Main USMLE - Boards and Beyond - Hematology Part 1

USMLE - Boards and Beyond - Hematology Part 1

0 / 0
How much do you like this book?
What’s the quality of the file?
Download the book for quality assessment
What’s the quality of the downloaded files?
Lectures and notes. Use WINrar or similar software to merge part 1 and 2.
Categories:
Year:
2019
Language:
english
File:
RAR, 290.00 MB
Download (rar, 290.00 MB)

You may be interested in Powered by Rec2Me

 

Most frequently terms

 
0 comments
 

You can write a book review and share your experiences. Other readers will always be interested in your opinion of the books you've read. Whether you've loved the book or not, if you give your honest and detailed thoughts then people will find new books that are right for them.
1

Jadavpur Journal of Comparative Literature

Tahun:
1961
Bahasa:
english
File:
PDF, 9,14 MB
0 / 0
2

Jadavpur Journal of Comparative Literature

Tahun:
1962
Bahasa:
english
File:
PDF, 26,13 MB
0 / 0
 

Hematology/HemeBookColor.pdf
 

i  

 
 

 

Boards and Beyond: 

Hematology Slides 

 
Slides from the Boards and Beyond Website 

 

Jason Ryan, MD, MPH 

 

2019 Edition 

 

 
  



 

ii  

 

 

  

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

iii  

Table of Contents 

 
Coagulation 1 Acute Leukemias 90 

Platelet Activation 10 Chronic Leukemias 95 

Hypercoagulable States 14 Hodgkin Lymphoma 99 

Coagulopathies 19 Non-Hodgkin Lymphoma 102 

Platelet Disorders 23 Plasma Cell Disorders 108 

Antiplatelet Drugs 30 Amyloidosis 112 

Anticoagulant Drugs 34 Myeloproliferative Disorders 115 

Hemolysis Basics 43 Antimetabolites 120 

Extrinsic Hemolysis 48 Alkylating Agents 125 

Intrinsic Hemolysis 53 Antitumor Antibiotics 129 

Microcytic Anemias 58 Microtubule Inhibitors 132 

Thalassemias 66 DNA Drugs 135 

Sickle Cell Anemia 73 Other Cancer Drugs 138 

Other Anemias 79 Porphyrias 143 

Blood Groups 84   

    
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

iv  

 

 

 

 



 

1  

 

  
 

 

 

 

 

 

 

 

THROMBUS 

ACTIVATED PLATELETS FIBRIN 

Thrombus Formation 

 
ENDOTHELIAL DAMAGE 

 

 

 
Coagulation 
Jason Ryan, MD, MPH 

Vasoconstriction 

• 1st line of defense against bleeding 

• Occurs in response to endothelial damage 

• Key mediator: endothelins 

• Proteins 

• Potent vasoconstrictors 

• Released by endothelial cells near site of damage 

• Endothelin receptor blockers used in pulmonary hypertension 

Coagulation Factors 

• Proteins synthesized in liver 

• Soluble in plasma 

• Activate when triggered by endothelial damage 

• Form an insoluble protein: Fibrin 

• Fibrin mesh prevents blood loss 

Serine 

Coagulation Factors 

• Most circulate as inactive enzymes (zymogens) 

• Many activate to become serine proteases 

• Serine: amino acid 

• Protease: cleaves proteins 

• Serine protease: protein cleavage enzyme, contains seri; ne 

Coagulation Cascade 

• Sequential activation of clotting factor zymogens 

• Constant low level of activation in serum 

• Amplification occurs with endothelial damage 

• Leads to fibrin generation 



 

2  

 

  
 

 

 

 

 

 

 

 

Xa X 

Coagulation Cascade 

• Center of cascade is activation of X  Xa 

•  (IIa) 

• Thrombin (IIa): Fibrinogen (I)  fibrin (Ia) 

• Fibrin forms plug to stop bleeding 

• Activation X  Xa makes fibrin 

Joe D/Wikipedia 

Coagulation Cascade 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Xa X 

Coagulation Cascade 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Direct Thrombin 

Inhibitors (DTIs) 

Hirudin 

Lepirudin 

Bivalirudin 

Desirudin 

Argatroban 

Dabigatran (PO) 

↓Fibrin Xa 

Xa inhibitors 

Rivaroxaban 

Apixaban 

↓Thrombin 

 
 

X 

Coagulation Cascade 

Tissue Factor 
Thromboplastin 

• Glycoprotein 

• Constitutively expressed in sub-endothelial cells 

• Not expressed by endothelial cells 

• No significant contact of with circulating blood 

• Exposed by endothelial damage 

• Major activator of coagulation system 

• Basis for Prothrombin Time and INR 

• Tissue factor added to blood sample 

• Time to form clot = PT 
TF:VIIa 

Coagulation Cascade 

• Primary event: Exposure of tissue factor 

• Interacts with factor VII  VIIa 

• TF:VIIa activates Xa 



 

3  

 

  
 

 

 

 

 

 

 

 

Fibrin 

Va 

VIIIa 

XIa Thrombin 

IIa 

Xa • Factor XIa activates IX  IXa 
• IX uses VIIIa as a co-factor 

• IXa can also activate Xa 

• More amplification 

Thrombin 

• Thrombin (IIa) makes more thrombin 

• Can activate cascade (positive feedback) 

• Factor V  Va 

• Factor XI  XIa IXa:VIIIa 

• Factor VIII  VIIIa 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

Xa X 

TF:VIIa 

Coagulation Cascade 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

 

Hemophilia 

Coagulation Cascade Factor VIII 

• Produced in endothelial cells (not the liver) 

• Circulates bound to von Willebrand Factor 

• vWF critical for platelet aggregation 

• vWF produced by endothelial cells and megakaryocytes 

• Binding to vWF increases VIII plasma half life 

• Released from vWF in response to vascular injury 

• Vascular injury  ↑ thrombin  becomes VIIIa 

 

VIII—vWF 

Multicomponent Complexes 

• Two complexes for conversion X  Xa 

• Three components bound together: 

• Active clotting factor functioning as enzyme 

• Co-factor 

• Substrate 

• Require phospholipids and calcium 

• Phospholipid: Occur on surfaces of cells 

• TF-bearing cells or platelets 

• Calcium: Co-factor 

Xa 

      Phospholipid  

X 

Ca+ 
VIIa 

TF 
• Phospholipid: TF-bearing cells 

• Enzyme: Factor VIIa 

• Co-factor: Tissue factor 

• Substrate: Factor X 

Multicomponent Complexes 
X 

• Extrinsic Xase 



 

4  

 

  
 

 

 

 

 

 

 

 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

Coagulation Cascade Multicomponent Complexes 
X 

• Intrinsic Xase 

• Phospholipid: Platelets 

• Enzyme: Factor IXa 

• Co-factor: Factor VIII (VIIIa) 

• Substrate: Factor X 

 
Ca+ 

VIIIa  
IX X 

      Phospholipid  

 

 

Xa 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

Coagulation Cascade 

Phospholipids 

Calcium 

Tannim101/Wikipedia- 

Calcium 

• Factor IV 

• Required for clot formation 

• Activated platelets release calcium 

• EDTA binds calcium in blood samples 

• Prevents clotting 

Factor XIII 

• Crosslinks fibrin 

• Stabilizes fibrin plug 

• Absence of XIII  inadequate clot formation 

• Requires calcium as co-factor 

• Activated by thrombin (IIa) formation 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

Coagulation Cascade 



 

5  

 

  
 

 

 

 

 

 

 

 

XIa XI 

XIIa XII 

Factor XII 
Hageman factor 

• Can activate factor XI (XIa) 

• Physiologic significance unclear 

• Important for testing of coagulation system 

• Activated by contact with negatively charges 

• Factor XII  XIIa via contact with silica 

• Basis for partial thromboplastin time (PTT) 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Ca++ 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

Coagulation Cascade 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va 

VIIIa 

XIa TF:VIIa 

IXa:VIIIa 

Coagulation Cascade 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

Coagulation Cascade 
XII XIIa 

 
XI   

T    
XIa 

IX IXa:VIIIa VIII 
T 

 

TF:VIIa Va 

X Xa 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

Va 

Xa X 

TF:VIIa 

IXa:VIIIa VIII 
T 

XI 
T 

XIa 

IX 

Extrinsic 

Pathway 

Coagulation Cascade 
XII XIIa Intrinsic Pathway 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

TF:VIIa Va 

X Xa 

IXa:VIIIa VIII 
T 

Activated Partial 

Thromboplastin Time 

(PTT) 

Add Plasma to (-) charge 

substance (silica) Time 

to form clot 

Coagulation Cascade 
XII XIIa 

 
XI 

T 
XIa 

IX 



 

6  

 

  
 

 

 

 

 

 

 

 

Intrinsic Pathway 
Contact Pathway 

• Requires kinins for normal function 

• Kinins = peptide hormones/signaling molecules 

• Short half lives 

• Circulate as inactive precursors: kininogens 

• Activated by kallikreins 

• Kinins link coagulation with inflammation 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

Xa X 

Va 
TF:VIIa 

Coagulation Cascade 

Prothrombin Time (PT) 

Add Plasma to TF 

Time to form clot 

Intrinsic Pathway 
Kinin System 

• Bradykinin 

• Vasodilator 

• Increases vascular permeability 

• Pain 

• Degraded by angiotensin converting enzyme (ACE) 

• ACE inhibitors can raise bradykinin levels 

• Dangerous side effect: angioedema 

• Also degraded by C1 inhibitor (complement system) 

• hereditary angioedema 

Prekallikrein (PK) Kallikrein 

 
High molecular weight kininogen 

Bradykinin 
HMWK 

XIIa XII 

Intrinsic Pathway 
Factor XII 

• Activates clotting and produces bradykinin 

• Requires PK, HMWK for normal function 

Prekallikrein (PK) Kallikrein 

 
High molecular weight kininogen 

Bradykinin 
HMWK 

XIIa XII 

Prekallikrein Deficiency 

• Rare condition 

• Results in markedly prolonged PTT 

• XII cannot activate normally 

• No bleeding problems 

Kinin System 
Key Points 

• Activated by factor XII 

• Link between coagulation and inflammation 

• Bradykinin 

• ACE inhibitors 

• Hereditary angioedema 

• Prekallikrein Deoiciency: ↑PTT 



 

7  

 

  
 

 

 

 

 

 

 

 

Antithrombin III 

• Serpin (inhibitor of serine proteases) 

• Inhibits serine proteases: factors II, VII, IX, X, XI, XII 

• Produced by liver 

• Activated by endothelium 

• Endothelium makes heparan sulfate molecules 

• Activate antithrombin 

• Basis for role of heparin drug therapy 

• Deficiency: Hypercoagulable state 

Coagulation Inhibitors 

• Important deactivators of coagulation 

• Antithrombin III 

• Proteins C and S 

• Tissue factor pathway inhibitor 

Proteins C and S 

• Glycoproteins synthesized in liver 

• Protein C: zymogen 

• Active form: activated protein C (APC) 

• APC primarily inactivates factors Va and VIIIa 

Proteins C and S 

• Protein C activated by thrombomodulin 

• Cell membrane protein 

• Found on endothelial cells 

• Thrombomodulin binds thrombin 

• Complex activates protein C to APC 

Protein 

S 

Inactivation 

Va, VIIIa 

Thrombomodulin: Thrombin 

Protein C APC 

Proteins C and S 

• APC requires protein S as co-factor 

• Protein S circulates in active form (not a zymogen) 

TFPI 
Tissue factor pathway inhibitor 

• Inactivates Xa via two mechanisms 

• Directly binds Xa 

• Binds TF/FVIIa complex  prevents X activation 

• Plasma levels increased with heparin administration 

• May contribute to antithrombotic effect 



 

8  

 

  
 

 

 

 

 

 

 

 

Plasminogen Activators 

• Tissue plasminogen activator (tPA) and urokinase 

• Synthesized by endothelial and other cells 

• Used as drug therapy for acute MI and stroke 

• Streptokinase: Streptococcal protein; activates plasminogen 

Plasminogen and Plasmin 

• Plasminogen synthesized by liver (zymogen) 

• Converted to active enzyme: plasmin 

• Main role of plasmin is breakdown of fibrin 

• Broad substrate specificity 

• Also degrades clotting factors, fibrinogen 

tPA 

Urokinase 

FDPs and D-dimer 

D-dimers 
Fibrin 

Degradation 

Products 

Plasmin Plasminogen 

Fibrin/Clot 

Mpt-matthew/Wikipedia 

FDPs and D-dimer 

• Fibrinogen has two domains: E (central) and D (side) 

• Crosslinking of fibrin (XIII) creates E linked two Ds 

      FDPs  

FDPs and D-dimer 

• D-dimer is a special type of FDP 

• Presence of D-dimers indicates clot breakdown 

• Breakdown of crosslinked fibrin from XIII 

• Elevated D-dimer used for diagnosis of DVT/PE 

D-dimers 

Plasmin 

Fibrin/Clot 

      FDPs  
      FDPs  

FDPs and D-dimer 

• ↑ FDPs seen in breakdown of clot 

• Also seen in absence of clot from fibrinogen breakdown 

• Plasmin can convert fibrinogen  FDPs 

• FDPs indicate plasmin activity only 

• Not necessarily clot breakdown 

D-dimers 

Plasmin 

Fibrin/Clot Fibrinogen 



 

9  

 

  
 

 

 

 

 

 

 

 

FDPs and D-dimer 
Key Points 

• Clot breakdown: FDPs and D-dimers 

• Hyperfibrinolysis: FDPs with normal D-dimer levels 

• ↑ D-dimer used to diagnosis thrombotic disorders 

• Elevated levels seen in DVT/PE 

• Sensitive but not specific 

• Elevated in many other disorders 

Primary Fibrinolysis 

• Rarely phenomena: Plasmin overactive 

• Causes ↑ FDP with normal D-dimer 

• “Hyperfibrinolysis” 

• Plasmin breakdown of fibrinogen (not fibrin)  FDPs 

• No clot or crosslinked fibrin  No d-dimers 

• Plasmin can deplete clotting factors 

• Increased PT/PTT with bleeding (like DIC) 

• Prostate cancer: release of urokinase 

• Cirrhosis: Loss of alpha2 antiplasmin from liver 

Gonegonegone /Wikipedia 

Vitamin K 

• Required for synthesis of many clotting factors 

• “Vitamin K dependent clotting factors” 

• Vitamin K dependent factors: II, VII, IX, X, C, S 

• Vitamin K deficiency: bleeding 

• Warfarin: Vitamin K antagonist 

MechESR/Wikipedia 

ESR 
Erythrocyte Sedimentation Rate 

• Rate of RBC sedimentation in test tube 

• Normal 0-22 mm/hr for men; 0-29 mm/hr for women 

• Increased in inflammatory conditions 

ESR 
Erythrocyte Sedimentation Rate 

• ESR increased by “acute phase reactants” in plasma 

• Serum proteins that rise in inflammation or tissue injury 

• Driven by cytokines 

• Most come from liver 

• Key acute phase reactants 

• Fibrinogen 

• Ferritin 

• C-reactive protein (binds bacteria; activates complement) 



 

10  

 

  
 

 

