BLOOD 2

BY
DANILO M. MENORCA, M.D.
HEME(PYRROLE +2)4
+1
 PYRROLE
B B

a a

N
 PYRROLE
CARBONS
a carbon – linked by
methylene bridges in a
tetrapyrrole.
B carbon – bear the subs
tituents*** of a specific
tetrapyrrole.
SUBSTITUENTS*
**

METHYL, VINYL
& PROPIONATE
(MVMVMPrPrM)
 HEME
M V
PYRROLE
M N M
PYRROLE N Fe N PYRROLE
Pr N V
PYRROLE
Pr M
IRON IN HEME HAS SIX
COORDINATION
His E7
STATES

++
PLANE Fe

His F8
 MYOGLOBIN
 A 153 A. A. POLYPEPTIDE IN EIGHT
RIGHT HANDED ALPHA HELICES
A H HELICES; N C TERMINAL
 INDIVIDUAL AMINO ACID (HELIX
LETTER + NUMBER OF DISTANCE
FROM N – TERMINAL).
 HISTIDINE F8 AND HISTIDINE E7
SIGNIFICANCE OF His F8 &
E7
 PERFORM UNIQUE ROLES IN OXY-
GEN BINDING.
- PROMOTE OXYGEN BINDING AT ITS
PREFERRED ANGLE.
- MAKE MYOGLOBIN EFFECTIVE FOR
OXYGEN STORAGE.
 STEARICALLY HINDERS CARBON MO-
NOXIDE AT ITS PREFERRED ANGLE.
 OXYGEN – BINDING CURVE
FOR M Y O G L O B I N
 %100
 S
 A 80
 T
 U 60
 R
 A 40
 T
 I 20
 O
N 0 20 40 60 80 100 120
HEMOGLOBIN

GLOBIN H E M E
4
COMMON
TYPES
 NORMAL ADULT HEMOGLOBIN (HbA)
a2B2
 FETAL HEMOGLOBIN (HbF)
a2y2
 SICKLE CELL HEMOGLOBIN (HbS)
a2S2
 MINOR ADULT HEMOGLOBIN (HbA2)
a2d2
 OXYGEN BINDING CURVE
FOR HEMOGLOBIN
 % 100
 S
 A 80
 T
 U 60
 R
 A 40
 T
 I 20
 O
 N 0 20 40 60 80 100 120
 DEOXYHEMOGLOBIN
NH3----------------------------------ASP----------HIS---
COO-

COO----ARG-------ASP---------------------LYS-------
NH3+

NH3----LYS--------------------------ASP----ARG------
COO-

COO---HIS--------------ASP-----------------------------
NH3+
T STATE VS R
STATE
a1 B2 a1 B2

a2
B1
a2 B1 15deg.

