a clinically oriented discussion of blood coagulation and related diseases and treatment. also discussing DIC, plasma fractions and anti-platelet drugs.

2. By
M. H. Farjoo M.D. , Ph.D. Bioanimator
Shahid Beheshti University of Medical Sciences
Drugs Used in Disorders of Coagulation
for Reform Students

3. Drugs Used in Disorders of Coagulation
 Overview of blood coagulation
 Classification of Drugs
 Anticoagulants
 Fibrinolytics
 Fibrinolytic Inhibitors
 Anti Platelets
 Plasma Derivatives (Fractions)
 Disseminated intravascular Coagulation (DIC)

4. Overview of Blood Coagulation
 Vasospasm
 Platelet adhesion and aggregation
 Activation of coagulation factors
 Fibrin synthesis

5. Platelet activation and thrombosis. Platelets circulate in an inactive form in the vasculature.
Damage to the endothelium and/or external stimuli activates platelets that adhere to the
exposed subendothelial von Willebrand factor and collagen. This adhesion leads to activation of
the platelet, shape change, and the synthesis and release of thromboxane (TxA2), serotonin ...

6. FDP: fibrin degradation product
PAI: plasminogen activator inhibitors
PL: phospholipids
TAFI: thrombin activatable fibrinolysis inhibitor
TF: tissue factor
tPA: tissue plasminogen activator
uPA: urokinase plasminogen activator.

7. , Ethylene Diamine Tetra acetic Acid

10. Anticoagulants
 4 major types of anticoagulants are available:
 Heparin and related products (parenterally)
 Direct thrombin inhibitors or Hirudin derivatives
 Direct Oral Factor Xa inhibitors
 Active coumarin derivatives, eg: Warfarin (oral)
 Heparin and the oral anticoagulant drugs do not
affect the fibrinolytic mechanism.
DOAC = Direct oral anticoagulant

11. Heparin
 Heparin has an average molecular weight of 15,000.
 Low-molecular-weight (LMW) fractions of heparin are
5000 Dalton.
 LMW heparins have greater bioavailability and longer
durations of action; thus, doses can be given once or
twice a day SC.
 LMW heparins include: Enoxaparin (Clexane), and
Dalteparin
 LMWH can be used for out-of-hospital management of
patients with deep vein thrombosis or pulmonary
embolism.

12. Heparin and LMW heparin

15. Enoxaparin (Clexane)

16. Enoxaparin (Clexane)

17. Enoxaparin (Clexane)

18. Dalteparin

19. Dalteparin

20. Heparin Indications
 Unfractionated an LMW heparins are used when
anticoagulation is needed immediately (start of
therapy).
 They are used for :
 Treatment of DVT, pulmonary embolism, and acute MI.
 In combination with glycoprotein IIb/IIIa inhibitors
during angioplasty and placement of coronary stents.
 Anticoagulant therapy in pregnancy (Heparin, LMWH,
and fondaparinux do not cross the placenta).

21. Heparin Administration
 Heparin should prolong the aPTT 2–3 times (normal
aPTT is 30-40 Sec.).
 A daily total dose of 35,000 U divided to 8–12 h
usually achieves an aPTT of twice the control value.
 For prevention of thromboembolism a SC dose of
5000 unit is given 2-3 times daily (daily dose 10,000-
15,000 unit).
 Must never be administered IM, (hematoma).
 Heparin may prolong prothrombin time (PT).

22. Deep Vein Thrombosis (DVT)

23. Deep Vein Thrombosis (DVT)

24. Deep Vein Thrombosis (DVT)

25. Heparin Toxicity
 The major adverse effect is bleeding.
 Protamine only partially reverses the effects of LMWH.
 Heparin (and to a lesser extent LMWH) may cause
thrombocytopenia in <0.5% of patients.
 The heparin-induced antibody, causes platelet aggregation
and thromboembolism which may lead to limb
amputation.
 Heparin or LMWH should be discontinued immediately if
thrombocytopenia occurs 5-10 days after therapy and a
platelet count drop of >50%.