 

 

 

 

 

 

THROMBUS 

ACTIVATED PLATELETS FIBRIN 

ENDOTHELIAL DAMAGE 

Thrombus Formation  

 

 
Platelet Activation 
Jason Ryan, MD, MPH 

Graham Beards/Wikipedia 

Platelets 

• Small cells derived from megakaryocytes 

• Do not contain a nucleus 

• Short lifespan: about 8-10 days 

• Production regulated by thrombopoietin (TPO) 

• Glycoprotein produced mostly in liver 

Platelets 

• Aid in hemostasis after vascular injury 

• Circulate in “inactive” form 

• Can “activate” due to: 

• Endothelial injury 

• Stimuli from other activated platelets 

• Activated platelets seal damaged vessels 

Exposed Subendothelium 

Adhesion 

Aggregation 

Platelets Actions 

• Adhesion to sub-endothelium 

• Aggregation: Platelet-platelet binding 

• Secretion: Release of granule contents 

• Net result: Seal openings in vascular tree 

Platelets 

Secretion 

Von Willebrand Factor 

• Large glycoprotein 

• Synthesized by endothelial cells and megakaryocytes 

• Stored in Weibel–Palade bodies in endothelial cells 

• Present in platelets (stored in alpha granules) 

• Some found in plasma 

• Released on vascular injury 

• Activated platelets degranulate 

• Endothelial cells release vWF 



 

11  

 

  
 

 

 

 

 

 

 

 

Membrane Glycoproteins 

• Glycoproteins (amino acids and glucose molecules) 

• Found on surface of platelets 

• Interact with other structures/molecules 

• Important for hemostasis 

• GPIb, GPIIb/IIIa 

VIII—vWF 

Von Willebrand Factor 

• Several roles in hemostasis 

• #1: Carrier protein for factor VIII 

• Factor VIII released in presence of thrombin (VIIIa) 

• #2: Binds platelets to damaged endothelium 

• #3: Binds activated platelets together (aggregation) 

Exposed Subendothelium 

Adhesion 

Aggregation 

Platelets Actions 

• Adhesion to sub-endothelium 

• Aggregation: Platelet-platelet binding 

• Secretion: Release of granule contents 

 
 
Platelets 

Secretion 

Subendothelial Collagen Subendothelial Collagen 

Platelet Adhesion 

• Vascular damage: exposure of collagen 

• Subendothelial collagen binds vWF 

• vWF binds GPIb on platelets 

 
 

vWF 

GPIb 

Active Platelet 
Inactive 

Platelet 

Platelet Aggregation 

• Mediated by GPIIb/IIIa receptor 

• Most abundant surface receptor on platelets 

• Platelet activation  GPIIb/IIIa changes conformation 

• Becomes capable of binding 

• Will not bind when platelets are inactive 

• “Inside-out” signaling (cell activity  altered receptor) 
Active 

IIB/IIIA 

Platelet Aggregation 

• GPIIb/IIIa binds fibrinogen or vWF 

• Links platelets together (aggregation) 

• Basis for IIB/IIIA receptor blocking drugs 



 

12  

 

  
 

 

 

 

 

 

 

 

Dr Graham Beards/Wikipedia 

Platelet Granules 

• Two types of platelet granules: alpha and dense 

• Contents promote hemostasis 

• Released on activation by: 

• Platelet binding to collagen 

• Granule contents from other platelets 

Secretion 

Platelet Secretion 

• Platelets activated by: 

• Binding to subendothelial collagen 

• Stimulation by activating substances 

• Secretion of stored activators  more activation 

Dr Graham Beards/Wikipedia 

Platelet Granules 

• Alpha granules (most abundant) 

• Fibrinogen 

• von Willebrand factor 

• platelet factor 4 

• Dense granules 

• ADP 

• Calcium 

• Serotonin 

Platelet Factor 4 
PF4 

• Released from alpha granules 

• Binds to endothelial cells 

• Numerous biologic effects described 

• Heparin induced thrombocytopenia 

• Rare, life-threatening effect of heparin administration 

• Antibodies formed to PF4 complexed with heparin 

• Antibodies bind PF4-  activation 

• Diffuse thrombosis 

• Low platelets from consumption 

Serotonin 

• Stored in dense granules 

• Released on platelet activation 

• Basis for serotonin release assay 

• Diagnostic test for HIT 

• Donor platelets radiolabeled with 14C-serotonin 

• Patient serum and heparin added 

•  release 

Adenosine Diphosphate 
ADP 

• Released from dense granules 

• Also released by red blood cells when damaged 

• Binds to two G-protein receptors: P2Y1 and P2Y12 

• Binding leads to ↓ cAMP formation 

• ↑ cAMP blocks platelet activation 

• Phosphodiesterase inhibitors  cAMP 



 

13  

 

  
 

 

 

 

 

 

 

 

Shizhao/Wikipedia 

Thromboxane A2 
TXA2 

• Powerful platelet activator 

• TXA2 receptors found on platelets 

• Basis for aspirin therapy 

Adenosine Diphosphate 
ADP 

• P2Y1 
• Calcium release, change in platelet shape 

• P2Y12 
• Platelet degranulation, ↑ aggregation 

• Many P2Y12 receptor blocking drugs 
• “ADP receptor blockers” 

• Inhibit platelet activity 

• Clopidogrel, prasugrel, ticlopidine, ticagrelor 

Thromboxane A2 
TXA2 

• Lipids in cell membranes  arachidonic acid (AA) 

• Enzyme: phospholipase A2 

• Occurs in endothelial cells near damaged endothelium 

• AA released at sites of vascular injury 

• Also stored in platelets 

• AA converted by platelets to TXA2 

• Enzyme: Cyclooxygenase (COX) 

• Aspirin: Inhibits COX  ↓ TXA2  platelet activation 

Crystal/Flikr 

Bleeding Time 

• Test of platelet function 

• Small cut to patient’s arm 

• Filter paper applied/removed until bleeding stops 

• Rarely done in modern era 



 

14  

 

  
 

 

 

 

 

 

 

 

Hypercoagulable States 

• Predisposition to venous or arterial thrombi 

• Often DVT/PEs (“Venous thromboembolism”) 

 
• Stroke 

• Myocardial infarction 

• Ischemic limb 

 

 
Hypercoagulable 

States 
Jason Ryan, MD, MPH 

Virchow’s Triad 

• Endothelial damage 

• Endothelium makes numerous natural anticoagulants 

• Nitric oxide, prostaglandins, antithrombin, tPA, APC 

• Stasis of blood 

• Normal blood flow prevents pooling of clotting factors 

• Hypercoagulability 

• Conditions that increase clot formation 

Wikipedia/Public Domain 

Hypercoagulable States 

• Post-op 

• Hypercoagulable (inflammation from surgery) 

• Stasis (immobile) 

• Endothelial damage (surgery) 

• Fall/Hip Fracture/Trauma 

• Hypercoagulable (inflammation from trauma) 

• Stasis (immobility) 

• Endothelial damage (trauma) 

• Long plane flights 
• Stasis (immobility) 

Public Domain 

Hypercoagulable States 

• Malignancy 

• Some tumors produce pro-coagulants (i.e. tissue factor) 

• Adenocarcinomas: some data that mucin is thrombogenic 

• Normal cells may produce pro-coagulants 

• Reaction to presence/growth of tumor 

• Decreased activity, surgery, bed rest 

Hypercoagulable States 

• Pregnancy 

• Probably evolved to protect against blood loss at delivery 

• Many clotting factor levels change 

• Increased fibrinogen 

• Decreased  protein S 

• Fetus also obstructs venous return  DVTs common 

• Oral contraceptive pills (OCPs) 

• Estrogen increases production coagulation factors 



 

15  

 

  
 

 

 

 

 

 

 

 

Holly Fischer/Wikipedia 

Hypercoagulable States 

• Nephrotic syndrome 

• Multiple mechanisms 

• Loss of anti-clotting factors in urine (ATIII) 

Hypercoagulable States 

• Elevated homocysteine (amino acid) 

• Associated with arterial and venous clots 

• High levels may cause: 

• Endothelial injury 

• Activation of some clotting factors 

• Elevated levels caused by: 

• Folate/B12/B6 deficiency 

• Homocystinuria (cystathionine beta synthase deficiency) 

• Levels lowered by folate 

• Most clinical trials of folate did not show benefit 

Pixabay/Public Domain 

Hypercoagulable States 

• Smoking 

• Associated with atherosclerosis and MI/Stroke 

• Some data linking smoking to DVT/PE 

• Evidence that smoking increases fibrinogen levels 

Inherited Thrombophilia 

• Inherited hypercoagulable states 

• Genetic tendencies to VTE 

• Most involve coagulation pathway defects 

• All associated with venous clots (DVT/PE) 

Factor V Leiden Mutation 

• Named for Leiden, Netherlands 

• Abnormal factor V 

• Not inactivated by activated protein C (APC) 

• Factor V remains active longer  hypercoagulability 

 

Thrombomodulin 

Protein 
APC

 

C 
Inactivation 

Va, VIIIa 

 
Protein 

S 

Factor V Leiden Mutation 

• Point mutation in factor V gene 

• Guanine to adenine change 

• Result: Single amino acid change 

• Arginine to glutamine substitution 

• Position 506 in factor V 



 

16  

 

  
 

 

 

 

 

 

 

 

Antithrombin III Deficiency 

• Inherited deficiencies due to gene mutations 

• Acquired deficiencies: 

• Impaired production (liver disease) 

• Protein losses (nephrotic syndrome) 

• Consumption (DIC) 

• Classically presents as heparin resistance 

• Escalating dose of heparin 

• No/little change in PTT 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Prothrombin Gene Mutation 

• Prothrombin 20210 gene mutation 

• Guanine to adenine change in prothrombin gene 

• Occurs at nucleotide 20210 

• Heterozygous carriers: 30% ↑ prothrombin levels 

Protein C or S Deficiency 

• Protein C: associated with warfarin skin necrosis 

• Initial warfarin therapy  ↓ protein C (short half life) 

•  C 

• Result: thrombosis of skin tissue 

• Large dark, purple skin lesions 

 
Thrombomodulin 

Protein 
APC

 

C 
Inactivation 

Va, VIIIa 

 
Protein 

S 

Antiphospholipid Syndrome 

• Caused by antiphospholipid antibodies 

• Occur in association with lupus or as primary disease 

Antiphospholipid Syndrome 

• Three important clinical consequences of antibodies 

• “Antiphospholipid syndrome” 

• #1: Increased risk of venous and arterial thrombosis 

• Most commonly DVT 

• Also CNS: stroke 

• Recurrent fetal loss 

• #2: Increased PTT 

• #3: False positive syphilis (RPR/VDRL) 

Antiphospholipid Syndrome 

• Anti-cardiolipin 

• False positive RPR/VDRL 

• Syphilis also produces these antibodies 

• “Lupus anticoagulant” 

• Interferes with PTT test (silica activation of XII) 

• False elevation 

• Anti-β2 glycoprotein 



 

17  

 

  
 

 

 

 

 

 

 

 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

XI   
T    

XIa 

IX IXa:VIIIa VIII 
T 

 

TF:VIIa Va 

X Xa 

Coagulation cascade 

requires phospholipids 

Lupus Anticoagulant 
XII XIIa 

Antiphospholipid Syndrome 
Antibody Detection 

• Anti-cardiolipin, Anti-β2 glycoprotein 

• Enzyme-linked immunosorbent assay (ELISA) testing 

• “Lupus anticoagulant” 

• Detected indirectly through coagulation assays 

Contact Factor 

Phospholipid 
Calcium 

Patient 

Serum 

Lupus Anticoagulant 
PTT Testing 

•  PTT 

Inhibitor 

↑PTT 
Normal 

Serum 

Inhibitor Nl 

Clotting Factors 

↑PTT 

+ 

` 

` d 

d 

` 

` d 

d 

Lupus Anticoagulant 
Mixing Study 

• Can show presence of lupus anticoagulant (inhibitor) 

50% VIII 

Normal PTT 
Normal 

Serum 

Hemophilia 

↓ Clotting Factors 

↑ PTT 

+ 

Lupus Anticoagulant 
Mixing Study 

• Clotting factor deficiency: PTT corrects to normal 

• Clotting factors ~50% normal  normal PT/PTT 

Lupus Anticoagulant 
Other Tests 

• Only ~50% patients with LA have ↑PTT 

• Other coagulation tests sometimes used 

• Dilute Russell viper venom time 

• Kaolin clotting time 

• Time to clot will be prolonged if LA present 

• Time to clot will not correct with mixing study 



 

18  

 

  
 

 

 

 

 

 

 

 

Antiphospholipid Syndrome 

• Syndrome = one laboratory plus one clinical criteria 

• Lab criteria (2 positive results >12 weeks apart): 

• Lupus anticoagulant 

• Anti-cardiolipin 

• Anti-β2-glycoprotein 

• Clinical criteria: 

• Arterial or venous thrombosis 

• Fetal death after 10 weeks of normal fetus 

• >=3 consecutive fetal losses before 10 weeks 

Lupus Anticoagulant Anti-cardiolipin Anti-β2 glycoprotein 

Clotting Test 

Mixing Study 
ELISA 

Antiphospholipid Antibodies 
Testing 

 
 

Blood Sample 

Hypercoagulable Workup 

• Panel of tests for hypercoagulable states 

• Sometimes performed in: 

• Unprovoked DVT/PE 

• Stroke/MI at an early age 

• Controversial 

• Expensive 

• Rarely changes management 

• Few data on management of identified states 

• Risk of bleeding with indefinite anticoagulation 

• Some tests altered by thrombus or blood thinners 

Hypercoagulable Workup 

• Antithrombin level 

• Protein C and S levels 

• Factor V Leiden gene mutation 

• Prothrombin gene mutation 

• Antiphospholipid antibodies 

• Cancer screening 



 

19  

 

  
 

 

 

 

 

 

 

 

Bleeding Disorders 

• Abnormal coagulation cascade 

• Hemophilia, Vitamin K deficiency 

• Abnormal platelets 

• Bernard-Soulier, Glanzmann’s Thrombasthenia 

• ITP, TTP 

 
• Mixed Disorders 

• Von Willebrand Disease, DIC, Liver disease 

 

 

 
Coagulopathies 
Jason Ryan, MD, MPH 

Bleeding Time 

• Test of platelet function 

• Small cut to patient’s arm 

• Filter paper applied/removed until bleeding stops 

• Rarely done in modern era 

Fibrin/Clot 

PT (II) Thrombin (IIa) 

Add Plasma to (-) charge 

substance (silica) 

Time to form clot 

Normal ~30s 

XIa XI 

IX IXa 

Xa X 

(PTT) 
VII 

XII 
VIIa 

XIIa 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

PTT 
Activated Partial Thromboplastin Time 

Fibrin/Clot 

Normal = 1 

Therapeutic = 2-3 

Thrombin (IIa) PT (II) INR =  Patient PT 
Control PT 

XIa XI 

IXa IX 

Xa X 

VIIa VII 

Prothrombin Time (PT) 

Add Plasma to TF 

Time to form clot 

Normal ~10s 

XIIa XII 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

PT 
Prothrombin Time 

Fibrin (Ia) Fibrinogen (I) 

