BLEEDING NOTES

1. HEMOSTASIS, SURGICAL
BLEEDING, AND
TRANSFUSION
Trix M. Asuncion MD.
General Surgery

2. Objectives
 To discuss the basic biology of hemostasis
and enumerate common congenital and
acquired hemostatic defects
 To discuss the basic principles of transfusion
and its indications
 To discuss bleeding in the intraoperative and
postoperative setting

3. HEMOSTASIS

4. Hemostasis
 Function is to limit blood loss from an injured
vessel

5. 1. Vasoconstriction
 Initial vascular response to injury
Endotheli
n
Thromboxane A2 – synthesized from
arachidonic acid from platelet
membranes
Endothelin – released from injured
endothelium
Serotonin - released during platelet
aggregation
Bradykinin and fibrinopeptides
TxA
2 5-
HT

6. 1. Vasoconstriction
 Dependent on local contraction of smooth
muscle
 more pronounced in vessels with medial smooth
muscles
 Varies with the degree of vessel injury

7. 2. Platelet Plug Formation
Platelets
• Anucleate fragments of
megakaryocytes
• Play an integral role in
hemostasis by forming a
hemostatic plug and by
contributing to thrombin
formation
• Life span 7-10 days
• Nomal range: 150 – 400 (x10³ /µL)
• Effective hemostasis can still
happen with as low as 50 x10³
/µL

8. STEPS IN PLATELET PLUG
FORMATION
1. Primary Hemostasis
• Endothelial injury
exposes the
subendothelial
collagen
• Platelets adhere to the
collagen through the
von Willebrand’s
factor which binds to
the collagen and
glycoprotein I/IX/V on
the platelet membranes
ADP & Serotonin are the primary mediators in platelet aggregation
Heparin does not interfere in this reaction
Arachidonic acid release PLATELET MEMBRANES Arachidonic acid Pr
(Vasodilator/inhibit Plt Aggregt’n
Prostaglandin Thromboxane (Vasoconstrictor/Platelet aggregation

9. Arachidonic acid metabolism
 cyclooxygenase
 Irreversibly inhibited by Asprin
 Reversibly blocked by NSAIDs
 Not affected by COX-2 inhibitors

10. STEPS IN PLATELET PLUG
FORMATION
2. Second wave of platelet aggregation
 The adhered platelets initiate a release
reaction to recruit other platelets (ADP, Ca2+,
serotonin, TXA2, and α-granule proteins)
 The release reaction has two outcomes
 1. Recruitment of more platelets
 2. compaction of the platelet plug making the process no
longer reversible
 Platelets are bound together by fibrinogen
linking together glycoprotein IIb / IIIa receptors
on activated platelets

11. STEPS IN PLATELET PLUG
FORMATION
 Secretion of thrombospondin
 Released by α -granule
 Stabilizes fibrinogen binding to activated platelet
surface and strengthens platelet-platelet interactions
 Secretion of Platelet factor 4 (PF4) and β-
thromboglobulin
 PF4 is a potent heparin antagonist
 Second wave Plt. Aggregation is Inhibited by:
 Aspirin
 NSAIDS
 cAMP
 NO

12. 3. COAGULATION
 Involves two pathways that leads into one
common pathway that catalyzes the formation
of fibrin
Clot formation
Prothrombin Time
Partial Thromboplastin
Time

13. Intrinsic vs Extrinsic
Intrinsic Pathway Extrinsic Pathway
Primary factors are ‘intrinsic’ to the
plasma
Requires Tissue Factor (TF) released
during subendothelial injury
II, IX, X, XI, XII , VIII II, VII, X
PTT PT
Common Pathway
• Leads to activation of prothrombin to thrombin in the
presence of calcium, factor V, and platelet
phospholipids
• Needs prothrombin activator (factor Xa) produced
from the 2 pathways

