The document discusses disorders of coagulation and thrombosis. It covers the pathways of coagulation, including the intrinsic, extrinsic, and common pathways. It discusses the roles of platelets, coagulation proteins, and the fibrinolytic system. It also discusses diseases that can cause excessive bleeding, such as von Willebrand disease, thrombocytopenia, and immune thrombocytopenic purpura (ITP). Disorders that can cause hypercoagulability like essential thrombocythemia are also mentioned. The pathways of hemostasis, platelet adhesion and aggregation, and natural anticoagulant pathways are described in detail.

1. Disorders of Coagulation
Pathway of coagulation and thrombosis
Diseases and disorders of…..
Platelets
Coagulation Proteins
Fibrinolytic pathway and therapy
Anticoagulation
and Anti-platelet Tx

2. Faces of Microangiopathy,
Hypercoagulability and Ischemia

3. Faces of Microangiopathy and
Ischemia

4. Faces of Microangiopathy and
Ischemia

5. Faces of Microangiopathy and
Ischemia

6. Faces of Microangiopathy and
Ischemia

7. Faces of Microangiopathy and
Ischemia

8. Faces of Microangiopathy and
Ischemia

9. Faces of Microangiopathy and
Ischemia

10. Coagulation and Thrombosis
Hemostasis- a physiological process that prevents
exsanguinations after injury; a complex inter-related
reaction involving the following five elements:
1. endothelium and the blood vessel:
synthesis of prostaglandins, NO, tPA, vWF,
ADPase, serotonin, thrombomodulin, III receptors
2. platelets
3. plasma proteins: the intrinsic, extrinsic,
and final common pathways
4. protease inhibitors
5. fibrinolytic system

11. Coagulation and Thrombosis
Injury- initiates a sequence of 4events:
a. vessel →vasoconstriction
b. platelet plug (adhesion)
c. stabilization/reinforcement by
extrinsic and intrinsic plasma
protein pathway
d. fibrinolysis
Virchow's Triad (1856)- for the development of
thrombosis:
a. Damage to the endothelium
b. Stasis or slowing of blood flow
c. Hypercoagulability of blood

12. Coagulation and clotting cascade:
a. Intrinsic system- “contact activation pathway”
composed of factors XII, XI, VIII → IXa
(IXa= plasma thromboplastin)
b. Extrinsic system “tissue factor pathway”
(generates tissue Thromboplastin Factor III
(III=Tissue Factor) – a lipoprotein in all tissues-
released from membranes of endothelial cells):
composed of Factors VII; III
c. Thrombin - a protease (an enzyme) which cleaves
fibrinogen into fibrinopeptides and fibrin
which quickly polymerizes into a fibrin gel.

15. Phase 1 Intrinsic (in the Blood) pathway
Phase 1 Contact Activation Pathway or the Intrinsic Pathway
("in the plasma")
Factor XII (Hageman factor- a glycoprotein synthesized into the liver)
is activated by collagen, endotoxins, platelets, kallikrein;
also becomes a plasminogen proactivator;
XIIa facilitates the conversion of XI to XIa in the presence of
HMW kininogen (Fitzgerald factor)
Factor XI (PTA a serine protease produced by the liver) becomes
activated (XIa)and activates
Factor IX in the presence of calcium (IV) and the Fitzgerald
factor

16. “Contact Activation “Intrinsic”
pathway
Factor IXa (PTC) + platelets →→→→ Activates
X → Xa
+ VIII (AHG)
+ calcium (IV)

17. Tissue Factor Pathway
Trauma to tissues-VII; III;
Tissue Factor (Thromboplastin) (III)
→(VIIa) will activate X to Xa
aka prothrombinase

18. The Final Common Pathway:
(begins with the activation of factor Xa and Va)
Phase III: Conversion of Prothrombin into Thrombin;
Prothrombin is factor II (a large single chain protein MW
73,000 protein) undergoes proteolytic cleavage to
produce thrombin only in the presence of :
Va (accelerator globulin) ; X (activated),
IV(calcium); and phospholipid;
Thrombin (II) , a two chain derivative of Prothrombin-
(MW 37,000) is proteolytic and converts fibrinogen(I)
into fibrin; thrombin also enhances the activity of II, V,
VII, VIII, XI, XIII, induces platelet aggregation, and
enhances action of plasmin.

19. Phase IV:
Conversion of fibrinogen into fibrinopeptides A & B;
fibrin insoluble monomer a "gel";
Fibrinogen (I) primary substrate for thrombin;
plasma protein-consists of three pairs of
polypeptide chains 200-400 mg/dl;
highest quantitiy of all the coagulation proteins.
Fibrin Stabilization and Cross-linking: of the soluble fibrin
monomers by factor XIII (fibrin stabilizing factor)
and XIIa by incorporation of the fibrinolysis inhibitors
alpha-2-antiplasmin and TAFI (thrombin fibrinolysis
inhibitor, aka “procarboxypeptidase B”)

20. Natural Anticoagulant pathway:
4 systems
1. Antithrombin III (AT-III) -inhibits thrombin
and Xa; when complexed with heparin sulfate
it quickly inactivates thrombin
2. Tissue-factor inhibitor (TFI) -expression of
TFI on the endothelium, and in circulation
complexes with factor IXa to form a
competitive inhibitor of factor TF/VIIa to
prevent further activation of X to Xa.