Thrombin (IIa) Prothrombin (II) 

Thrombin Time 

Add Thrombin to sample 

Time to form clot 

XIa XI 

IX IXa 

Xa X 

VIIa VII 
XIIa XII 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

Thrombin Time 



 

20  

 

  
 

 

 

 

 

 

 

 

Alexei Nikolaevich 
• Also called Christmas disease 

Hemophilias 

• X-linked recessive diseases 

• Gene mutations: Run in families; also occur de novo 

• Hemophilia A: Deficiency of factor VIII 

• Hemophilia B: Deficiency of factor IX 

Hektor/Wikipedia 

Type of Bleeding 

• Abnormal platelets 

• Mucosal bleeding, skin bleeding, petechiae 

• Abnormal coagulation factors 

• Joint bleeding, deep tissue bleeding 

Hemophilias 

• Present with spontaneous or easy bruising 

• Recurrent joint bleeds is common presentation 

• Screening: PTT will be prolonged 

• Factors VIII, IX both part of intrinsic pathway 

• PT, bleeding time, platelet count all normal 

Fibrin (Ia) Fibrinogen (I) 

XIIIa 

Thrombin (IIa) Prothrombin (II) 

Endothelial 

Damage 

X Xa 

Va TF:VIIa 

IXa:VIIIa VIII 
T 

      Phospholipid  

XI 
T  

XIa 

IX 

X VIIIa 
IX

 XIIa XII 

Ca+ Coagulation Cascade 

Biggishben~commonswiki 

Hemophilias 
Treatment 

• Replacement factor VIII and IX 

Hemophilias 
Treatment 

• Desmopressin (dDAVP) 

• Used in mild hemophilia A 

• Analogue of vasopressin (ADH) with no pressor activity 

• Increases vWF and factor VIII levels 

• Releases VIII from Weibel-Palade bodies(endothelial cells) 



 

21  

 

  
 

 

 

 

 

 

 

 

Hemophilias 
Treatment 

• Aminocaproic acid 

• Antifibrinolytic drug 

•  plasmin 

• Less breakdown of formed clots 

Desmopressin 

• Also has vasodilating properties 

• Key side effects: flushing, headache 

• Other uses: 

• von Willebrand disease 

• Central diabetes insipidus (mimics ADH) 

• Bedwetting (decreases urine volume) 

Cryoprecipitate 
“Cryo” 

• Obsolete therapy for hemophilia A 

• Precipitate that forms when FFP is thawed 

• Separated from plasma by centrifugation 

• Contains factor VIII, fibrinogen 

• Also factor XIII and von Willebrand factor (VWF) 

• Often used as source of fibrinogen 

• DIC 

• Massive trauma with blood transfusions 

Martin Brändli /Wikipedia 

Coagulation Factor Inhibitors 

• Antibodies 

• Inhibit activity or increase clearance of clotting factor 

• Inhibitors of factor VIII most common 

• Often occur in association with: 

• Malignancy 

• Post-partum 

• Autoimmune disorders 

• Can be treated with prednisone 

Coagulation Factor Inhibitors 

• Can present similar to hemophilia 

• Deficient activity of VIII  bleeding 

• Prolonged PTT 

• Mixing study will differentiate from hemophilia A 

50% VIII 

Normal PTT 
Normal 

Serum 

Hemophilia A 

No VIII 

↑ PTT 

+ 

Mixing Study 

• Clotting factors ~50% normal  normal PT/PTT 



 

22  

 

  
 

 

 

 

 

 

 

 

Vitamin K Deficiency 

• Results in bleeding 

• Deficiency of vitamin K-dependent factors 

• II, VII, IX, X 

• Key lab findings: 

• Elevated PT/INR 

• Can see elevated PTT (less sensitive) 

• Normal bleeding time 

Inhibitor 

↑PTT 
Normal 

Serum 

Inhibitor 

Normal VIII 

↑PTT 

+ 

` 

` d 

d 

` 

d ` 

d 

Mixing Study 

• Clotting factors ~50% normal  normal PT/PTT 

Vitamin K Deficiency 

• Dietary deficiency rare 

• GI bacteria produce sufficient quantities 

• Common causes: 

• Warfarin 

• Antibiotics (deplete GI bacteria) 

• Newborns (sterile GI tract) 

• Malabsorption (Vitamin K is fat soluble) 

"Blausen gallery 2014". 

Wikiversity Journal of Medicine. 

Blood Transfusion 

• Large volume transfusions  dilution clotting factors 

• Packed RBCs: devoid of plasma/platelets 

• Removed after collection 

• Saline or IVF: No clotting factors 

• Treated with fresh frozen plasma 

Liver Disease 

• Loss of clotting factors 

• Advanced liver disease  ↓ clotting factor synthesis 

• Most clotting factors produced in liver 

• Exception: Factor VIII produced in endothelial cells 

• PT more sensitive to liver disease (vitamin K) 

• Thrombocytopenia also common 

• Decreased hepatic synthesis of thrombopoietin 

• Platelet sequestration in spleen from portal hypertension 



 

23  

 

  
 

 

 

 

 

 

 

 

Bleeding Disorders 

• Abnormal coagulation 

• Hemophilia, Vitamin K deficiency 

• Abnormal platelets 

• Bernard-Soulier 

• Glanzmann’s Thrombasthenia 

 
• Uremia 

• Mixed Disorders 

• Von Willebrand Disease, DIC 

 

 
Platelet 

Disorders 
Jason Ryan, MD, MPH 

Hektor/Wikipedia 

Type of Bleeding 

• Abnormal platelets 

• Mucosal bleeding, skin bleeding, petechiae 

• Abnormal coagulation factors 

• Joint bleeding, deep tissue bleeding 

Bleeding Time 

• Test of platelet function 

• Small cut to patient’s arm 

• Filter paper applied/removed until bleeding stops 

• Rarely done in modern era 

Wiscott-Aldrich 

Immunodeficiency 
Bernard-Soulier 

Deficiency IB 

Glanzman’s 

Thrombasthenia 

Deficiency IIB/IIIA 

Inherited Platelet Disorders 

Inherited 

Platelet 

Disorders 

Glanzmann’s Thrombasthenia 

• Autosomal recessive disorder 

• Functional deficiency of GPIIb/IIIa receptors 

• Bleeding, often epistaxis 

• Key diagnostic finding: 

• Prolonged bleeding time 

• Blood smear: Isolated platelets (no clumping) 

• Absent platelet aggregation in response to stimuli 

• Abnormal platelet aggregometry 

• Platelets mixed with ADP, arachidonic acid 



 

24  

 

  
 

 

 

 

 

 

 

 

Bobjgalindo/Wikipedia 

Giant Platelets 

• Can be seen in association with thrombocytopenia 

• Caused by rare inherited disorders 

• Bernard-Soulier, others 

Bernard-Soulier Syndrome 

• Autosomal recessive disorder 

• Deficiency of GPIb platelet receptors 

• Platelets cannot bind vWF 

• Also results in large platelets 

• Bleeding, often epistaxis or menorrhagia 

• Key lab findings: 

• Prolonged bleeding time 

• Thrombocytopenia 

• Large platelets on blood smear 

Wiskott-Aldrich Syndrome 

• Immunodeficiency syndrome of infants 

• X linked disorder of WAS gene (WAS protein) 

• Necessary for T-cell cytoskeleton maintenance 

• Triad: 

• Immune dysfunction 

• ↓ platelets 

• Eczema 

Active Platelet 
Inactive 

Platelet 

Active 

IIB/IIIA 

ITP 
Idiopathic thrombocytopenic purpura 

• Disorder of decreased platelet survival 

• Commonly caused by anti-GPIIB/IIIA antibodies 

• Consumption splenic macrophages 

ITP 
Idiopathic thrombocytopenic purpura 

• Diagnosis of exclusion 

• Rule out other causes of bone marrow suppression 

• Treatment: 

• Steroids 

• IVIG (blocks Fc receptors in macrophages) 

• Splenectomy 

TTP 
Thrombotic thrombocytopenic purpura 

• Disorder of small vessel thrombus formation 

• Consumes platelets  thrombocytopenia 

• ↓ activity of vWF cleaving protease ADAMTS13 



 

25  

 

  
 

 

 

 

 

 

 

 

Von Willebrand Factor 
Multimers 

• Large multimers stored: 

• Endothelial Weibel–Palade bodies 

• Platelet α-granules 

• Large multimers can obstruct blood flow 

• ADAMTS13 prevents obstruction 

• Enzyme (metalloprotease) 

• Breaks down multimers of vWF 

• Prevents thrombotic occlusion 

Von Willebrand Factor 
Multimers 

• vWF synthesized a protein monomer 

• Occurs in endothelial cells and megakaryocytes 

• Monomers link in endoplasmic reticulum  dimers 

• vWF dimers move to Golgi  multimers 

vWF 

Platelet 

ADAMTS13 

ADAMTS13 

TTP 
Cause 

• Severe ADAMTS13 deficiency 

• Usually <10% normal activity 

• Usual cause: acquired autoantibody to ADAMTS13 

• Result: vWF multimers in areas of high shear stress 

• Obstruction small vessels 

Paulo Henrique Orlandi Mourao 

MAHA 
Microangiopathic hemolytic anemia 

• Hemolytic anemia (↑LDH, ↓ haptoglobin) 

• Caused by shearing of RBCs as they pass through 
thrombi in small vessels 

• Blood smear: schistocytes 

• Seen in: 

• TTP 

• HUS 

• DIC 

TTP 
Thrombotic thrombocytopenic purpura 

• Fever 

• Inflammation from small vessel occlusion and tissue damage 

• Neurological symptoms 

• Headache, confusion, seizures 

• Renal failure 

• Petechiae and bleeding 



 

26  

 

  
 

 

 

 

 

 

 

 

Mr Vacchi /Wikipedia 

TTP 
Treatment 

• Plasma exchange: removes antibodies 

• Platelet counts monitored to determine efficacy 

TTP 
Thrombotic thrombocytopenic purpura 

• Lab tests: 

• Hemolytic anemia 

• Thrombocytopenia 

• Schistocytes on blood smear 

• PT/PTT should be normal 

• Contrast with DIC 

• May see elevated d-dimer 

Hemolytic Uremic Syndrome 
HUS 

• Many similarities with TTP 

• Also caused by platelet-rich thrombi in small vessels 

• MAHA, thrombocytopenia, acute kidney injury 

• Usually no fever or CNS symptoms 

• kidney injury 

• Commonly seen in children 

• Commonly follow GI infection E. Coli O157:H7 

• Shiga-like toxin causes microthrombi 

DIC 
Disseminated Intravascular Coagulation 

• Widespread activation of clotting cascade 

• Diffuse thrombi (platelets/fibrin)  ischemia 

• Consumption of clotting factors and platelets 

• Destruction of red blood cells  anemia 

DIC 
Disseminated Intravascular Coagulation 

• Occurs secondary to another process 

• Obstetrical emergencies 

• Amniotic fluid contains tissue factor 

• DIC seen in conjunction with amniotic fluid embolism 

• Sepsis 

• Endotoxin –> activates coagulation cascade 

• Cytokines 

Andy king50/Wikipedia 

DIC 
Disseminated Intravascular Coagulation 

• Leukemia 

• Especially acute promyelocytic leukemia (APML) 

• Cancer: well-described hypercoagulable state 

• Excess coagulation: DIC 

• Rattlesnake bites 

• Thrombin-like glycoproteins within venom 

• Diffuse activation of clotting 



 

27  

Confusion GI Illness 

Child Fever 

Platelet/Fibrin 

Thrombi 

ITP, TTP, HUS, DIC 
Platelet 

Thrombi 

 

  
 

 

 

 

 

 

 

 

DIC 
Disseminated Intravascular Coagulation 

• Treatment: underlying disorder 

• Fresh frozen plasma: replace clotting factors 

• RBCs, platelets 

• Cryoprecipitate (for low fibrinogen) 

DIC 
Disseminated Intravascular Coagulation 

• Elevated PT/PTT/Thrombin time 

• Consumption of factors 

• Low platelets 

• Consumption of platelets 

• Low fibrinogen (consumption) 

• Microangiopathic hemolytic anemia 

• Low RBC (anemia) 

• Schistocytes on blood smear 

• Elevated D-dimer 

 ITP TTP HUS DIC 

↓ Platelets + + + + 

Hemolytic 

Anemia -- + + + 

↑PT/PTT -- -- -- + 

 

Uremia 

• Renal dysfunction  bleeding 

• Poor aggregation and adhesion of platelets 

• Caused by uremic toxins in plasma 

• Uremic platelets work normally in normal serum 

• Prolonged bleeding time 

• Normal platelet count 

• Normal coagulation testing 

Thrombocytopenia 

• Decreased production of platelets 

• Chemotherapy, leukemia 

• Sepsis (bone marrow suppression) 

• Platelet sequestration 

• Splenomegaly 

• Portal hypertension 

• Platelet destruction 

• ITP, TTP 

Thrombocytopenia 

• Normal platelet count: 150,000/ml to 400,000/ml 

• Bleeding occurs when <10,000 

• Treatment: Platelet transfusions 



 

28  

 

  
 

 

 

 

 

 

 

 

Von Willebrand Disease 

• Most common inherited bleeding disorder 

• Affects up to 1 percent of population 

• Gene mutations  ↓ level or function of vWF 

• Most cases autosomal dominant (males=females) 

Von Willebrand Disease 

• Deficient function of von Willebrand Factor 

• Large glycoprotein 

• Synthesized by endothelial cells and megakaryocytes 

• Present in platelets 

• Two key roles in hemostasis 

• Carrier of factor VIII (intrinsic coagulation pathway) 

• Binds platelets to endothelium and other platelets 

Von Willebrand Disease 

• Usually mild, non-life-threatening bleeding 

• Easy bruising 

• Skin bleeding 

• Prolonged bleeding from mucosal surfaces 

• Severe nosebleeds 

• Menorrhagia 

Von Willebrand Disease 
Diagnosis 

• Normal platelet count 

• Normal PT 

• Increased PTT (depending on severity) 

• Usually no joint/deep tissue bleeding 

• Increased bleeding time 

Abnormal 

vWF defective 
Normal 

vWF active 

Platelet 

Aggregometry 

Serum 
Patient’s 

Ristocetin
 

Von Willebrand Disease 
Diagnosis 

• Ristocetin cofactor activity assay 

• Ristocetin: antibiotic off market due to ↓platelets 

• Binds vWF and platelet glycoprotein Ib 

• Causes platelet aggregation if vWF present 

Von Willebrand Disease 
Treatment 

• vWF concentrate 

• Desmopressin 

• Increases vWF and factor VIII levels 

• Releases vWF from endothelial cells 

• Aminocaproic acid 

• Antifibrinolytic drug 

•  plasmin 

• Less breakdown of formed clots 



 

29  

 

  
 

 

 

 
 

 

 

 

Heyde’s Syndrome 

• GI bleeding associated with aortic stenosis 

• Angiodysplasia 

• Vascular malformations of GI tract 

• Prone to bleeding 

• Commonly occur in aortic stenosis patients 

• Deficiency of von Willebrand factor 

• High shearing force caused by aortic stenosis 

• Uncoiling of vWF multimers 

• Exposes cleavage site for ADAMST13 

• Improves after aortic valve surgery 



 

30  

 

  
 

 

 

 

 

 

 

 

THROMBUS 

ACTIVATED PLATELETS FIBRIN 

Thrombus Formation  

 

 
Antiplatelets 
Jason Ryan, MD, MPH 

Thrombolytics 

tPA   

Urokinase 

Streptokinase 

Antiplatelets 

Aspirin ADP 

Blockers IIB/IIIA 

Inhibitors 

Phosphodiesterase Inhibitors 

THROMBUS 

Anticoagulants 

Heparin 

Warfarin 

Direct Thrombin 

Inhibitors 

Factor Xa inhibitors 

ACTIVATED PLATELETS FIBRIN 

Thrombus Formation 

Thromboxane (from arachidonic acid) 

Adenosine diphosphate (ADP) 

↓cAMP (via ADP) 

Activated 

Platelet 
De-activated 

Platelet 

IIB/IIIA 

Antiplatelets 

Platelet Activation 

Thromboxane A2 

X 

Aspirin 
Arachidonic acid 

Lipids (cell membranes) 

Aspirin 

Cyclooxygenase 

Phospholipase A2 

Aspirin 

• Inhibits COX-1 and COX-2 

• Both found in platelets 

• Blunts conversion of AA to TXA2 

• ↓ platelet activity 

• Also inhibits production of prostaglandins 



 

31  

 

  
 

 

 

 

 

 

 

 

Ricciotti E, FitzGerald G; Prostaglandins and Inflammation 

Arterioscler Thromb Vasc Biol. 2011 May; 31(5): 986–1000. 