14. Extrinsic Pathway

15. Intrinsic Pathway

16. Formation of Fibrin
Thrombin Fibrinogen
Fibrin
Fibrinopeptide
A
Fibrinopeptide B
• Fibrinopeptide A removal: permits
end-end polymerization of fibrin
• Fibrinopeptide B removal: allows
side-side polymerization of fibrin
• Fibrin formation leads to clotting
• Stabilized by thrombin activatable
fibrinolysis inhibitor (TAFI)
MEMBRANE
SURFACE

17. REGULATION OF THE
COAGULATION CASCADE
 Feedback inhibition
 Enzymes leading to thrombin formation are
deactivated as a feedback
 Fibrinolysis
 Breakdown of the fibrin clot and subsequent repair of
the injured vessel with deposition of connective
tissue are triggered
 Tissue factor pathway inhibitor (TFPI)
 Blocks extrinsic tissue factor-VIIa complex
 Antithrombin III
 neutralizes procoagulant proteases and weakly
inhibits tissue factor-VIIa complex

18. REGULATION OF THE
COAGULATION CASCADE
 Protein-C System
 Thrombin binds to thrombomodulin and activates
protein-C to activated protein C (APC), which then
forms a complex with its cofactor, protein S, on a
phospholipid surface
 The APC–protein S complex cleaves factors Va and
VIIIa
 So they are NO longer able to participate in the
formation of tissue factor VIIa or prothrombinase
complexes
 Factor V Leiden
 Genetic mutation in factor V; a variant of factor V
 Resistant to cleavage by activated protein-C (APC)
predisposing them to venous thromboembolic events

19. 4. Fibrinolysis
 As part of the wound-healing process, the
fibrin clot undergoes lysis
 Breakdown of the clot within the lumen of
the vessel permits restoration of blood flow,
the fibrin clot in the vessel may be replaced
with connective tissue
 Initiated at the same time as the clotting
mechanism under the influence of circulating
kinases, tissue activators, and kallikrein that
are present in many organs including the
vascular endothelium.

20. 4. Fibrinolysis
 Bradykinin- endothelial-dependent
vasodilator
 HMWK(high molecular weight kininogen by
kallikren- enhances the release of tPA.
 Alpha-antiplasmin- inhibit plasmin
 Ensure that clot lysis does not occur too quickly.
 Circulating plasmin is inhibited by:
 Alpha-antiplasmin
 tPA
 urokinase

21. 4. Fibrinolysis
FIBRIN is degraded by plasmin
 PLASMIN comes from PLASMINOGEN
 Tissue plasminogen activator (tPA) is
synthesized by endothelial cells and
released by thrombin stimulation
 Urokinase plasminogen activator (uPA) is
synthesized by endothelial cells and
urothelium

22. FDP=FIBRIN DEGRADATION PRODUCTS
D-DIMERS- marker for thrombosis if (+) in circulati
E-NODULES

24. CONGENITAL HEMOSTATIC
DEFECTS (HEMOPHILIA)
Hemophili
a A
Hemophili
a B
(Christma
s disease
Hemophili
a C
Factor VIII
deficiency
Factor IX
deficiency
Factor XI
deficiency
80% of
cases
20% of
cases
Prevalent
in
Ashkenazi
Jewish
population
X-linked
recessive
X-linked
recessive
Autosomal
recessive
Spontaneo
us
bleeding,
easy
Spontaneo
us
Bleeding,
easy
Spontaneo
us bleeding
is rare

25. DETERMINATION OF CLINICAL SEVERITY
THROUGH MEASURABLE PLASMA LEVEL
PLATELET
FACTOR
LEVELS
SEVERITY BLEEDING CONSEQUENCES
Less than 1% Severe Spontaneous bleeding
1% to 5 % Moderate Less spontaneous bleeding;
Bleed severely during
trauma or surgery
5% to 30% Mild Minor bleeding after major
trauma or surgery

