pts with unexplained pulmonary infiltrates, bony lesions, ocular or craniofacial abnormalities; in children < 2 yo with characteristic rashes or multi-organ dz
o Radiographs show sharply demarcated bone lesions
o Dx based on bx showing prominence of Langerhans cells (cell surface CD1a and CD S-100.
o Good prognosis if confined to skin, lymph nodes or bone
o Common to have remitting and exacerbating course.
79
• What are the myeloproliferative d/os?
o Abnormal proliferation of one or more hematopoietic cell lines or CT elements.
o Essential Thrombocythemia (Thrombocytosis)
o Myelofibrosis
o Polycythemia Vera
80
• What is Essential Thrombocythemia (Thrombocytosis)?
o Increased platelet ct, megakaryocyte hyperplasia, and hemorrhagic or thrombotic tendency
o Usu seen in ages 50-70
o Platelet survival is normal, but may decrease dt splenic sequestration
81
• What are ssx of ETC?
o Weakness, HA, and paresthesias of hands and feet
o Mild bleeding - epistaxis, easy bruising, GI bleeding
o Digital ischemia
o SM (60%)
o Erythromelalgia- erythematous burning hands
o Thrombosis- TIA, stroke, retinal, PE, DVT, may cause spontaneous abortion in pregnant pts
o Serious complications are rare
82
• How is ETC diagnosed?
o consider in pts who have splenomegaly, elevated plts or abn morphologies
o CBC, smear, BM exam, cytogenetics (Philadelphia chromosome, ABL-BCR) to distinguish ET from CML
o Plt count mb 500,000 to >1,000,000
o smear: plt aggregates, giant plts, megakaryocyte fragments
o BM: megakaryocytic hyperplasia, with abundant platelets. Marrow Fe is present
o Must have normal Hct, MCV, and Fe studies, no Philadelphia chromosome, no ABL-BCR translocation
o Absence of teardrop-shaped RBCs
o No significant increase in BM fibrosis (idiopathic myelofibrosis)
o Exclusion of other d/os that cause thrombocytosis
83
• What is px of ETC?
o Life expectancy is near normal, but leukemic progression can occur in < 2% with cytotoxic drug exposure
84
• What is Thrombocytosis (2nd Thrombocythemia)
o Chronic inflammatory d/os, acute infection, hemorrhage, Fe def, hemolysis, tumors
o Plt function normal, count is <1,000,000
o MPDs: 50% have platelet aggregation abnormalities
o Treat underlying d/o
85
• What is Myelofibrosis?
o Excessive marrow fibrosis and loss of hematopoietic cells
o Marked extramedullary hematopoiesis (liver, spleen)
o Usu primary, results from neoplastic change in marrow stem cells
o Stem cells stimulate marrow fibroblasts to produce excessive collagen
o MB 2nd to other conditions: Malignancies (Leukemias, PV, Multiple myeloma, lymphoma, cancers with bone METs); Infections (TB, osteomyelitis); Toxins (radiation, benzene, thorium dioxide); AI d/os (SLE, rare)
o Marrow failure eventually occurs, with anemia and thrombocytopenia
o Peak incidence 50-70 yrs
86
• What are ssx of myelofibrosis?
```
o FATIGUE
o Asx early- ~30% pts asx
o SM, malaise, weight loss, fever
o HM in 50%
o 10% develop rapidly progressing leukemia
```
87
• How is MF diagnosed?
o Suspect in pts with SM, splenic infarction, anemia, or unexplained elevations in LDH
o Obtain CBC, smear, BM, cytogenetic testing
o Exclude other causes of MF, usu with bone marrow exam
o Blood cell morph is variable:
o Usu see normocytic-normochromic anemia, mild poik, reticulocytosis, polychromatophilia, nRBCs
o More advanced cases see severely misshapen RBCs and teardrop cells
o WBCs usu high, but variable
o Platelets eventually decrease as dz progresses
88
• What is px of MF?
o median survival is 5 yrs from onset
| o Poor prognosis if constitutional sxs, anemia, cytogenetic abnormalities present.
