Internal medicine - hematology Flashcards
1
Q
Anemia definition
A
A reduction in one or more of the major red blood cell measurements obtained as a part of the complete blood
count
2
Q
Mostly used parameters in measuring anemia?
A
Hemoglobin
Hematocrit
3
Q
Hemoglobin levels cut off for anemia?
A
Female: < 11.9 g/dL
Male < 13.6 g/dL
4
Q
Hematocrit cut of level for anemia
A
Female < 35%
Male < 40%
5
Q
Severe anemia level?
A
Hb 7-8 g/dL
Clinical features are present at this time
6
Q
three categories of anemia
A
Microcytic: MCV < 80 f/L
Normocytic: MCV 80-100 f/L
Macrocytic: MCV > 100 f/L
7
Q
Causes of microcytic anemia
A
IDA
ACD
B-thalassemia
Lead poisoning
Sideroblastic anemia
8
Q
Causes of Normocytic anemia
A
CKD
Aplastic Anemia
Blood loss
Hemolytic Anemia
9
Q
Causes if Macrocytic anemia
A
Reticulocytosis
Liver disease
Alcohol use
Myodysplastic syndrom
Hypothyroidism
Multiple Myeloma
Folic acid or Vit B deficiency
10
Q
TIBC stands for?
A
Total Iron Binding Capacity and differentiates between Iron deficiency anemia and Anemia of chronic disease
11
Q
Mentzer Index
A
MCV/RBC
Index <13 → suggests a thalassemia trait
Index >13 → suggests that the patient has an IDA or ACD
12
Q
Reticulocytes
A
Reticulocytes are immature red blood cells produced by Bone marrow. rage is 0.5-1.5%
13
Q
how do you know if the anemia is hypoproliferative or hyperproliferative?
A
You look at the reticulocyte % in the CBC
Hypo < 2%
Hyper > 2%
14
Q
States causing hyperproliferative anemia
A
→ Hemorrhage
→ Hemolytic anemia
15
Q
states causing hypoproliferative anemia
A
→ Leukemia
→ Aplastic anemia
→ Pure red cell aplasia
16
Q
Etiology of IDA
A
- Not enough consumed
- Increased utilization
- excessive loss
- incomplete absorption
17
Q
what to think if patient is refractory to oral iron treatment for IDA
A
autoimmune gastritis, and Helicobacter pylori
18
Q
total Iron in adult?
A
3.5-5g
19
Q
Daily iron loss?
A
< 1mg/day
20
Q
how is iron lost physiologically?
A
Exfoliation of intestinal epithelial and skin cells
The bile
Urinary excretion.
21
Q
where is most of the bodies iron found?
A
The heme portion of hemoglobin or myoglobin
In normal adults, hemoglobin contains 2/3 of the iron in the body.
22
Q
how long does an infant iron storage last?
A
4 months
23
Q
Dietary iron source
A
- 90% in the form of iron salts (nonheme iron) – absorption influenced by the persons storage
- 10% of dietary iron is in the form of heme iron, derived primarily from the hemoglobin and myoglobin of meat.
24
Q
factors influencing uptake of iron
A
Orange juice doubles the absorption of nonheme iron from the entire meal, whereas tea decreases it by 75%
25
In oral intake what state is iron in?
Fe3+ Ferric state
26
where is Iron reduced from oral form Fe3+ to Ferrous form?
In the stomach due to stomach secretions, referred to as reducing agents, include glutathione, ascorbic acid, and sulfhydryl
27
main iron absorption site?
Duodenum and jejunum
28
what shuttles iron in the body?
Transferrin transport iron between donating tissues and transmembrane transferrin receptors
29
what increases in the circulation during iron deficiency?
circulating transferrin receptors
30
what are the three sequential phases developing during IDA
Stage 1: Pre latent—decrease in storage iron
Stage 2: Latent—decrease in iron available for erythropoiesis
Stage 3: Anemia—decrease in circulating red blood cell parameters and decrease in oxygen delivery to peripheral tissue
31
clinical symptomes of IDA
Fatigue, lethargy
Pallor
Tachycardia, angina, dyspnea on exertion
32
what are the two types of anemias in macrocytic?
Megaloblastic or non-megaloblastic
33
causes of Macrocytic megaloblastic anemia
Vit B12 deficiency
Folate deficiency
Fanconi Anemia
Medications
34
medication causing megaloblastic anemia
o Phenytoin
o Sulfa drugs
o Trimethoprim
o Hydroxyurea
o MTX
o 6-mercaptopurine
35
what is the deal with the cells in megaloblastic anemia?
Insufficient nucleus maturation relative to cytoplasm expansion due to defective DNA synthesis and repair
36
what is the main reason for anemia in ACD?
Inflammation release cytokines IL6 and HEPCIDIN! which inhibits uptake and release and decrease response to EPO
37
etiology of ACD
→ Inflammation (rheumatoid arthritis, SLE)
→ Malignancy (lung cancer, breast cancer, lymphoma)
→ Chronic infections (tuberculosis)
38
what classification of anemia is ACD
First it presents as a normocytic anemia then becomes microcytic anemia
39
Classification of hemolytic anemia
1. By cause of hemolysis (intrinsic/extrinsic)
2. By Location (intravascular/extravascular)
40
Intrinsic causes of hemolytic anemia
1. RBC membrane defects: hereditary spherocytosis, Paroxysmal nocturnal hemoglobinuria
2. Enzyme defects: G6P dehydrogenase deficiency, PKD deficiency
3. Hemoglobinopathies: sickle cell disease, thalassemia
41
Extrinsic causes of hemolytic anemia?
Prosthetic heart valves
HUS
TTP
DIC
AIHA
CLL
Babesia
Hypersplenism
42
Causes if intravascular hemolytic anemia
Toxins
G6PD deficiency
Ab mediated
PNH
TTP, DIC, HUS, HELLP, SLE
43
causes of extravascular hemolytic anemia
destruction primarily by the spleen
sickle cell anemia
PKD deficiency
Spherocytosis
Ab mediated
44
Signs of hemolysis
* Jaundice
* Pigmented gallstones
* Splenomegaly
* Back pain and dark urine in severe hemolysis
with hemoglobinuria
45
signs of increased hematopoiesis
* BM expansion: widening of the diploic space of the
skull, biconcave deformity of the vertebral bodies
* Cortical thinning and softening of bone, ↑ risk of pathologic
fractures
* Extramedullary hematopoiesis: hepatosplenomegaly
46
How to differentiate between Ab mediated or non Ab-mediated hemolytic anemia?