26. Heparin Contraindications
 Hypersensitivity to the drug
 Active bleeding & hemophilics
 Thrombocytopenia & purpura
 Severe hypertension, intracranial hemorrhage
 Infective endocarditis & active tuberculosis
 Ulcerative lesions of the GI tract
 Threatened abortion
 Visceral carcinoma & advanced hepatic or renal disease
 Recent surgery of the brain, spinal cord or eye
 Patients undergoing lumbar puncture or regional
anesthesia

27. Reversal of Heparin Action
 Discontinuance of the drug and Protamine sulfate.
 Excess protamine also has anticoagulant effect.
 Use 100 unit (1 mg) per 100 USP units of heparin or
enoxaparin within 30 min of heparin injection.
 Protamine is given IV at a slow rate (maximum 50
mg over 10 min), and not to exceed total 50 mg.
 Protamine binds only long heparin molecules so, it
partially reverses activity of LMWH.

28. UAH: Unités anti-héparine

31. Direct Thrombin Inhibitors
 Dabigatran is the prototype.
 It is used in patients with heparin-induced
thrombocytopenia.
 Their action is monitored with aPTT.
 Dabigatran has predictable pharmacokinetics, which
allows for fixed dosing.
 Dabigatran is used for prevention of stroke and
systemic embolism in atrial fibrillation (AF).

32. Dabigatran capsule 75 mg
Price of each package (30 Caps.) 96,000 Toman

33. Dabigatran capsule 110 mg
Price of each package (30 Caps.) 141,000 Toman

34. Dabigatran capsule 150 mg
Price of each package (30 Caps.) 192,000 Toman
Price of each single tablet 6,400 Toman

35. Direct Oral Factor Xa inhibitors
 Rivaroxaban is the prototype and has a rapid onset of
action.
 It is given as fixed oral doses and do not require
monitoring.
 It directly bind to and inhibit both free factor Xa and
factor Xa bound in the clotting complex.
 It is used for thromboembolism following hip or knee
surgery and prevention of stroke in AF.

36. Rivaroxaban tablet 10 mg
Price of each package (30 tablets) 98,400 Toman
Price of each single tablet 3,280 Toman

37. Rivaroxaban tablet 15 mg
Price of each package (30 tablets) 105,000 Toman
Price of each single tablet 3,500 Toman

38. Rivaroxaban tablet 20 mg
price of each package (30 tablets) 120,000 Toman
Price of each single tablet 4,000 Toman

39. Strategy for Anticoagulant Reversal
 To reverse the effects of DOACs use:
 A specific reversal agent, eg: idarucizumab (especial
agent), and andexanet alfa (Not in Iran)
 Nonspecific agents eg: prothrombin complex
concentrates (PCCs)
 Antifibrinolytic agent
 Desmopressin (DDAVP)
 Drug removal from the circulation (hemodialysis)
and/or GI tract.

43. Warfarin
 Warfarin blocks synthesis of prothrombin (II), VII, IX,
and X as well as the anticoagulant proteins C and S
 There is an 8 to 12 hour delay in its action
 Inhibition of coagulation is dependent on the half-lives
of inhibited factors

45. Warfarin-induced skin necrosis in
heterozygous protein C or protein S deficiency
Both protein C and S depend on vitamin K
for normal function.

46. Warfarin-induced skin necrosis in heterozygous protein C or
protein S deficiency in an Iranian woman

47. Warfarin
 Warfarin crosses the placenta readily and can cause
abnormal bone formation and hemorrhagic disorder in
the fetus.
 It should NEVER be administered during pregnancy.
 It is monitored by prothrombin time or International
Normalized Ratio (INR).
 Dosage is adjusted to achieve an INR of 2 – 3

48. Warfarin tab
Available forms in Iran

49. Warfarin Drug Interaction
 The most serious are those that increase the risk
of bleeding and include:
 Pharmacokinetic:
 Amiodarone, Cimetidine, Metronidazole,
Trimethoprim-sulfamethoxazole, Fluconazole
 Pharmacodynamic:
 Aspirin (high dose), Third-generation
cephalosporins, Heparin, Dabigatran, Rivaroxaban,
 Body factors
 Hepatic disease, Hyperthyroidism

50. Warfarin Reversal of Action
 Stopping the drug.
 Fresh-frozen plasma (FFP).
 Vitamin K
 Rapid infusion of vitamin K1 can produce dyspnea,
chest and back pain, and DEATH.