21. Natural Anticoagulant pathway:
4 systems
3. Protein C- Protein S pathway (thrombomodulin)-
thrombin binds to thrombomodulin on the
endothelial cell, creating a complex that can
bind and activate protein C; which then
complexes in the blood or on the surface of
platelets with protein S; Protein C degrades
clotting factors, Va, VIIa, to prevent clotting.
4. Endogenous Fibrinolytics: TPA & urokinase and
Plasmin

22. Plasma Proteins:
Total Protein in the blood 6-8 gm/dl.
All the plasma proteins are synthesized in liver except
gamma globulins.
60% of plasma proteins are made up of the protein
albumen (3-5 gm/dl). , which are major contributors to
osmotic pressure of plasma which assists in the transport
of lipids and steroid hormones.
Globulins make up 35% of plasma proteins and are used in
the transport of ions, hormones and lipids assisting in
immune function
4% is fibrinogen which is essential in the clotting of blood
and can be converted into insoluble fibrin. Regulatory
proteins which make up less than 1% of plasma proteins
are proteins such as enzymes, proenzymes and hormones.

23. Platelets: Adhesion and Aggregation:
• Normal platelet count 150,000-300,000;
about 2/3 of platelets are stored in the
platelet pool in the spleen.
• Platelets are derived from
megakaryocytes; no nucleus, no
organelles, live 7-10 days
• Platelets also participate in the coagulation
cascade (intrinsic-extrinsic system);
–there are receptors on the platelet for Xa.
• The endothelium has anti-thrombotic
activity:

24. Vessel damage- Platelet Effect
The inner surface of blood vessels
is lined with a simple squamous
endothelium that, in normal
hemostasis, acts to inhibit platelet
activation by producing nitric
oxide, endothelial-ADPase, PGI-2,
and t-PA, and thrombomodulin

25. Normal anti-thrombotic protection.
1. Normally Prostacyclin (PGI-2), the
endothelial cell prostaglandin causes
vasodilation and decreased platelet
adhesion by increases cAMP;
2. Normally endothelial cells express
ADPase (CD39) which converts
circulating ADP to cAMP and thus
clears away the platelet activator, ADP.

26. Normal anti-thrombotic protection
3. Normally, endothelial cell derived nitric oxide (NO)
from NOS, which causes vasodilation.
However, the surface of the platelet consists of a
trilaminar plasma membrane covered with
glycoproteins (receptors) and acid
mucopolysaacharides --adheres to exposed
subendothelial collagen.
4. t-PA - is released into the blood very slowly by the
damaged endothelium after several days (when the
bleeding has stopped), the clot is broken down.

28. Coagulation and Thrombosis
Part 1- “All About Platelets”
The Platelet Cause of:
Thrombophilia-Hypercoagulability-
Prothromobotic state
Hemophilia- bleeding tendencies

29. Thrombocytes- Release reaction
• Platelets are not only instrumental in
hemostasis, they also have a role in
inflammation, antimicrobial activity,
angiogenesis, tumor growth and
metastasis.
• Platelets are unable to perform these
functions in the absence of their
receptors.

30. Platelet Aggregation- Release reaction-
When platelet receptors are are activated (form
adhesion molecules-e.g. to clump together).
Release reaction- recognized platelet receptors are:
integrins, leucine-rich repeats receptors, selectins,
tetraspanins, transmembrane receptors,
prostaglandin receptors, lipid receptors,
immunoglobulin receptors, tyrosine kinase receptors
When the endothelial layer is injured, collagen,
or the subendothelial matrix, and vWF from
the endothelium stimulate the platelets change
shape, and degranulate;

31. Platelet Aggregation- Release Reaction
Platelets are also activated by thrombin
(formed with the help of tissue factor-III).
Can also be activated by a negatively charged
surface, such as glass. Non-physiological flow
conditions (especially high values of shear
stress) caused by arterial stenosis or artificial
devices (Mechanical Heart Valves, blood
pumps etc) can also lead to platelet
activation; interaction of the platelet with
endothelium (collagen) creates two
phospholipase enzymes A2 and C;

32. Platelet Aggregation and Release reaction
Begins w/the Arachidonic acid
pathway for the creation of
prostaglandins (i.e. platelet
produced) thromboxane A2- (TXA-2)
released from cytoplasm of platelet;
TXA-2 causes activation of Ca+
dependent GPIIb-IIIa fibrinogen
receptors on the platelet (most
abundant receptor)