Eicosanoids 

Prostaglandins 

Thromboxanes 

Leukotrienes 

Cyclooxygenase 
Lipoxygenase 

Arachidonic acid 

Eicosanoids 

Lipids (cell membranes) 

Phospholipase A2 

NSAIDs 
Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac 

• Aspirin is technically NSAID 

• NSAIDS reversibly inhibit COX-1 and COX-2 

• Aspirin irreversibly inhibits COX-1 and COX-2 

• Decreases activity for lifetime of platelet (7-10days) 

• All NSAIDs may cause bleeding 

• All NSAIDs reduce pain, inolammation via ↓ PGs 

Aspirin 
Common antiplatelet uses 

• Coronary disease 

• Acute myocardial infarction/unstable angina 

• Secondary prevention 

• Stroke 

• Acute ischemic stroke 

• Secondary prevention 

Aspirin 
Adverse Effects 

• Bleeding 

• Gastritis/Ulcers 

• COX important for maintenance of GI mucosa 

• Tinnitus 

• Caused by salicylate (aspirin metabolite: salicylic acid) 

• Alters cochlear nerve function 

• Rare: Usually occurs with very high doses 

• Resolves with discontinuation 

Aspirin 
Adverse Effects 

• Reye’s syndrome 

• Liver failure and encephalopathy 

• Associated with aspirin use in children 

• Aspirin not generally used in kids (exception: Kawasaki) 



 

32  

 

  
 

 

 

 

 

 

 

 

TTP 
Thrombotic Thrombocytopenic Purpura 

• Associated with thienopyridine drugs 

• Severe thrombocytopenia 

• Microangiopathic hemolytic anemia 

• Neurologic abnormalities 

• Deficient activity of ADAMTS13 

• Antibodies to ADAMTS13 

• Added to aspirin for prevention of MI, Stroke 

• Major adverse effect is bleeding 

• Rare, dangerous adverse effect: TTP 

Ticlopidine 

Thienopyridines 
Ticlopidine, clopidogrel, prasugrel 

• Irreversible P2Y12 receptor blockers 

• Block effects of ADP on platelets 

• Used in aspirin allergy 

Ticagrelor 

• Cyclo-pentyl-triazolo-pyrimidine (CPTP) 

• NOT a thienopyridine 

• Reversible antagonist to P2Y12 receptor 

• Unique side effect: Dyspnea 

• Mechanism unclear 

Phosphodiesterase Inhibitors 
PDE Inhibitors 

• Inhibit phosphodiesterase III in platelets 

• PDE breaks down cAMP 

• ↑ cAMP  ↓ platelet activation 

• Two drugs in class: dipyridamole, cilostazol 

Dipyridamole 

• PDEIII inhibitor 

• Inhibits platelet activation 

• Also blocks adenosine uptake by cells 

• Adenosine = vasodilator 

• Raises adenosine levels vasodilation 

• Used with aspirin for stroke prevention (antiplatelet) 

• Used in chemical cardiac stress testing (vasodilator) 

Cilostazol 

• PDEIII inhibitor 

• Inhibits platelet activation 

• Also raises cAMP in vascular smooth muscle 

• Vasodilator 

• Rarely used for anti-platelet effects 

• Used in peripheral arterial disease 



 

33  

 

  
 

 

 

 

 

 

 

 

Tirofiban Eptifibatide 

IIB/IIIA Receptor Blockers 

• Abciximab, eptifibatide, tirofiban 

• Bind and block IIB/IIIA receptors 

• Abciximab: Fab fragment of antibody to IIB/IIIA 

• IV drugs used in acute coronary syndromes/stenting 

Phosphodiesterase Inhibitors 
Dipyridamole, Cilostazol 

• Many side effects related to vasodilation 

• Headache 

• Flushing 

• Hypotension 

IIB/IIIA Receptor Blockers 

• Main adverse effect is bleeding 

• Can cause thrombocytopenia 

• May occur within hours of administration 

• Mechanism poorly understood 

• Must monitor platelet count after administration 

Active Platelet 
X 

Inactive 

Platelet 

X 

IIB/IIIA 

Blockers Aspirin (TXA2) ADP 

Blockers PDE Inhibitors 

(↑cAMP) 

Antiplatelet Drugs 



 

34  

 

  
 

 

 

 

 

 

 

 

• Peripheral circulation • Critical Limb Ischemia 

Thrombus Location 

• Left atrial appendage 

• Coronary artery 

• Deep vein/pulm artery 

Disease 

• Atrial Fibrillation 

• Myocardial Infarction 

• DVT/PE 

Thrombus Disorders  

 

 
Anticoagulant Drugs 
Jason Ryan, MD, MPH 

Antithrombotic Drugs 

• Acute therapy: Help eliminate clot already formed 

• Prevention: Lower risk of clot in high risk patients 

THROMBUS 

ACTIVATED PLATELETS FIBRIN 

Thrombus Formation 

Thrombolytics 

tPA 

Antiplatelets 

Aspirin 

ADP Blockers 
IIb/IIIa Inhibitors 

Phosphodiesterase Inhibitors 

THROMBUS 

Anticoagulants 

Heparin 

Warfarin 

Direct Thrombin Inhibitors 

Factor Xa inhibitors 

ACTIVATED PLATELETS FIBRIN 

Blood thinners Bleeding 

• Thrombus formation very beneficial 

• Prevents/stops bleeding 

• BLEEDING: common side effect 

• Can occur with all antithrombotic/antiplatelet drugs 



 

35  

 

  
 

 

 

 

 

 

 

 

Fibrin/Clot Fibrinogen 

PT (II) Thrombin (IIa) 

XIIa XII 

XIa XI 

IXa IX 

Xa X 

VIIa VII 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

Coagulation Cascade 

GI Bleeding 

CNS Bleeding 

Bruising 

Myocardial Infarction 

Pulmonary Embolism 

Deep Vein Thrombosis 

Stoke 

Clotting versus Bleeding 

Fibrin/Clot Fibrinogen 

PT (II) Thrombin (IIa) 

Add Plasma to (-) charge 

substance (silica) 

Time to form clot 

Normal ~30s 

XIa XI 

IX IXa 

Xa X 

(PTT) 
VII 

XII 
VIIa 

XIIa 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

PTT 
Activated Partial Thromboplastin Time 

Fibrin/Clot Fibrinogen Normal = 1 
Therapeutic = 2-3 

PT (II) Thrombin (IIa) INR =  
Patient PT 

Control PT 

XIa XI 

IXa IX 

Xa X 

VIIa VII 

Prothrombin Time (PT) 

Add Plasma to TF 

Time to form clot 

Normal ~10s 

XIIa XII 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

PT 
Prothrombin Time 

Fibrin/Clot Fibrinogen 

PT (II) Thrombin (IIa) 

Add Thrombin to sample 

Time to form clot 
Xa X 

XIa XI 

IXa    IX Thrombin Time 

VIIa VII 
XIIa XII 

Intrinsic Pathway Silica Extrinsic Pathway Tissue Factor 

Thrombin Time Heparin 

• Polymer (glycosaminoglycan) 

• Occurs naturally (found in mast cells) 

• Molecules with varying chain lengths 

• Used in two forms: 

• Unfractionated: widely varying polymer chain lengths 

• Low molecular weight: Smaller polymers only 



 

36  

 

  
 

 

 

 

 

 

 

 

Unfractionated Heparin (UFH) 

• Given IV or SQ  acute onset 

• Increases PTT 

• Effects many components of intrinsic pathway 

• HeparIN = INtrinsic (PTT) 

• Will also increase thrombin time 

• Can increase PT at high dosages 

• Lots of binding to plasma proteins, cells 

• Highly variable response from patient to patient 

• Dose must be adjusted to reach goal PTT 

Fibrin/Clot Fibrinogen 

UF Heparin 
Thrombin PT 

ATIII 

XIIa XII 

XIa XI 

IXa IX 

Xa X 

UF Heparin 
Activates ATIII 

VII VII 

Silica Intrinsic Pathway Extrinsic Pathway Tissue Factor 

Unfractionated Heparin 

Protamine 

• Reversal agent for unfractionated heparin 

• Less effective with LMWH 

• Binds heparin  neutralizes drug 

• Used in heparin overdose 

• Used in cardiac surgery 

• High dose heparin administered for heart-lung bypass 

• Quick reversal at completion of case 

Unfractionated Heparin (UFH) 

• Uses: 

• Acute management: DVT/PE, MI, Stroke 

• Prophylaxis for DVT in hospitalized patients (SQ) 

Unfractionated Heparin (UFH) 

• Side Effects 

• Mainly bleeding and thrombocytopenia 

• Osteoporosis (long term use) 

• Elevated AST/ALT (mild) 

Heparin and Thrombocytopenia 

• Many patients  mild (10-20%) ↓ platelets 

• “Non-immune” thrombocytopenia 

• Direct suppressive effect platelet production 

• Heparin-induced thrombocytopenia (HIT) 

• Immune-mediated reaction 

• Immune complexes bind platelet factor 4-heparin 

• Type II hypersensitivity reaction 



 

37  

 

  
 

 

 

 

 

 

 

 

HIT 
Heparin-induced thrombocytopenia 

 

• 5-10 days after exposure to heparin 

• Abrupt fall in platelets (>50%) 

• Arterial/vein thrombosis 

• Rare: 0.2 – 5% Heparin patients 

• Patients with HIT must use alternative drugs 

• Lepirudin, Bivalirudin (direct thrombin inhibitors) 

Thrombosis 

↓Platelets 
Platelet 

Aggregation/Activation 

Removal by 

Splenic 

Macrophages 

IgG-Hep-PF4 

Complexes 

 
 

Binding to 

Platelet Surface 

PF4 

Release 

IgG antibodies 

Hep-PF4 

Heparin-PF4 

HIT 
Heparin-induced   thrombocytopenia 

 

• Presumptive diagnosis: 

• Significant drop in platelet count 

• Thrombosis formation 

• Definitive diagnosis: HIT antibody testing 

• Autoantibodies to platelet factor 4 complexed with heparin 

Fibrin/Clot Fibrinogen 

UF Heparin 
PT Thrombin 

ATIII 

XIa XI 

IXa IX 

Xa X 

VII VII 

Silica Intrinsic Pathway 

XIIa XII 

Extrinsic Pathway Tissue Factor 

Low Molecular Weight Heparin 
Enoxaparin 

Fibrin/Clot Fibrinogen 

LMWH 
PT Thrombin 

ATIII 

XIa XI 

IXa IX 

Xa X 

VII VII 

Silica Intrinsic Pathway 

XIIa XII 

Extrinsic Pathway Tissue Factor 

Low Molecular Weight Heparin 
Enoxaparin 

Low Molecular Weight Heparin 
Enoxaparin 

• Dose based on weight – no titrating 

• Reduced binding to plasma proteins and cells 

• Given SQ 

• Lower incidence of HIT (but may still cause!) 



 

38  

 

 
 

 

 

 

 

 

 

 

Low Molecular Weight Heparin 
Enoxaparin 

• If monitoring required, must check anti Xa levels 

• Limited/insensitive affect on PTT 

• Standard dose based on weight 

• Usually no monitoring used 

• Exceptions: Obesity and renal failure 

High Xa activity Low Xa activity 

cromophore   Xa Substrate  

Sample 

Anti-Xa Level 

Fibrin/Clot 

Xa 

 
PT Thrombin 

X 

VII VII 

Direct inhibitors 
Tissue Factor Rivaroxaban 

Apixaban 
Indirect inhibitors (ATIII) 

Unfractionated Heparin 

LMWH 

Factor Xa Inhibitors 

Factor Xa Inhibitors 

• Rivaroxaban, Apixaban 

• Used in atrial fibrillation as alternatives to warfarin 

• Do not require monitoring of PT/INR 

• Standard dosing 

• Can increase PT and PTT (Xa in both pathways) 

• Will not affect thrombin time 

Fibrin/Clot 

Fibrin Fibrinogen 

PT Thrombin 

Xa X 

Hirudin 

Lepirudin 

Bivalirudin 

Desirudin 

Argatroban 

Dabigatran (PO) 

VII VII 

Direct Thrombin Inhibitors 

Direct Thrombin Inhibitors (DTIs) 
Tissue Factor 

Plasma Concentration 

LMWH 

Low Molecular Weight Heparin 
Enoxaparin 

• Will not affect thrombin time (like UF heparin) 

• PTT not sensitive to LMWH-induced changes 

• Unlike UF heparin, only factor X effected 

 

UFH 

P
T

T
 



 

39  

 

  
 

 

 

 

 

 

 

 

Direct Thrombin Inhibitors 
Uses 

• Patients with HIT 

• Hirudin, lepirudin, bivalirudin, desirudin, argatroban 

• Stop heparin, start DTI 

• PTT often monitored 

• Acute coronary syndromes, coronary interventions 

• Bivalirudin 

• Atrial fibrillation 

• Dabigatran (oral) 

• Standard dosing: does not require PT/INR monitoring 

Direct Thrombin Inhibitors 
Uses 

• Can prolong PT, PTT, and thrombin time 

• Thrombin activity common to all tests 

• Only UF heparin and DTIs prolong thrombin time 

• Requires an inhibitor of thrombin function 

• UF Heparin: ATIII 

• DTIs: Direct drug effect 

Warfarin 

• Vitamin K Factors: II, VII, IX, and X 

• Warfarin: Antagonist to vitamin K 

• ↓ levels of all vitamin K dependent factors 

Activated Clotting 

Factor 
Clotting Factor 

Precursor 

CO2 

N—CH2—C 

CH2 O 

CH2 

-OOC COO- 
γ carbon 

+ 

γ carboxylation 

N—CH2—C 

CH2 O 

CH2 

COO- 

γ-carboxyglutamate 

(Gla) 

Residue Vitamin K 
Glutamate 

Residue 

Vitamin K 

• Forms γ-carboxyglutamate (Gla) residues 

Vitamin K 

• Found in green, leafy vegetables (K1 form) 

• Cabbage, kale, spinach 

• Also egg yolk, liver 

• Also synthesized by GI bacteria (K2 form) 

Activated Clotting 

Factor 

Clotting Factor 

Precursor 

CO2 

N—CH2—C 

CH2 O 

CH2 

-OOC COO- 

N—CH2—C 

CH2 O 

CH2 

COO- 

Oxidized 

Vitamin K 

Reduced 

Vitamin K 

Warfarin 

- 
Epoxide 

Reductase 

Warfarin 
Vitamin K Antagonist 



 

40  

 

  
 

 

 

 

 

 

 

 

Fibrin/Clot Fibrinogen 

XIIa XII 

XIa XI 

IXa IX 

Xa 

 
PT Thrombin 

X 

VII VII 

Silica Intrinsic Pathway Extrinsic Pathway Tissue Factor 

Vitamin K Dependent Factors Warfarin 

• Takes days to achieve its effects 

• Time required for clotting factor levels to fall 

• Dose adjusted to reach target PT/INR 

• Drugs effect varies with diet (vitamin K) 

•  INR 

• Some drugs interfere with metabolism 

Vitamin K Dependent Factors 

• Factor VII has shortest half life 

• First level to fall after Warfarin administration 

• Only PT captures factor VII activity 

• PTT less sensitive to Warfarin 

• Thrombin time normal 

Warfarin 
Prothrombotic Effects 

• Protein C: anti-clotting factor with short half-life 

• Also vitamin K dependent 

• Initial warfarin Rx  protein C deficient 

• This is pro-thrombotic 

•  antithrombotic 

Warfarin 
Prothrombotic Effects 

• Should you start another drug (heparin) anytime you 
start warfarin? 

