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Blood and Lymphatics > B&L Week 2 > Flashcards

B&L Week 2 Flashcards

1
Q

what are the three steps in platelet plug formation?

A
  1. adhesion
  2. aggregation
  3. activation
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2
Q

describe the adhesion phase in platelet plug formation

A

involves adhesion of platelets ot vessel wall

  1. exposed COLLAGEN of the subendothelium (i.e due to damage) binds to platelet surface GpIa/IIa
  2. subendothelium von Willebrand factor binds platelet GpIbIX
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3
Q

describe the activation phase of platelet plug formation

A

involves activation and secretion of granule contents

  1. collagen exposure activates prostaglandin synthesis within platelets–> TXA2 formation occurs
  2. this results in the release of ADP, serotonin, fibrinogen and enzymes from intracellular granules
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4
Q

describe the aggregation phase of platelet plug formation

A
  1. the released ADP and thromboxane A2 cause additional platelets to aggregate
  2. after GpIbIX binds to von Willebrand Factor (vWF), GpIIbIIIa is exposed and binds to fibrinogen, which binds to other platelets
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5
Q

describe the process of fibrin clot formation

A
  1. vessel injury also exposes tissue factor (TF–a membrane protein on subendothelial vessel wall) which initiates the coagulation system
  2. the coagulation cascade occurs on the platelet plug surface (i.e IIa and Xa occurs on phospholipids)
  3. intrinsic pathway and extrinsic pathway meet at factor Xa which converts prothrombin to thrombin–> fibrinogen to fibrin–> crosslinked fibrin aided by Factor XIIIa
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6
Q

what is the intrinsic clotting pathway

A

Factor XI–> Factor XIa catalyzes…

Factor IX–> Factor IXa (some also feeds in from extrinsic pathway) catalyses…

Factor X–> Factor Xa (aided by Factor VIIIa from Factor VIII catalyzed by thrombin in feedback loop) catalyzes…
—common pathway starts—
prothrombin–> thrombin (aided by V–>Va which is also catalyzed by thrombin in feedback loop) catalyzes…

  1. fibrinogen–> fibrin
  2. Factor XIII–> Factor XIIIa

Factor XIIIa helps catalyze fibrin–> crosslinked fibrin

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7
Q

what is the extrinsic clotting pathway

A

vascular injury–> tissue factor exposed–> TF forms complex with Factor VII which becomes an activated complex that catalyzes…

  1. Factor IX–> Factor IXa (which feeds into intrinsic pathway)
  2. Factor X–> Factor Xa (which then joins with the intrinsic pathway and the common pathway starts)
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8
Q

where does Factor V/Va play a role?

A

formation of Va is catalyzed by thrombin in a feedback loop

along with factor Xa, factor Va also helps convert prothrombin to thrombin

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9
Q

where does factor VIII/VIIIa work?

A

formation of VIIIa is catalyzed by thrombin in feedback loop

along with factor IXa, helps convert factor X–> factor Xa to feed into common pathway

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10
Q

in addition to feeding back into the conversion of factor V–>Va and factor VIII–> VIIIa, what other conversion does thrombin catalyze in a feedback loop?

A

factor XI–>XIa to further/start the intrinsic pathway

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11
Q

by what process is clotting terminated?

A
  1. endothelial cells produce THROMBOMODULIN, ANITHROMBIN and TFPI–> they also activate fibrinolytic mechanisms through production of tissue plasminogen activator 1, urokinase, plasminogen activator inhibitor and annexin 2
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12
Q

what does thrombomodulin do?

A

binds to thrombin, activates protein C and S, and ultimately inactivates Va and VIIIa

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13
Q

what does antithrombin do?

A

inhibits VIIa, XIa, IXa and IIa (thrombin)

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14
Q

what does TFPI do?

A

inhibits proteases, mainly VIIa/TF

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15
Q

what does plasmin do?

A

comes from plasminogen, which is activated by tissue plasminogen activator to form plasmin

plasmin cleaves fibrin

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16
Q

where are platelets produced

A

bone marrow by megakaryocytes

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17
Q

how many platelets can be produced by one megakaryocyte

A

4000

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18
Q

what is the main regulator of platelet production

A

thrombopoietin (increases the number and maturation rate of megakaryocytes)

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19
Q

what is a normal platelet count

A

150-400 X 10^9/L

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20
Q

how does size differ between old and new platelets

A

new platelets are larger than old platelets

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21
Q

what percentage of circulating platelets are trapped at any one time within the spleen

A

up to 1/3

can be up to 90% if patient has massive splenomegaly

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22
Q

what is the normal life span of platelets

A

7-10 days

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23
Q

how are platelets removed from circulation

A

50% removed by the spleen
33% removed by the liver
17% removed by bone marrow/lymph nodes/other tissues

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24
Q

describe the size and shape of platelets

A

discoid shape

3-5um diameter

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25
Q

describe the structure of platelets

A
  1. external glycoprotein coat–> many platelet receptors, important for platelet adhesion and aggregation
  2. plasma membrane–> invaginations increase surface area for coagulation factor absorption; membrane phospholipids provide critical template for coagulation cascade reactions
  3. platelet cytosol contains A. alpha granules (proteins associated with adhesion and clotting) and B. dense granules (calcium, nucleotides, serotonin)
  4. NO NUCLEUS
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26
Q

what is the primary function of platelets

A

formation of initial hemostatic plug at site of vascular injury

  1. adhesion to vessel wall
  2. secretion of granule contents
  3. aggregation

*progression activation of platelet leads to significant shape change

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27
Q

how does a platelet achieve adhesion to vessel wall

A
  1. normal platelet flow is halted by engagement of GpIaIIa with exposed COLLAGEN in subendothelium
  2. subendothelial microfibrils bind von Willebrand factor which then binds to GpIbIX (on platelets)

….platelets become more spherical, extrude pseudopods and form a monolayer

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28
Q

how do platelets achieve secretion of granule contents

A
  1. collagen exposure–> activates prostaglandin synthesis–> arachadonic acid cascade–> thromboxane A2 formation
  2. activation of phospholipase C–> increased Ca2+ concentration within platelets–> granule release
  3. release ADP, serotonin, fibrinogen, enzymes
  4. triggers further conformational change and activation
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29
Q

how do platelets achieve aggregation

A
  1. GpIbIX binding leads to activation of GpIIbIIIa, which exposes binding sites for fibrinogen
  2. fibrinogen binds platelets to each other
  3. this is NOT the coagulation cascade
  4. ADP and thromboxane A2 recruit other platelets
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30
Q

how are the steps of 1. secretion of granule contents and 2. aggregation in the formation of a platelet plug related?

A

release of ADP and TXA2 recruit other platelets and these then become activated releasing more ADP and TXA2 and so on and so forth

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31
Q

what role do platelets play in coagulation?

A
  1. phospholipid is required for 2 steps of the coagulation cascade, Xa and IIa
  2. membranes of activated platelets provide exposed phospholipid surface
  3. bound fibrinogen also helps localize the clot
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32
Q

what two factors in particular are required to bind platelets to each other?

A

GpIIbIIIa on the platelet surfaces and fibrinogen linking them

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33
Q

what two factors in particular are required to anchor platelets to sites of endothelial damage?

A

von willebrand factor (on endothelium) and GpIbIX on the platelets

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34
Q

what are the three groups of abnormalities in primary hemostasis (and each of their two sub groups?)

A
  1. vessel wall–> either congenital or acquired
  2. platelet–> qualitative (defect in platelet function) and quantitative (low platelet count)
  3. von willebrand disease–> either congenital or acquired
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35
Q

what are the three main groups of QUALITATIVE congenital platelet function abnormalities?

A
  1. receptor defect–> problem with the membrane
  2. storage pool defect–> problem with hemoglobin
  3. secretory defect–> problem with enzymes
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36
Q

what are two qualitative platelet platelet receptor deficiency disorders?

A
  1. Bernard Soulier Syndrome (GpIb)–> adhesion defect; variable bleeding and large platelets
  2. Glanzmann thrombasthenia (GpIIbIIIa)–> defective aggregation, significant bleeding
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37
Q

what is a qualitative congenital platelet release/secretory defect disorder?

A

defective signal transduction with impaired granule content release–> inhibits activation

causes aspirin-like defect

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38
Q

list 3 qualitative congenital platelet granule content/storage pool platelet disorders

A
  1. Grey platelet syndrome
  2. Hermansky Pudlak syndrome
  3. Quebec platelet disorder
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39
Q

what is grey platelet syndrome?

A

qualitative congenital platelet granule content disorder

absent alpha granules

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40
Q

what is Hermansky Pudlak syndrome

A

qualitative congenital platelet granule content disorder

dense granule deficiency, associated with oculocutaneous albinism

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41
Q

what is Quebec platelet disorder

A

qualitative congenital platelet granule content disorder

rare autosomal dominant disorder–> 40 members in 1 canadian family

excessive platelet urokinase production–> leads to impaired clot stability and delayed bleeding

patients response to fibrinolysis inhibitors

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42
Q

what are the qualitative acquired platelet function defect categories?