89
• What is Polycythemia Vera?
o Chronic MPD showing an increase in red cell mass.
o Increased production of all cell lines, including WBCs, RBCs, plts.
o RBCs only is primary erythrocytosis
o More common in males. 5/1,000,000 prevalence.
o RBC production is independent of EPO
o Progression: eventually 25% have reduced RBC survival, inadequate erythropoiesis. Anemia, thrombocytopenia, and MF may develop. WBC and RBC precursors seen in circulation. Volume expands, then hyperviscosity, predisposing to thrombosis. Platelet dysfunction can lead to bleeding.
90
• What are ssx of PCV?
```
o often asx
o May see increased blood volume/viscosity, leading to HA, weakness, lightheadedness, visual disturbances, fatigue, dyspnea.
o Pruritis after hot baths
o Red face, engorged retinal arteries
o Erythromelalgia
o SM and HM common
o Bleeding, bruising or thrombosis common from defective platelets
o Impaired circulation
```
91
• How is PCV diagnosed?
o Often suspected from abnormal CBC: Major and minor criteria see slide #34
o Hct >54% in men or >49% in women , Plt count >400,000, WBC >12,000
o Increased RBC cell mass
o Arterial oxygen saturation>92%
o Clear diagnosis in pts with elevation of all 3 peripheral blood cells, SM, and no cause for 2nd erythrocytosis
o WBC normal or elevated; platelets increased, abnormal morph
o Peripheral WBC and RBC precursors, marked aniso, poik, microcytes, elliptocytes, tear drop cells.
o Low or low normal EPO (high in hypoxia, EPO-generating tumors)
o May also see: hyperuricemia due to RBC breakdown, B12 mb high
92
• What are other causes of erythrocytosis? Px for PCV?
o Hypoxia, smoking, tumors, male hormones, lung dz, high altitude, diuretics and dehydration (relative, due to hemoconcentration)
o Px: 50% of symptomatic pts die within 18 mos of dx without tx
o Causes of death are thrombosis, then from development of leukemia
93
• What are the leumemias?
o Acute Leukemias: (AML and ALL)
o Chronic Leukemias: CLL, CML
o Myelodysplastic Syndrome (MDS)
94
• What are leukemias? Causes?
o Cancers of BM and circulating WBCs, spleen, lymph nodes
o The cells remain immature and produce a growth inhibition factor that suppresses the rest of the marrow
o Tumors may proliferate in any organ, causing local symptoms
o Causes: unclear; hereditary components; viruses; chemicals and radiation
95
• What are ssx of leukemia?
o anemia, hemorrhage, infection, fever, bone pain, bruising, petechiae, LAD, HSM, infiltrates in skin and brain
96
• what are classifications of leukemia?
o Acute/ chronic refer to the cellular maturity of the malignant cells.
o Acute: cells are less differentiated (babies)
o Chronic: more mature cells (adults)
o Divided into myelocytic and lymphocytic types based on the cell type involved. (FAB classifications)
97
• What are the acute leukemias?
o Rapidly progressing, with BM quickly replaced with blast cells arising from an undifferentiated stem cell.
o The cells may accumulate in any organ, replace normal marrow, and spread quickly. Marrow and CNS are most severely affected.
o ALL: predominantly in children under age 10, mb seen after age 45; peaks ages 3-5. Most common pediatric cancer
o AML: affects all ages but median age of onset is 50 yo. Mb a 2nd cancer after chemo or radiation therapy
98
• What are ssx of acute leukemia?
o Sxs usu only present for days to weeks at dx
o Most common initial sxs are dt disrupted hematopoiesis: anemia, infection, easy bruising, and bleeding; Petechiae, epistaxis, bleeding gums, menstrual irregularity
o Other sxs are non-specific: pallor, fatigue, fever, malaise, weight loss, tachycardia, chest pain
o BM infiltration may cause bone or joint pain
o May see LAD, SM, HM, skin rashes
99
• How is acute leukemia diagnosed? Ddx?