• Yes, but this is usually not an issue 

• For clot disorders (DVT/PE) heparin used for acute onset 

•  therapy 

• One exception: Atrial fibrillation 

• No active clot; just risk of clot 

• Often start warfarin without heparin 

• Brief increase in risk of clot is very low 

Warfarin 
Adverse Effects 

• Crosses placenta 

• Avoided in pregnancy 

• Fetal warfarin syndrome: abnormal fetal development 

• Unfractionated heparin often used (does not cross) 

• Side Effects: 

• Mainly bleeding 

• Skin necrosis 



 

41  

 

  
 

 

 

 

 

 

 

 

Warfarin 
Uses 

 

• Stroke prevention atrial fibrillation 

• Mechanical heart valves 

• DVT/PE 

Warfarin Skin Necrosis 

• Rare complication of therapy 

• Occurs in patients with protein C deficiency 

• Can also occur with very high dosages 

• Initial exposure to warfarin  ↓ protein C 

• Result: thrombosis of skin tissue 

• Large dark, purple skin lesions 

Chronic Oral Anticoagulation 

• Several Indications 

• Atrial Fibrillation 

• Mechanical heart valve 

• Prior DVT or PE 

• Prior Standard: Warfarin 

• Oral drug, Low Cost 

• Downside: Requires INR checks (monthly blood draw) 

Novel Oral Anticoagulants (NOACs) 
Alternatives to Warfarin 

• Factor Xa inhibitors 

• #1: Rivaroxaban 

• #2: Apixaban 

• Direct Thrombin inhibitors 

• #3: Dabigatran 

• Upside: No INR checks…consistent dose 

• Downsides 

• Cost $$ 

• Reversal agents - Idarucizumab 

Powerful, “clot busters” 

Used in acute MI, stroke 

MAJOR bleeding risk 

tPA   

Streptokinase 

Urokinase 

Thrombolysis 

D-dimers Fibrin 

Degradation 

Products 

Clots 

Plasmin Plasminogen 

Fibrin 

Reversal of drugs 

• Fresh Frozen Plasma (FFP) 

• Plasma after removal of RBC, WBC, and Plt 

• Frozen for storage 

• Once thawed, must be used within 24hrs 

• Clotting factors degrade 

• Corrects deficiencies of any clotting factor 

• PT/PTT will normalize after infusion 



 

42  

 

  
 

 

 

 
 

 

 

 

Reversal of drugs 

• Vitamin K 

• Reverses warfarin 

• Used with ↑ INR in absence of serious bleeding 

• Given PO or IV 

• IV can cause anaphylaxis 

• INR 3-5: Hold warfarin 

• INR 5-9: Hold warfarin, Oral vitamin K 

• INR >9: Consider IV vitamin K, FFP 

 
Severe bleeding + ↑INR = administer FFP 



 

43  

 

  
 

 

 

 

 

 

 

 

Hemolysis 

Hemolysis 

• Destruction of red blood cells 

• Causes a normocytic anemia 

 

 

 
Hemolysis Basics 
Jason Ryan, MD, MPH 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

Hemolysis 
Extrinsic versus Intrinsic 

• Extrinsic cause 

• Cause is extrinsic to the red cell 

• Antibodies 

• Mechanical trauma (narrow vessels) 

• RBC infection 

• Intrinsic cause 

• Cause is intrinsic to red blood cells 

• Failure of membrane, hemoglobin, or enzymes 

• Membrane: Hereditary spherocytosis 

• Enzyme: G6PD deficiency 

• Hemoglobin: Sickle cell anemia (Abnormal Hgb) 

Extrinsic 

AIHA 

MAHA 

Mechanical 

Infection 

Intrinsic 

PNH 

PK 

G6PD 

Spherocytosis 

Sickle Cell 

HbC 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

TCA Cycle 

Lactate NAD+ Acetyl-CoA 

LDH 

Pyruvate 

Pyruvate 

Kinase 
ATP 

Phosphoenolpyruvate 

Hemolysis 
Consequences 

• Normocytic anemia 

• Elevated plasma LDH 

• Lactate dehydrogenase 

• Glycolysis enzyme 

• Converts pyruvate  lactate 

• Spills out of RBCs 



 

44  

 

  
 

 

 

 

 

 

 

 

Reticulocyte Count 

• ↑ reticulocytes: normal marrow response to anemia 

• Key blood test in normocytic anemias 

• Normocytic anemia: ↓ production or ↑ destruction 

• Reticulocyte count differentiates between causes 

• Low retic count: Underproduction 

• High retic count: Increased destruction (hemolysis) 

↑ Reticulocyte 

↑ EPO 

Hemolysis 

Reticulocytes 

• Immature red blood cells 

• Usually about 1-2% of RBCs in peripheral blood 

• Increased reticulocyte count: Hallmark of hemolysis 

Corrected RC = 8% * (11/45) = 2% 

Hct 11 

Retic 8% 
Hct 45 (normal) 

Retic 1% (normal) 

Reticulocyte Count 

• Normal: 1 to 2 % 

• Anemia: 4-5% 

• Must be corrected for degree of anemia 

• If <2%  inadequate bone marrow response 

Corrected 
Retic % 

RPI = 
Maturation 

Time 

Reticulocyte Production Index 

• Normal reticulocytes circulate ~1day 

• In anemia  premature release of reticulocytes 

• Can live longer  circulate longer 

• RPI corrects for longer life of reticulocytes in anemia 

• RPI < 2% seen with bone marrow failure 

Bilirubin 
Heme 

Hemolysis 
Consequences 

• Elevated unconjugated (indirect) bilirubin 

• Not water soluble 

• Bound to albumin in plasma 

James Heilman, MD 

Jaundice 



 

45  

 

  
 

 

 

 

 

 

 

 

Hemolysis 
Intravascular versus Extravascular 

• Intravascular hemolysis 

• Occurs inside blood vessels 

• Extravascular hemolysis 

• Occurs in liver and spleen 

• Both cause normocytic anemia and ↑ retic count 

Emmanuelm/Wikipedia 

Gallstones 

• ↑ risk in hemolysis 

• Pigment stones 

• Contain bilirubin 

• Less common type of gallstone (more common: cholesterol) 

Extravascular Hemolysis 

• Liver 

• Receives large portion cardiac output 

• Can remove severely damaged RBCs 

• Spleen 

• Destroys poorly deformable RBCs 

• Cords of Billroth: Vascular channels that end blindly 

• Found in red pulp of spleen 

• RBCs must deform to pass through slits in walls of cords 

• Old (“senescent”) or damaged RBCs remain in the cords 

• Phagocytosed by the macrophages 

• Hemolysis disorders  ↑ splenic removal of RBCs 

Artery 

Red Pulp 

Spleen 

Intravascular Hemolysis 

• Destruction of RBCs inside blood vessels 

• Outside of spleen 

• Mechanical trauma 

• Narrowed vessels 

• Small vessels: thrombus (“microangiopathic”) 

• Large vessels: mechanical heart valves 

Haptoglobin 

• Plasma protein 

• Binds free hemoglobin 

• Haptoglobin-hemoglobin complex removed by liver 

• ↓ serum haptoglobin with hemolyisis 



 

46  

 

  
 

 

 

 

 

 

 

 

Haptoglobin 

• Produced by the liver 

• Acute phase reactant 

• Increased levels with inflammation 

• Decreased levels in cirrhosis 

Kormoczi G. Influence of clinical factors on the haemolysis marker haptoglobin. 

Eur J Clin Invest 2006 Mar;36(3) 

Haptoglobin 

• Intravascular: Hgb released directly into plasma 

• Haptoglobin very low or undetectable 

• Extravascular: Some Hgb released from spleen 

• Haptoglobin can be low or normal 

• Classically taught as low in intravascular only 

• Studies show can be low in both types 

Hemolyisis 
Urine findings 

• No bilirubin 

• Unconjugated bilirubin not water soluble 

• Cannot pass into urine 

Hemolyisis 
Urine findings 

• Intravascular hemolyisis 

• Haptoglobin saturation  free excess hemoglobin 

• “Hemoglobinemia” 

•  hemoglobinuria 

• Some reabsorbed in proximal tubules 

• Iron converted into ferritin  hemosiderin in tubular cells 

• Tubular cells slough into urine 

• Prussian blue stain on sediment shows hemosiderinuria 

James Heilman, MD - 

Hemolyisis 
Urine findings 

• Hemoglobin part of urine dipstick 

• Hgb may turn urine red/brown 

• Also occurs in rhabdomyolysis 

• Myoglobin from muscle damage 

• No red cells plus + Hgb 

Hemolysis 
Classic Findings 

• Normocytic anemia 

• ↑ LDH 

• ↑ Indirect bilirubin 

• ↑ Reticulocyte count 

• ↓ Haptoglobin (lower in intravascular) 

• Urine Hgb and hemosiderin (intravascular) 



 

47  

 

  
 

 

 

 

 

 

 

 

Parvovirus B19 

• Healthy patients: 

• RBC production returns 10 to 14 days; mild/no anemia 

• Hemolysis patients 

• Increased RBC turnover 

• Lack of erythropoiesis leads to severe anemia 

• Pallor, weakness, and lethargy 

Parvovirus B19 

• DNA virus 

• Replicates in RBC progenitor cells 

• ↓erythropoiesis 

Parvovirus B19 

• “Aplastic Crisis” in patients with chronic hemolysis 

• Sickle cell anemia 

• Hereditary spherocytosis 

• Beta thalassemia major 

• Classic scenario: 

• Worsening anemia with LOW reticulocyte count 

Back and Abdominal Pain 

• Seen in some hemolytic syndromes 

• Abdominal pain can be caused by splenomegaly 

• May be due to smooth muscle spasm 

• Nitric oxide: scavenged by free hemoglobin 

• Common in some hemolytic disorders 

• Paroxysmal nocturnal hemoglobinuria 

• G6PD deficiency 



 

48  

 

  
 

 

 

 

 

 

 

 

Extrinsic 

AIHA 

MAHA 

Mechanical 

Infection 

Intrinsic 

PNH 

PK 

G6PD 

Spherocytosis 

Sickle Cell 

HbC 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

 

 

 
Extrinsic Hemolysis 
Jason Ryan, MD, MPH 

Extrinsic Hemolysis 

• Antibodies 

• Trauma/shearing 

• Red cell infections 

AIHA 
Autoimmune Hemolytic Anemia 

• Red cell destruction from autoantibodies 

• Results in extravascular hemolysis 

• Red cell membrane removed in pieces by spleen 

• Can be “warm” or “cold” 

Warm AIHA 

• Most common type of AIHA 

• Antibodies bind at body temp 37oC (“warm”) 

• IgG antibodies against RBC surface antigens 

Warm AIHA 
Signs and symptoms 

• Anemia 

• Fatigue 

• Pallor (pale skin) 

• Dyspnea 

• Tachycardia 

• Extravascular hemolysis 

• Jaundice 

• Splenomegaly 



 

49  

 

  
 

 

 

 

 

 

 

 

Direct Antiglobulin Test 
DAT or Coombs Test 

• Test for red blood cell antibodies 

• Patient RBCs plus anti IgG antiserum 

• Positive if agglutination occurs 

• Indicates patient’s RBCs covered with IgG 

Ed Uthman 

Warm AIHA 
Diagnostic Findings 

• Spherocytes 

• Smaller than normal RBCs 

• Spherical 

IgG on RBCs Antibodies 

Anti-IgG Positive Patient 

RBCs 

+ 

Negative 

No IgG on RBCs 

Direct Antiglobulin Test 
DAT or Coombs Test 

Indirect Antiglobulin Test 
Indirect Coombs 

• Also a test for red blood cell antibodies 

• Not generally used in warm/cold AIHA 

• Tests for antibodies in the serum 

• Patient’s serum (not RBCs) tested 

• Added to RBCs 

• Indicates antibodies to RBC components 

Positive 

Antibodies 

in serum 

to RBCs 

RBCs 
Patient 

Serum 

+ 

Indirect Antiglobulin Test 
Indirect Coombs 
 

Negative No 

antibodies to 

RBCs 

Antiglobulin Tests 

• Direct antiglobulin test 

• Test for antibodies bound to RBCs 

• Commonly used in hemolytic anemias 

• Indirect antiglobulin test 

• Test for antibodies in serum 

• Will serum react with RBCs? 