A
  1. drugs
  2. systemic conditions
  3. hematologic disease
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43
Q

what drugs cause qualitative acquired platelet disorders?

A
  1. aspirin/NSAIDs–> inhibit cyclooxygenase; reduced TXA2 synthesis–> impaired activation and aggregation (in the case of aspirin, this effect is irreversible for the life of the platelet)
  2. Clopidogrel–> inhibits ADP binding to receptor–> impaired ADP mediated aggregation (irreversible for life of platelet)
  3. Heparin–> binds platelets–> can inhibit aggregation
  4. IIbIIIa inhibitors–> potent inhibitors of platelet aggregation–> mimics Glanzmann thrombasthenia
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44
Q

what are the qualitative acquired platelet disorders stemming from systemic conditions?

A
  1. renal failure (uremia)

2. cardiopulmonary bypass

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45
Q

what are the qualitative acquired platelet disorders stemming from hematologic disease

A
  1. myelodysplatic syndromes
  2. myeloproliferative syndromes (platelet dysfunction may occur especially with very high platelet counts)
  3. paraproteinemias (protein causes on specific impairment of adhesion and aggregation)
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46
Q

what is PFA-100

A

screening tool to assess platelet aggregation

will be abnormal in von willebrands disease and some congenital platelet function defects

affected by ASA/NSAIDs

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47
Q

how do you distinguish between qualitative and quantitative platelet disorders using…

  1. history
  2. laboratory testing
A
  1. history
    - chronicity of problem
    - family history of bleeding disordesr
    - comorbid conditions (i.e renal failure, known MPN)
    - medications
  2. laboratory testing
    - CBC
    - peripheral blood morphology
    - chemistry (renal function, SPEP if appropriate)
    - specialized testing
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48
Q

what are the mechanisms of quantitative platelet disorders/thrombocytopenias?

A
  1. reduced production
  2. sequestration
  3. increased destruction/consumption
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49
Q

what are congenital causes of reduced production of platelets (thrombocytopenia)

A

may have associated platelet function defect (usually bernard Soulier syndrome)

usually have large/giant platelets; some have other hallmark morphologic features (i.e white cell inclusions in May-Hegglin anomaly)

some are associated with congenital anomalies

platelet transfusions are effective but should be reserved for serious bleeding or surgery

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50
Q

what are acquired causes of reduced production platelets (thrombocytopenia)

A
  1. nutritional–> B12 or folate deficiency
  2. infiltrative–> hematologic or non hematologic
  3. marrow failure syndromes –> myelodysplastic syndrome, aplastic anemia
  4. medication–> i.e chemotherapy

platelet transfusions are effective–> rarely required unless platelet count is less than 10 or significant bleeding

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51
Q

what causes increased sequestration/hypersplenism?

A

spleen normally sequesters up to 1/3 of circulating platelet pool–> increases in any cause of splenomegaly

  1. congestive splenomegaly–> Budd Chiari; cirrhosis/portal HTN
  2. reactive splenomegaly–> infections (i.e EBV, malaria), hemolytic anemias, some autoimmune diseases
  3. infiltrative–> benign (sarcoidosis, amyloidosis, storage disease) or malignant (nearly all are hematologic)

platelet transfusions are of limited effect because spleen just continues sequestering

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52
Q

what are causes of increased consumption of platelets (causing thrombocytopenia)

A
  1. ITP (immune thrombocytopenia/idiopathic thrombocytopenia)
  2. drug induced i.e heparin induced thrombocytopenia (HIT)
  3. sepsis
  4. DIC
  5. microangiopathic hemolytic anemia (HUS, TTP)
  6. significant blood loss
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53
Q

what is ITP?

A

immune/idiopathic thrombocytopenia

platelet equivalent of AIHA–> RES, spleen mediated clearance of antibody coated platelets

antibody is not readily identifiable; spleen is NOT enlarged

children–> most commonly post-viral and self-limiting

adults–> usually chronic, may be relapsing, remitting

  • more common in women
  • can be associated with connective tissue disease (i.e SLE, lymphoproliferative disease i.e CLL)
  • can be triggered by medication (i.e sulfa drugs)

increased platelet turnover

platelet count variable, clinical manifestations are rare unless platelets are less than 30

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54
Q

what is the clinical presentation of ITP

A

clinical manifestations are rare unless platelets are less than 30

easy bruising, mucosal bleeding, petechiae

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55
Q

how do you treat ITP

A

in adults, only treat if platelets are less than 30 or patient requires an invasive procedure

can treat with

  • steroids
  • IVIG
  • splenectomy
  • immunosuppressive drugs

platelet transfusions are ineffective

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56
Q

what is HIT

A

heparin induced thrombocytopenia

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57
Q

what is the mechanism of heparin induced thrombocytopenia (HIT)

A

heparin-dependent antibody mediated platelet activation

PF4 in alpha granules secreted upon platelet activation–> avidly binds circulating heparin–> complex is immunogenic

IgG-heparin-PF4 complex binds platelet surfaces via platelet Fc receptors and via heparin receptors

binding causes platelet activation, degranulation and platelet aggregation

severe thromboembolic predisposition and consumptive thombocytopenia

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58
Q

when is the usual onset of HIT?

A

4-14 days after initiation of heparin therapy

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59
Q

what is the incidence of HIT

A

1-5% of patients exposed to heparin, depending on patient population

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60
Q

what is the incidence of venous and/or arterial thromboembolism at 30 days

A

50%

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61
Q

what is the Tx for HIT

A

stop heparin

usually give alternative anticoagulant

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62
Q

what is DIC

A

disseminated intravascular coagulation

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63
Q

what is the mechanism of DIC

A

diffuse activation of the coagulation cascade, consuming clotting factors–> coagulopathy

thrombocytopenia often occurs in DIC due to increased consumption of platelets

DIC is most commonly caused by

  1. sepsis
  2. malignancy
  3. obstetrical emergency

most cases are dominated by bleeding–> rarely can lead to MAHA/thrombosis (malignancy)

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64
Q

what is the treatment for DIC

A

must treat underlying cause

supportive platelet and plasma transfusion depending on clinical scenario and platelet count

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65
Q

name two thrombotic microangiopathies

A

hemolytic uremic syndrome (HUS)

thrombotic thrombocytopenic purpura (TTP)

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66
Q

what are microvascular occlusive disorders

A

a group of disorders (i.e HUS, TTP) characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes

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67
Q

what triggers the microvascular occlusive disorders

A
  1. toxin-mediated endothelial damage (HUS)
  2. congenital absence of metalloprotease named ADAMRS13 (familial TTP)
  3. autoantibody causing deficiency of ADAMTS13 (primary TTP)
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68
Q

what does ADAMTS13 do?

A

malfunctions in this metalloprotease have been implicated in TTP

normally, this metalloprotease would cleave unusually long von willebrand factor multimers, but when there is a problem with this compound, unusually long VWF multimers persist and cause adhesion and aggregation of platelets improperly

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69
Q

what is the classic PENTAD for TTP

A
  1. thrombocytopenia
  2. microangiopathic hemolytic anemia
  3. fever
  4. neurologic symptoms and signs
  5. renal impairment

accumulation of large VWF multimers–> platelet aggregation–> microthombi

if left untreated, has a mortality of 90%!!!

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70
Q

what is the Tx for TTP

A

MEDICAL EMERGENCY

  1. plasma exchange–> removes autoantibody and large VWF multimers; replacement plasma provides fresh source of metalloprotease enzyme; requires placement of large bore central line; daily treatments until platelet count normalizes
  2. aspirin often added to reduce micro thrombi
  3. corticosteroid for refractory or relapsed cases

PLATELET TRANSFUSIONS ARE CONTRAINDICATED

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71
Q

what are two major categorizations for the mechanisms of common bleeding disorders?

A
  1. platelet and platelet-related abnormalities

2. coagulation factor abnormalities

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72
Q

what are 4 platelet or platelet related causes of bleeding disorders?

