Hemostasis, Surgical bleeding, and Transfusion: basic science for general surgical residents. Facebook: Happy Friday Knight

1. Hemostasis, Surgical Bleeding
and Transfusion
Facebook: Happy Friday Knight
Department of Surgery
Thailand

2. TXA2
Endothelin
Serotonin
Bradykinin
fibrinopeptides
plasmin

3. Congenital Factor Deficiencies

4. Coagulation Factor Deficiencies
• Hemophilia A
• Von Willibrand’s Disease
• Hemophilia B
• Factor XI deficiency (Hemophilia C)
• Deficiency of Factor II, V, X
• Factor VII deficiency
• Factor XIII deficiency

5. Hemophilia
• A = factor VIII deficiency
• B = factor IX deficiency
• Sex-linked recessive disorder
• May not bleed immediately after trauma
• Severity:
– <1% : severe: spontaneous bleeding
– 1 – 5% : moderately severe: bleeding severely after
trauma and minor surgery
– 5 – 30% : mild

6. Hemophilia: Treatment
• Genetic counseling
• Factor replacement
– FFP 1 ml contends FVII 1 U, FIX 1 U
– FFP 1 U = 200 ml = FVIII 200 U, FIX 200 U
– Cryoprecipitated 1 U = 80 – 100 ml
– Plasma volume = 40 ml/kg
– FVIII 1 U/BW 1 kg => increases activity 2%
– FIX 1 U/BW 1 kg => increases activity 1%
– However, maximum dose is 10 – 20 ml/kg (increases
activity 30%) due to volume overload

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8. Platelet Functional Defects
• Include abnormalities of:
– Platelet surface proteins
– Platelet granules
– Enzyme defects
• Such as:
– Bernard-Soulier Syndrome
– Glanzmann Thrombasthenia
– Hermansky-Pudlak Syndrome

9. Acquired Hemostatic Defects

10. • Platelet abnormalities
• Acquired hypofibrinogenemia
• Coagulopathy of trauma
• Acquired coagulation inhibitors
Acquired Hemostatic Defects

11. Platelet
Abnormalities
Brunicardi FC et al. Schwartz’s Principles of Surgery.
10th ed. McGraw-Hill Education, 2015. page 90

12. Idiopathic Thrombocytopenic Purpura (ITP)
• Or Immune Thrombocytopenic Purpura
• Diagnosis by exclusion
• Secondary causes:
– Drugs: heparin, quinine, quinidine, sulfonamide,
thiazide
– Virus: Dengue, malaria, HIV
– Autoimmune: SLE,

13. Brunicardi FC et al.
Schwartz’s Principles of
Surgery. 10th ed. McGraw-Hill
Education, 2015. page 90

14. Heparin-induced thrombocytopenia (HIT)
• Ab against platelet factor 4 (PF4) formed
during heparin exposure, affect platelet
activation and endothelial function  resultant
in thrombocytopenia and intravascular
thrombosis
• Platelets fall 5 – 7 days after starting heparin
• Suspected in patients on heparin with
plt<100,000, or falls 50% from baseline

15. • Stop heparin
• Start alternative anticoagulant
– Lepirudin, argatroban, danaparoid
– Argatroban for patients with renal insufficiency
Heparin-induced thrombocytopenia (HIT):
Treatment

16. TTP and HUS
• Hemolytic Uremic syndrome: MAHA, uremia,
thrombocytopenia
• Thrombotic thrombocytopenic purpura: HUS +
fever + neurologic signs/symptoms
• Both are the result of platelet activation and
formation of platelet thrombi
• Treatment:
– Discontinuation of involved drugs
– FFP
– Plasma exchange

17. Sequestration
• From: portal hypertension, sarcoid, lymphoma,
Gaucher’s disease
• Total body platelet mass is normal but large
amount is in enlarged spleen
• Splenectomy is not indicated to correct
thrombocytopenia caused by portal
hypertension

18. Qualitative Platelet Defects
• Related to platelet function
• May present a normal platelet count
• Etiology:
– Massive transfusion
– Therapeutic platelet inhibitor: ASA, clopidogrel,
prasugrel, dipyridamole, GP Iib/IIIa inhibitors
– Diseases: liver disease and uremia