COMBS test - positive means Ab mediated
47
what is the reticulocyte index in hemolytic anemia?
above 2%
48
what are factors highly suggesting hemolytic anemia?
→ Anemia + accelerated erythropoiesis (reticulocytotisis)
→ In addition to evidence of RBC destruction in serum and/or urine studie
49
define Aplastic anemia
Pancytopenia caused by bone marrow insufficiency (not Aplastic crisis due to parvovirus infection)
50
Etiology of Aplastic anemia
* Idiopathic in > 50% of cases (may follow acute hepatitis)
* Medication side effects
* Toxins: cleaning solvents, insecticides
* Ionizing radiation
* Viruses: HBV, EBV, CMV, HIV
51
Medication causing aplastic anemia
"Can't Make New Blood Cells Properly"
Carbamazepine, Methimazole, NSAIDs, Benzenes, Chloramphenicol, Propylthiouracil
52
what is the difference between aplastic anemia and aplastic crisis?
In aplastic crisis there is anemia only, not pancytopenia
53
How is the EPO level in aplastic anemia?
High
54
Findings on a BM biopsy in aplastic anemia
Hypocellular fat-filled marrow (dry bone marrow tap)
RBCs normal morphology
55
Define acquired thrombophilia
A predisposition to INCREASED coagulation that typically manifests with recurrent thromboembolism
56
Clinical features suggesting acquired thrombophilia
VTE under age of 50
Unprovoked
Weak risk factors
Unusual location
Frequent obstetric complications
Arterial TE in young with no CV risk
57
what to consider in a young patient with stroke but no CV risk?
Antiphospholipid syndrom
58
Name 12 causes of acquired thrombophilia
1. Surgery
2. Trauma
3. Malignancy
4. Immobilization
5. Smoking
6. Obesity
7. Antiphospholipid syndrome
8. Necrotic syndrome
9. OCP or HRT
10. Heparin induced
11. Pregnancy
12. Advanced age
59
VTE is an umbrella term for?
PE and DVT
60
Virchow's triad?
Hypercoagulability
Venous stasis
Endothelial damage
61
Transient risk factors for thrombosis?
1. Surgical
2. Immobilization
3. Estrogen induced
4. IV devices
5. Patient factors like obesity, smoking IV drug use
62
Chronic illness increasing risk of thrombosis?
Malignancy
Nephrotic syndrom
AI disorders like ALPA and IBD
Hereditary thrombophilia
63
Give three named signs of a DVT?
Homans sign: Calf pain in dorsal flexion
Meyer sign: Compression of the calf causes pain
Payr sign: Pain when pressure is applied over medial part of sole
64
Wells Criteria categories?
Medical history
Immobilization
Clinical features
Differential diagnosis (gives -2 points)
65
Interpretation of Wells criteria results?
0: low
1-2: intermediate
> 3: high
66
why do we do the Wells scoring?
to determine pre-test probability (PTP) and decide what to start with in the diagnostic steps
67
D-dimer levels
< 500 ng/ml - negative
> 500 ng/ml - positive
68
positive US findings on DVT
Non compressibility of the obstructed vein
Intraluminal hyperechoic mass
Distention of the affected vein
On Doppler imaging: Absent venous flow
69
is the sensitivity and specificity the same in every location for US DVT diagnosis?
proximal DVT is 90% but distal is 65%
70
border between distal and proximal DVT
popliteal vessels
71
why is it important to assess lab studies before treatment of DVT
to assess for organ function and bleeding risk before giving anticoagulation
72
what is the framework of AC treatment in DVT?
Start with bridging parenteral AC then long-term oral AC
73
timeframe if bridging AC in DVT treatment?
first 5-10 days giving parenteral and oral together until INR is maintained
74
When to give lead in AC in DVT
For Dabigatran and Edoxaban lead-in therapy is needed before the first dose (no overlapping)
75
DOACS
Apixaban (Factor Xa inhibitors)
Rivaroxaban (Factor Xa inhibitors)
Edoxaban (Factor Xa inhibitors)
Dabigatran (direct thrombin inhibitor)
76
what are the 5 parameters we look at to assess the coagulation system?
1. activated partial thromboplastin time (aPTT) - 35 sec
2. Prothrombin time (PT) - 10-30 sec
3. INR - < 1
4. Thrombin time (TT) - < 20 sec
5. Bleeding time
77
what does aPTT measure?
intrinsic pathway
78
what does PT measure?
Extrinsic pathway
79
what does TT measure?
common pathway
80
when is aPTT elevated?
* Hemophilia
* Vitamin K deficiency
* DIC
* Possibly in von Willebrand disease
* SLE (if lupus anticoagulant is present)
* Monitoring of unfractionated heparin (UFH) therapy
81
when is PT elevated?
* Vitamin K deficiency
* Factor VII deficiency
* DIC
* Monitoring of vitamin K antagonist therapy (INR)
82
when i TT elevated?
Low fibrinogen levels caused by liver disease or overconsumption (DIC)
Increased antithrombin activity (heparin)
Accelerated fibrinolysis (overconsumption, DIC)
83
what is also needed in the intrinsic coagulation cascade besides CF?
Phospholipids and Ca2+
84
Define antiphospholipid syndrome
Antiphospholipid syndrome (APS) is an AI disease associated with increased risk of thrombosis due to the presence of pro-coagulatory antibodies.
APS can manifest in isolation or alongside other autoimmune diseases such as systemic lupus erythematosus (SLE)
85
Primary etiology of Antiphospholipid syndrome?