A
  1. ITP
  2. secondary thrombocytopenia
  3. aspirin use
    4 .von willebrand disease
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73
Q

what is the mechanism of lack of platelets in ITP

A

increased platelet desctruction–> idiopathic, may be seen in association with other diseases

abnormal IgG prematurely removes platelets from circulation via macrophages of reticuloendothelial system (especially in the spleen)

IgG is commonly directed via GpIIbIIIa

shortens platelet lifespan to just a few hours (hence causes thrombocytopenia)

total megakaryocytes and platelet turnover increase in parallel

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74
Q

what is the onset of ITP

A

insidious, with petechial hemorrhage, easy bruising, menorrhagia in women

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75
Q

Tx of ITP

A

corticosteroids (prednisone)

high dose IVIG (for life threatening hemorrhage)

immunosuppressive drugs

monoclonal Abs (Rituximab)

splenectomy (for refractory patients)

platelet transfusions (only lasts for a few hours)

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76
Q

what is secondary thrombocytopenia

A

increased platelet destruction

due to HIV infection, H. pylori infection, CLL and Hodgkin’s lymphoma (marrow infiltration via lymphoproliferative disorders), autoimmune hemolytic anemia, collagen vascular diseases (SLE), drug induced (heparin, quinine, quinidine, chemotherapy) and post-transfusion reaction

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77
Q

how does aspirin use cause a platelet related bleeding disorder

A

inhibition of cyclooxygenase (COX 1 and 2) leading to impaired thrombozane A2 synthesis–> consequent impairment of platelet aggregation via AA, collagen and ADP

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78
Q

where is VWF normally produced

A

in megakaryocytes and endothelial cells

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79
Q

what is the role of VWF

A

2 roles:

  • promotes platelet adhesion to subendothelium at high shear rates
  • carrier molecules for Factor VIII (protection from premature destruction)
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80
Q

what are the typical symptoms of VW disease?

A

typically mucocutaneous bleeding (platelet disorder) ie epistaxis, menorrhagia, operative hemorrhage

rarely hemarthroses and muscle hematomas (deep tissue bleeding due to factor problem)

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81
Q

list 7 bleeding disorders that can be classified as coagulation factor abnormalities

A
  1. hemophilia
  2. vitamin k deficiency
  3. factor disease due to liver disease
  4. DIC
  5. warfarin use
  6. heparin use
  7. lupus anticoagulant
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82
Q

what is hemophilia

A

-hereditary coagulation disorders

-hemophilia A–> factor VIII deficiency
factor VIII is synthesized in liver and endothelial cells; missense/framseshift/deletion/flip-tip inversion at factor VIII gene

-hemophilia B–> factor IX deficiency
factor IX is vitamin K dependent

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83
Q

Tx for hemophilia A

A

factor VIII replacement

DD-arginine vasopressin with fluid restriction (for milder hemophiliacs)

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84
Q

Tx for hemophilia B

A

recombinant factor IX

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85
Q

how does vitamin K cause a coagulation factor bleeding disorder

A
  • fat soluble vitamin K obtained from green vegetables and gut bacteria synthesis
  • inadequate diet, malabsorption, inhibition of vitamin K by drugs (i.e warfarin) can cause deficiency
  • vitamin K functions in gamma-carboxylation of glutamic acid in coagulation factors–> this enables factors to bind Ca2+ and attached to the platelet phospholipid
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86
Q

how are the liver and vitamin K coagulopathies related?

A

the synthesis of vitamin K dependent clotting factors happens in the liver (factor II, VII, IX, X and protein C)

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87
Q

How can liver deficiency cause coagulopathies?

A

by messing with:

  • vitamin K-dependent factor synthesis
  • causing factor V, fibrinogen deficiency (severe)
  • thrombocytopenia from hypersplenism or immune complex-mediated platelet destruction
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88
Q

how can liver dysfunction cause coagulopathies?

A

through dysfibrinogenemia (abnormal fibrin polymerization, and thus dysfunctional fibrin clot formation)

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89
Q

what is DIC?

A

coagulation factor related bleeding disorder

widespread inappropriate intravascular deposition of fibrin with CONSUMPTION of coagulation factors and platelets

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90
Q

what can cause DIC?

A

consequence of abnormal release of procoagulants, endothelial damage, or platelet aggregation

i.e infections (HIV, CMV)
malignancy
hypersensitivity (anaphylaxis, incompatible blood transfusion)
widespread tissue damage (surgery, trauma, severe burns)

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91
Q

what is the pathophysiology of DIC

A
  • consequence of abnormal release of procoagulants, endothelial damage, or platelet aggregation
  • increased activity of thrombin overwhelming normal removal by natural anticoagulants (i.e tissue factor release)
  • excessive fibrin monomers formed by thrombin, which form complexes with fibrinogen and interfere with fibrin polymerization–> coagulation defect
  • intense fibrinolysis stimulated by thrombi interferes with fibrin polymerization –> coagulation defect
  • thus, combined action of thrombin and plasmin cause DEPLETION of fibrinogen and all coagulation factors
  • bleeding problems compounded by thrombocytopenia caused by consumption of platelets
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92
Q

how does warfarin cause bleeding disorders

A

it is a vitamin K antagonist

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93
Q

how might heparin use cause a bleeding disorder

A

normally used to prevent clotting

potentiates activity of antithrombin and inhibits thrombin (IIa) and factors IXa, Xa and IXa

LMWH has greater ability to inhibit factor Xa than to inhibit thrombin

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94
Q

describe the coagulopathy related to lupus anticoagulant

A
  • actually an antiphospholipid antibody associated with venous and arterial thromboses (in vivo)
  • interferes with lipoprotein-dependent stages of coagulation IN VITRO (detected by prolonged aPTT)
  • activates and stimulates coagulation cascade IN VIVO (known mechanism)–> clotting tendency….. pathologic thromboses of arteries and veins, including PLACENTAL vasculature… possible placental infarct and pregnancy loss
  • associated with antiphospholipid antibody syndrome–> occurrence of venous and arterial thrombosis and/or recurrent miscarriage in association with persistent antiphospholipid antibody
  • anticoagulant in vitro, procoagulant in vivo
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95
Q

what key findings must you seek on history in someone with a potential bleeding disorder

A
  • bleeding
  • family Hx of hematologic conditions
  • medications: ASA, warfarin, heparin, anti-inflammatories
  • age at first bleeding, consistency of symptoms throughout life–> to determine inherited vs. acquired
  • Hx of severe bleeding–> spontaneous vs. provoked; requirement for medical attention; Tx given
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96
Q

what would the following physical/hx findings indicate with regard to the potential etiology of a bleeding disorder

  1. mucocutaneous
  2. soft-tissue/joint
  3. one site/localized bleed
  4. multiple sites
A
  1. mucocutaneous–> disorder of primary hemostasis
  2. soft tissue/joint–> disorders of secondary hemostasis
  3. one site/local bleed–> could be structural or single organ related
  4. multiple sites–> more likely hemostatic problem
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97
Q

describe the course of investigations for a bleeding disorder

A
  1. initial evaluation, Hx and physical–> 2. initial hemostasis tests: CBC, platelets, PTT, PT/INR, fibrinogen/TT –> 3a. either other cause identified-thrombocytopenia, abnormal PT, low fibrinogen, abnormal TT OR 3b. prolonged PTT that corrects on 1:1 mixing study or no abnormalities

if 3b–> VWD assays and factor VIII tests

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98
Q

what does an elevated PTT indicate?

A

indicates a problem in the INTRINSIC pathway

several options:

A. factor DEFICIENCY: 8, 9, 11, 12 or VWD disorder

  • factor 12 deficiency does not cause bleeding
  • factor 11 in uncommon
  • factor 8 and 9 are X linked so uncommon in women
  • factor 8 is carried on VWD and therefore can be low in VWD disorder

B. coagulation factor INHIBITOR–>

  • lupus anticoagulant
  • heparin
  • acquired factor 8 inhibitor
  • *follow up with mixing study if elevated PTT
  • mixing study differentiates between factor deficiency and inhibitor
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99
Q

why would you do a mixing study if elevated PTT

A

follow up with mixing study if elevated PTT

  • mixing study differentiates between factor deficiency and inhibitor
  • if PTT improves on 50:50 mix then its a factor deficiency
  • if PTT remains elevated then an inhibitor is present
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100
Q

what does elevated PTT indicate?

A

problem in the EXTRINSIC pathway

i.e factor 7 deficiency

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101
Q

what can elevated PTT and PT indicate?

A

problem in the COMMON pathway or in fibrinogen

  1. factor deficiency common pathway–> 1, 2, 5, 10
  2. factor deficiency of multiple factors, both intrinsic and extrinsic (12, 11, 9, 8, and 7)
  3. hemophilia A/factor 8
  4. hemophilia B/factor 9
  5. vitamin K (2, 7 9, 10)
    6 liver disease (TT not prolonged because fibrinogen is synthesized in extra-hepatic sites and not just the liver)
  6. DIC (increased consumption)–> all coagulation times are prolonged

*to differentiate between vitamin K deficiency or liver disease just give vitamin K and you’ll see improvement within a few hours

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102
Q

what can elevated TT indicate?

A

problem with prothrombin (factor 2)

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103
Q

what elements of a history would suggest the cause of abnormal bleeding as hematologic?

A
  • hematologic bleeding can be due to platelet problems, VWF defects or deficiency, or coagulation factor problems
  • hx should be focused on history of bleeding, medications, family fx of bleeding, detailed hx of any trauma that elicited bleeding, diet, social etc…
  • key questions:
    1. is the bleeding at one or multiple sites?
    2. age at first bleeding symptom
    3. consistency of bleeding symptoms
    4. is it spontaneous or provoked by trauma, childbirth or procedures
    5. any previous reasons for medical attention including previous transfusions
    6. any previous treatment given
    7. how severe is the bleeding
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104
Q

what elements of a history would suggest the cause of abnormal bleeding is non-hematologic?