19. Acquired hypofibrinogenemia
• Disseminated intravascular coagulation (DIC)
• Primary fibrinolysis
• Myeloproliferative Diseases
• Coagulopathy of Liver Disease

20. Disseminated Intravascular Coagulation
• Etiology:
– sepsis
– Injuries resulting in embolization: brain, bone marrow,
amniotic fluid
– Malignancy
– Organ injuries: severe pancreatitis
– Liver failure
– Vascular abnormalities: large aneurysm
– Snake bites
– Drugs
– Transfusion reactions
– Transplant rejection

21. http://www.sharinginhealth.ca/conditions_and_diseases/disseminated_intravascular_coagulation.html

22. https://medacad.wikispaces.com/Disseminated+Intravascular+Coagulation

23. DIC: Treatments
• Correct the primary cause
• FFP
• In thrombosis predomination:
– Heparin
– Examples: VTE, severe purpura fulminans

24. http://bestpractice.bmj.com/best-practice/monograph/245/resources/image/bp/2.html
Purpura fulminans: coagulation in small blood
vessels at skin resulting skin necrosis; associate with
pneumococcal and meningococcal septicemia

25. Primary fibrinolysis
• may occur in patients following prostate
resection (releasing urokinase) or
extracorporeal bypass
• Treatment: ɛ-aminocaproic acid and
tranexamic acid

26. Myeloproliferative Diseases
• polycythemia vera
• Increased blood viscosity  increased stasis
 spontaneous thrombosis
• Spontaneous hemorrhage also noted
• Treatment: reduction of thrombocytosis by low
dose ASA, phlebotomy, hydroxyurea

27. • Effecting both platelet and coagulation
• Result: thrombocytopenia and prolonged PT
• Etiology of thrombocytopenia:
– Hypersplenism
– Reduced production of thrombopoietin (TPO)
– Immune-mediated destruction of platelets
• Treatment for invasive procedure: platelet
transfusion
Coagulopathy of Liver Disease

28. • Role of liver in coagulation system:
– Synthesis of coagulation factors
– Absorption of vitamin K depending on bile
production
• Disturbance in coagulation mechanism
increases both bleeding and thrombotic risk
• Treatment: FFP
Coagulopathy of Liver Disease

29. Coagulopathy of Liver Disease
Brunicardi FC et al. Schwartz’s Principles of Surgery. 10th ed. McGraw-Hill Education, 2015. page 92

30. Coagulopathy of Trauma
• Vicious cycle
• Mechanisms:
– Dilutional effect
– Shock inducing systemic activation of
anticoagulant and fibrinolytic pathways
• Treatment: FFP transfusion

31. Mattox KL et al. Trauma. 7th ed. McGraw-Hill Medical, 2013. page 221

32. Acquired Coagulation Inhibitors
• Antiphospholipid syndrome (APLS):
– Lupus anticoagulant
– Anticardiolipin antibodies

33. Anticoagulation and Bleeding

34. • When:
– aPTT ratio < 1.3 in heparinized patients
– INR < 1.5 in patients on warfarin
– Reversal of anticoagulation therapy is not
neccessary

35. Pharmacologic Interventions
• Heparin, Factor Xa, Direct Thrombin
inhibitors
• Warfarin
• Antiplatelet agents
• Fibrinolytic agents

36. Heparin
• Selective inhibitor of thrombin
• Half life 90 – 120 min
• Use: VTE prophylaxis
• Dose: 80 U/kg IV bolus, then 18 U/kg/hr
titrate 50 -100 U/hr q6hr
• Monitoring: aPTT ratio 1.5 – 2.0 q6hr
• Revered with protamine sulfate (1 – 1.5 mg for
100 U of heparin)

37. LMWH and others
• LMWH = low molecular weight heparin
– :Factor Xa inhibitor
– :enoxaparin, Fondaparinux, Rivaroxaban (oral form),
dabigatran
• Dose: enoxaparin 100mg/ml, 3 ml per vial
– <50 kg: 0.4 ml
– >50 kg: 0.6 ml
– CrCl < 30: OD
– CrCl > 30: q12hr
• No monitor