Idiopathic
Ass with HLA-DR7
86
Secondary etiology of antiphospholipid syndrome
* SLE (most common cause of secondary APS)
* Rheumatoid arthritis
* Neoplasms
* HIV, hepatitis A, B, C
* Bacterial infections (syphilis, Lyme disease, tuberculosis)
87
main categories of clinical features in APS
Venous
Arterial
Capillary
Pregnancy
Non-thrombotic manifestation
88
Diagnostic criteria for APS
Minimal: 1 clinical + 1 laboratory must be present
89
Clinical APS presentation
Thrombosis
Premature birth < 34w
Multiple miscarriages
90
Lab findings in APS
2 antibody-positive blood tests at least 3 months apart
Lupus anticoagulant, anti-apolipoprotein antibodies, or anti-cardiolipin antibodies
Prolonged PTT
91
treatment of APS
Anticoagulation with Warfarin (DOAC is other option).
In pregnancy: LMWH and Aspirin, because Warfarin is teratogenic.
Anticoagulation helps prevent miscarriage
92
Define Hemophilia
Hereditary disorder of CF therefor leading to serious bleeding
93
types of hemophilias
Hemophilia A: VIII (most common)
Hemophilia B: IX
Hemophilia C: XI (very rare)
94
what parameter is prolonged in hemophilia?
aPTT is prolonged
95
Etiology of hemophilia?
X-linked AR inheritance (most common in males)
96
main symptom of hemophilia?
Spontaneous and late onset bleedings (especially in joints like knee)
97
what is the consequence of bleeding in the joints?
Hemophilic arthropathy
98
how is hemophilia diagnosed?
Patient history
Genetic testing
aPTT (prolonged)
Platelet count (normal)
PT (normal)
99
treatment options in hemophilia
substitute CF
Desmopressin (increase vWF release - increase F VII)
Antifibrinolytic therapy: E-Aminocaprionic acid
Emicizumab in Hemophilia A binds IX and X
100
Define vWD
Bleeding disorder characterized by a deficiency or dysfunction of von Willebrand factor (vWF). vWF is involved in platelet adhesion and prevents degradation of factor VIII. Therefore, vWF
deficiency or dysfunction impairs primary hemostasis as well as the intrinsic pathway of secondary hemostasis.
101
Types of inherited vWD
Type I Deficiency mild to moderate
Type II Dysfunction
Type III Complete absence
102
Causes of acquired vWD
1. Lymphoproliferative and myeloproliferative diseases
2. Autoimmune diseases (SLE)
3. CV defects (VSD, aortic stenosis)
4. Hypothyroidism
5. SE of drugs (valproic acid)
103
Symptoms of vWD
Mucocutaneous, gingiva and gum bleeding
Ecchymoses, easy bruising
Epistaxis
Petechiae
Prolonged bleeding from minor injuries
Bleeding after surgical procedures or tooth extraction
GI bleeding
Menorrhagia (affects up to 92% of women with vWD)
Postpartum hemorrhage
104
treatment of vWD
1. Desmopressin
2. vWD factor + F VIII concentrates
3. Antifibrinolytics
105
Define the reason for using anticoagulants
Treatment and prevention of embolic events
106
Vitamin K anticoagulants mechanism?
Inhibit Vit K epoxide so no recycling of the active and reduced form of Vit K
107
what must be measured i Vit K anticoagulants?
INR, prolonged PT time
108
antidote for Warfarin?
Give Vit K
109
DOACS?
Dabigatran DT
Rivaroxaban FX
Apixaban FX
Edoxaban FX
110
Dabigatran antidote?
Idarucizumab
111
Rivaroxaban and Apixaban antidote?
Adexanet-a
112
which DOAC does not have an antidote?
Edoxaban
113
Indications of DOACS
Prophylaxis of thromboembolism following:
o DVT and/or pulmonary embolism
o Prolonged immobilization after surgery (knee or hip surgery)
o Nonvalvular atrial fibrillation
114
Lab change in Warfarin?
increased PT and INR
115
Lab changes in direct thrombin inhibitors?
TT only
116
Lab changes in FXa inhibitors?
both PT and aPTT
117
Contraindications of anticoagulants
→ Coagulopathies
→ Acute bleeding, GI bleeding
→ Severe arterial hypertension, aneurysm
→ Recent cardiovascular events, endocarditis, stroke
→ Surgery or interventional procedures
→ Severe renal insufficiency
→ Pregnancy and breastfeeding
118
Special contraindication for Dabigatran?
concurrent administration of ketoconazole, itraconazole, cyclosporin
119
Prophylaxis and therapeutic administration of UFH
Prophylaxis: subcutaneous
Therapeutic: IV
120
what must be monitored during UFH administration?
Baseline platelet count must be taken and watch out for thrombocytopenia
121
What are the parenteral anticoagulants?
Heparin UFH and LMWH
122
choise of parenteral anticoagulants in kidney disease?
UFH because it has hepatic clearance
123
Low molecular weight heparin types?
Enoxaparin
Dalteparin
Tinzaparin
124
target of LMWH?
FXa
125
Do we have an antidote for LMWH?
can use protamin but only partial function
126
synthetic heparin?
Fondaparanux
127
can we give all parenteral anticoagulants as IV?
Just UFH, rest is subcutaneous
128
Indication for low dose therapy with heparin?
DVT prophylaxis in:
long term bedrest
PO
129
Indication for high dose therapy with heparin?
Immediate anticoagulation effect for:
Atrial fibrillation
DVT
Pulmonary embolism
Acute coronary syndrome
Myocardial infarction
Mechanical heart valve replacement
VTE prophylaxis for patients with hemodialysis, heart-lung machine
130
what anticoagulants can you switch to if you have HIT?
Direct FXa inhibitors
131
types of HIT?
Immune-mediated heparin-induced thrombocytopenia (type 2 HIT)
Non-immune heparin associated thrombocytopenia (type 1 HIT)
132
Define DIC
Characterized by thrombosis, hemorrhage, and organ dysfunction caused by systemic activation of the clotting cascade, which leads to platelet consumption + exhaustion of CF (LOSS OF LOCALIZED COAGULATION)
133
Types of DIC?