A
  • non hematologic bleeding is mainly due to any trauma or other abrasion on intact blood vessels
  • a details Hx on any trauma or PAIN due to damage of endothelium of blood vessels should be elicited

*same key questions as for hematologic causes–> use these questions to distinguish between the two

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105
Q

what elements of a physical exam would help you distinguish between hematologic versus non hematologic causes of abnormal bleeding?

A
  1. hematologic–> active bleed or bruising with the absence of signs of additional organ trauma is indicative of hematologic causes
  2. non-hematologic–> source of potential bleed should be found (in addition to indications of trauma such as skin abrasions or damage to other organs)
106
Q

how can laboratory testing be used to distinguish between hematologic and non-hematologic cause for abnormal bleeding?

A

**mainly guided by hx and physical exam

  • CBC and differential (can give indication if the body’s physiological response to bleeding is appropriate–> ie are platelets elevated?)… this could also show if there are any other outstanding hematological problems (i.e pancytopenia due to a hematological malignancy)
  • PT + PTT + TT are basic screening tests to see if clotting factors are functioning properly
  • further workup can be done depending on what was brought up in the hx
107
Q

what in a history could help distinguish whether the cause of abnormal hematologic bleeding is due to platelets or clotting factors?

A
  • hx should be focused on history of bleeding, medications (ASA, heparin, NSAIDs, clopidogrel), family hx of bleeding, detailed hx on any trauma that elicited bleeding, diet, social etc…
  • for platelets: inquire about any hx of easy bruising, epistaxis, menorrhagia, bleeding after dental procedures, GI bleeding, prolonged bleeding
  • for clotting factors: ask about previous hx of soft tissue bleeding (large diffuse bruising) or joint bleeding (joint swelling)
108
Q

how can the physical exam help distinguish between abnormal hematologic bleeding caused by platelets versus clotting factors

A

-for platelets:
ay signs of nose bleeds, GI bleeds on DREs or gum bleeding; petechiae or purpura suggest a larger underlying problem when there are low platelet counts

-for factors:
diffuse hematomas are suggestive of soft tissue bleedings (deep bleeding); any signs of swollen joints should be noted

109
Q

how can lab tests help distinguish the cause of abnormal hematologic bleeding as being due to platelets versus factors

A
  1. for platelets:
    - platelet count (as part of CBC)
    - platelet morphology on peripheral blood smear
    - RBC and WBC morphology on blood smear (may indicate other signs such as burr cells found in renal failure for example)
    - bleeding time (insensitive test)
    - PFA-100 to assess the proper qualitative function of platelets
    - miscellaneous tests (B12/folate for platelet deficiency, medication levels, kidney, liver and thyroid tests)
  2. for factors:
    - PT, PTT, TT to fully assess the clotting cascade
    - factor levels (mainly VIII and IX for hemophilias) and vitamin K levels
    - liver function tests to assess for severe liver damage (must be extensive to elicit decreased amounts of clotting factors)
    - thyroid function tests
110
Q

how can the hx be used to distinguish between qualitative and quantitative platelet disorders causing abnormal hematologic bleeding

A
  1. qualitative:
    - ask about hx of bleeding disorders to elicit any congenital causes of bleeding
    - current medications that impair platelet function (NSAIDs, ASA, clopidogrel, heparin, IIbIIIa inhibitors)
    - medical conditions affecting function of platelets (renal failure, cardiopulmonary bypass, MDS, paraproteinemias)

________

  1. quantitative:
    - ask about history of bleeding disorders to elicit any congenital causes of bleeding

A. causes of decreased production

  • nutritional deficiencies (B12, folate)
  • presence of infiltrative diseases, marrow failure syndromes or medication that may be causing low platelet levels (i.e chemo)

B. causes for splenomegaly

  • ask about liver problems (cirrhosis causing portal HTN and splenomegaly) that may lead to thrombocytopenia
  • infections like EBV or malaria causing splenomegaly
  • infiltrative diseases causing splenomegaly

C. causes for increased consumption
-ask about previous diagnosed diseases states indicating increased platelet consumption (i.e ITP, TTP, HIT, DIC, sepsis)

111
Q

how can the physical exam be used to distinguish between qualitative and quantitative platelet disorders causing abnormal hematologic bleeding

A

it is difficult to differentiate qualitative and quantitative causes based on physical exam

for quantitative: check for speno or hepatomegaly, and check for bone pain or general muscle wasting suggesting malignancy (marrow failure states)

112
Q

how can lab tests be used to distinguish between qualitative and quantitative platelet disorders causing abnormal hematologic bleeding

A
  1. qualitative:
    - platelet count (some congenital platelet defects are associated with low platelet count)
    - platelet morphology on peripheral blood smear (pale poorly granulated platelets in MDS for example)
    - bleeding time (not commonly used)
    - PFA-100 to assess platelet aggregation
  2. quantitative:
    - platelet count gives a good indication if the problem stems from the number of platelets in the system (although some qualitative causes can also lead to lower platelet counts)
113
Q

how can you use hx to distinguish between clotting factor deficiency versus clotting factor inhibition as a cause of abnormal hematologic bleeding?

A

hx should be focused on hx of bleeding, medications, family hx, detailed hx on any trauma that elicited bleeding, diet (vitamin K), social etc…

  1. for deficiency:
    - vitamin K deficiency from diet
    - other special disease states such as liver disease (due to decreased production of some factors)
    - with the hx of bleed, congenital causes should be taken into account (i.e hemophilias, VWF disease etc…)
  2. for inhibitor:
    - medications (i.e heparin, warfarin)
    - ask about any possible autoimmune disease states (antibodies may form complexes against clotting factors)
114
Q

how can you use physical exam to distinguish between clotting factor deficiency versus clotting factor inhibition as a cause of abnormal hematologic bleeding?

A
  • check for hepatomegaly

- hard to distinguish deficiency from inhibitor states on general physical exam

115
Q

how can you use lab tests to distinguish between clotting factor deficiency versus clotting factor inhibition as a cause of abnormal hematologic bleeding?

A
  • PTT, PT, TT to assess the clotting cascade
  • factor levels (mainly VIII and IX for hemophilias) and vitamin K levels
  • liver function tests to assess for severe liver damage

MIXING STUDY is the main tests to distinguish deficiency from inhibitor if PTT, PT or TT studies are abnormal

116
Q

what is the “mental pathway” when determining the causes of abnormal bleeding?

A
  1. hematologic or non-hematologic?
  2. if hematologic, is it due to platelets or factors?
  3. is its due to platelets is it qualitative or quantitative?
  4. if its due to factors, is it due to deficiency or inhibition?
117
Q

what are the two components of splenic pulp?

A
  1. white pulp–> lymphoid nodules

2. red pulp–> splenic tissues rich in RBCs

118
Q

what is splenic white pulp?

A

lymphoid nodules

play an important immunological role

119
Q

what is splenic red pulp?

A

splenic tissue rich in RBCs

destruction of senescent RBCs–> worn out or fragile RBCs, which have lost pliability, cannot re-enter circulation and are phagocytosed by macrophages

consists of SPLENIC CORDS that are separated by SPLENIC sinuses

120
Q

what are splenic cords

A

found in splenic red pulp

contain reticular cells and fibers, T and B cells, macrophages, plasma cells and RBCs

121
Q

what are reticular cells

A

specialized fibroblasts

122
Q

what type of fiber makes up reticular fibers

A

type III collagen

123
Q

how are cells of the spleen supported?

A

by a fine meshwork of reticular fivers (type III collagen)

124
Q

how are reticular fibers synthesized?

A

by reticular cells

125
Q

what is the “hierarchy” of the vasculature of the spleen?

A

splenic artery—> trabecular arteries—> central arteries—> penicillar arterioles

126
Q

describe the route of the splenic artery

A

enters the hilum of the spleen and divides into trabecular arteries

127
Q

describe the route of the trabecular arteries in the spleen

A

stem from the splenic artery

enter the parenchyma of the spleen by following connective tissue trabaculae

become central arteries at the point that the arteries leave the trabeculae and enter the parenchyma (no longer following along with connective tissue trabeculae)

128
Q

describe the route of the central arteries in the spleen

A

stem from the trabecular arteries

are enveloped by a sheath of T cells called the peripheral lymphatic sheath (PALS)

peripheral white pulp surrounds the PALS

marginal zone sinuses surround the peripheral white pulp

129
Q

what is the function/structure of the peripheral white pulp that surround the PALS/central arteries in the spleen?

A

contains a germinal center for B cells maturation

contains mostly B cells

130
Q

what is the structure/function of the marginal zone sinuses that surround the peripheral white pulp in the spleen?