o CBC and smear done first
o Leukemia suggested by pancytopenia and peripheral blasts. May have high WBCs in 50+% of cases.
o BM to confirm, always. 30-95% blast cells. Typing is confirmed with B-Cell, T-Cell and myeloid antigen testing, and lymphocyte flow cytometry.
o May also see hyperuricemia, hyperphosphatemia, hyper or hypokalemia, elevated transaminases or LDH, hypoglycemia, hypoxia.
o Lumbar puncture, head CT if CNS sxs are present, B-cell ALL, high WBCs, high LDH
o Chest x-ray, CT if mediastinal mass is present
o Abdominal imaging (U/S, CT, MRI) if SM/HM are present.
o Ddx: aplastic anemia, infectious mononucleosis, B12/folate def, leukemoid reactions to infectious dz, JIA, other malignancies
100
• What is px of acute leukemia?
o Complete cure is possible, esp in younger pts.
o Worse prognosis in infants and elderly, or with hepatic or renal dysfunction, CNS involvement, myelodysplasia, or high WBC ct.
o 3-6 month survival w/o tx
o ALL: chance of remission greater than 95% in children and 70-90% in adults
o AML: remission in 50-85%. Long term dz-free rates are 20-40%.
101
• What are chronic leukemias?
o abnormal leukocytosis with or without cytopenia in otherwise asx person. Significantly different findings in CLL and CML
102
• what is CLL?
o increased numbers of mature-appearing defective lymphocytes in nodes and blood
o Lymphocytes accumulate in marrow, then spread to lymph nodes and other lymphoid tissue.
o 98% involve malignant transformation of B cells.
o Other tumors may develop in addition to the leukemia
o Average age of diagnosis is 60. Twice as common in men and there mb a genetic predisposition.
o Many subtypes of CLL: prolymphocytic, T-cell, hairy cell, etc.
103
• What are ssx of CLL?
o insidious, often asx development
o sx: Weakness and fatigue, anorexia, weight loss, sensation of abdominal fullness, fever of unknown cause, night sweats
o S: SM, HM, generalized LAD, eventually mb pallor
o May see hypogammaglobulinemia late, decreased resistance to infection; Pneumonia, herpes zoster common
104
• How is CLL diagnosed?
o Often found incidentally on CBC
o Confirm with smear and BM exam.
o Hallmark finding is sustained absolute lymphocytosis peripherally and in BM
o 10% have moderate anemia, thrombocytopenia, neutropenia
o May see hypogammaglobulinemia, and rarely elevated LDH
105
• What is px for CLL?
o Mean survival about ten years after diagnosis
o 2nd tumors common
o May progress very quickly but this is less common
o Worse prognosis with dx at later stages (thrombocytopenia, anemia)
106
• What is CML?
o stem cell malignancy overproducing granulocytes
o 15% of all adult leukemias are CML
o Occurs at any age but rare before 10, Median 45-55
o Overgrow the marrow and can spread anywhere
o MF occurs with marrow exhaustion
107
• What are ssx of CML?
o initially vague, with perhaps fatigue, anorexia, weight loss, minor LAD, night sweats and abdominal fullness
o Enlarged spleen in 60-70% of cases, worsening with time
o Bleeding problems mbcome severe and very high platelets
o Fever, marked LAD, maculopapular rash are ominous signs
o Chronic phase lasts months to years
o Sometimes see 2nd accelerated phase with treatment failure, worsening anemia, thrombocytopenia
o Terminal phase or “blast crisis” in which blast cell tumors develop
108
• How is CML diagnosed?
o often after incidental findings on CBC, or during SM exam
o WBC >100,000/uL
o Elevated granulocytes (600,000/uL
o Hb level > 10
o smear aids in differential: Dominantly immature granulocytes, abs eosinophilia and basophilia
o Low LAP
o BM bx: Hypercellular marrow, may see MF (late)
o Dx confirmed with Philadelphia chromosome (95%)
o Accelerated dz: anemia, thrombocytopenia, MF
109
• What is ddx of CML? Px?