38. Warfarin
• Standard for long term arterial and venous
thromboembolism prophylaxis
• Vitamin K antagonist: inhibit factor II, VII, IX,
X, protein C and S
• Major complications:
– Bleeding
– Recurrent thrombosis
– Skin necrosis

40. Warfarin: Management
• Starts with warfarin 3 mg/day
• F/U PT next 3 – 5 days
• Therapeutic INR range: 2 - 3
• Adjust dose by 5 – 20% of mg/wk

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43. Antiplatelet Agents
• ASA, ticlopidine, clopidogrel, prasugrel,
dipyridamole
• Usage: prevention of cardiovascular events:
MI, stroke, PAD

45. Fibrinolytic Agents
• Plasminogen activator
• examples: urokinase, streptokinase, rtPA
• Applications:
– STEMI and stroke fast track
– Acute limb ischemia and peripheral bypass graft
occlusion
– Controversy in DVT and PE
• Complications: bleeding, rethrombosis

46. Mulholland MW et al. Greenfield’s Surgery
Scientific Principles and Practise. 5th ed.
Philadelphia: LIPPINCOTT WILLIAMS &
WILKINS, 2011. page 86

47. Local Hemostasis
• : the goal is to prevent further blood loss from
a disrupted vessel that has been incised or
transected
• Mechanical procedures
• Thermal agents
• Topical hemostatic agents

48. Mechanical Procedures
• Oldest method: digital direct pressure (at
bleeding site VS proximal)
• Tourniquet, Pringle maneuver
• Packing during laparotomy
• Simple ligature
• Transfixion suture for pulsatile arteries
• Bone wax

49. https://en.wikipedia.org/wiki/Ligature_(medicine)
Simple ligature: adequate for most veins and
small (2 – 3 mm) arteries

50. https://quizlet.com/3066909/vcs-81100-suture-techniques-flash-cards/
Transfixion suture for pulsatile arteries to
prevent the tie coming off

51. Thermal Agents (electrocautery)
• Generates heat by alternating current source 
transmitted via conduction from instrument to
tissue  protein denaturation  coagulation
• A negative grounding placed beneath the
patient to avoid skin burns

52. Topical Hemostatic Agents
• The ideal topical hemostatic agent has
significant hemostatic action, minimal tissue
reactivity, nonantigenicity, in vivo
biodegradability, ease of sterilization, low cost,
and can be tailored to specific needs
• Clotting activation
• Just adjunct, not main
• Examples: Gelfoam, Surgicel, Avitene,
Floseal, Vitagel

53. Transfusion

54. http://labmed.ascpjournals.org/content/42/4/235.full.pdf+html

55. Whole Blood
• Shelf life: 42 days
• 350 – 500 ml
• Rarely use

56. Packed red blood cell (PRC)
• 200 ml
• Shelf life 42 days under 1 – 6oC
• Product of choice
• 1 PRC: increases Hb 1g/dL, Hct 3%
• Leucocyte-poor and leucocyte depleted PRC:
use to prevent febrile nonhemolytic transfusion
reaction

57. Platelets
• Normal: 150,000 – 450,000 / mcL
– <100,000: bleeding after major trauma/surgery
– <50,000: minor trauma
– <10,000 – 20,000: spontaneous bleeding
• Life span 7 – 10 days
• Shelf life 120 hr
• Most common abnormality of hemostasis in
surgical patients

58. Platelets: treatment
• Blood component:
– Platelet concentrates: (PC) 1U = 50 ml = increases
platelet 5,000 – 8,000
– Single donor platelet (SDP) = 200 ml = increases
platelet 20,000
• PC transfusion (U) = 0.1 U/kg x BW
• Cross-matching is not necessary
• Keep platelet when:
– >100,000 : major surgery
– > 50,000 : minor surgery, LP
– >10,000 – 20,000: spontaneous bleeding prevention

59. Fresh Frozen Plasma (FFP)
• 250 ml
• Store of vitamin K-dependent factor (II, VII,
IX, X) and factor V
• Stored up to 5 days after warmed up
• Use: massive transfusion, coagulopathy and
factors deficiency
• Cross-matching is essential

60. Typing and Crossmatching
• Routinely ABO and Rh
• Between donor’s RBC and recipient’s serum
• In Rh –ve patient: Rh +ve blood is acceptable but
not in women in child-bearing age
• In emergency transfusion: O-ve or type-specific
• Timing:
– Full crossmatch: 45min – 1hr
– Type-specific: 5-10min
– O-ve: availiable stat!