A

serves to form a bridge between the innate and adaptive immune system response

a heavy concentration of macrophages is present in this region and serves to take up blood-borne pathogens

B cells in this region can be activated by macrophages or can directly respond to blood-borne pathogens

131
Q

describe the route of the penicillar arterioles

A

stem from the central arteries, once they enter the red pulp and branch

132
Q

what is the open circulation theory (RE: blood supply in the spleen)

A

blood leaves the penicillar arterioles and enters the splenic parenchyma

from there, they squeeze through the walls of the sinusoids to drain out of the organ via the pulp/trabecular/splenic veins

133
Q

what is the closed circulation theory (RE: blood supply in the spleen)

A

penicillar arterioles drain directly into the sinusoids and thus the blood always remains in closed vessels

134
Q

what is the basic structure and function of the thymus

A

site for T cell maturation

has two lobes, which are joined by connective tissue–> each lobe is enclosed by a connective tissue capsule that sense septa into the organ

septa serve to further divide each lobe into numerous lobules

135
Q

describe the two parts of the thymus lobules

A
  1. cortex–> darker peripheral zone containing more T lymphocytes, therefore staining darker
    - contains extensive population of developing T lymphocytes, epithelial reticular cells (ERCs) and macrophages
    - developing T lymphocytes are very darkly stained cells
    - ERCs are fewer in number and are stellate cells with pale staining oval nuclei–they are derived from foregut endoderm and serve as supportive cells that provide a 3D framework to the thymus
  2. medulla–> lighter central zones
    - contains the same cells as the cortex but fewer T cells
    - T cells in the medullae are differentiated
    - presence of HASSALL’S CORPUSCLES–> contain flattened ERCs that are arranged in a concentric manner and are filled with keratin filaments–> their function is unknown
136
Q

how does the thymus change over a person’s lifetime

A

as the thymus matures over a person’s lifetime, it undergoes involution (shrinkage)–> this is under the control of steroid hormones

parenchyma becomes replaced by adipose tissue

boundary between the cortex and medulla becomes indistinct

137
Q

what is the structure and function of the thymic-blood barrier

A

processes of ERCs wrap themselves around the thymic arterioles and capillaries and are therefore also called “nurse cells”

thymic arterioles and capillaries are particularly impermeable to proteins in the circulating plasma due to a thick basal lamina and non-fenestrated endothelium

together, these prevent most circulating antigens from reaching the cortex of the thymus and thus constitute the thymic-blood barrier

it prevents premature exposure of lymphocytes to foreign and self antigens so that an immune reaction does not occur.

138
Q

what are the common hematological malignancies we need to know

A 
acute myeloid leukemia (AML)
acute lymphoid leukemia (ALL)
chronic lymphocytic leukemia (CLL)
chronic myelogenous leukemia (CML)--a myeloproliferative disorder
myelodysplastic syndrome
multiple myeloma
139
Q

pathophysiology of ALL

A

a lymphoid malignancy arising in the bone marrow, in which all the malignant cells are BLASTS

more common in children than in adults (most common malignancy in children)

mutations in a hematopoietic stem cell lead to immportality and blast arrest, as well as lymphoid differentiation

trillions of malignant cells fill the marrow and suppress normal hematopoiesis

140
Q

what are the symptoms associated with ALL

A

symptoms of cytopenia:

anemia (fatigue, pallor)
neutropenia (infections)
thrombocytopenia (bruising, bleeding)

141
Q

how is ALL diagnosed

A

sometimes all 3 cell lines are low, sometimes just 1 or 2

CBC and peripheral blood smear will identify cytopenia and blasts in blood

bone marrow aspirate and biopsy are diagnostic

**leukemia lymphoblasts lack specific morphological (no granules) or cytochemical features, therefore diagnosis depends on immunophenotyping

cytogenics: philadelphia chromosome in ~25% of adult ALL cases

flow cytometry on marrow blasts shows that cells are lymphoid and they are all blasts

142
Q

pathophysiology of AML

A

AML is basically the same as ALL except the malignant cells are myeloid (rather than lymphoid) blasts

most common in adults than children

uncontrolled growth of blasts in marrow leads to:

  • suppression of normal hematopoietic cells
  • appearance of blasts in peripheral blood
  • accumulation of blasts in other sites
  • metabolic consequences of a large tumor mass
143
Q

what are the two etiological distinctions for AML

A
  1. primary–> de novo

2. secondary–> hematologic malignancies (MPD or MDS) or previous chemotherapy agents

144
Q

how might you know its AML versus ALL

A

Auer rods (red needle like inclusions withing the cytoplasm of some AML blasts)–> pathognomonic of AML

145
Q

diagnosis of AML

A

Auer rods (red needle-like inclusions within the cytoplasm of some AML blasts) which are pathognomonic of AML

presents with symptoms of pancytopenia (fatigue, bruising etc…)

in some cases, blasts can trigger DIC

diagnosis requires a bone marrow aspirate and biopsy–with special tests on blasts i.e flow cytometry

cytogenetics, immunophenotyping

146
Q

what is the blast count from the bone marrow aspirate in AML?

A

in AML > 20%

normal is

147
Q

pathophysiology of chronic lymphoid leukemia (CLL)

A

lymphoid malignancy in BM in which not all malignant cells are blasts (in fact, malignant cells are all mature lymphoid cells)

mutations in hematopoietic stem cell lead to immortality and mature lymphoid differentiation

malignant cells start in BM and spill into blood

disease of older adults

same disease as small lymphocytic lymphoma (SLL) except that CLL arises in the bone marrow and SLL arises in the lymph node

148
Q

diagnosis of CLL

A

made on basis of blood and marrow findings

lymphocyte counts in CLL may be very high (>30% of all nucleated cells) but each cells looks relatively normal (special tests are required to prove they are malignant)

peripheral blood smear–> lymphocytes are small and mature; smudge cells

patients are often asymptomatic

symptomatic patients present with fatigue, weight loss, anorexia (may have splenomegaly)

high lymphocyte counts (non0functioning malignant lymphocytes, thus susceptible to infections)

malignant cells spread to lymph node in some cases

may develop cytopenia but this can take years to occur

149
Q

pathophysiology of multiple myeloma

A

malignancy of PLASMA cells (made from B cells)

mutations in a plasma cell makes it malignant and its copies spread through (and suppress) the marrow

massive spread of plasma cells leads to destruction of bone (multiple lytic lesion; bone lysis leads to hypercalcemia and pathological fractures)

malignant cells secrete clonal immunoglobin (meaning more of this immunoglobin is produced than all others)

production of cytokines (ie IL-6) by the malignant plasma cells causes much of their localized damage and creates an environment in which the malignant cells thrive

malignant plasma cells can also produce paraprotein, which is an abnormal antibody that can cause kidney damage/dysfunction

150
Q

diagnosis of multiple myeloma

A

serum protein electrophoresis shows a single band, representing the single clonal antibody which is being massively overproduced by the malignant plasma cell

serum protein electrophoresis shows monoclonal gammopathy (also called presence of M-protein) and find it in urine as well (protein produced by plasma cells)

bone marrow aspirate and biopsy shows significantly increased plasma cells in bone marrow (>30% plasma cells)

plasmacytoma on tissue biopsy

bone pain and pathological fractures from bone lysis

hypercalcemia from bone lysis

renal failure due to monoclonal gammopathy and hypercalcemia

thrombocytopenia, leukopenia

anemia from bone marrow suppression by malignant plasma cells and from renal failure (low EPO)

recurrent infections–> monoclonal gammopathy suppresses normal Ab production

151
Q

what are lymphomas

A

hematologic malignancies arising in lymphoid tissue, usually within a lymph node but frequently within extra-nodal tissue (i.e in the GI tract)

can spread around body to another lymph node or even to the bone marrow

152
Q

what is hodgkin lymphoma

A

tumor consists mostly of reactive inflammatory cells with malignant Reed-Sternberg cell lymphocytes

153
Q

what are Reed-Sternberg cell lymphocytes?

A

large multinucleated or have bilobed nucleus with prominent eosinophilic inclusion-like nucleoli only found in Hodgkin lymphoma

154
Q

what is non-hodgkin’s lymphoma

A

all the cells in the tumor are malignant lymphocytes

155
Q

diagnosis of lymphomas

A

lymph node biopsy (in order of increasing sensitivity–> fine needle aspiration, needle core biopsy, excisional)

pathology–> analyze tumor regarding morphology, phenotype, genotype

156
Q

what is the Ann Arbor staging method used in the diagnosis of lymphomas?