 

50  

 

  
 

 

 

 

 

 

 

 

Øyvind Holmstad/Wikipedia 

Methyldopa 
α methyldopa 

• Antihypertensive drug of choice in pregnancy 

• Agonists to CNS α2 receptors 

• Synapses believe too much sympathetic outflow 

• Decrease sympathetic tone in body 

• Associated with warm AIHA 

Warm AIHA 
Associated Conditions 

• Most cases idiopathic 

• Associated with: 

• Lupus 

• Non-Hodgkin lymphoma 

• Chronic lymphocytic leukemia (CLL) 

Methyldopa 
α methyldopa 

• Triggers production of RBC antibodies 

• Unclear mechanism 

• Drug may alter Rh antigens on red cells 

• Red cells bind antibody in absence of drug 

• Direct Coombs test: positive 

Penicillin 

• High doses can lead to hemolytic anemia 

• PCN binds to surface RBCs (“hapten”) 

• Elicits immune response only when bound 

• Antibodies against PCN bound to RBCs 

• Direct Coombs test: positive 

Warm AIHA 
Treatment 

• Glucocorticoids 

• Immunosuppressants 

• Splenectomy 

Cold AIHA 

• Less common type of AIHA 

• Antibodies bind at <30oC (“cold”) 

• Occurs in limbs 

• Also fingertips, toes, nose, ears 

• May present with painful fingers/toes 

• Purple discoloration 

• Symptoms associated with cold exposure 



 

51  

 

  
 

 

 

 

 

 

 

 

Anti-C3 Positive 

Antibodies C3 on RBCs 

Patient 

RBCs 

+ 

Negative 

No C3 on RBCs 

Direct Antiglobulin Test 
DAT or Coombs Test 

Martin Brändli /Wikipedia 

Cold AIHA 
Cold Agglutinin Disease 

• Caused by IgM antibodies that agglutinate RBCs 

• RBCs warmed in central organs  IgM lost 

• Leaves bound C3 on RBCs 

• DAT positive only for C3 

Cold AIHA 
Cold Agglutinin Disease 

• Usually causes extravascular hemolyisis 

• C3 coated RBCs removed by spleen 

• Often engulfed whole 

• Spherocytosis less common than in warm AIHA 

• Intravascular hemolysis rarely occurs 

• Complement usually does not activate 

• RBCs: complement inhibitory molecules (CD55/CD59) 

• Complement must be significantly activated to lyse cells 

Cold AIHA 
Associated conditions 

• Can be seen in chronic lymphocytic leukemia (CLL) 

• Often occurs secondary to infection 

• Mycoplasma pneumonia 

• Epstein–Barr virus (Infectious mononucleosis) 

Public Domain/Wikipedia 

Cold AIHA 
Treatment 

• Avoid cold (stay warm!) 

• Immunosuppressants 

Paulo Henrique Orlandi Mourao 

MAHA 
Microangiopathic hemolytic anemia 

• Shearing of RBCs in small blood vessels 

• Thrombi in microvasculature  narrowing 

• Blood smear: schistocytes 

• Seen in: 

• TTP 

• HUS 

• DIC 



 

52  

 

  
 

 

 

 

 

 

 

 

Mechanical Hemolysis 

• Shear forces destroy RBCs in large blood vessels 

• Seen in: 

• Aortic stenosis 

• Mechanical heart valves 

• Left ventricular assist devices 

• Hemolytic anemia may occur 

• Schistocytes can be seen on blood smear 

Public Domain 

Malignant Hypertension 

• Associated with MAHA 

• Endothelial injury  thrombus formation 

• Improved with BP control 

CDC/Public Domain 

Malaria 

Trophozoite Ring 
Babesia 

Ring Forms 

Red Blood Cell Infections 

• May cause hemolytic anemia 

• Classic infectious agents: Malaria, Babesia 



 

53  

 

  
 

 

 

 

 

 

 

 

Extrinsic 

AIHA 

MAHA 

Mechanical 

Infection 

Intrinsic 

PNH 

PK 

G6PD 

Spherocytosis 

Sickle Cell 

HbC 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

 

 

 
Intrinsic Hemolysis 
Jason Ryan, MD, MPH 

PNH 
Paroxysmal Nocturnal Hemoglobinuria 

• RBC destruction via complement system 

• Loss of protective proteins in RBC membrane 

• Decay Accelerating Factor (DAF/CD55) 

• MAC inhibitory protein (CD59) 

• Predominantly intravascular hemolysis 

• Some extravascular hemolysis 

• Macrophage destruction of RBCs opsonized with C3 fragments 

PNH 
Paroxysmal Nocturnal Hemoglobinuria 

• Acquired genetic mutation in stem cell 

• Loss of glycosylphosphatidylinositol (GPI) anchor 

• Attaches proteins to cell surface 

• Lead to loss of DAF/CD59 on RBC cell membranes 

• Platelets/WBCs may also have lysis 

PNH 
Paroxysmal Nocturnal Hemoglobinuria 

• Classically causes sudden hemolysis at night 

• Slowing of respiratory rate with sleep 

• Also shallow breathing 

• Mild ↑CO2  mild resp. acidosis  ↑ complement activity 

• Fatigue, dyspnea 

• Anemia from hemolysis 

• May also lose iron in urine 

• Iron-deficiency is common 

PNH 
Paroxysmal Nocturnal Hemoglobinuria 

• Abdominal pain (smooth muscle tension) 

• Thrombosis 

• Leading cause of death 

• Usually venous clots 

• Unusual locations: portal, mesenteric, cerebral veins 

• Some patients develop acute myeloid leukemia (AML) 

• Stem cell mutation progresses to acute leukemia 

• Lifetime risk: 5 percent or less 



 

54  

 

  
 

 

 

 

 

 

 

 

PNH 
Diagnosis 

• Suspected with hemolysis, unexplained thrombosis 

• Labs may show evidence of hemolysis 

• LDH, Low haptoglobin 

• Urine hemoglobin or hemosiderin 

• Direct antibody testing (Coombs) will be negative 

• Flow cytometry confirms diagnosis 

• Monoclonal antibodies to GPI-anchored proteins 

• Cells will be deficient in GPI-anchored proteins 

Erectile Dysphagia Abdominal 

Dysfunction  Pain 

Platelet 

Lysis 

↑ Smooth Muscle 

Tone Thrombosis 

Renal Failure 

NO depletion 
Free plasma Hgb 

Hemoglobinuria 

Binds 

Nitric Oxide 

PNH 
Paroxysmal Nocturnal Hemoglobinuria 
 

Hemolysis 
Anemia 

Eculizumab 

• Anti-complement therapy 

• Antibody that binds to complement component C5 

• Prevents cleavage to C5a and C5b 

• Blocks formation of membrane attack complex (MAC) 

• Protects against intravascular hemolysis 

• Does not protect against extravascular hemolysis 

• C3 fragments still bind RBCs  spleen 

• Treated patients may still have mild anemia 

• Results in stable Hgb levels, fewer transfusions 

• Membrane failure  phagocytosis in spleen 

TCA Cycle Lactate 

Pyruvate 

Kinase 

Pyruvate 

• Deficiency of pyruvate kinase 

• Key enzyme in glycolysis 

• RBCs most effected 

• No mitochondria 

• Require PK for anaerobic metabolism 

Pyruvate Kinase Deficiency 
Phosphoenolpyruvate 

Pyruvate Kinase Deficiency 

• Autosomal recessive disorder 

• Usually presents as newborn 

• Extravascular hemolysis 

• Splenomegaly 

• Disease severity ranges based on enzyme activity 

G6PD Deficiency 
Glucose-6-Phosphate Dehydrogenase 

• Key enzyme in HMP shunt 

• HMP shunt necessary for generation of NADPH 

• NADPH protects RBCs from oxidative damage 



 

55  

 

  
 

 

 

 

 

 

 

 

Hemolysis 
Exposure 

to   

Trigger 

G6PD Deficiency 
Glucose-6-Phosphate Dehydrogenase 

• X-linked recessive disorder (males) 

• Most common human enzyme disorder 

• Recurrent hemolysis after exposure to trigger 

• Red cells become rigid 

• Consumed by splenic macrophages (extravascular) 

• Some lysis in blood vessels (intravascular) 

G6PD Deficiency 
Glucose-6-Phosphate Dehydrogenase 

• H2O2 toxic to RBCs 

• H2O2 generation triggered by: 
• Infections 

• Drugs 

• Fava beans 

• Need NADPH to degrade H2O2 

• Absence of required NADPH  hemolysis 

G6PD Deficiency 
Triggers 

• Infection: Macrophages generate free radicals 

• Fava beans: Contain oxidants 

• Drugs: 

• Antibiotics (sulfa drugs, dapsone, nitrofurantoin, INH) 

• Anti-malarials (primaquine, quinidine) 

• Aspirin, acetaminophen (rare) 

Africa 

Spain 

Turkey 
Greece Italy 

France 

G6PD Deficiency 
Glucose-6-Phosphate Dehydrogenase 

• High prevalence in Africa, Asia, the Mediterranean 

• May protect against malaria 

G6PD Deficiency 
Classic presentation 

• Patient from Africa, Asia, Mediterranean 

• Jaundice, dark urine, anemia 

• May have back pain (free Hgb) 

• Onset after exposure to trigger 

Bite cells Heinz bodies 

G6PD Deficiency 
Glucose-6-Phosphate Dehydrogenase 

• Classic findings: Heinz bodies and bite cells 

• Heinz bodies: oxidized Hgb precipitated in RBCs 

• Seen with Heinz body stain (“Heinz body preparation”) 

• Bite cells: phagocytic removal by splenic macrophages 



 

56  

 

  
 

 

 

 

 

 

 

 

Ed Uthman 

Hereditary Spherocytosis 

• Hereditary disorder 

• Can be autosomal dominant or recessive 

• Results in spherocytes 

• Slightly smaller than normal RBCs 

• Spherical shape 

• Lacks central pallor 

G6PD Deficiency 
Diagnosis and Treatment 

• Diagnosis: 

• Fluorescent spot test 

• Detects generation of NADPH from NADP 

• Add glucose-6-phosphate and NADP to red cells 

• Positive test if blood spot fails to fluoresce under UV light 

• Must test outside of acute attack 

• Triggers  destruction of enzyme-poor cells 

• Remaining cells may have normal enzyme levels 

• Treatment: 

• Avoidance of triggers 

Public Domain 

Hereditary Spherocytosis 

• Cytoskeleton abnormality 

• Abnormal proteins that tie cytoskeleton to RBC membrane 

• Common involves spectrin 

• Other proteins: ankyrin, band 3, band 4.2 

Hereditary Spherocytosis 

• O2 carrying function of spherocytes normal 

• Disease from chronic destruction in spleen 

• Splenomegaly (growth of splenic macrophages) 

• Increased bilirubin 

• Jaundice 

• Bilirubin gallstones 

Spherocyte Normal 

Same Vol. 

Smaller Cell 

↑MCHC 

Hereditary Spherocytosis 

• Volume does not change over time 

• Results in a high MCHC 

• MCV usually normal or low 

• Spherocytes: low MCV 

• Reticulocytes: high MCV 

Normal 
Spherocytosis 

Hereditary Spherocytosis 

• Progressive loss of cell membrane 

• Over time, more and more membrane lost 

• Results in a high RDW 

N
u

m
b

e
r 

o
f 

c
e
ll

s 



 

57  

 

  
 

 

 

 

 

 

 

 

Hereditary Spherocytosis 

• Risk of aplastic crisis with parvovirus B19 infection 

• Patients dependent on marrow to replace hemolyzed cells 

• Initial presentation may be a child with infection 

• Hemolysis compensated until B19 exposure 

• Spherocytosis seen on blood smear 

• Don’t confuse with G6PD 

Poiseuille's Law 

Π r (radius) 4 Q 
R = Δ P = 

8 η (viscosity) L (length) 

Hereditary Spherocytosis 

• Loss of membrane flexibility  more rigid cells 

• High resistance to blood flow in small vessels 

Hereditary Spherocytosis 
Diagnosis 

• Osmotic fragility test 

• Spherocytes: susceptible to osmotic lysis 

• Poor ability to swell like normal RBCs 

• Will lyse in hypotonic solution 

• Measure Hgb release in hypotonic solution 

• Osmotic fragility will be ↑ if spherocytosis present 

Hereditary Spherocytosis 

• Treatment: Splenectomy 

• Spherocytes will persist but hemolysis resolves 

• Howell–Jolly bodies appear 

• Some RBCs leave marrow with nuclear remnants 

• Normally cleared by spleen 

• Presence in peripheral blood indicates splenic dysfunction 

• Classic finding: spherocytes and Howell-Jolly bodies 

• Indicates patient post-splenectomy for spherocytosis 

Paulo Henrique Orlandi Mourao /Mikael Häggström 

Howell-Jolly Bodies 



 

58  

 

  
 

 

 

 

 

 

 

 

MesserWoland/Wikipedia 

Red Blood Cell Measurements 

• RBC count 

• Part of CBC with white cell count and platelets 

• Hemoglobin 

• Concentration in g/dl 

• Hematocrit 

• Volume % of red cells 

 

 

 
Microcytic Anemias 
Jason Ryan, MD, MPH 

Normal Values  RBC 

= 5 million cells/ul Hgb 

= 15g/dl Hct = 45% 

Rule of 3 

• Hgb = 3 x Red Blood Cell Count 

• Hct = 3 x Hgb 

RBC Indices 

• Measured by automated blood counters 

• Measures of mean characteristics of RBCs 

• Used in evaluation of anemias 

RBC Indices 

• Mean corpuscular volume (MCV) 

• Normal range: 80 to 100 femtoliters 

• Mean corpuscular hemoglobin (MCH) 

• Amount (mass) of hemoglobin per red cell 

• Usually reported in picograms (per cell) 

• Mean corpuscular Hgb concentration (MCHC) 

• Concentration of Hgb in red cells 

• Usually reported g/dL 

Anemia Classification 

• MCV commonly used to classify anemias 



 

59  

 

  
 

 

 

 

 

 

 

 

Heme 

Richard Wheeler and Zephyris 

Hemoglobin 

• Globin chains 

• Proteins 

• 4 chains in 2 pairs 

• Protoporphyrin 

• Iron 

• Microcytic anemia 

• Loss of iron 

• Loss of globins (thalassemia) 

• Loss of heme (lead, sideroblastic) 

Roberto J. Galindo 

Microcytic Anemias 

• Usually due to ↓ hemoglobin in red cells 

• Usually associated with ↓ MCH and MCHC 

• Low hemoglobin  hypochromic RBCs on smear 

Duodenal 

Epithelial 

Cell 

Heme 
Fe2+ Fe3+ 

Iron Absorption 

• Heme iron 

• Found in meats 

• Easily absorbed 

• Non-heme iron 

• Absorbed  in Fe2+ state Vitamin C 

• Aided by vitamin C 

Fe2+ 
FP 

Duodenal 

Epithelial 

Cell 

Iron Metabolism 

• Iron consumed in diet 

• Uptake to plasma regulated by enterocytes 

• Iron transporter: ferroportin 

• Transports iron out of enterocytes and other cells 

• Few mechanisms to excrete excess iron 
• Small amount in sweat, sloughing of skin/GI cells 

Heme
 

Fe2+ 
• Women lose iron from menstruation 

Iron Metabolism 

• Iron always bound to a protein 

• Transport protein: transferrin 

• Transported in blood via transferrin 

• ↑ transferrin when iron stores are low 

• Storage protein: ferritin 

• Stored intracellularly as ferritin 

• Stored in macrophages of liver and bone 

Clinical Iron Measurements 



 

60  

 

  
 

 

 

 

 

 

 

 

Achoubey/Wikipedia 

Iron Deficiency 
Inadequate GI uptake 

• Babies 

• Iron stores depleted ~ 6months 

• Recommendation: add iron-containing foods 

• Exclusive breast feeding  iron deficiency 

Iron Deficiency 

• Lack of iron from gut 

• Loss of iron (usually as blood) 