Acute
Chronic
134
Categories of DIC etiology? (10)
Infections
Trauma
Organ Failure
Malignancy
Toxins
Immunologic
Vascular malformation
Dilution
Drug interactions
135
Clinical presentation of DIC
▪ Hematemesis, hematochezia, hematuria
▪ Oozing of blood from surgical wounds or intravenous lines
▪ Petechiae, purpura, ecchymoses
▪ Massive hemorrhage: hemothorax, hemoperitoneum
136
what is the main reason of organ failure in DIC?
primarily due to Hypercoagulation
137
Diagnosis of DIC?
Must do a coagulation panel every 6-8h or until stable
138
Lab parameters in DIC:
↑ aPTT, ↑ PT
↓ Fibrinogen
↑ D-dimer
↑ Bleeding time
Coagulation factors: ↓ factor V and ↓ factor VIII
139
what cells are seen on a smear in DIC?
schistocytes
140
core-stone treatment in DIC?
FIRST: Manage underlying cause
RBC
FFP
Platelets
Antifibrinolytic treatment
141
when is RBC transfusion indicated?
Hemoglobin < 7g/dl
142
When in platelet transfusion indicated?
Active bleeding or high risk of bleeding: platelet count < 50,000/mm3
No bleeding: platelet count < 10,000–20,000/mm3
143
when is free frozen plasma indicated?
when PT and aPPT is x1.5 their normal value
144
Define thrombocytopenia
Platelet count below the normal range (< 150,000/mm3) that is most commonly due to either impaired platelet production in the bone marrow or increased platelet turnover in the periphery.
145
Major categories for etiology of impaired production of platelets?
BM failure
BM suppression
Congenital cause
Infection
Malignancy
Nutritional
146
Major categories for etiology of increased turnover of platelets in the periphery
Immune mediated ITP
Drug induced ITP
DIC
TTP
Pregnancy
Infection
Mechanical damage
147
Levels of platelets in midl, moderate and severe thrombocytopenia?
Mild 70-150.000
Moderate 20-70.000
Severe < 20.000
148
When to think about ITP as a diagnosis?
if isolated thrombocytopenia with no other cause
149
treatment of thrombocytopenia
Treat cause
Stop medication than can cause it
If mild, new CBC in 1-4 weeks
Severe: IVIG or platelet transfusion
150
AB that can cause thrombocytopenia?
Linezolid
Vancomycin
TMP-SMX
Penicillin
Ceftriaxone
Rifampin
151
Define thrombocytosis
Thrombocytosis is generally defined as a substantial increase in circulating platelets over the normal upper limit of 450 G/L
152
Three major classifications of thrombocytosis
1. Hereditary or familial thrombocytosis associated with germline mutations of the thrombopoietin (THPO) gene
2. Thrombocytosis associated with myeloproliferative neoplasms and/or myelodysplastic disorders
3. Reactive (secondary thrombocytosis)
153
Conditions causing reactive thrombocytosis
▪ Chronic/acute blood loss/ chronic inflammatory diseases, chronic infections
▪ Asplenic states and splenectomy
▪ Malignancies
▪ Rebound thrombocytosis following treatment of immunological thrombocytopenic purpura
▪ Pernicious anemia
▪ Discontinuance of myelosuppressive drugs
▪ Myelodysplastic anemia
▪ Hemolytic anemias
154
Define essential thrombocytopenia
Isolated uncontrolled proliferation of platelets not caused by another condition
155
Genetic markers for essential thrombocytopenia
o JAK2 mutation: 50–60% of patients
o CALR mutation: 26% of patients
o MPL mutation: 4% of patients
156
treatment of thrombocytosis
Treat cause
Mild: observe or give low dose aspirin
Severe: Hydroxyurea, Interferon alpha to reduce platelets
157
What are the two types of thrombotic microangiopathies?
TTP
HUS
158
Define TTP
Thrombotic thrombocytopenia purpura is a a thrombotic microangiopathy in which microthrombi, consisting primarily of platelets, form and occlude the microvasculature due to acquired autoantibodies against a proteolytic enzyme that cleaves von Willebrand factor (vWF).
159
what is the main difference between the thrombotic microangiopathies TTP and HUS?
TTP: due to autoantibodies against the protease normally cleaving vWF
HUS: due to bacterial toxin causing endothelial damage --> thrombosis
160
At what age is the occurrence of HUS and TTP normal to see?
TTP primarily adults
HUS primarily children
161
Pentad of findings in TTP
▪ Fever
▪ Neurological abnormalities
▪ Thrombocytopenia
▪ Microangiopathic hemolytic anemia
▪ Impaired renal function
162
is TTP an emergency?
YES - immediate plasmapheresis
163
Etiology of TTP
▪ Acquired (∼ 95%): autoantibodies against ADAMTS13
▪ Congenital (∼ 5%): gene mutations resulting in deficiency of ADAMTS13
164
what may be the ONLY presentation in TTP?
microangiopathic hemolytic anemia + thrombocytopenia
165
what scoring do we calculate in TTP
PLASMIC score
166
Treatment in TTP
→ Admit all patients with suspected or confirmed TTP to an ICU.
→ Obtain prompt central venous access.
→ Provide supportive care for all patients.
→ Consult hematology for guidance.
→ Initiate treatment with: Plasma exchange therapy and Glucocorticoid
167
Hemolysis studies in TTP and HUS
▪ ↑ Reticulocytes
▪ ↑ LDH
▪ ↓ Haptoglobin and hemoglobin
▪ Schistocytes on smear
▪ Jaundice in HUS
168
Define HUS
Thrombotic microangiopathy in which microthrombi form and occlude the arterioles and capillaries. HUS predominantly affects children < 5 years and is caused by bacterial toxins, most commonly the Shiga-like toxin of enterohemorrhagic Escherichia
coli (E. coli) O157:H7.
169
what bacterial toxins cause hus?