o ddx: leukemoid reactions from infection (increased LAP, normal eosinophils and basophils, MF (nRBCs, tear drop cells, anemia, thrombocytopenia)
o px: New therapies prolong survival to >2 years if used during chronic phase. If accelerated dz or blast crises occur, death is usu in 3-6 mos
110
• what is Myelodysplastic Syndrome (MDS)?
o Group of d/os resulting from somatic mutation of hematopoietic precursors. 5 or more subtypes exist.
o Thought to be pre-leukemic and mb associated with therapies that produce leukemia
o Hypercellular or sometimes normal marrow which is ineffective in making myeloid cells (anemia, thrombocytopenia, neutropenia)
o Anemia is common, mb abn cells in all lines (or 1)
111
• What are ssx of MDS?
o variable and reflect affected cell line
o Pallor, weakness, fatigue (anemia)
o Fever, infections (neutropenia)
o Increased bleeding, petechiae, epistaxis, mucosal bleeding (thrombocytopenia)
o Exercise intolerance, angina, dizziness, cognitive impairment
o Will often transform into acute leukemia form
112
• How is MDS diagnosed?
o Suspect in pts with refractory anemia, leukopenia, thrombocytopenia
o Rule out 2nd cytopenias
o Dx with smear and bone marrow revealing morph abnormalities in 10-20% of a cell line
o Anemia is most common, with macrocytosis (hi MCV) and anisocytosis (hi RDW)
o Some thrombocytopenia mb seen
o WBCs normal, high or low
o Granularity of neutrophils and eosinophils is variable
o May see hypo- or hyper-segmented neutrophils
o May see monocytosis
o Abn cytogenetic pattern usu involving chromosomes 5 or 7
113
• What is px of MDS?
o Varies greatly depending on subtype. > 5 yr survival in pts with refractory anemia.
o Excess blasts dec survival
114
• What is LA?
o Abnormal inc size or consistency or regional lymph nodes.
| o mb manifestation of regional or systemic dz
115
• What are some causes of LA?
o Reactive and infiltrative
o Reactive: infectious and non-infectious
o Infectious: bacterial (TB, pyogenic); fungal (coccidiomycosis); viral (CMV, mono); parasites (toxo)
o non-infectious: sarcoidosis; AI; dermatopathic; drug induced
o Infiltrative: benign (histiocytosis); malignant (leukemia, lymphoma, metastatic carcinoma)
116
• What Qs should you ask to dx LA?
o Systemic sxs? Fever, sweating, weight loss, itching
o Recent febrile illness?
o Contact with pets? (toxo)
o Drugs, esp anticonvulsants
117
• What PE should be done for LA?
o PE needs to be very thorough, all LN and check liver and spleen
o Inguinal and femoral nodes: mb normal to have some mild LA; worse if asymmetrical; bx if no explanation
o Generalized LA: systemic problem; do a full workup
o Cervical and supraclavicular nodes need to be evaluated by an ENT prior to bx
118
• What should be considered in ddx of LA?
o 35% of head and neck tumors present with METs to the local nodes
o In adult first consider mono (hx recent URI with atypical lymphs on the smear, and regression after 3-4 wks)
o Pts with lymphoma usu have asx cervical and regional LA.
o Mediastinal and hilar nodes: if asx consider sarcoidosis, and confirm with bx; Mediastinal nodes almost always indicate malignancy. Consider Hodgkins Lymphoma.
o Axillary nodes: examine the breasts (BR CA) and mammogram or U/S, bx as indicated.
119
• What are lymphomas?