26. VON WILLEBRAND’S DISEASE
(VWD)
 Low (↓) Factor VIII; primary defect is low (↓)
vWF
 MOST COMMON congenital bleeding disorder
 Autosomal dominant
 Bleeding that is characteristic of platelet
disorders
 Easy bruising
 Mucosal bleeding, menorrhagia in women

27. VON WILLEBRAND’S DISEASE
(VWD)
Two functions of VW
factor:
 Carrier for Factor VIII
 For normal platelet
adhesion to exposed
subendothelium
Three types:
 Type 1 – Partial
Quantitative Deficiency
 Type 2 – Qualitative
Deficiency
 Type 3 – Total
Deficiency

28. DEFICIENCY OF FACTORS II
(PROTHROMBIN), V AND X
 RARE disorders
 ALL are inherited as autosomal recessive
traits
 Factor V is less stable in plasma
 Deficiency in this factor may be
accompanied with factor VIII deficiency.
 Half life of prothrombin (Factor II) is 72 hrs
 Half life of Factor X is 48 hrs
 Treatment: Fresh Frozen Plasma

29. FACTOR VII DEFICIENCY
 RARE autosomal recessive disorder
 Bleeding is uncommon unless plasma levels is <
3%
 The most common bleeding manifestations are:
 Easy bruising
 Mucosal bleeding (epistaxis or oral bleeding)
 Postoperative bleeding
 Half life: 4hrs in fresh frozen plasma (FFP)

30. FACTOR XIII DEFICIENCY
 RARE; autosomal recessive; 1:1 (M:F)
 Associated with Severe bleeding diathesis
 Bleeding typically delayed (clot is formed but
susceptible to fibrinolysis)
 S/Sx: Umbilical stump bleeding; Spontaneous
abortion usual in women; High risk of
intracranial bleeding
 Half life in FFP: 9-14 days
 Treatment: Fresh Frozen Plasma,
Cryoprecipitatae, or Factor XIII concentrate

31. PLATELET FUNCTIONAL
DEFECTS
 Inherited functional defects
 Abnormalities of platelet surface proteins
 Thrombasthenia (Glanzmann’s disease)
 Absence of glycoproteins (1B, 2A) receptor for
fibrinogen and vWD
 Platelets do not aggregate
 Gp IIb/IIIa complex is either lacking or present but
dysfunctional
 Treatment: Platelet Transfusion
 Bernard Soullier Syndrome
 Defect in glycoprotein (1B,9,5) receptor for vWD that is
necessary for platelet adhesion to subendothelium
 Treatment: Platelet Transfusion

32. PLATELET FUNCTIONAL
DEFECTS
 Abnormalities of platelet granules (intrinsic
platelet defects or storage pool disease)
 Loss of dense granules (storage sites for ADP,
ATP, Ca+2, inorganic phosphate)
 Hermansky-Pudlak Syndrome
 Loss of α-granules (storage for PF4, β
thromboglobulin)
 Gray Platelet Syndrome

33. PLATELET FUNCTIONAL
DEFECTS
Enzyme defects
 Cyclooxygenase deficiency
Quantitative Platelet Defects
 Due to failure of platelet production
brought about by marrow
 Inherited thrombocytopenia is rare
 Related diseases, shortened platelet survival

34. ACQUIRED HEMOSTATIC
DEFECTS
PLATELET ABNORMALITIES
 Failure of production
 General Marrow Disorder - leukemia,
myelodysplastic syndrome, severe vitamin B12 or
folate deficiency, chemotherapeutic drugs,
radiation, acute ethanol intoxication, or viral
infection

35. ACQUIRED HEMOSTATIC
DEFECTS
Shortened platelet survival
 Immune thrombocytopenia
 Disseminated intravascular coagulation
(DIC), thrombotic thrombocytopenic purpura
(TTP), and hemolytic uremic syndrome (HUS)
 Drugs (heparin, quinidine, quinine gold
salts sulfonamides, valproic acid, chorthiazide)

36. ACQUIRED HEMOSTATIC
DEFECTS
Sequestration
 Sequestration of platelets in an enlarged
spleen from any cause (portal hypertension,
sarcoid, lymphoma, Gauchers disease)
 Total body platelet mass is normal but larger
fraction of platelet mass is sequestered in the
spleen
 Thrombocytopenia is the MOST COMMON
abnormality of hemostasis that results in
bleeding in the surgical patient.