A

1= single lymph node region OR extranodal site involved

2= two or more lymph node regions OR extra nodal sites involved on the same side of the diaphragm

3= involvement of both sides of the diaphragm, including one organ or area near the lymph node or spleen

4= disseminated involvement of one or more extralymphatic organs, including: liver, BM, nodular involvement of lungs

157
Q

pathophysiology of myelodysplastic syndrome

A

clonal disorder affecting hematopoietic maturation

characterized by ineffective hematopoiesis–> marrow is trying to make new cells, but the dysplasia shows that cell development is abnormal and many cells die (apoptosis) before they can leave the marrow

BM failure with resultant cytopenias, often culminating in florid acute leukemia

cytopenia even though the BM is hypercellular

sequence of successive DNA mutations in an early blood cell precursor–> evolution of this cell into a “clone” (self reproducing abnormal cell, growth advantage over normal marrow cells)

158
Q

diagnosis of myelodysplastic syndrome

A

anemia +/- thrombocytopenia +/- neutropenia

bone marrow aspirate/biopsy shows hypercelluar BM with cells that have dysplastic features such as abnormalities of nuclear shape (hyperlobated neutrophils)

peripheral blood film shows:

  • RBC macrocytosis with normal B12 and folate and no other causes of macrocytosis such as cirrhosis or EtOH
  • WBCs have decreased granulocytes and abnormal morphology (i.e bilobed or unsegmented nuclei–> pelger abnormality)
  • platelets–> thrombocytopenia, abnormalities of size and cytoplasm (i.e giant hypergranular platelets)
159
Q

list 4 myeloproliferative disorders

A

chronic myeloid leukemia (CML)

polycythemia vera (PV)

essential thrombocythemia (ET)

idiopathic myelofibrosis (IMF)

160
Q

what is the basic pathophysiology behind the myeloproliferative disorders

A

clonal myeloid stem cells abnormalities leading to overproduction of one or more cell lines (leading to abnormalities in erythrocytes, platelets and other cells of myeloid lineage)

161
Q

pathophysiology of CML

A

myeloid malignancy arising in the bone marrow in which not all malignant cells are blasts

mutations in a hematopoietic stem cell, which must include a bcr-abl (an active tyrosine kinase) rearrangement (usually t[9;22])

malignant cells fill marrow and often colonize the spleen

**most common myeloproliferative disorder

malignant cells retain the capacity to mature past the blast cell stage, so you see a full range of myeloid maturation

162
Q

what is the one thing almost every case of CML has in common?

A

one specific mutation–> philadelphia chromosome (t[9;22])

163
Q

diagnosis of CML

A

testing of blood and bone marrow, including genetic testing of philadelphia chromosome

peripheral blood smear shows 1. leukoerythroblastic picture (immature RBC and granulocytes present, i.e myelocytes and normoblasts) and 2. presence of different mid-stage progenitor cells

marrow is hypercellular, with marked myeloid hyperplasia in bone marrow

often see clustering of megakaryocytic

fatigue and weight loss due to anemia and hypermetabolic states

massive splenomegaly, may present with LUG discomfort, early satiety

CBC shows high neutrophil count with many immature neutrophil forms and mature neutrophils

commonly eosinophilia and basophilia

164
Q

what differentiates CML from AML

A

the presence of different mid-stage progenitor cells on peripheral blood smear

165
Q

what is polycythemia vera

A

stem cell disorder characterized by elevated RBC mass accompanied by increased white cell and platelet production

primary polycythemia–> excessive RBC production from an abnormal marrow, without EPO stimulation

166
Q

what must you rule out in the diagnosis of PV

A

other causes of elevated hematocrit

i.e spurious polycythemia–> in dehydration, Hct appears increased because less plasma volume

true polycythemia/secondary polycythemia–> marrow response to hypoxia or high EPO levels due (chronic hypoxia due to lung carcinoma; renal cell carcinoma)

check pO2 to rule out hypoxia
check EPO levels to rule out this as a cause

167
Q

what is the mutation associated with primary PV

A

mutated JAK2 protein that binds to the EPO receptor–> binding promotes signalling independent of EPO stimulation and hypersensitivity to cytokines

168
Q

what are the specialized lab tests used to confirm PV

A

EPO-independent stem cell colony growth assay

JAK2 mutation testing

169
Q

what are the WHO diagnostic criteria for PV

A

*two A criteria +1 other A or 2 B criteria are required

A criteria:

  • elevated red cell mass >25% above mean predicted value
  • no cause of secondary erythrocytosis (arterial pO2 >92%)
  • palpable splenomegaly
  • clonal genetic abnormality other than bcr-abl fusion gene

B criteria:

  • thrombocytopenia
  • leukocytosis
  • BM biopsy revealing panmyelosis with erythoid and megakaryocytic proligeration
  • low serum EPO levels
170
Q

what is essential thrombocythemia?

A

overproduction of platelets in absence of recognizable stimulus

platelet counts are very high–> always >600, often greater than 1000

negative philadelphia chromosome

acquired JAK2 mutation

ET shows megakaryocyte hyperplasia

platelets can be functional or dysfunctional–> patients can clot or bleed

thrombotic complications can include DVT, MI, cerebrovascular accident

bleeding complications can include excessive bruising, GI bleeding

171
Q

what is idiopathic myelofibrosis

A

megakaryocytes in marrow not only produce platelets, but also secrete PLATELET-DERIVED GROWTH FACTOR, a cytokine that stimulates fibrosis

megakaryocyte proliferation can either lead to too many platelets (ET) or to fibrosis (IMF)

in IMF, fibrosis fills the marrow space, leaving little or no room for hematopoiesis

172
Q

diagnosis of IMF

A

on blood film:
leukoerythroblastosis with tear drop RBCs, nucleated RBCs, variable polychromasia, large platelets and megakaryocyte fragments

on BM biopsy:
fibrosis, atypical megakaryocyte hyperplasia, thickening and distortion of bony trabeculae (osteosclerosis)

173
Q

what hematologic malignancy presents with philadelphia chromosome in ~25% of all adult cases

A

ALL

174
Q

what hematologic malignancy would show Auer rods?

A

AML

175
Q

what would the blast count be in AML

A

> 20% (versus >5% normal)

176
Q

where does SLL arise? CML?

A

Cml–> BM

Sll–> lymph node

177
Q

in what hematologic malignancy might you expect to see bone lysis and hypercalcemia, as well as pathological fractures?

A

multiple myeloma, due to massive spread of plasma cells leading to destruction of bone

178
Q

in what hematologic malignancy might you expect to see a single band on serum protein electrophoresis representing a single clonal antibody that is being massively overproduced?

A

multiple myeloma

179
Q

what you expect the bome marrow asporate and biopsy to show in multiple myeloma?

A

> 30% plasma cells

180
Q

why might you see renal failure in multiple myeloma

A

due to monoclonal gammopahty and hypercalcemia

181
Q

how are Hodgkin’s and non-Hodgkin’s lymphomas differentiated on the cellular level?

A

Hodgkin’s displays Reed-Sternberg cell lymphocytes, which are large, multinucleated or bilobed nucleus cells with prominent eosinophilic inclusion-like bodies (none found in non-Hodgkin’s)

in non-Hodgkin’s, all cells in the tumor are malignant lymphocytes whereas Hogkin’s tumors consist mostly of reactive inflammatory cells

182
Q

what would you see on a bone marrow aspirate/biopsy of someone with MDS?

A

hypercellular BM with cells that have dysplastic features such as abnormalities of nuclear shape (hyperlobated neutrophils)

183
Q

what would you see on a peripheral blood film of someone with MDS?

A

RBC macrocytosis with normal B12 and folate and no other causes of macrocytosis such as cirrhosis or EtOH

WBCs may display decreased granulocytes and abnormal morphology (ie. bilobed or unsegmented nuclei= Pelger abnormality)

Platelets display thombocytopenia and abnormalities of size and cytoplasm (i.e giant hypogranular platelets)

184
Q

which hematologic malignancy is MOST associated with the philadelphia chromosome?

A

CML

essentially every case of CML shares this specific mutation

185
Q

what would you expect to see on the peripheral blood smear of someone with CML

A

leukoerythroblastic picture–> immature RBCs and granulocytes present, such as myelocytes and normoblasts

presence of different mid-stage progenitor cells differentiates it from AML (in AML all cells are blasts)

186
Q

would you expect to find splenomegaly in CML?

A

yes

187
Q

define primary polycythemia

A

excessive RBC production from an abnormal marrow, without EPO stimulation

mutated JAK2 protein binds to EPO-receptor, which promotes signalling independent of EPO stimulation and hypersensitivity to cytokine

188
Q

what are two underlying causes for secondary polycythemia?

A

hypoxia or high EPO

189
Q

why do you need to make sure the patient is not dehydrated if you suspect polycythemia?

A

because dehydration can make the hematocrit appear increased because less plasma volume present

190
Q

do you see philadelphia chromosome in essential thrombocythemia?

A

no

191
Q

do patients clot or bleed in essential thrombocythemia?

A

can do either depending on if excess platelets are functional or not

192
Q

what would you expect to see on a peripheral blood film of someone with idiopathic myelofibrosis?

A

leukoerythroblastosis with tear drop RBCs, nucleated RBCs, variable polychromasia, large platelets and megakaryocyte fragments

193
Q

what would you expect to see on a BM biopsy of someone with IMF?