53. Warfarin Reversal of Action
based on INR
*1-2.5 mg PO for patients at increased risk for bleeding.
†Intravenous (IV) infusion should be given slowly.
FFP = fresh-frozen plasma; INR = international normalized ratio; 4F-PCC = four factor prothrombin
complex concentrate; PO = orally; PRN = as needed; rFVIIa, recombinant factor VIIa.

54. Warfarin Reversal of Action
 4-factor prothrombin complex concentrate (PCC) is
used for emergency cardiac surgery in patients taking
warfarin.
 Activated PCC or aPCC (FEIBA), contains activated
factor VII.
 aPCC has a greater prothrombotic risk compared with
unactivated PCC, and is rarely used.

55. PCC products
Unactivated prothrombin complex concentrates (PCCs)
4 factor: Kcentra (Not in Iran)
Contains factors II, VII, IX, and X in
inactive forms
3 factor: Profilnine SD (Not in Iran)
Contains factors II, IX, and X (little to
no factor VII)
Activated prothrombin complex concentrate (aPCC)
4 factor: FEIBA
Contains factors II, VII, IX, and X;
factor VII is mostly activated*

56. aPCC (FEIBA) Vial, powder, 500 [IU]
Price in Iran:
2,234,000 Toman (500 IU)
4,468,000 Toman (1000 IU)

57. Overview of the Anticoagulants

59.  Fibrinolysis is fulfilled by conversion of plasminogen
to plasmin.
 Fibrinolysis is therapeutic for thrombotic disease.
 Elevated D-dimer indicates recent or ongoing
intravascular coagulation.
 D-dimer is used for:
 Deep vein thrombosis (not specific, but high negative
predictive value)
 Pulmonary embolism
 DIC
 Primary hyperfibrinolysis
Fibrinolytics

60. Tranexamic acid
t-PA analog (Alteplase),

61. D-dimer

62. Fibrinolytics
 Fibrinolytic drugs activate formation of plasmin
 The drugs include:
 Streptokinase
 Alteplase & Anistreplase (plasminogen+streptokinase)
 Tissue plasminogen activator (t-PA)
 Indications include: multiple pulmonary emboli (PE),
central DVT, acute MI.

63. Alteplase Powder for Injection 50 mg
Prcie in Iran: 1,660,000 Toman

64. Streptokinase; Price in Iran:
250,000 IU = ??
750,000 IU = 110,000 Toman
1,500,000 IU = 94,000 – 343,000 Toman

65. Urokinase

66. Fibrinolytics

67. Fibrinolytics
 Absolute contraindications of fibrinolytics:
 Any hemorrhagic stroke or stroke of unknown origin
 Central nervous system damage or neoplasm
 Major trauma, surgery, or head injury in the past 3 weeks
 Gastrointestinal bleeding in past month
 Significant ongoing bleeding

68. Tranexamic acid
t-PA analog (Alteplase),

69. Fibrinolytic Inhibitors
 Tranexamic acid inhibits plasminogen activation and is
used for:
 Adjunctive therapy in hemophilia.
 Therapy for bleeding from fibrinolytic drugs.
 Treatment of menorrhagia (only if other options fail, and only if
there is not a high risk of thrombosis)
 In addition to oxytocin for prevention of postpartum hemorrhage
(PPH) in high-risk situations.
 Melasma (second choice after hydroquinone)
 Adverse effect is intravascular thrombosis.