37. ACQUIRED
HYPOFIBRINOGEMIA
 Defibrination syndrome - DIC
 Pathologic fibrinolysis in metastatic prostate
carcinoma, sepsis, shock, portal hypertension,
neoplasia, cirrhosis
 Myeloproliferative diseases - marked
thrombocytosis in polycythemia vera
 Coagulapathy of liver disease - ALL
coagulation factors synthesized by hepatocytes
 Acquired coagulation inhibitors - lupus
anticoagulant (Russels viper venom test), factor
VIII inhibitors

38. Other causes:
 Paraprotein disorders - abnormal globulin
or fibrinogen that interferes with clotting or
platelet function
 Hypersplenism - oversequestration of
platelets
 Anticoagulation and bleeding
 Treatment with anticoagulants such as
heparin, warfarin, factor Xa inhibitors
 Manifests as ecchymosis, petechiae,
hematoma

39. Other causes:
 Cardiopulmonary bypass - over
heparinization, thrombocytopenia, protamine
excess
 Coagulopathy of Trauma
 Caused by shock and tissue injury
 Hypoperfusion  release of TM from endothelial cells
 Thrombin+TM complex  activation of protein C,
enhancement of fibrinlysis, and decrease in the
conversion of fibrinogen to fibrin.

40. VITAMIN K
 Factors II, VII, IX, and X need Vitamin K
for its production in the liver
 Coumadin (warfarin) inhibits production of
Vitamin K in the gut
 Antibiotics result in deficiency by killing
Vitamin K producing bacteria in the gut

41. BLEEDING PARAMETERS
Bleeding Time
 The MOST RELIABLE in vivo test of hemostatic
function
 Tests platelet function
Prothrombin time (PT)
 Measures the extrinsic and common pathway of
coagulation
 International Normalized Ratio (INR)
 INR = PTpatient/PTnormal = 0.8-1.2 seconds
 Reference range of PT is 12 to 15 seconds
 Measures Factors VII, X, V, II (prothrombin), I
(fibrinogen)

42. BLEEDING PARAMETERS
Activated partial thromboplastin time (aptt)
 Measures the intrinsic and common
pathway of coagulation
 Measures factors XII, high molecular
weight kininogen (HWMK), prekallikrein,
XI, IX, VII, X, V, II, and I

43. BLEEDING PARAMETERS
Thrombin Time
 Measures the time it takes to form a clot in
the plasma from a blood sample with an
anticoagulant and an excess of thrombin
 Assessment of fibrinogen pathology
 Diagnosis bleeding disorders and assess
fibrinolytic therapy

44. EXCESSIVE BLEEDING IN AN
INTRAOPERATIVE AND
POSTOPERATIVE PATIENT

45. Surgical Bleeding
 Ineffective hemostasis
 blood transfusion
 undetected
hemostatic defect
 consumptive
coagulopathy
 fibrinolysis
 Excessive bleeding
from the operative
field

46.  To prevent further blood loss from a disrupted
vessel that has been incised or transected by
interrupting the flow of blood to the involved area
or by direct closure of the blood vessel
 Digital pressure
 Ligation – small vessels
 Transfixion suture – pulsating arteries
 Direct pressure (Packing) – diffuse bleeding
 Thermal Agents
 Topical Agents
Mechanical Hemostasis

47. Bleeding due to Transfusion
 Thrombocytopenia
 Hypothermia
 Dilutional coagulopathy
 Platelet dysfunction
 Fibrinolysis
 Hypofibrinogenemia
 Hemolytic transfusion reaction