```
o Group of neoplasms arising from RE and lymphatic systems.
o Hodgkin lymphoma
o Non-HL
o Burkitt’s lymphoma
o Mycosis Fungoides
```
120
• What is HL?
o Malignant proliferation of cells in the lymphoreticular system. More localized than NHL but can be disseminated.
o Unknown cause: mb genetic susceptibility, toxin exposure, past infx with EBV, smoking, immunosuppression, systemic inflammatory dzs. Past infx with varicella, MMR and pertussis is neg assoc with development
o Slightly more in M, rare 65yrs
121
• What are ssx of HL?
o Painless cervical LAD. May have pain in affected organs with alcohol ingestion (reason unclear).
o Intense pruritis may occur early on
o Hilar and mediastinal LAD
o Eventually get night sweats, fever, weight loss, nodular enlarged nodes.
o Pancytopenia, paraplegia, Horner’s syndrome and laryngeal paralysis
122
• How is HL diagnosed?
o Suspect in pts with painless LA or mediastinal AD detected on routine CXR. Confirm with CT or PET scan.
o LN bx
o CBC, ESR, Alk phos, LDH, renal and hepatic function tests
o Dx by Reed Sternberg cells (large, binucleated cells) in nodes and sometimes other sites
o Other labs mb abnormal, but not diagnostic:
o slight to mod inc in neutrophils
o Lymphocytopenia
o Eosinophilia and thrombocytosis
o Anemia: hypochromic and microcytic, in advanced dz
o elevated ALP with bone involvement, elevated LDH
123
• what is ddx of HL? Px?
o Ddx: Similar LA in infectious mono, toxoplasmosis, CMV, NHL, leukemia, sarcoidosis, macroglobulinemia, myeloma
o Px: 75% cure rate (5+ yr survival) with chemo, but many complications with therapy
124
• What is NHL?
o Group of d/os involving malignant proliferation of lymphoid cells; 80-85% are B Cell.
o More common than HL and occurs in all age groups, but incidence inc with age.
o Subtypes relate to the cell involved (precursor B cell neoplasms, mature B cell, precursor T cell, mature T cell). Mb indolent or aggressive.
125
• What are ssx of NHL?
o Most pts present with asx peripheral LAD
o Anemia initially in 1/3 of pts
o Symptoms usu dt compression of organs by enlarged nodes
o Aggressive form: rapidly growing LN, fever, night sweats, weight loss, elevated LDH and uric acid
o Indolent: Asx, alow growing LA, cytopenias, HSM
126
• How is NHL diagnosed?
o Suspect in pts with painless LA or mediastinal LA detected on CXR.
o Labs same as HL but no Reed Sternberg cells.
o Will see destruction of LN architecture and invasion of the capsule.
o Immunophenotyping to determine cell of origin
127
• What is ddx of NHL? Px?
o Ddx: infectious mono, toxoplasmosis, CMV, leukemia, sarcoidosis, lung carcinoma, TB
o Px: T Cell dz worse than B cell. Int’l Px Index considers 5 risk factors: advanced age, elevated LDH, number of sites, and stages. More risk factors = poorer px
128
• What is Burkitt’s Lymphoma?
o Highly undifferentiated B cell lymphoma involving areas outside the nodes
o Seen mostly in central Africa, primarily in children. 30% of childhood lymphomas in US are Burkitt’s. 95% in Africa is related to EBV
o Thought to be spread by an insect vector. Occurs frequently in pts with AIDS.
o In US, abdominal dz predominates.
o The most rapidly growing human tumor.
129
• What is Mycosis Fungoides?
o Rare T cell tumor of skin and sometimes the internal organs
o Insidious onset as an itchy plaque that spreads. Difficult to dx, until skin bx is done in later stages.
o Usu in people over 50; life expectancy 7-10 years
130
• What are the plasma cell d/os?
o A large group of d/os where a clone of Ig producing cells proliferates, producing lots of inactive Ig’s or fragments.
o Macroglobulinemia (Waldenstrom’s Macroglobulinemia)
o Multiple Myeloma
131
• What is Macroglobulinemia (Waldenstrom’s Macroglobulinemia)?
o Malignant plasma cell d/o
o B cells make excessive IgM.
o Looks like lymphoma in the lab
132
• What are ssx of macroglobulinemia?