Shiga toxin from enterohemorrhagic E. coli O157:H7
Shiga toxin from shigella dysenteriae
Pneumococcus
170
Mechanism of thrombus formation in HUS
Toxins cause endothelial cell damage (especially in the glomerulus)
Damaged endothelial cells secrete cytokines that promote vasoconstriction and platelet microthrombus formation at the site of damage
171
what is the reason for hemolysis in TTP and HUS
RBCs are mechanically destroyed as they pass through the platelet microthrombi occluding small blood vessels resulting in schistocytes
172
what is the triad of clinical presentation in HUS
Thrombocytopenia
Microangiopathic hemolytic anemia
Impaired renal function
173
what NOT to give in HUS
Antibiotics may increase likelihood of HUS
174
Typical presentation of a HUS patient
Preschooler with diarrheal illness for the past 5–10 days and presents with petechiae, jaundice, and oliguria.
175
Define ITP
Immune thrombocytopenia (ITP) is a type of thrombocytopenia involving formation of auto-Ab against platelets. May be a primary disease or secondary to a known trigger.
176
Classification of ITP
Primary
Secondary
Newly Diagnosed
Persistent
Chronic
177
Etiology of secondary ITP
→ Autoimmune disorders: SLE, antiphospholipid syndrome
→ Malignancy: lymphoma, leukemia (particularly CLL)
→ Infection: HIV, HCV
→ Drugs: quinine, beta-lactam antibiotics, carbamazepine, heparin, vaccines, linezolid, sulfonamides, vancomycin, TMP-SMX, antiepileptics
178
Pathophysiology of ITP
Antiplatelet antibodies bind to platelets → sequestration by spleen and liver → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response (in most cases)
179
Lab studies in ITP
▪ CBC: ↓ platelet count (< 100,000/mm3)
▪ Coagulation panel: usually normal
▪ Bleeding time: may be prolonged
▪ Peripheral blood smear: normal to large platelets
180
Treatment of ITP
If asymptomatic then just observe
Dexamethasone OR prednisone
Non-responsive to corticosteroids: IVIG OR anti-Rho(D) immunoglobulin
181
Define Lymphoproliferative disorders
Heterogenous group of diseases characterized by uncontrolled production of lymphocytes that cause monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration.
182
Two groups of lymphoid malignancies?
Non-Hodgkins lymphoma
Hodgskings lymphoma
183
Non-Hodgkins lymphomas? (8)
▪ Diffuse large B-cell lymphoma
▪ Follicular lymphoma
▪ Mantle cell lymphoma
▪ Marginal zone lymphoma
▪ Burkitt’s Lymphoma
▪ Primary CNS lymphoma
▪ Adult T-cell lymphoma
▪ Mycosis Fungoides
184
Low grade NHL
Slow-growing or undulant lymphadenopathy (over months or years)
Hepatosplenomegaly
Cytopenia’s: Patients may present with anemia or bleeding, or increased susceptibility to infection
185
High grade NHL
Rapidly growing mass/nodes
Constitutional symptoms or B symptoms
186
Diagnosis of NHL
CT of organs and Biopsy (MUST) of both nodal and tissue
Labs
▪ Uric acid: usually elevated
▪ LDH: usually elevated
▪ Serum β2-microglobulin: may be elevated
▪ Others: CRP, ESR
187
Hodgkins Lymphoma
▪ Classical HL (CHL)
Nodular sclerosis (most common)
Mixed cellularity
Lymphocyte-depleted
Lymphocyte-rich CHL
▪ Nodular lymphocyte-predominant HL (NLPHL)
188
What are the B symptoms
1. Weight loss > 10% the last 6 months
2. Fever > 38 degrees
3. Night sweats
189
what does B symptoms tell us about the disease
Symptoms indicated poor prognosis in lymphoma. Thus, in case of B symptoms the tumor is upstaged under most classification systems. The presence of these symptoms correlates with an elevated level of inflammatory cytokines in the body fluids
190
Specific B symptoms in Hodgkin's lymphomas
Pel-Ebstein fever: Intermittent fever with periods of high temperature for 1–2 weeks, followed by afebrile periods for 1–2 weeks.
Relatively rare but very specific for HL.
191
Define Lymphadenopathy?
Enlargement of lymph nodes most commonly occurring during benign inflammatory processes.
192
Large groups of lymphadenopathy etiology?
Infection: bacterial, viral, fungal, parastis
Malignancy: ALL, HL; metastasis
Medication: penicillin, MTX, Allopurinol
Autoimmune: SLE, RA, Sjogrens
Other: sarcoidosis, Kawasaki
193
what is lymphadenitis?
Proliferation and formation of immune cell clusters as a result of localized/systemic inflammation (most common cause of lymphadenopathy)
194
Indication for malignant lymphadenopathy?
Hard, nonmobile, nontender lymph nodes (Exceptions: sarcoidosis or tuberculosis)
195
Indication of benign lymphadenopathy?
Soft, mobile, and tender lymph nodes are likely benign
196
difference between Non-Hodgkin lymphoma and Hodgkin lymphoma?
Reed-Sternberg cells
197
Define CLL
B-cell malignancy that manifests with lymphocytic leukocytosis. CLL is the most common type of leukemia in adults and is typically diagnosed in older individuals (≥ 65 years of age).
198
Classification of CLL
Chronic lymphoid leukemia (manifests as leukocytosis)
Small lymphocytic lymphoma (when manifestation is primarily in the lymph nodes)
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CLL etiology
Older age
Family history
Enviromental: detergents
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how are the CLL cells?
immature B-cells with CD5, 19, 20, 23 markers
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Clinical presentation of CLL
▪ About 50% remain asymptomatic resulting in late or incidental diagnosis.
▪ Weight loss, fever, night sweats, fatigue (B symptoms)
▪ Painless lymphadenopathy
▪ Hepatomegaly and/or splenomegaly may occur.
▪ Repeated infections
▪ Mycosis (candidiasis)
▪ Viral infections (herpes zoster)
▪ Symptoms of anemia and thrombocytopenia
▪ Dermatologic symptoms
Leukemia cutis
Chronic pruritus
Chronic urticaria
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What is CLL diagnosis based on?
Diagnosis requires persistent monoclonal lymphocytosis plus CLL immunophenotype confirmed by flow cytometry.