Iron Deficiency 
Inadequate GI uptake 

• Malabsorption 

• Any disease affecting duodenum or acid production 

• more Fe3+ 

• Status post gastrectomy 

• Proton pump inhibitors 

• Rarely malnutrition 

Iron Deficiency 
Loss of iron 

• Bleeding 

• Menorrhagia 

• Peptic ulcers 

• Colon cancer 

• Adult or post-menopausal female with iron 

deficiency must have work-up for colon cancer 

Iron Deficiency 
Other causes 

• Pregnancy 

• “Negative iron balance” in pregnancy 

• Expansion in mothers Hgb mass 

• ↑ demand of fetal growth 
Øyvind Holmstad/Wikipedia 

• Prenatal vitamins often contain iron and folate 

Ceridwen/Wikipedia 

Iron 

TIBC 
% Sat = Pregnancy/OCPs 

• Increase plasma transferrin 

• Percent saturation may be low 

• Low ferritin often used to diagnose iron deficiency 



 

61  

 

  
 

 

 

 

 

 

 

 

Iron Deficiency Iron Deficiency 
Rare causes 

• Hookworms 

• Consume blood in intestines 

• Ancylostoma duodenale 
Pixabay/Public Domain 

• Necator americanus 

• Plummer–Vinson syndrome 

• Rare condition; poorly understood cause 

• Iron deficiency anemia, beefy red tongue, esophageal webs 

Iron Deficiency Anemia 

• Microcytic, hypochromic anemia 

• ↓ RBCs (anemia) 

• Small cells 

• Hypochromic (low hemoglobin) 

• ↓ MCV, MCH, MCHC 

• Initially may be normocytic 

• Marrow makes fewer RBCs; maintains Hgb 

Protoporphyrin 

• Heme = Iron + protoporphyrin 

• Erythrocyte protoporphyrin level 

• Rarely used blood test 

• Will be elevated in iron deficiency 

• No Fe for protoporphyrin to bind with 

• Also elevated in lead poisoning 

• Inhibits addition of iron to protoporphyrin 

• Major uses: screening 

• Iron deficiency or lead poisoning 

Iron Deficiency Anemia 
Treatment 

• Iron supplementation 

• Usually oral therapy 

• Rarely IV iron can be used 

RBC Size 

Iron Deficiency 

Anemia Normal 

Red Cell Distribution Width 
RDW 

• Spectrum of RBC size 

• Often wider in iron, B12/Folate deficiency 

• Normal RDW makes iron deficiency unlikely 

• Can be normal in mild thalassemia 

N
u

m
b

e
r 

o
f 

c
e
ll

s 



 

62  

 

  
 

 

 

 

 

 

 

 

Anemia of Chronic Disease 
Mechanisms 

• Triggered by cytokines 

• Mild decrease in RBC survival 

• Inadequate EPO level/response 

• Lower EPO than expected for degree of anemia 

• Less increase in RBC production by EPO 

• Lack of availability of iron 

• Trapped in storage form 

• Key mediator: hepcidin 

Anemia of Chronic Disease 

• Anemia in association with inflammation 

• Common in rheumatoid arthritis, lymphoma 

• Many other chronic conditions 

• Usually a mild anemia (Hgb > 10g/dL) 

• Symptoms from anemia are rare 

Hepcidin 

• Acute phase protein 

• Produced in liver 

• Has anti-bacterial properties 

• Affects iron metabolism 

• Inhibits iron transport 

• Binds to ferroportin in enterocytes, macrophages 

• Iron trapped in cells as ferritin 

• Contributes to anemia of chronic disease 

• Key finding ACD: ↑ ferritin 

Anemia of Chronic Disease 

• Usually normocytic/normochromic 

• Microcytic/hypochromic in about 25% cases 

• Low iron availability may lead to small red cells 

• MCV usually mildly decreased (70-80) 

• Important to distinguish from iron deficiency 

• Does not respond to iron 

• First line therapy: treat underlying disease 

Anemia of Chronic Disease 
Diagnosis 

• Serum iron is low 

• Thought to be protective 

• Bacteria may use iron for growth/metabolism 

• Ferritin is usually increased 

• Iron trapped in storage form 

• Ferritin is acute phase reactant 

• Increase may not represent increased storage iron 

• Transferrin (TIBC) is usually decreased 

• Transferrin rises when total body iron low 

• % saturation usually normal 

Elevated 

when body 

storage iron 

is low 

Iron Studies 



 

63  

 

  
 

 

 

 

 

 

 

 

ALA Synthase: Rate-limiting Step 

up of: δ-ALA, Protoporphyrin 

Heme 

Porphobilinogen Protoporphyrin 

Fe2+ 

Ferrochelatase 

Succinyl-CoA 

δ-ALA 
δ-ALA

 

Synthase 

Glycine 

δ-ALA 

dehydratase 

Heme Synthesis Lead Poisoning 

• Exposure to lead: 

• Adults: Inhalation from industrial work (battery factory) 

• Children: Eating lead paint (old house) 

• Inhibits heme synthesis via two enzymes in RBCs 

• Delta-aminolevulinic acid (δ-ALA) dehydratase 

• Ferrochelatase 

• ↓ heme synthesis  microcytic, hypochromic anemia 

• Iron studies: normal or low 

Lead Poisoning 
Diagnosis 

• Plasma lead level 

• ↑ delta-aminolevulinic acid (δ-ALA) 

• ↑ erythrocyte protoporphyrin 

isis325/Flikr 

Lead Poisoning 
Diagnosis 

• Blood smear: basophilic stippling 

• Blue granules in cytoplasm of red cells 

• Lead inhibits pyrimidine 5’ nucleotidase 

• Normally digests pyrimidines in ribosomes/RNA 

• Leads to accumulation of pyrimidines/RNA in RBCs 

• Also seen in thalassemia, other anemias 

Lead Poisoning 
Symptoms 

• Abdominal pain (“lead colic”) 

• Constipation 

• Headache 

• “Lead lines" 

• Blue pigment a gum-tooth line 

• Caused by reaction of lead with dental plaque 

• Nephropathy 

• Injury to proximal tubules (Fanconi-type syndrome) 

• Glucose, amino acids, and phosphate wasting 

• Neuropathy 

• Common symptom: Drop wrist and foot 

Lead Poisoning 
Symptoms 

• Children may have prominent neurologic effects 

• Behavioral issues 

• Developmental delay 

• Failure to reach milestones (i.e. language) 

• Many states screen children with lead level testing 

• Usually at 1-2 years of age 



 

64  

 

  
 

 

 

 

 

 

 

 

Paulo Henrique Orlandi Mourao 

Sideroblastic Anemia 

• Sideroblasts: 

• Found in normal bone marrow 

• Nucleated red cell precursors 

• Contain granules with non-heme iron 

• Sideroblastic anemia 

• Usually microcytic anemia 

• Sideroblasts in peripheral blood 

Lead Poisoning 
Treatment 

• Removal of exposure to lead 

• Chelation therapy 

• Dimercaprol (2,3-dimercapto-1-propanol) 

• Calcium disodium EDTA (ethylenediaminetetraacetate) 

• DMSA (2,3-dimercaptosuccinic acid; succimer) 

Glycine 

Protoporphyrin δ-ALA 

Heme 
Succinyl-CoA 

Fe2+ 

Sideroblastic Anemia 

• Failure to make protoporphyrin 

• Iron cannot bind  heme 

• Iron accumulation in mitochondria 

Heme δ-ALA 

Succinyl-CoA 

δ-ALA 

Synthase 

Glycine 

B6 

Sideroblastic Anemia 

• Usually secondary to a toxin 

• Alcohol (mitochondrial poison) 

• Vitamin B6 deficiency (Isoniazid) 

• Lead poisoning (controversial) 

Heme δ-ALA 

Succinyl-CoA 

δ-ALA 

Synthase 

Glycine 

B6 

Sideroblastic Anemia 

• X-linked sideroblastic anemia 

• Rare, inherited deficiency of ALA synthase 

• Most common hereditary sideroblastic anemia 

• Often responds to treatment with vitamin B6 

Sideroblastic Anemia 
Lab Findings 

• Microcytic, hypochromic anemia 

• Iron studies show iron overload 

• ↑ serum iron 

• ↑ ferritin 

• ↓ TIBC (transferrin) 

• Low erythrocyte protoporphyrin levels 



 

65  

 

  
 

 

 

 
 

 

 

 

α thalassemia β thalassemia 

Lead Poisoning 

Sideroblastic ↓ β ↓ α 

Iron Deficiency Anemia 

Chronic Disease (also 

normocytic) 

↓ Heme ↓ Globin ↓ Iron 

Microcytic Anemias 

Microcytic Anemia 



 

66  

Anemia Classification 

• MCV commonly used to classify anemias 

 

  
 

 

 

 

 

 

 

 

Microcytic 
MCV<80 

Normocytic 
MCV 80-100 

Macrocytic 
MCV>100 

Iron deficiency Iron deficiency Folate/B12 deficiency 

Anemia Chronic Disease Anemia Chronic Disease Orotic Aciduria 

Thalassemia Hemolysis Liver disease 

Lead poisoning Aplastic anemia Alcoholism 

Sideroblastic Anemia Kidney disease Reticulocytosis 

 

 

 

 
Thalassemias 
Jason Ryan, MD, MPH 

Roberto J. Galindo 

Microcytic Anemias 

• Usually due to ↓ hemoglobin in red cells 

• Usually associated with ↓ MCH and MCHC 

• Low hemoglobin  hypochromic RBCs on smear 

Thalassemia 

• Decreased or absent production of globin chains 

• Alpha thalassemia: alpha globin 

• Beta thalassemia: beta globin 

All Hgb has two alpha globins 

Other chain determines type 

Hemoglobin F 

Fetal 
α2 γ2 

Gamma (γ) 

Hemoglobin A2 

(<5%) 
α2 δ2 

Beta (β) 

 
Delta (δ) 

Hemoglobin A 

(95%) 
α2 β2 

Alpha (α) 

Globins and Hemoglobin 

All Hgb has two alpha globins 

Other pair determines type 

Hemoglobin F 

Fetal    

α2 γ2 

Gamma (γ) 

Hemoglobin A2 

(<5%) 
α2 δ2 

Beta (β) 

 
Delta (δ) 

Hemoglobin A 

(95%) 
α2 β2 

Alpha (α) 

Globins and Hemoglobin 



 

67  

 

  
 

 

 

 

 

 

 

 

Mnolf/Wikipedia 

Hgb Electrophoresis 

• Electrical charge applied to sample on gel 

•  moved 

• Determines HgbA, HgbA2, HgbF, HgbS 

• Used to diagnose hemoglobinopathies 

• Thalassemia 

• Sickle cell disease 

All Hgb has two alpha globins 

Other pair determines type 

Hemoglobin F 

Fetal 

α2 γ2 

Gamma (γ) 

Hemoglobin A2 

(<5%) 
α2 δ2 

Beta (β) 

 
Delta (δ) 

Hemoglobin A 

(95%) 
α2 β2 

Alpha (α) 

Globins and Hemoglobin 

Thalassemia 

• Spectrum of severity 

• Thalassemia minor 

• Often asymptomatic 

• Identified on routine blood testing or blood smear 

• Thalassemia major 

• Severe loss of globin production 

• Lifelong transfusions or death 

--/-- --/-α 

--/αα 
-α/-α 

α-/αα 

• Gene deletions  ↓α chains  alpha thalassemia 

αα/αα 

α α 

α α Alpha Thalassemia 

• Four genes code for alpha chains 

• Two on each copy of chromosome 16 

α α α α 

α α α α 

α α α α 

α α α α 

α-/αα 

α α 

α α 
• No symptoms 

• Carrier state 

Alpha Thalassemia Minima 

• Normal red cells 

--/αα 
-α/-α 

α α 

α α 
• Can have normal red cells 

• Sometimes mild anemia 

• ↓ MCV/MCH/MCHC 

Alpha Thalassemia Minor 
Alpha Thalassemia Trait 

• No symptoms 



 

68  

 

  
 

 

 

 

 

 

 

 

--/-α 

α α 

α α 

HbH Disease 

• Very little alpha globin production 

• Excess beta globin 

• HbH forms: 4 beta chains 

• Easily damaged 

• Affinity for oxygen 10x HbA 

• Useless for oxygen delivery 

• HbH forms after birth 

• No β chains in HbF 

• More β produced  HbH 

-α/-α 

More risk 

to offspring --/αα 

AFRICANS ASIANS 

Alpha Thalassemia Minor 
Alpha Thalassemia Trait 

• Common among Asians and Africans 

• Alpha minor can be cis (αα/--) or trans (α-/α-) 

• Asians more commonly have cis type 

• Africans: trans 

α α α α 

α α α α 

--/-α 

α α 

α α 

HbH Disease 

• Hypochromic, microcytic anemia 

• Low MCV, MCH, MCHC 

• Similar glucose-6-phosphate dehydrogenase deficiency 

--/-α 

α α 

α α 

HbH Disease 

• Abnormal RBC deformability 

• Extravascular hemolysis 

• Splenomegaly 

• Indirect hyperbilirubinemia 

• Elevated LDH 

• HBH easily oxidized 

• Risk for intravascular hemolysis 

• Occurs with oxidant stressors (infection, drugs) 

--/-α 

α α 

α α 

HbH Disease 

• Diagnosis: DNA testing 

• Electrophoresis insensitive 

• Some production A and A2 

• May see HbH depending on amount 

Public Domain 

--/-α 

α α 

α α HbH Disease 

• Treatment: 

• Splenectomy 

• Transfusions 

• Long term risk: iron overload 



 

69  

 

  
 

 

 

 

 

 

 

 

Beta Thalassemia 

• ↓ β globin chain synthesis 

• Two genes code for beta chains 

• One on each copy of chromosome 11 

β 

β 

• Fetal death usually occurs or death hours after birth 

--/-- 

Hgb Barts 

• No α globin 

• Cannot form HbF 

• Hgb Barts forms in utero 

• Four gamma globin chains 

• Cannot release oxygen to tissues 

• Affinity for oxygen 10x HbA 

• Hydrops fetalis 

• Massive total body edema 

• High output heart failure 

α α 

α α 

Beta Thalassemia Minor Beta Thalassemia 
Minor 

 

• Also called beta thalassemia trait β 

• Heterozygotes: single abnormal gene β 

• Reduced β globin production 
+/- 

• Asymptomatic 

• May see mild anemia on routine blood work 

• Diagnosis by electrophoresis 

• ↑ HgbA2 (α2δ2 – no beta chains) 

• Normal <5% 

 

 

 

 

 

-/- +/- 

Beta Thalassemia 

Major 

Beta Thalassemia 

Minor 

Beta Thalassemia 

• Often caused by mutations (NOT deletions) 