A

fibrosis
atypical megakaryocyte hyperplasia
thickening and distortion of bony trabeculae (osteosclerosis)

194
Q

what must you look for on physical exam with someone in whom you expect a hematologic malignancy

A

look for signs of cytopenia or organ infiltration
1. thrombocytopenia–> petechiae/ecchymoses/purpura
2. anemia–> pallor
3. neutropenia–> signs of infection
4. hepatomegaly/splenomegaly/
lymphadenopathy

195
Q

what are specific things you would ask on history for someone in whom you suspect a hematological malignancy

A

age
previous chemo
previous cancer

symptoms of cytopenia:
anemia–> fatigue, pallor, dyspnea
neutropenia–> repeated infections
thrombocytopenia–> bruising, bleeding

systemic sx–> night sweats, fever, weight loss

sx of splenomegaly–> upper left shoulder pain, early satiety

196
Q

what is the overall goal of ordering a “coagulation screening panel”

A

a series of tests that differentiates between hematologic and non-hematologic bleeding, and platelet versus factor causes (if hematologic)

197
Q

what tests are associated with the coagulation screening panel?

A
  1. PT/INR
  2. aPTT
  3. CBC
  4. TT

**non-hematologic bleeding (i.e structural vascular disorder) will NOT results in abnormal coagulation tests

198
Q

what does the following test, included on the coagulation screening panel, test for; what do the results mean?

PT/INR

A

PT is prothrombin time–> measures how long it takes blood to clot

assess extrinsic and common pathways

199
Q

what does the following test, included on the coagulation screening panel, test for; what do the results mean?

aPTT

A

aPTT is activated partial thromboplastin time

long time means your blood is taking longer to clot (short aPTT times are not very clinically relevant)

assesses intrinsic and common pathways

mixing studies on mildly elevated PTT values (50:50 patient and normal control plasma) can differentiate between factor deficiency and factor inhibitor (i.e lupus anticoagulant, which is a pathologic factor inhibitor)

200
Q

what does the following test, included on the coagulation screening panel, test for; what do the results mean?

CBC with differential

A

assess RBCs and Hb (anemia), platelets (thrombocytopenia) and neutrophils (neutropenia)

201
Q

what does the following test, included on the coagulation screening panel, test for; what do the results mean?

TT

A

assesses the activation of fibrinogen to fibrin–> activation of factor 1 to 1a

excess thrombin is added to the reaction, which also includes an anticoagulant, and the time it takes for the blood to clot in the presence of this excess thrombin is measured

activity of thrombin is not actually tested, despite the tests name

202
Q

in addition to the coagulation screening panel, what other tests may be ordered in the assessment of a patient with a suspected hematological malignancy?

A
  1. liver enzymes and serum creatinine (AST, ALT, GGT, albumin, INR)–> rule out possible secondary causes of bleeding
  2. peripheral smear (basic)–> look at cell morphology and size
  3. bone marrow core biopsy (look at BM architecture, presence of fat spaces, normal cell variety; assess hypercellularity, invasion of trabecular bone/spicules, different cell maturation stages)–> need clinical suspicion of hematological malignancy
  4. bone marrow aspirate (assess free cells for morphology, i.e blasts, mitosis, predominance of any lineage (erythroid, myeloid, lymphoid)–> i.e auer rods are pathognomonic for CML
  5. flow cytometry–> done to further characterize tumor cells and guide treatment; assess relative numbers of hematopoietic cells and their maturation states
  6. karyotype, cytogenetic analysis, FISH, PCR–> to further characterize tumor cells and guide tx; morphological analysis of chromosomes from tumor cells i.e philadelphia chromosome
  7. CSF sample–> assess severity and spread of malignancy and guide tx
  8. CXR–> mediastinal masses/widening due to hilar lymphadenopathy
  9. CT/ultrasound of the abdomen if concerned about lymphoma
203
Q

what are ways to categorize hematologic malignancies

A
  1. bone marrow versus lymph node
  2. if bone marrow, acute versus chronic
  3. myeloid versus lymphoid
204
Q

list the acute hematologic malignancies

A

AML

ALL

205
Q

what are three ways that AML and ALL are classified?

A
  1. malignancy of bone marrow
  2. acute
  3. AML–> myeloid; ALL–> lymphoid
206
Q

what differentiates the chronic from the acute bone marrow malignancies

A

acute–> all blasts; cells in maturation arrest

chronic–> not all blasts; cells are maturing

207
Q

what are the chronic myeloid bone marrow hematologic malignancies

A
  1. myeloproliferative disorders (MPD)–> cells are proliferating too much
    - chronic myeloid leukemia (CML)
    - polycythemia vera (PV)
    - essential thrombocythemia (ET)
    - idiopathic myelofibrosis (IMF)
  2. myelodysplastic syndrome–> cells are maturing abnormally
208
Q

what is a way to characterize the difference between the two chronic myeloid malignancies (MPDs versus MDS)

A

MPD–> cells are proliferating too much

MDS–> cells mature abnormally

209
Q

list the two chronic lymphoid bone marrow malignancies

A
  1. chromic lymphoid leukemia (CLL)
  2. multiple myeloma (MM)–> plasma cells; NOT a leukemia because the malignant cells usually remain in the bone marrow, rather than entering circulation like in leukemias
210
Q

what are ways to categorize hematologic malignancies

A
  1. bone marrow versus lymph node
  2. if bone marrow, acute versus chronic
  3. myeloid versus lymphoid
211
Q

list the acute hematologic malignancies

A

AML

ALL

212
Q

what are three ways that AML and ALL are classified?

A
  1. malignancy of bone marrow
  2. acute
  3. AML–> myeloid; ALL–> lymphoid
213
Q

what differentiates the chronic from the acute bone marrow malignancies

A

acute–> all blasts; cells in maturation arrest

chronic–> not all blasts; cells are maturing

214
Q

what are the chronic myeloid bone marrow hematologic malignancies

A
  1. myeloproliferative disorders (MPD)–> cells are proliferating too much
    - chronic myeloid leukemia (CML)
    - polycythemia vera (PV)
    - essential thrombocythemia (ET)
    - idiopathic myelofibrosis (IMF)
  2. myelodysplastic syndrome–> cells are maturing abnormally
215
Q

what is a way to characterize the difference between the two chronic myeloid malignancies (MPDs versus MDS)

A

MPD–> cells are proliferating too much

MDS–> cells mature abnormally

216
Q

list the two chronic lymphoid bone marrow malignancies

A
  1. chromic lymphoid leukemia (CLL)
  2. multiple myeloma (MM)–> plasma cells; NOT a leukemia because the malignant cells usually remain in the bone marrow, rather than entering circulation like in leukemias
217
Q

are there any myeloid malignancies affecting the lymph node?

A

no

218
Q

what are the malignancies that affect the lymphoid tissue of the lymph node?

A

lymphomas–> non-hodgkins and hodgkins

219
Q

how would you characterize MM?

A

a chronic, lymphoid malignancy of the bone marrow

220
Q

how would you characterize AML?

A

an acute, myeloid malignancy of the bone marrow

221
Q

how would you characterize lymphoma?

A

a malignancy of the lymphoid tissue of the lymph node

222
Q

how would you characterize MPDs

A

chronic myeloid malignancy of the bone marrow

223
Q

how would you characterize MDS

A

chronic myeloid malignancy of the bone marrow

224
Q

what are some signs and symptoms of a bleeding problem

A 
epistaxis (node bleed)
gingival hemorrhage
oral mucous membrane bleeding 
skin hemorrhage (petechiae, ecchymoses) 
excessive bleeding in razor knicks
hemoptysis (rare)
hematemesis (rare)
hematuria (rare)
rectal bleeding
menorrhagia
post partum hemorrhage
spontaneous abortions 
hemarthroses (especially in hemophilia)
225
Q

in the presence of the following clinical symptom, what bleeding disorder might you suspect?

cephalhematomas in newborns
hemarthroses
hematuria and
intramuscular, intracerebral and retroperitoneal hemorrhages

A

severe hemophilias A and B
severe deficiencies of factor VII, X or XIII
severe type 3 VWF disease
afibrinogenemia

226
Q

in the presence of the following clinical symptom, what bleeding disorder might you suspect?

injury related bleeding and mild spontaneous bleeding

A 
mild and moderate hemophilias A and B
severe factor XI deficiency
moderate deficiencies of fibrinogen and factors II, V, VII or X
combined factors V and VIII deficiency
alpha2-antiplasmic deficiency
227
Q

in the presence of the following clinical symptom, what bleeding disorder might you suspect?

bleeding from stump of umbilical cord and habitual abortions

A

afibrinogenemia
hypofibrinogenemia
dysfinbrinogenemia
factor XIII deficiency

228
Q

in the presence of the following clinical symptom, what bleeding disorder might you suspect?

impaired wound healing

A

factor XIII deficiency

229
Q

hematoma

A

localized collection of blood outside the blood vessels, usually in liquid form and within the tissue

typically presents as a raised swelling

230
Q

in the presence of the following clinical symptom, what bleeding disorder might you suspect?