61. Autologous Transfusion
• 5 U can be collected for elective surgery
• Patient should have Hb 11 g/dL or Hct 34%
• First unit is in 40 days before operation,
interval 3 – 4 days, and the last can be at 3
days before operation
• Recombinant human erythropoietin (RHuEPO)
accelerates generation of RBC

62. Tranexamic Acid (Tranxamine, TXA)
• Inhibitor of plasminogen activation and
plasmin activity
• thus preventing clot breakdown rather than
promoting new clot formation
• Not affect platelet count
• Application: CAGB, liver transplantation, hip
and knee arthroplasty
• ADR: GI and visual disturbances,
thromboembolic event

63. Indications for Blood Replacement
• Improvement in oxygen-carrying capacity
• Treatment of anemia
• Volume replacement (bleeding > 2L)

64. Anemia: Treatment
• Preoperative Hct: 30%, Hb: 10 g/dL
• In critical illness and chronic anemia: keep Hb
7 – 9 g/dL
• In patients with ischemic heart disease: Hb 7
g/dL

65. Damage Control Resuscitation
• Prevention of lethal triad
• Composed of:
– Permissive hypotension (hypotensive resuscitation,
SBP < 90 mmHg, MAP 65 mmHg)
– minimizing crystalloid-based resuscitation
– immediate release and administration of
predefined blood products

68. Complications of Transfusion
• Hemolytic Reactions
• Nonhemolytic Reactions
• Allergic Reactions
• Respiratory Complications
• Transmission of Diseases

70. Hemolytic Reactions
• Acute (within 24 hr)
– ABO incompatibility  lab error
– S/S: fever, hypotension, DIC, Hburia, Hbemina, renal
insufficiency
– Treatment and prevention: stop transfusion
• Delayed (2 – 10 days)
– Non-ABO antigens
– Clinical: fever, pain on plug site, flushing, chest pain
– Lab: Anemia, indirect hyperbilirubinemia, direct
Coomb’s test +ve
– Prevention: identify Ab

71. Nonhemolytic Reactions
• Febrile
– Fever > 1oC, 1% of transfusion
– Mechanism: cytokines, host Ab
– Prevention: LPRC
• Bacterial contamination
– Fever and sepsis
– Most common: Gram-negative (grow in 4oC)
– Treatment: antibiotics
– Prevention: stored platelet < 4days

72. Allergic Reaction
• 1% of all transfusions
• Common in FFP and platelets
• S/S: usually mild: urticaria, rash, flushing
– Anaphylactic shock is rare but develops
• Caused by transfusion of antigens or
antibodies which the recipient is
hypersensitive
– IgA deficiency
• Treatment: antihistamine

73. Respiratory Complications
• Transfusion-associated circulatory overload
(TACO)
• Transfusion-related acute lung injury (TRALI)

74. TACO
• Rapid infusion of fluid
• Common in elderly with heart disease
• Clinical: increases CVP, dyspnea, cough
• Management:
– CVP monitoring
– Diuresis
– Slowing infusion rate
– Minimizing fluids

75. TRALI
• Non-cardiogenic pulmonary edema related to
transfusion
• S/S: dyspnea, fever, rigors
• CXR: bilateral pulmonary infiltration
• Mostly occurs within 1-2 hrs, before 6 hrs
• Mechanism: Anti-HLA or Anti-HNAAb attack
circulatory and pulmonary leukocytes
• Treatment: discontinuation and pulmonary
support
• Prevention: limit female donor

76. Transmission of Diseases
• Hepatitis B
• Hepatitis C
• HIV
• Malaria
• Chagas disease
• CMV
• Brucellosis
• syphilis

77. Tests of Hemostasis

78. Tests of Hemostasis
• Platelet count
• Bleeding time
• VCT and WBCT
• PT and aPTT
• TEG

79. Bleeding Time
• Detecting platelet and vascular dysfunctions
• Most commonly use: Ivy method
– Cuff 40 mmHg and 5 mm stab incision at flexor
surface of forearm
– Normal: 7 min (5 – 15 minutes)