T FORM R FORM
CO2 TRANSPORT AND
BUFFER
 EXHALED
 2CO2 + H2O 15%
HbNHCOO
 2H2CO3
PERIPHERAL
L 2HCO3- + 2H+ Hb.4O2
TISSUES
 U 4O2
 N 2H+ +
2HCO3-
 G 4O2 Hb.2H+
 S 85%
HEMOGLOBINOPATHY
 METHEMOGLOBINEMIA
 SULFHEMOGLOBINEMIA
 CARBOXY HEMOGLOBIN
 SICKLE CELL HEMOGLOBIN
 HEMOGLOBIN CHESAPEAKE
 HEMOGLOBIN M (TWO VARIANTS)
 THALASSEMIC HEMOGLOBIN VARIANTS
 HEREDITARY PERSISTENCE OF FETAL
H’GLOBIN
 OTHER SELECTED ABNORMAL
HUMAN HEMOGLOBIN
 DESIGNATION
SUBST’TION POSITION SYMPTOMS
Hb E GLU to LYS B26 MHA
YAKIMA ASP to HIS B99 PCM
TORINO PHE to VAL A43 IBA
RAINIER TYR to HIS B145 PCM
M. IWATA HIS to TYR A87 MHA
J CAPETOWN ARG to GLU A92 MHA
HAMMERSMITH PHE to SER B42 IBA
BIOMEDICAL
 ANEMIAS
 HEMOPHILIA
 PORPHYRIAS
 POLYCYTEMIA
 THALASSEMIAS
 MYOGLOBINURIA
 HEMOGLOBIN A1C
 VON WILLEBRAND DISEASE
T H R O M B O S I
S
THREE PHASES:
 1. TEMPORARY
PLATELET
AGGREGATE
 2. STABLE
HEMOSTATIC
PLUG
 3. DISSOLUTION
 H E M O S T A S I S
T H R O M B O S I S
 PROTEINS IN BLOOD COAGULATION
 1. ZYMOGENS
FACTORS II, VII, IX, X, XI, XII
 2. COFACTORS
FACTORS III, V, VIII
 3. FIBRINOGEN OR FACTOR I
 4. TRANSGLUTAMINASE OR FACTOR XIII
 5. REGULATORY PROTEINS (PROTEIN C,
PROTEIN S, THROMBOMODULIN)
THE COAGULATION PATHWAY

INTRINSIC
(XII, XI, IX, X)

EXTRINSIC
(VII, X)
 THE COAGULATION PATHWAY
 XII PK,HK XIIa
 HK
 XI Ca X1a VII VIIa/TISSUE FACTOR
 IX Ca IXa
 VIII VIIIa Ca PL
 Ca+PL X Xa X
 V Va XIII
 PROTHROMBIN THROMBIN
 FIBRINOGEN FIBRIN MONOMER XIIIa
 CROSS LINKED FIB. POLYMER FIBRIN POLYMER
 POSITIVE FEEDBACK
 VITAMIN K – DEPENDENT
P R O T E I N S

PROCOAGULANTS
FACTORS II & VII
FACTORS IX & X
ANTICOAGULANTS
PROTEINS C &
S
SOME
MECHANISMS
 BINDING OF FACTORS Va, Xa, Ca++ & PRO-
 THROMBIN TO ACTIVATED PLATELETS
 Prethrom – bin

 F-1.2
 NH3 S-S
 - - - - - - - -
COO
 Ca++ Ca++
 ---------- Va Xa Platelet
 -------------------------------------------------------
SOME
MECHANISMS
 FORMATION OF FIBRIN CLOT
 THROMBIN
 (Fibrinopeptide) (Fibrin chain)
 NH3 ARG---------GLY-----------“-------
COO
 FIBRIN-(CH2)4-NH3+ (monomers) H2N-CO(CH2)2-
FIBRIN
 NH4+ FACTOR XIIIa
 (Transglutaminase)
 .
 .
 FIBRIN----CH2CH2CH2CH2 –NH COCH2CH2-----
ANTICOAGULANT
S
MAJOR THROMBIN INHIBITORS:
ANTITHROMBIN
ALPHA2-MACROGLOBULIN
MINOR THROMBIN INHIBITORS:
HEPARIN COFACTOR II
a1 ANTITRYPSIN
a2 ANTIPLASMIN
ANTICOAGULANT
S
P O T E N T I A T O R OF
ENDOGENOUS ANTITHROMBIN
ACTIVITY.
HEPARIN
LMW HEPARIN
INHIBITOR OF VITAMIN K DEPEN
DENT CLOTTING FACTORS.
D I S O R D E R
S
CLOTTING SYSTEM DEFICIENCY
FACTOR VIII DEFICIENCY
FACTOR IX DEFICIENCY
VON WILLEBRAND
FACTOR*******
DEFICIENCY
*******STABILIZES FACTOR VIII
AND
PROMOTES PLATELET
S
 ACTIVATORS:
TISSUE PLASMINOGEN
ACTIVATORS
PROUROKINASE
STREPTOKINASE
BACTERIAL PRODUCTS
 INHIBITORS:
ALPHA1 ANTITRYPSIN
ALPHA2 ANTIPLASMIN
 MECHANISMS OF FIBRINOLYSIS
ACTIVATION AND INHIBITION
 STREPTOKINASE + PLASMINOGEN