recurrent severe epistaxis and chronic iron deficiency anemia

A

hereditary hemorrhagic telangiectasis

231
Q

what are some symptoms

A

q

232
Q

deep tissue hemorrhage

A

a sign of FACTOR type bleeding

examples include hemearthrosis and deep tissue hematoma

233
Q

petechiae

A

tiny, non-blanching, pinpoint sized blotches that usually appear in clusters similar to a rash

blotches are less than 3mm in size

the presence of petechiae suggests PLATELET type bleeding

234
Q

purpura

A

blotches similar to petechiae only larger in size–> between 3-10 mm

blotches are also non-blanching

the presence of purpura may indicate non-hematological defects (i.e vasculitis)

235
Q

describe the formation of platelets from a megakaryocyte

A

megakaryocytes mature via endomitotic synchronous replication (DNA replication in absence of cytokinesis)

plasma membrane invaginations form (platelet demarcation membrane)

cytoplasm becomes granular

cytoplasmic fragmentation–> 1000-5000 platelets per megakaryocyte

236
Q

what lab tests are used to diagnose acute leukemias

A

CBC–cytopenias

peripheral blood smear– usually see blasts

bone marrow aspirate/biopsy– sheet of blasts, reduced fat spaces

237
Q

what test is used to distinguish between AML and ALL based on cell type

A

flow cytometry on bone marrow can be used to determine whether the cells are lymphoid or myeloid blasts and subclassify further based on morphology

238
Q

what is the mechanism by which acute leukemia causes anemia and thrombocytopenia

A

acute leukemia causes damage to the bone marrow, displacing normal bone marrow cells with a high number of immature (blasts and thus acute leukaemia) white blood cells

this leaves little space for growth of other types of blood cells (i.e platelets and RBCs) and therefore you get symptoms of anemia and thrombocytopenia

239
Q

what are the steps of differentiation of granculocyte (neutrophil, eosinophil, basophil) white blood cells in the bone marrow

A
  1. myeloblast–> variable size, large nucleus, no granules–> mitosis–>
  2. promyelocytes–> slightly larger, developed primary cytoplasmic granules–> divide and differentiate–>
  3. myelocytes–> have specific/secondary cytoplasmic granules–> separate lineages can now be ID-ed–> divide and differentiate–>
  4. metamyelocytes–> start of post-mitotic maturation
    - -> non-dividing cells, cytoplasm is filled with specific granules–>
  5. “band” cells, which are a form between metamyelocytes and fully mature granulocytes, may occur in the periphery and may be held in reserve in the bone marrow–>
  6. mature granulocyte
240
Q

describe the maturation process of lymphocytes

A

hematopoietic stem cell differentiates–> lymphoblast dividing–> pro lymphocyte (some B and T cell specific surface markers)

  1. immature T lymphocytes travel to thymus with surface markers–> gain maturation and antigenic differentiation in the thymus
  2. immature B cells develop in the bone marrow and eventually circulate in blood until differentiate upon encountering an antigen
241
Q

what lab tests are used to diagnose acute leukemias

A

CBC–cytopenias

peripheral blood smear– usually see blasts

bone marrow aspirate/biopsy– sheet of blasts, reduced fat spaces

242
Q

what test is used to distinguish between AML and ALL based on cell type

A

flow cytometry on bone marrow can be used to determine whether the cells are lymphoid or myeloid blasts and subclassify further based on morphology

243
Q

what is the mechanism by which acute leukemia causes anemia and thrombocytopenia

A

acute leukemia causes damage to the bone marrow, displacing normal bone marrow cells with a high number of immature (blasts and thus acute leukaemia) white blood cells

this leaves little space for growth of other types of blood cells (i.e platelets and RBCs) and therefore you get symptoms of anemia and thrombocytopenia

244
Q

what is involved in the induction therapy for ALL?

A
  • goals or this section of therapy are to eliminate initial leukemia burden, restore normal bone marrow function and improve patient performance status
  • multidrug regimens are administered for 4-6 weeks until patient is in remission, with response to therapy assessed by examination of the bone marrow
  • after the start of induction therapy, the use of hematopoietic growth factors reduces myelosuppression and allows more intense doses of chemo to be used
  • after admin of induction chemo, when blood counts have recovered, a bone marrow biopsy should be performed to confirm that the patient is in complete remission, defined as the absence of bone marrow blasts cells–> persistence of blasts carries very poor prognosis and these patients should receive a second round of induction therapy
  • if disease is refractory to chemo, they should proceed directly to allogenic stem cell transplantation although chances of cure are low
245
Q

goal of tx of ALL

A

in patients with good performance, goal is cure of disease

246
Q

are the three stages of ALL tx

A
  1. remission/induction
  2. consolidation
  3. maintenance
247
Q

what is involved in induction therapy for ALL

A
  • after attainment of clinical remission
  • goals are to attain a durable complete clinical remission by elimination of residual leukemia cells (minimal residual disease) and to prevent emergence of drug-resistant clones
  • consolidation consists of sequential use of multidrug regimens that may be a modification of the induction regimens over a period of 6 months
248
Q

what are some adjuctive therapies used in ALL and what do they treat?

A
  1. hematopoetic growth factors to limit the effects of myelosuppression
  2. transfusion of blood products when required, prophylactic
  3. therapeutic antimicrobial therapies for neutropenic fever or infectious complications
  4. regimens to reduce uric acid nephropathy as a consequence of tumor lysis syndrome (using therapeutic uric oxidase i.e Rasburicase, loop diuretics and hemodialysis)
249
Q

what is involved in the induction therapy for ALL?

A
  • goals or this section of therapy are to eliminate initial leukemia burden, restore normal bone marrow function and improve patient performance status
  • multidrug regimens are administered for 4-6 weeks until patient is in remission, with response to therapy assessed by examination of the bone marrow
  • after the start of induction therapy, the use of hematopoietic growth factors reduces myelosuppression and allows more intense doses of chemo to be used
  • after admin of induction chemo, when blood counts have recovered, a bone marrow biopsy should be performed to confirm that the patient is in complete remission, defined as the absence of bone marrow blasts cells–> persistence of blasts carries very poor prognosis and these patients should receive a second round of induction therapy
  • if disease is refractory to chemo, they should proceed directly to allogenic stem cell transplantation although chances of cure are low
250
Q

how long does ALL induction therapy usually last

A

4-6 weeks

251
Q

how is response to ALL induction therapy judged

A

examination of bone marrow

252
Q

what is involved in induction therapy for ALL

A
  • after attainment of clinical remission
  • goals are to attain a durable complete clinical remission by elimination of residual leukemia cells (minimal residual disease) and to prevent emergence of drug-resistant clones
  • consolidation consists of sequential use of multidrug regimens that may be a modification of the induction regimens over a period of 6 months
253
Q

what is involved in maintenance therapy for ALL

A

all patients with ALL require continued but less intensive chemo regimen following the consolidation phase to maintain long term remission

if relapse occurs MORE than 2 years after initial tx, treatment regimens similar to the original protocol may be considered

for patients who relapse within 2 years or are resistant to conventional tx, options include a more intensive regiment (i.e high dose CYTARABINE or hyper-CVAD) or a clinical trial

all patients experiencing disease relapse should be considered for ALLOGENIC SCT and/or entry into a clinical trial

254
Q

when is allogenic stem cell transplantation recommended

A

although still somewhat controversial, allogenic sct is usually recommended to high risk patients with ALL in first remission and in those in second and subsequent remissions

for patients who relapse, this is the only curative approach

255
Q

why is CNS prophylaxis used on the tx of ALL

A
  • used to reduce leukemic CNS relapse/involvement
  • tx is initiated in the induction phase and continues throughout tx course
  • involves intrathecal and/or high dose systmeic chemo
256
Q

what is the prognosis for ALL in children

A

complete remission and overall 5 year survivial rates are approx 80%-85%

complete remission is the most important prognostic factor–> patients who do not achieve CR or who relapse have a dismal prognosis

CR involves recovery of blood counts, bone marrow containing

257
Q

what factors affect prognosis for ALL?

A
  1. age at diagnosis
  2. WBC count
  3. CNS status at diagnosis
  4. immunophenotype
  5. cytogenetics
258
Q

how does age affect ALL prognosis

A

children between age 1-9 have best prognosis

259
Q

how does WBC count affect ALL prognosis

A

elevated WBC at diagnosis >50 X 10^9/L have a poorer prognosis–> the greater the level of leukocytosis the poorer the prognosis

260
Q

how does CNS status at diagnosis affect ALL prognosis

A

CNS disease at diagnosis confers a poorer prognosis and is associated with an increased risk of both systemic and CNS tx failure

261
Q

hoes does immunophenotype affect ALL prognosis

A

precursor B cell ALL has best prognosis

T cell ALL has a poor prognosis

other phenotypes have a poorer prognosis; the phenotype determines alternative tx strategies

262
Q

does does cytogenetics affect ALL prognosis

A

hypodiploidy and the presense of specific translocations, ie philadelphia chromosome or t[4;11] are associated with a poorer prognosis than normal karyotypes

Blood and Lymphatics (2 decks)

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