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the 3 things you always do in diagnosis CLL
1. Obtain a CBC
3. Peripheral blood smear
4. Flow cytometry
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CLL diagnosis criteria
1. Persistent (≥ 3 months) lymphocytosis (≥ 5000 cells/mm3)
2. CLL immunophenotype confirmed by flow cytometry
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cytopenia's in CLL
* Anemia (usually normochromic, normocytic)
* Thrombocytopenia
* Granulocytopenia
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what do you base treatment of CLL on?
RAI criteria
Low risk: expectant treatment
Intermediate risk: if symptoms, if not - expectant
High risk: target, chemo, stem cells
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most used treatment in CLL
Targeted therapies with Ibrutinib + Rituximab
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Define Multiple myeloma
Malignant uncontrolled proliferation and diffuse infiltration of monoclonal plasma cells in the BM
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What does the cells of MM produce?
Monoclonal proteins (M proteins such as Ig)
Free light chains (Bence Jones proteins)
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Classification of MM?
→ IgG and IgA: typical multiple myeloma; majority of patients
→ Bence Jones myeloma (free light chains excreted in urine): 15–20%
→ IgD, IgE, and IgM: very rare subtypes of multiple myelomas
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Pathophysiology of MM (4 points that are important)
1. BM suppression - anemia, leukopenia, thrombocytopenia
2. Pro osteoclastic factors - osteolysis and hypercalcemia
3. Ig overproduction causing dysproteinemia and kidney damage
4. hyperviscosity syndrom in serum
remember CRAB!!!
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Diagnostic criteria of MM
Histopathology is met (BM biopsy shows > 10% clonal BM plasma cells
+ 1 myeloma defining event (CRAB)
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what does serum protein electrophoresis in MM show
M spike (gamma spike)
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treatment of MM
Asymptomatic: watch and wait
Symptomatic: HSCT, Chemotherapy if HSCT not possible
Supportive: transfusion and G-CSF, EPO for pancytopenia
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can you cure MM
not really, only by HSCT but very rarely cures
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Hodgkin lymphoma definition?
Reed Sternberg cells
CD50 and CD 30 Positive
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Age onset in Hodgkin lymphoma
Bimodal: 1 peak at 25-30/ second peak at 50-70
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Etiology of Hodgkin lymphoma
Not really known
Strong association with Epstein-Barr virus (EBV)
Immunodeficiency: organ transplantation, immunosuppressants, HIV
Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis)
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Clinical presentation Hodgkin lymphoma
Painless lymphadenopathy of a SINGLE group of LN
B signs
Pel-Ebstein fever
Alcohol-induced pain
Pruritis
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Which lymph nodes are commonly involved in Hodgkin lymphoma
Cervical (60–70%) > axillary (25–35%) > inguinal (8–15%)
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Alcohol effect in Hodgkin lymphoma
Pain in involved lymph nodes after ingestion of alcohol. Relatively rare but highly specific for HL.
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staging of Hodgkin lymphoma
Lugado staging (based on Ann Harbor system)
I. 1 lymph node
II. One side of diaphragm
III. Both sides of diaphragm
IV. Disseminated
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Diagnosis in Hodgkin lymphoma
Primarily based on medical history, clinical presentation and node biopsy (histo is obligatory)
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treatment of Hodgkin lymphoma
Stage I-II Chemo+radio
Stage III-IV Chemo+radio
Relaps: high dose chemo + HSCT
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which Hodgkin lymphoma has poor prognosis?
Lymphocyte depleted classical HL
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Define Myeloproliferative neoplasm
A group of disorders characterized by a proliferation of normally developed (nondysplastic) multipotent
hematopoietic stem cells from the myeloid cell line.
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Types of Myeloproliferative neoplasms
❖ Essential thrombocythemia
❖ Polycythemia vera
❖ Primary myelofibrosis
❖ Chronic myeloid leukemia (CML)
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Initial studies in Myeloproliferative neoplasms
CBC
Blood smear
CT/US
Lab's
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Lab findings in Myeloproliferative neoplasms
Elevated LDH, uric acid, and/or leukocyte alkaline phosphatase
Indicates high disease burden and high cell turnover
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Confirmatory study in Myeloproliferative neoplasms
Genetic testing + BM biopsy
▪ Philadelphia chromosome (BCR-ABL): present in almost all cases of CML
▪ Driver mutations (e.g., JAK2, CALR, MPL): associated with PV, ET, and PMF
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Mutation in CML
Philadelphia chromosome: BCR-ABL in 95%
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what are the two types of hematopoietic stem cell transplant methods we have?
autologous and allogeneic stem cell transplantation
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Define autologous HSCT
1. Removal of patient OWN HSC
2. High dose chemo and full body irradiation
3. Retransfuse back the HSC harvested before
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Define Allogenic HSCT
Transfer HSC of sibling or donor to recipient
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Indication of Autonomous HSCT
Germ cell tumor
MM
Lymphoma
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Indication of allogenic HSCT
Leukemia
Aplastic anemia, severe immunodeficiency
Relaps lymphoma or MM
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Graft source in allogenic or autonomous HSCT
Allogenic: peripheral
Autonomous: BM
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Advantage of Autonomous HSCT
Low risk of GvHD
Late onset post-transplant infection
Low risk of graft rejection
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Disadvantages of autonomous HSCT
high risk of early onset post-transplant infection
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Advantage of Allogenic HSCT
GvH effect: Donor T-cells attack host tumor remaining after the high dose chemo
Low risk of early onset post-transplant infection
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Disadvantages of Allogenic HSCT
Moderate-high risk of GvHD
increased risk of graft rejection
moderate-high risk of late onset post-transplant infection
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Define acute leukemias
Acute leukemias are malignant neoplastic diseases that arise from either the lymphoid or myeloid cell line.