STREPTOK’ASE
 PLASMI’GEN
 (-) COMPLEX
 PLASMI’GEN t-PA UROKINASE
 ACTIVATOR
 INHIBITOR (-)
 PLASMIN ALPHA2
 ANTIPLASMIN
 FIBRIN FIBRIN DEGRADATION
P.
PLATELET
ACTIVATION
A D H E S I O N
R E L E A S E OF
GRANULES
AGGREGATION
DIAGRAM: VWF
COLLAGEN THROMBIN ADP
TxA2
PROS’CYCLIN

OOOOOOOOOOOOOOO
GP GP GP PAR PAR TP P2Y1 P2Y12
IP
Ia-IIa VI Ib-Ix 1 4 + + (-)

ooooooooooooooo (+)

PLCy + + PLCB PKC Pltn PLA2 AC

IP3 DAG + A’chidonate
= PIP2 COX-1
Ca2+ = P. PL TxA2 + CAMP
ENDOTHELIAL
CELLS
 SYNTHESIZE
PROSTACYCLIN
 SYNTHESIZE HEPARAN SO4
 SYNTHESIZE PLASMINOGEN
ACTIVATORS
 SOURCE OF NO & T’MODULIN
 EXHIBIT ADPase ACTIVITY
S
ASPIRIN
C’DOGREL
ABCIXIMAB
LABORATORY
TESTS
PLATELET
COUNT
BLEEDING TIME
COAGULATION
aPTT PTT
R E S P I R A T I O
N
FROM Cl Cl-
 LUNGS KHCO3 K+ + HCO3- HCO3-
Na+
 O2 O2 + HHb HHbO2


 KHCO3+HHbO2 KHbO2+H2CO3
NaHCO3
 H2CO3 H2O +
 HbO2NHCOOH CO2 CO2
 HbO2NH2 +
R E S P I R A T I O
N
TISSUE CO2 + HbNH2
TISSUE
 CO2 HbNHCOOH
 CO2 + H2O H2CO3
 KHbO2 KHb + O2 O2
 H2CO3 + KHB HHb +
 KHCO3
HCO3-
 KHCO3 K + HCO3- + Na+
ACID-BASE
BALANCE
 [B] [A]
 pH = pK + log -----------
 [HA]
ACID-BASE
BALANCE
 pK for H2CO3 =
6.1
 [B+] [HCO3] 20
 ------------------ = ---
--
 [H2CO3] 1
ACID-BASE
BALANCE
pK for BH2PO4-=6.8
 [B+] [HPO4=] 4
 -------------------- = ---
--
 [BH2PO4-] 1
ACID-BASE
BALANCE
PLASMA BUFFERS
 (BICARB, PO4, P. PROTEINS)

RED BLOOD
CELLS
 BUFFERS
 (BICARB, PO4,
 NORMAL VALUES
PLASMA HCO3- = 22-
26mmol/L
PLASMA CO2 = 35-45mmHg
PPRESSURE O2 = 80-
100mmHg
O2 SAT’RATION = 95 –
98%
N
ACID – BASE BALANCE
*PRIMARY ALKALI DEFICIT (metabolic acidosis)
 PRIMARY ALKALI EXCESS (metabolic alkalosis)
 PRIMARY CO2 EXCESS (respiratory acidosis)
 PRIMARY CO2 DEFICIT (respiratory alkalosis)

**COMPENSATED METABOLIC ACIDOSIS

 COMPENSATED METABOLIC ALKALOSIS
 COMPENSATED RESPIRATORY ACIDOSIS
 COMPENSATED RESPIRATORY ALKALOSIS

 *ACUTE **CHRONIC (Fully,