48. Bleeding due to Disseminated
Intravascular Coagulopathy
 Systemic activation of the coagulation system
 deposition of fibrin clots and microvascular
ischemia and may contribute to the development
of multiorgan failure
 Exhaustion of coagulation proteins and platelets
may result in bleeding complications

49. Bleeding due to Sepsis
 Gram-negative sepsis may result in
thrombocytopenia
 Meningococcemia, Clostridium perfringens
sepsis, and staphylococcal sepsis may result
in defibrination and hemostatic failure

50. TRANSFUSION

51. Introduction
 First widely accepted during the late 19th
century
 Widely used in world war I
 Whole blood was the standard therapy until
the 1970s when blood component therapy
became available
 Breakthroughs
 Landsteiner (1900) – discovery of the ABO
grouping
 Levine and Stetson (1939) – discovery of the Rh
grouping

52. Replacement Therapy
 Typing and Cross-matching
 The basis of blood transfusion
 In principle a person can only be transfused with the blood
of the same ABO and Rh group
 This is why cross-matching b/w the donor’s RBC and the
recipient’s sera is necessary before transfusion
 However in emergency situations blood type O- can be
transfused to all patients and an Rh- person can be transfused
with an Rh+ blood
 Autologous transfusion
• Up to 5 units (1st is at 40 days before and the last is at 3
days before the surgery)
• The patient should have at least a Hgb of 11mg/dL and a
Hct of 34

53. Replacement Therapy
Form Advantages Disadvantages Others
Whole Blood -Once the gold
standard
-Rarely used today
-Difficult to store
-related to adverse
inflammatory response
and multiple organ
failure
- Shelf life =
42 days
- Low RBC
viabiltity
RBCS - product of choice for
most clinical situations
requiring resuscitation
- reduces reactions
caused by plasma
componens
- Frozen RBCs are
not yet available for
emergencies
- Improved
RBC viability

54. Replacement Therapy
Form Advantage Disadvantage Others
Leukocyte-
Reduced and
Leukocyte-
Reduced/Washe
d Red
Blood Cells
- prevents almost all
febrile, nonhemolytic
transfusion reactions,
alloimmunization to
HLA I antigens, and
platelet transfusion
refractoriness and
CMV transmission
- Predisposition to
post-op bacterial
infection and
multiorgan failure
(according to some
studies)
- Standard
RBC product in
most
developed
countries
Fresh Frozen
Plasma
- usual source of the
vitamin K - dependent
factors and is the only
source of factor V
- Similar infectious risk
as other forms
- Better
availability than
other forms
Platelet
concentrates
- Used in
thrombocytopenia
Similar infectious risk
as other forms

55. Indications for Blood Replacement
and its Products
 Improvement of O2 carrying Capacity
 Anemia
 In the past - Hgb <10mg/dL and Hct <30 preop
 Today – Hgb <7-9mg/dL
 Volume Replacement
 Most common indication for blood transfusion in
surgical patients
 >20% blood loss in patients w/ normal lab values

56. Concepts in resuscitation
 OLD practice: Crystalloid RBC plasma
platelet(1970)
 NEW Concept: DAMAGE CONTROL
RESUSCITATION
 Aimed to halt and prevent rather than treating the
TRIAD OF DEATH (Coagulopathy, Acidosis,
Hypothermia)
 RATIONALE:
 Old: high incidence of truncal hemorrhage and
deaths in Trauma which can potentially be
prevented.
 Received significant blood transfusion >4-6 units

57. DAMAGE CONTROL
RESUSCITATION
 Crystalloids packed RBC
Platelet/Plasma
 Components:
 Permissive hypotension (SBP= 60-80mmhg)
 Minimized crystalloid based resuscitation
 Blood products (RBC, Plasma, Platelet)
 Ratio: 1:1:1(RBC, Plasma, Platelet)
After liters of crystalloids

58. Complications of Transfusion

59. Complications of Transfusion

60. Complications of Transfusion
 Transmission of Infections
 CMV, Syphilis, HBV, HCV, HIV, etc.

61. THANK YOU!