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Define AML
Acute leukemias are characterized by the proliferation of immature, nonfunctional WBCs (blasts) in the bone marrow, which impairs normal hematopoiesis. This leads to pancytopenia, which manifests with symptoms and signs of anemia (decreased RBCs), clotting disorders (decreased platelets), and immunocompromise (decreased fully functional, mature WBCs)
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Preexisting hematopoietic disorders that increase risk of AML
o Myelodysplastic syndromes
o Aplastic anemia
o Myeloproliferative disorders (CML)
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Classification of AML
French-American-British (FAB)
M0-M7 and based on histopathological appearance of the cells
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What is happening in BM during AML
Rapid proliferation of dysfunctional blasts
Accumulation of leukemic white blood cells in the bone marrow Disrupted normal hematopoiesis
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Downs syndrom and AML
10-20 times higher chance of developing AML
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What happens to the blast cells in AML, what organs do they most frequently infiltrate?
Immature blasts enter the bloodstream → infiltration of other organs (particularly the CNS, testes, liver, and skin)
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Clinical picture of leukemias (both AML ALL)
Sudden onset of symptoms and rapid progression (days to weeks)
Anemia: fatigue, pallor, weakness
Thrombocytopenia: epistaxis, bleeding gums, petechiae, purpura
Immature leukocytes: frequent infections, fever
Hepatosplenomegaly (caused by leukemic infiltration)
Oncologic emergencies can be the first sign of leukemia
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Specific clinical signs of AML
▪ Leukemia cutis (or myeloid sarcoma): nodular purple skin lesions
▪ Gingival hyperplasia (AML subtype M4 and M5)
▪ Signs of CNS involvement: headache, visual field changes (uncommon)
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How is the WBC count in AML
The white blood cell count (WBC) may be elevated, normal, or low and is NOT a reliable diagnostic marker.
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Lab indications of AML
LDH
Uremic acid
Blast cells > 20% myeloblasts
Leukemic hiatus (Blast+ mature cells but nothing in between)
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Immunophenotyping in AML
CD 13, 33, 34, 117,
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AML treatment
Systemic chemo
Intrathecal chemo if CNS
Targeted chemo for specific phenotyping
HSCT
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Chemo in AML
→ Anthracyclines (idarubicin, high-dose daunorubicin)
→ Antimetabolites (cytarabine, methotrexate)
→ Hypomethylating agents (azacytidine)
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Intrathecal chemotherapy: administration of chemotherapeutic agents
Example is triple therapy with methotrexate, cytarabine, and hydrocortisone directly into the subarachnoid space via lumbar puncture or using an intraventricular catheter with a reservoir placed under the scalp
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Factors increasing risk of ALL
Prior bone marrow damage due to alkylating chemotherapy or ionizing radiation
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Genetic factors increasing risk of ALL
o Down syndrome: 10–20x higher
o Neurofibromatosis type 1
o Ataxia telangiectasia
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Specific clinical features in ALL
▪ Fever, night sweats, unexplained weight loss
▪ Painless lymphadenopathy
▪ Bone pain (presenting as limping in children)
▪ Airway obstruction due to mediastinal/thymic infiltration
▪ Features of SVC syndrome
▪ Meningeal leukemia → headache, neck stiffness, visual field changes
▪ Testicular enlargement (rare finding)
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Chemo in ALL
Alkylating agents: Cyclophosphamide
Anthracyclines: Daunorubicin
Antimetabolites: Cytarabine, methotrexate
Alkaloids: Vincristine
Glucocorticoids: Dexamethasone
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Chemo regime in ALL
Induction 4-8 weeks
Consolidation 4-8 months
Maintenance 2-3 years
Reintroduction if required
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Define Polycythemia vera
Polycythemia vera is a chronic myeloproliferative neoplasm most commonly caused by a gain of function mutation in the JAK2 gene, leading to erythrocytosis with or without increases in granulocytes and platelets.
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what does JAK2 code for?
A non-receptor tyrosine kinase in hematopoietic progenitor cells. JAK2 is essential for the regulation of erythropoiesis, thrombopoiesis (megakaryopoiesis), and granulopoiesis.
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Clinical features of polycythemia vera
1. Often asymptomatic
2. Nonspecific symptoms: fatigue, difficulty concentrating, insomnia,
abdominal pain
3. Constitutional symptoms: weight loss, sweating
4. Hyperviscosity triad: mucosal bleeding, neurological/visual changes
5. Plethora: flushed face with a purple hue; cyanotic lips
6. Pruritus: Itching typically worsens when the skin meets warm water
7. Erythromelalgia
8. Hypertension
9. Splenomegaly, less commonly hepatomegaly
10. Peptic ulcer disease
11. Gout
12. Symptoms of thrombotic and hemorrhagic complications
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When to suspect PV
High hemoglobin and hematocrit + normal oxygen saturation
Patients with features or complications ass with polycythemia vera
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3 major diagnostic criteria in PV
1 minor criteria
MAJOR
o Peripheral blood screen for JAK2 mutation
o Erythrocytosis >25% of normal value
o Hypercellular BM
MINOR
o Low EPO
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Diagnostic criteria on PV
ALL three major criteria must be there
OR JAK2 negativ but 2 major + 1 minor
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Indications of primary vs secondary PV?
Erythrocytosis + normal oxygen saturation + low EPO
strongly suggestes polycythemia vera.
Erythrocytosis + decreased oxygen saturation + high EPO
suggests secondary polycythemia caused by chronic hypoxia
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High risk vs Low risk in PV
o Low-risk: no history of thrombosis and ≤ 60 years of age
o High-risk: history of thrombosis and/or > 60 years of age
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General management of PV
o Regular therapeutic phlebotomy PLUS low-dose aspirin
o Manage modifiable cardiovascular risk factors
o Treat ass symptoms: allopurinol: gout, antihistamines: pruritus.
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what increases risk of VTE in essential thrombocytopenia?