80. VCT and WBCT
• Use with patients with snake bites
• Venous Clotting Time (VCT)
– 3 tubes with blood 1 ml per each  after 5 min,
bend 90o of tube q1min until no blood comes
– Normal: < 20 min
• Whole Blood Clotting Time (WBCT)
– 1 tube, 2 ml, waiting for 20 minutes and bend the
tube, if not clot  positive

81. Prothrombin Time (PT)
• measures the function of factors I, II, V, VII,
and X.
• Best for detecting vitamin K deficiency and
monitoring warfarin therapy
• Due to variations: International Normalized
Ratio (INR) becomes choice to report PT value
• Normal: INR 1.3 – 1.5
• INR = measure PT / normal PT

82. Activated Partial Thromboplastin Time
(APTT)
• measures function of
– factors I, II, and V of the common pathway
– factors VIII, IX, X, and XII of the intrinsic
pathway
• Suite for monitoring of heparin therapy
• Normal: aPTT ratio 1.5 – 2.5

83. Thromboelastography (TEG)
• Or ROTEM (Rotational Tromboelastometry)
• Whole blood-viscoelastic testing
• dynamically
• measures the interactions of coagulation
factors, inhibitors and cellular components
during the phases of clotting and subsequent
lysis over time

84. https://www.rotem.de/en/methodology/thromboelastometry/

85. Q & A

86. How to prepare autologous blood
transfusion?
• First unit is in 40 days before operation,
interval 3 – 4 days, and the last can be at 3
days before operation
• 5 U
• Patient should have Hb 11 g/dL or Hct 34%
• Recombinant human erythropoietin (RHuEPO)
accelerates generation of RBC

87. When should heparin-induced thrombocytopenia
be suspected?
When thrombosis occurs while receiving heparin
or when there is a fall in the platelet count by
greater than 50% or to below 100,000/μl.

88. What are the major endogenous activators of
plasminogen?
Tissue plasminogen activator (tPA) and
urokinase

89. How dose warfarin work as an anticoagulant?
Interfering with vitamin K-dependent factor: II,
VII, IX, X, protein C, protein S

90. How long will ASA affect the platelets?
7 days entire platelet life due to irreversible
effect

91. A 45-year-old woman with deep vein thrombosis
is taking warfarin (Coumadin), 5 mg/d. Seven days after
initiation of therapy, she has warfarin-induced skin necrosis.
Which of the following statements regarding this condition
is true?
(A) It commonly occurs after warfarin therapy.
(B) It usually involves the upper extremities.
(C) It improves with an increase in the dose of Coumadin.
(D) It improves with a decrease in the dose of Coumadin.
(E) It requires cessation of Coumadin and infusion of
heparin.

92. After undergoing a transurethral resection of the
prostate, a 65-year-old man experiences
excessive bleeding attributed to fibrinolysis. It is
appropriate to administer which of the
following?
(A) Heparin
(B) Warfarin (Coumadin)
(C) Volume expanders and cryoprecipitate
(D) Aminocaproic acid (Amicar)
(E) Fresh-frozen plasma and vitamin K

93. References
Brunicardi FC et al. Schwartz’s Principles of Surgery. 10th ed.
McGraw-Hill Education, 2015.
Blecha MJ. General Surgery Absite and Board Review. 4th ed.
McGraw-Hill, 2008.
Cayten CG et al. Lange Q & A Surgery. 5th ed. McGraw-Hill, 2007.
Mattox KL et al. Trauma. 7th ed. McGraw-Hill Medical, 2013.
Mulholland MW et al. Greenfield’s Surgery Scientific Principles and
Practise. 5th ed. Philadelphia: LIPPINCOTT WILLIAMS & WILKINS,
2011.
Semer NB et al. Practical Plastic Surgery for Nonsurgeons.
Philadelphia: Hanley & Belfus, 2001.
วิทยา ศรีดามา. อายุรศาสตร์ 1. กรุงเทพฯ: โรงพิมพ์แห่งจุฬาลงกรณ์มหาวิทยาลัย, 2549.
สมาคมแพทย์โรคหัวใจประเทศไทย. แนวทางการรักษาผู้ป่วยด้วยยาต้านการแข็งตัวองเลือดชนิดรับประทาน.
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