o Dt circulating antigen/ab complexes
o Hyperviscosity syndrome, circulatory impairment
o Fatigue, weakness, weight loss
o Skin and mucosal bleeding
o Neurologic sx- visual impairment, headache, peripheral neuropathy
o Cold intolerance (Raynaud’s)
o LA, HSM
o Circulatory problems/volume overload may result in heart impairment
o MOST COMMON- weakness, fever, weight loss, oozing blood from nose/gum and recurrent infections
133
• How is macroglobulinemia diagnosed?
o Suspect in pts with sxs of hyperviscosity, particularly if anemia is present
o Usu incidentally with protein electrophoresis. ELP determines nature of the abnormal globulin
o Typical findings: N/N anemia, profound rouleaux formation, very high ESR
o Occasionally: leukopenia, relative lymphocytosis, thrombocytopenia
o Cold agglutinins, RF mb present
o Coagulation abnormalities mb present
o BM: increased plasma cells, lymphocytes, mast cells
o Hi Serum plasma viscosity
134
• What is px for macroglobulinemia?
o variable, many last more than 5 yrs
135
• what is Multiple Myeloma?
o dt plasma cell tumors with production of monoclonal Ig’s (IgG, IgA) and/or Bence Jones proteins
o Most common >40, males, African-Americans
136
• What are ssx of MM?
o Most common: Persistent unexplained bone pain, esp in back or thorax; Weight loss; Fatigue; Recurrent bacterial infections; Renal failure
o Pathological fractures and vertebral collapse
o Anemia
o Rare to see an enlarged liver or spleen, or LA
137
• When should you suspect MM?
o pts > 40 with persistent unexplained bone pain (esp at night or at rest), and who have the above typical sxs
o or unexplained blood or urine protein levels, hypercalcemia, renal insufficiency, or anemia
138
• How is MM diagnosed?
o Start with CBC, ESR, CMP, CRP
o N/N Anemia in 80%, with rouleau. Normal WBCs, platelets
o BUN, creatinine, uric acid, CRP, calcium often elevated
o serum protein high with an M spike on ELP
o Serum protein electrophoresis (SPEP) and Serum free monoclonal light chain (FLC)
o M-Protein in 80-90%, Bence Jones protein in 10-20%
o X-rays of bone show punched out lesions or diffuse osteoporosis in 80%
o BM bx shows increased plasma cells in sheets or clusters
139
• What is ddx of MM? px?
o Ddx: labs are important to dx; PE may not be helpful
| o Px: progressive and fatal, median survival 3-5 yrs.
140
• What are the d/os of Fe overload?
o Excess Fe is deposited in the tissues as hemosiderin causing tissue damage called hemochromatosis
o Primary Hemochromatosis
o 2nd Fe Overload
141
• What is Primary Hemochromatosis?
o Inherited d/o with excessive Fe accumulation causing tissue damage
o AR mutation of the HFE gene.
o Increased Fe absorption from GI tract. Controlled by Hepcidin, from liver
o Causes generation of reactive free hydroxyl radicals
142
• What are ssx of primary hemochromatosis?
o Symptoms are rare before middle age
o Women: fatigue develops early
o Men: weakness, skin hyperpigmentation, arthralgia, impotence, liver cirrhosis or DM is initial presentation
o Hypogonadism in both sexes
o Liver Dz is most common complication leading to cirrhosis or carcinoma
o Heart failure, hyperpigmentation, DM, arthropathy
143
• How is primary hemochromatosis diagnosed? Tx?
o Suspect in pts with typical sxs, esp with unexplained hepatic abnormalities, and in pts with family hx
o Test serum Fe, transferrin saturation, serum ferritin, and gene assay
o Serum Fe (>300), transferrin sat (>50%), and ferritin are high
o Liver bx if ferritin is markedly high. Cirrhosis affects px
o Tx: phlebotomy
144
• What is 2nd Fe Overload?
o Can result from thalassemias or sideroblastic anemias (in defective erythropoiesis Fe absorption increases)
o Exogenous Fe administration may cause
o Repeated or massive transfusions may cause
o Liver dz may cause overload