• Wide spectrum of disease depending on mutation 

• βo = no function; β1 = some function 

βo,1 β 

βo,1 βo,1 

β 

β 

Africa 

Spain 

Turkey 
Greece Italy 

France 

Beta Thalassemia 

βo,1 
 

-/- 

βo,1 

Beta Thalassemia Major 
Cooley’s Anemia 

• No or severely limited β globin production 

• Anemia beginning 1st year of life 

• HgbF (α2γ2) production wanes 

• Ineffective erythropoiesis 

• Alpha chains form tetramers 

•  damage 

• Failure to produce RBCs 

• Splenomegaly 

• Spleen clears any abnormal RBCs in plasma 



 

70  

 

  
 

 

 

 

 

 

 

 

RBC Abnormalities 

• Microcytosis (small RBCs) 

• Hypochromia (loss of Hgb) 

• Anisocytosis 

• Wide variation in sizes of RBCs 

• Increased red cell distribution width (RDW) 

• Poikilocytosis (abnormal shapes) 

• Basophilic stippling 

• Nucleated RBCs 

• Target cells 

-/- 

Beta Thalassemia Major 
Cooley’s Anemia 

• Hypochromic, microcytic anemia 

• Abnormal red blood cells shapes 

• Erythroid hyperplasia 

• Extramedullary hematopoiesis 

βo,1 

βo,1 

isis325/Flikr 
Prasad CSBR 

Basophilic Stippling 

• Residual RNA in red cells 

• Often seen with nucleated RBC 

• Seen in thalassemia 

• Also lead poisoning 

Dr Graham Beards 

Target Cells 

• Target formed in center of RBC 

• Small dark area in center of cell 

• Due to ↑ surface area-to-volume ratio 

• Extra cell membrane  target appearance 

Target Cells 

• Decreased cell volume 

• Thalassemia 

• Can be seen in iron deficiency 

• Increased cell membrane 

• Liver disease (↑ cholesterol in membrane) 

• Splenic dysfunction (↓ removal excess membranes) 

Erythroid Hyperplasia 

• Massive expansion of bone marrow 

• ↑↑ EPO without normal response 

• Consequence of severe anemia in beta major disease 

• Abnormalities of skull and facial bones 

• “Chipmunk facies” 

• Crew cut appearance of skull on x-ray 

• Delayed skeletal maturation 

• Widening of marrow spaces  osteoporosis 



 

71  

 

  
 

 

 

 

 

 

 

 

Parvovirus B19 

• Infection may cause aplastic crisis 

• Beta major patients highly dependent bone marrow 

Extramedullary hematopoiesis 

• Hematopoiesis outside of bone marrow 

• Consequence of severe anemia in beta major disease 

• Liver and spleen produce RBCs 

• Hepatosplenomegaly 

• Often produces nucleated RBCs 

Beta Thalassemia Major 
Cooley’s Anemia 

• Diagnosis: Electrophoresis 

• Increased Hgb forms that do not require beta chains 

• ↓ or absent HbA (α2β2) 

• ↑ HbA2 (α2δ2) 

• ↑ HbF (α2γ2) 

Public Domain 

Beta Thalassemia Major 
Cooley’s Anemia 

• Treatment: Blood transfusions 

• Long term risk: iron overload 

Beta Thalassemia Intermedia 

• Symptomatic beta thalassemia 

• Does not require transfusions 

• Chronic hemolytic anemia 

• Bone marrow expansion 

• Hepatosplenomegaly 

CDC/Public Domain 

Malaria 

• Alpha and beta thalassemia protective vs. malaria 

• ↓ growth in RBCs of plasmodium falciparum 

 
Trophozoite Ring 



 

72  

 

 
 

 

 

 
 

 

 

 

α Thalassemia β Thalassemia 

↑ HgbA2 

↑ HgbF 
HbH 

Hgb Barts 

Chronic Disease 

Suspect 

Thalassemia 

Low Iron 

Iron Deficiency 

Lead Poisoning 

Sideroblastic Anemia 

Thalassemia 
Key Points 

Microcytic, Hypochromic 

Anemia 

RBC Size 

Red Cell Distribution Width 
RDW 

• Spectrum of RBC size 

• Wider in iron deficiency 

• Can be normal in mild thalassemia 

• Normal RDW makes iron deficiency unlikely 

Iron Deficiency 
Normal Anemia 

N
u

m
b

e
r 

o
f 

c
e
ll

s 



 

73  

 

  
 

 

 

 

 

 

 

 

Extrinsic 

AIHA 

MAHA 

Mechanical 

Infection 

Intrinsic 

PNH 

PK 

G6PD 

Spherocytosis 

Sickle Cell 

HbC 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

 

 

 
Sickle Cell Anemia 
Jason Ryan, MD, MPH 

Sickle Cell Anemia 

• Autosomal recessive disorder 

• Abnormal β hemoglobin chains 

• Beta chains found in hemoglobin A (α2 β2) 

• Makes up 95% of Hgb 

HbS (α2S2) 
Sickle Cell 

Disease 

HbS (α2S2) 

 

HbA (α2β2) 

Sickle Cell 

Trait 

Sickle Cell Anemia 

• Root cause is abnormal beta globin gene 

• Single base substitution 6th codon of β gene 

• Adenine changed to thymine 

• Abnormal genes produce HbS 

βS 

βS 

β 

βS 

β 

β 

Glutamate 

(Normal Hgb) 

Valine 

(HbS) 

-O 

Sickle Cell Anemia 

• Substitution of valine for glutamate in beta chains 

• Glutamate: polar (hydrophilic) 

• Valine: non-polar (hydrophobic) 

• Alters shape of beta chains 

In utero and at birth: ↑ HbF ↓ HbA 

Hemoglobin F 

Fetal    

α2 γ2 

Gamma (γ) 

Hemoglobin A2 

(<5%) 
α2 δ2 

Beta (β) 

 
Delta (δ) 

Hemoglobin A 

(95%) 
α2 β2 

Alpha (α) 

Globins and Hemoglobin 



 

74  

 

  
 

 

 

 

 

 

 

 

Sickle Cell Anemia 

• Two major problems result from sickle cells 

• #1: Hemolytic anemia 

• #2: Vaso-occlusion of small blood vessels 

Scooterdmu/Flikr 

Madboy74 

Sickle Cell Anemia 

• Deoxygenated HbS is poorly soluble 

• Polymerization when O2 low 

• Also in dehydration, acidosis 

• Red blood cells form crescents 

• Appearance of a sickle 

• Causes a ↓ ESR 

Sickle Cell Anemia 
Hemolysis 

• Sickling is reversible 

• Cells continuously sickle/de-sickle in circulation 

• Over time this leads to RBC membrane damage 

• Results in extravascular hemolysis 

• Anemia 

• Jaundice 

• Elevated unconjugated bilirubin 

• Pigment gallstones 

• Some intravascular hemolysis may also occur 

Sickle Cell Anemia 
Erythroid Hyperplasia 

• ↑↑ EPO 

• Massive expansion of bone marrow 

• Consequence of severe anemia: 

• Also seen in beta thalassemia major 

• Abnormalities of skull and facial bones 

• “Chipmunk facies” 

• Crew cut appearance of skull on x-ray 

• Delayed skeletal maturation 

• Widening of marrow spaces  osteoporosis 

Sickle Cell Anemia 
Parvovirus B19 

• Infection may cause aplastic crisis 

• Crisis also seen in spherocytosis, thalassemia 

Sickle Cell Anemia 
Vaso-occlusion 

• Sickle cells may occlude microvasculature 

• May affect any organ 

• Classic clinical manifestation: 

• Swollen hands (“dactylitis”) 

• Acute pain crises 

•  infections 

• Acute chest syndrome 

• Renal dysfunction 



 

75  

 

  
 

 

 

 

 

 

 

 

Jmarchn/Wikipedia 

Sickle Cell Anemia 
Avascular Necrosis 

• Bone collapse 

• Most commonly femoral head 

• Also associated with long term steroid use 

Sickle Cell Anemia 
Dactylitis 

• Pain/swelling in hands or feet 

• Fingers may look like “sausage” digits 

• Common initial symptom among children 

Sickle Cell Anemia 
Pain Crises 

• Episodes of acute pain (“sickle cell crisis”) 

• Sudden onset of pain 

• Most common type of vaso-occlusive event 

• May affect any part of body 

• Abdomen, bones, joints, soft tissue, fingers,  toes 

• Swollen hands and/or feet especially in children 

• Treatment: Hydration and pain medications 

Paulo Henrique Orlandi Mourao /Mikael Häggström 

Sickle Cell Anemia 
Splenic Failure 

•  asplenia 

• Early in disease: splenomegaly (macrophage hyperplasia) 

• Late in disease: Fibrosis and atrophy 

• Howell-Jolly bodies will appear in peripheral blood 

Sickle Cell Anemia 
Splenic Failure 

• Increased risk of infections by encapsulated bacteria 

• Strep pneumoniae and H influenza 

• Bacteremia/sepsis from S. Pneumoniae 

• Patients must be vaccinated 

• Osteomyelitis from Salmonella species 

• Infection of infarcted bones 

• Most common cause SCA is Salmonella (usually S. Aureus) 

Sickle Cell Anemia 
Splenic Sequestration Crisis 

• Vaso-occlusion in spleen  pooling of red cells 

• Marked fall in hemoglobin level 

• Rapidly enlarging spleen 

• Risk of hypovolemic shock especially in children 

• Occurs in spleens yet to develop fibrosis 

• May occur before sickle cell disease is diagnosed 



 

76  

 

  
 

 

 

 

 

 

 

 

Sickle Cell Anemia 
Chest Syndrome 

• Chest pain and shortness of breath 

• Infiltrate on chest x-ray 

• Looks like pneumonia 

• Treatment: 

• Fluids and pain medication (similar to pain crisis) 

• Antibiotics, oxygen, bronchodilators 

• Transfusions as needed 

Sickle Cell Anemia 
Chest Syndrome 

• Leading cause of death in adults with SCD 

• Vaso-occlusion of pulmonary microvasculature 

• Often triggered by infection (pneumonia) 

• Increased sickling in lungs 

• Once begun  inflammation/acidosis  more sickling 

Sickle Cell Anemia 
Renal Dysfunction 

• Occlusion of vasa recta in renal medulla 

• Medulla has low oxygen and high osmolality 

• Promotes sickling 

• May impair concentrating ability 

• Cannot raise urine osmolality even with H20 deprivation 

• Causes nocturia and polyuria 

1200mOsm Inner Medulla 

600mOsm Outer Medulla 

    Cortex 300mOsm 

The Nephron 

Image courtesy of Piotr Michał Jaworski 

Sickle Cell Anemia 
Renal Dysfunction 

• Papillary necrosis 

• Sloughing of renal papilla due to renal vaso-occlusion 

• Usually painless 

• Gross hematuria and proteinuria 

Sickle Cell Anemia 
Treatment 

• Immunizations 

• Hydroxyurea 

• Raises amount of HbF 

• Mechanism unclear 

• Transfusions 

• Iron overload may develop 

• Bone marrow transplant is curative 

• Median survival 42-48 years 



 

77  

 

  
 

 

 

 

 

 

 

 

Sickle Cell Diagnosis 
Disease or Trait 

• Electrophoresis 

• Will show presence of HbS 

• Different amounts disease versus trait 

• Sickling Test 

• Sodium metabisulphite reduces the oxygen tension 

• HbS becomes insoluble 

•  visualized 

• Other hemoglobin types remain in solution 

• Positive if any amount HbS present (disease or trait) 

HbA (α2β2) 

HbS (α2S2) 
Sickle Cell 

Trait 

Sickle Cell Trait 

• One mutated beta globin gene 

• Usually no sickling 

• Normal beta gene more effective  >50% beta globins 

• Need >50% HbS for sickling 

• One exception: Renal medulla 

• May see loss of concentrating ability 

• ↑ risk of renal medullary carcinoma (> than sickle disease) 

β 

βS 

Electrophoresis Malaria 

• Sickle trait protective against p. falciparum 

• Cells sickle when infected  ↑ clearance 

• Does not protect against infection 

• When infection does occur it is milder 

• Patients still need malaria prophylaxis 

• African Americans: 8 to 10% have sickle cell trait 

• Sub-Saharan Africa: ~30% 

HbA with ↓ beta globins βo,1 

HbS (α2S2) βS 

Sickle Cell/Beta Thalassemia 

• One beta gene: sickle cell 

• One beta gene: beta thalassemia 

• Clinical manifestations similar to sickle cell 

• Vary depending on beta thalassemia gene function 

• βo: Similar to sickle cell disease 

• β1: Less severe 

Glutamate 
Lysine 

-O 

Hemoglobin C 

• Rare mutation of beta gene (different from SCA) 

• Glutamic acid replaced by lysine (not valine) 

• Heterozygotes: Mild anemia (extravascular hemolysis) 



 

78  

 

  
 

 

 

 
 

 

 

 

Hemoglobin SC 

• One HbS gene plus one HbC gene 

• More common than homozygous HbC disease 

• At risk for same complications as sickle cell disease 

• Lower frequency of complications 

Isis325/Flikr 

Hemoglobin C 

• Presence of HbC crystals on smear 

• Induces red cell dehydration: ↑ MCHC 



 

79  

 

  
 

 

 

 

 

 

 

 

Anemias 

• Microcytic 

• Normocytic, hemolytic 

• Normocytic, non-hemolytic 

• Macrocytic 

 

 

 
Other Anemias 
Jason Ryan, MD, MPH 

Extrinsic 

AIHA 

MAHA 

Mechanical 

Infection 

Intrinsic 

PNH 

PK 

G6PD 

Spherocytosis 

Sickle Cell 

HbC 

Aplastic 

Anemia 

Renal 

Failure 

↓ Iron 

ACD 

Low Iron Low EPO 
Abnormal

 
Marrow 

Hemolytic 

(Increased Destruction) 

Non-hemolytic 

(Low Production) 

Normocytic Anemias 
Normocytic Anemia 

MCV 80-100 

Madhero88/Wikipedia 

EPO 
Erythropoietin 

• Synthesized in the kidney 

• Interstitial cells peritubular capillary 

• Found in cortex of the kidney 

• Released in response to hypoxia 

• Decreased production in renal failure 

• Results in a normocytic anemia 

Image courtesy of BruceBlaus 

Kidney Anatomy EPO Injections 

• Darbepoetin alfa (Aranesp) 

• Epoetin alfa (Epogen) 

• Used to treat anemia of chronic kidney disease 

• FDA Black Box warning 

• Generally reserved for patients with severe anemia 



 

80  

 

  
 

 

 

 

 

 

 

 

Vocabulary 

• “Aplasia”: Defective or absent development 

• Bone marrow failure 

• Bone marrow cannot produce cells 

• Results in pancytopenia 

• Many causes: fibrosis, tumors 

• “Myelophthisis:” displacement of bone-marrow tissue 

• Aplastic anemia: 

• Specific type of bone marrow failure 

•  marrow 

Aplastic Anemia 

• Loss of hematopoietic precursors in bone marrow 

• Results in pancytopenia 

• ↓ WBC, ↓ Platelets, ↓ RBC 

Chalin Drosera 

Aplastic Anemia 
Hallmarks 

• Pancytopenia 

• Acellular or hypocellular bone marrow 

• Bone marrow biopsy for diagnosis 

• Absence of cells/replacement with fat 

Aplastic Anemia 
Symptoms 

• Pancytopenia