▪ Age ≥ 60 years
▪ History of thrombosis
▪ Presence of JAK2 V617F mutation
▪ CV risk factors: diabetes, hypertension, history of smoking
▪ Leukocytosis ≥ 11 × 109/L
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Lab studies indicating essential thrombocytopenia
o CBC: isolated sustained thrombocytosis (> 450 x 109/L)
o ↑ LDH and uric acid
o Pseudo-hyperkalemia
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Define Myelofibrosis
Any MPN leading to bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly
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primary vs secondary myelofibrosis
Primary myelofibrosis: occurs spontaneously
Secondary myelofibrosis: result of disease progression in patients previously diagnosed with MPN, like PV or ET
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Genetic markers in myelofibrosis
▪ JAK2 mutation: 50–60% of patients
▪ CALR mutation: 18–32% of patients
▪ MPL mutation: 5–9% of patients
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peripheral blood smear in myelofibrosis
▪ Dacrocytes (teardrop cells)
▪ Leukoerythroblastosis (overt fibrotic stage)
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management in myelofibrosis
▪ Asymptomatic then observe
▪ Targeted therapy: JAK2 inhibitors (ruxolitinib)
▪ Allogeneic hematopoietic stem cell transplantation:
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symptoms of myelofibrosis
→ Constitutional symptoms
→ Anemia
→ Symptomatic splenomegaly
→ Thromboembolic events
→ Petechial bleeding
→ Increased infections
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Define CML
Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm involving hematopoietic stem cells that results in overexpression of cells of myeloid lineage, especially granulocytes. It is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome
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pathophysiology behind CML
BCR-ABL encodes a non-receptor tyrosine kinase with increased
enzyme activity resulting in uncontrolled proliferation of functional granulocytes
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Clinical phases of CML
1. Chronic phase can last for 10 years
2. Accelerated phase
3. Blast crisis (like AML)
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symptoms indicating CML
→ Severe leukocytosis on routine laboratory testing
→ Splenomegaly
→ Constitutional symptoms (e.g., malaise, fatigue)
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Diagnostic confirmation in CML
Identification of the Philadelphia chromosome and/or the BCR-ABL1 fusion gene.
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How can you test for BCR-ABL in CML?
Cytogenetic testing with FISH
Molecular testing by quantitative RT-PCR
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Treatment in CML
TKIs: first-line and second-line treatment
Adjunctive medical treatment or HSCT if other treatments fail
Blas crisis: treat as AML with systemic chemo
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Define Myelodysplastic syndrome
Group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells, causing impaired hemostasisi.
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Types of myelodysplasias?
Primary: idiopathic
Secondary: chemo, radiation, PNH, Benzen
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Clinical features of MDS
▪ Asymptomatic in 20% of cases
▪ Depending on the affected cell line:
▪ Erythrocytopenia (70% of cases) → symptoms of anemia
▪ Leukocytopenia with high susceptibility to bacterial infections
▪ Thrombocytopenia: petechial bleeding
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what type of anemia is seen in MDS
Normocytic anemia which is refractory to treatment
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what does BM biopsy show in MDS
Hypercellular with blast cells
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Treatment of MDS
Depends on a patient's presentation, age, and comorbidities.
More aggressive therapy (chemotherapy, stem cell transplantation) is generally reserved for younger, healthier patients.
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What is the only curative option in MDS
HSCT but only done in < 50 years old and late stage MDS
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Histopathology in NHL
Immunophenotype (flow cytometry, immunohistochemistry) Detects surface antigens, determines the specific cell type and identifies markers
B-cell lymphomas: CD20 positive
T-cell lymphomas: CD3 positive
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Treatment of NHL
→ Select treatment based on the subtype of NHL, staging, and prognosis
→ Most patients will receive treatment with systemic chemotherapy and/or radiotherapy.
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Systemic chemo in NHL
→ Antifolates: high-dose Methotrexate (M)
→ Alkylating agents: Cyclophosphamide (C)
→ Topoisomerase II inhibitors: Hydroxydaunorubicin (H)
→ Alkaloids: Vincristine/Oncovin (V/O)
→ Steroids: Prednisolone (P)
→ Immunotherapy: e.g., rituximab (R)
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NHL Follicular cell lymphoma
▪ Most common low-grade lymphoma in adults
▪ Slow progression, painless course + alternating pattern of lymphadenopathy and splenomegaly
▪ Translocation t(14;18) → dysregulation of apoptosis
▪ Heavy-chain Ig (chromosome 14) and Bcl-2 gene (chromosome 18) → overexpression of Bcl-2
▪ Centrocyte: nodular, small cells with cleaved nuclei
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NHL Marginal zone B-cell lymphoma
Pathology: mature B-cell tumor; BRAF mut common
Clinical features
▪ Symptomatic pancytopenia
▪ Massive splenomegaly
▪ No lymphadenopathy
▪ B symptoms are rare.
Usually TRAP stain positive
Hairy cells on biopsy
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NHL diffuse large B-cell lymphoma
▪ Most common NHL in adults - high grade
▪ Caused by mutations in Bcl-2, Bcl-6, and p53
▪ Primary CNS lymphoma (subtype of DLBCL)
▪ Associated with EBV and AIDS
▪ Focal neurologic deficits, neuropsychiatric symptoms
▪ Solitary ring-enhancing lesion on MRI
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Burkitts Lymphoma NHL
▪ Most common in children
▪ Translocation t(8;14) in 75% of cases: → overactivation of c-myc proto-oncogene → activation of transcription
Forms
▪ Sporadic: typically located in the abdomen or pelvis
▪ Endemic: associated with EBV and is typically located in the maxillary and mandibular bones
▪ Immunodeficiency-associated: e.g. HIV infection
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NHL mantle cell lymphoma
▪ Most common in adult men
▪ Translocation t(11;14) involving cyclin D1 (chromosome 11) and heavy-chain Ig (chromosome 14) → levels of cyclin D1 → promotes the transition of cells to S phase
▪ CD5+
▪ Spreads rapidly; most patients are diagnosed with advanced disease
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Mycosis fungoides: NHL
▪ Only skin involvement
o Pruritic cutaneous plaques and patches that develop brownish nodules
o Pautrier microabscesses
Sezary syndrome: peripheral smear: CD4+ T-cells with profoundly grooved nuclei: Sézary cells - red rash and itching
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NHL adult T-cell lymphoma
▪ Occurs almost exclusively in adults
▪ Caused by the human T-cell lymphotropic virus (HTLV)
▪ Associated with IV drug use
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How to identify chromosomal abnormalities?
FISH