70. Tranexamic Acid, 250 mg
Price of each pack in Iran: 50,000 Toman

71. Tranexamic Acid, 500 mg / 5 ml

72. Tranexamic Acid, Topical

73. Fibrinolytic Inhibitors
 Aprotinin inhibits fibrinolysis by free plasmin
 Approved for use in patients undergoing
coronary artery bypass grafting

74. Aprotinin 10 million IU/1ml (10 ml)
Price in Iran: 50,000 Toman

76. Anti Platelet Drugs
 Irreversible cyclooxygenase inhibitors
 Aspirin
 ADP receptor inhibitors (P2Y12 inhibitors)
 Clopidogrel (Plavix)
 Prasugrel
 Ticlopidine
 Glycoprotein IIB/IIIA inhibitors (IV use only)
 Eptifibatide
 Tirofiban
 PDE & Adenosine reuptake inhibitors
 Dipyridamole

77. Eptifibatide
Tirofiban

78. Clopidogrel
Prasugrel
Ticlopidine

79. Clopidogrel 75 mg
Price of each pack: 23,400 Toman
Price of each single tablet: 780 Toman

80. Ticlopidine Tablet
Price of each Pack: 10,200 Toman

81. Dipyridamole Tablet;
Price in Iran:
25 mg: 13,000 Toman
75 mg: 17,000 Toman

82. Dipyridamole 10 mg/ 2ml
Price of each ampoule: 2,400 Toman

83. Eptifibatide
0. 75 mg/ 1 ml & 2mg/ 1 ml

85. Plasma Derivatives (Fractions)
 Spontaneous bleeding occurs when factor activity is less
than 5–10% of normal.
 Factor VIII deficiency (classic hemophilia) & factor IX
deficiency (Christmas disease) are the most common
heritable coagulation defects.
 Cryoprecipitate is used to treat fibrinogen defects in DIC
& liver disease.
 Desmopressin acetate increases the factor VIII activity
and is used for minor surgery (tooth extraction).

86. Blood Product Characteristics

87. Cryoprecipitate

88. FFP

89. Platelet Concentrate

90. Albumin

91. Comparison of FFP and Cryoprecipitate
FFP Cryoprecipitate
Volume 250 to 300 mL 10 to 20 mL
Time to prepare 30 minutes 30 minutes
Fibrinogen 700 to 800 mg 150 to 250 mg
Other coagulation
factors
All, including factors
II, VII, VIII, IX, X, XI,
and vWF
Factors VIII, XIII,
and vWF
On average, for equal volumes, Cryoprecipitate has ~ 3,600 mg
of Fibrinogen compared to FFP.

92. Desmopressin Spray Nasal 10 ug/dose, 5 ml
Price in Iran: 20,000 Toman

93. Desmopressin (Minirin) Tablet Sublingual 60 μg
Price in Iran: 120,000 Toman

95. DIC Introduction
 There are inhibitors that inactivate the coagulation
proteins as they escape from the site of vessel injury.
 They include: α1-antiprotease, α2-macroglobulin,
α2-antiplasmin, and antithrombin.
 If this system is overwhelmed, Disseminated
Intravascular Coagulation (DIC) occurs.
 DIC is seen in: massive tissue injury, abruptio
placentae, or bacterial sepsis.

96. DIC. Note the characteristic skin hemorrhage ranging from small purpuric
lesions to larger ecchymoses.

97. DIC (Purpura ulminans)
A large, retiform, purpuric lesion is present on the leg. Purpura
fulminans is characterized by the presence of extensive purpura.

98. DIC
Widespread retiform purpura are present in this patient
with DIC.

99. DIC Treatment
 Identify and eliminate the underlying cause.
 No treatment if mild, asymptomatic, and self-limited.
 In active bleeding or high risk for bleeding
administer:
 FFP (1 unit of FFP increases coagulation factors by
3% in an adult without DIC)
 Platelet concentrates (1–2 U/10 kg body weight)
 Cryoprecipitate in brisk hyperfibrinolysis or low levels
of fibrinogen.

100. DIC Treatment
 Heparin is indicated for DIC manifested by
thrombosis or acrocyanosis and without active
bleeding.
 Antifibrinolytic agents are generally contraindicated
except with life-threatening bleeding and failure of
blood component therapy.
 Clotting factor concentrates are NOT used because
single factor replacement has limited efficacy for
control of bleeding.

102. Thank you
Any question?