33. Platelet GP receptors
Glycoprotein platelet surface receptors for:
GP1: vWF (VIIIB) , V, IX
P2Y : ADP and Ca
GPIV: collagen
GPIIb-IIIA: fibrinogen, thrombin ( via III)
ADP stimulated
thromboxane A2/prostaglandin H2 (TxA2/PGH2)
receptor: factors V
factors IX
This will produce a platelet plug in 3-5 minutes
(Bleeding time)

34. Platelet Granules and Receptors

35. Release Reaction
Platelet cytoplasm contains alpha, delta and lambda
granules;
alpha- contains: fibrinogen (I); VIIIb (vWF);
V (proaccelerin); thromboglobulin; PDGF;
platelet factor 4; fibronectin;
PAI-1 and α2-antiplasmin
delta (“dense granules”)- Ca+; ATP, ADP; serotonin;
pyrophosphate
lambda- glucuronidase; histone; phosphatase

36. ADP
the most significant promoter of platelet
aggregation
exposure of the plasma membrane to ADP facilitates
the glycoprotein receptor (GP2Y) to bind to
fibrinogen.
Phase I: ADP or epinephrine
(Ca+ dependent)
Phase II: ADP released from platelet
This is the platelet function test or assay we use to
check if platelets are function on pts using anti-
platelet Rx e.g. ASA or Plavix

37. Rx that Affect ADP Platelet aggregation
Rx that potentiate ADP induced aggregation:
a. catecholamines
b. Thrombin
c. collagen
d. prostaglandins: Thromboxane-TXA2 (platelet cell
membrane)
Rx that inhibits ADP induced aggregation:
a. prostaglandins: (Prostacyclin- PGI-2 (from endothelial cell)
enhances the production and activity of cAMP
b. adenosine (cAMP): blocks release reaction
c. dipyridamole (Persantine-a phosphodiesterase inhibitor)
d. nitroglycerine: ie endothelium derived nitric oxide

38. Platelet Disorders
A. Excessive bleeding disorders due to platelets
vonWillebrands Disease- most common
Thrombocytopenia
Immune thrombocytopenic purpura (ITP)
Disseminated Intravascular Coagulation (DIC)
Glanzmann’s thromboasthenia-defect in the platelet
activation; defect in GPIIB/IIIA receptor
B. Thrombosis and ischemia due to platelets
Essential (primary) thrombocythemia
(thrombocytosis)
Thrombotic thrombocytopenic purpura (TTP)
Heparin Induced thrombocytopenia (HIT)

39. Excessive bleeding disorders due to
platelets-vWD-Von Willebrand Disease
the most common hereditary hemorrhagic disorder
in humans;
varying degrees of bleeding tendency usually in the
form of easy bruising, epistaxis, gingival bleeds,
heavy menstruation, and blood loss during
childbirth.
Severe internal bleeding and bleeding into joints are
uncommon in all but the most severe type, vWD
type 3.
vWF gene is located on the short arm p of
chromosome 12 (12p13.2).

40. Excessive bleeding disorders due to
platelets---vWD-VIII
Dx: measuring amount of vWF in a vWF antigen assay and
the functionality of vWF with a glycoprotein (GP)Ib binding
assay Tx:
1. Desmopressin (DDAVP is a synthetic analogue of the
ADH;) stimulates the release of vWF from the Weibel-
Palade bodies of endothelial cells, thereby increasing the
levels of vWF (and factor VIII) three- to five-fold.
2. recombinant von Willebrand factor (rVWF), and von
Willebrand factor/factor VIII (vWF/FVIII) concentrates.
3. Synthetic fibrinolysin inhibitors-Aminocaproic acid (PO
or IV 5-30 gms/d)

41. Excessive bleeding disorders due to
platelets -Thrombocytopenia
• Definition: Platelet count <100,000/mm3
• <50,000/mm3—hemorrhage from minor
trauma
• <15,000/mm3—spontaneous bleeding
• <10,000/mm3—severe bleeding
Causes:
• Hypersplenism, autoimmune disease,
hypothermia, and viral or bacterial
infections that cause DIC

42. Excessive bleeding disorders due to
platelets -Thrombocytopenia
inherited or acquired;
due to decreased production;
increased destruction,
or medication induced; < 50,000 requires Tx
Decreased production- Dehydration, Vitamin B12 or
folic acid deficiency; Leukemia or myelodysplastic
syndrome or aplastic anemia; Decreased production
of thrombopoietin by the liver in liver failure;
Sepsis, systemic viral or bacterial infection;

43. Thrombocytopenia
• Increased destruction- Idiopathic thrombocytopenic
purpura; Thrombotic thrombocytopenic purpura;
Hemolytic-uremic syndrome; Disseminated
intravascular coagulation; Paroxysmal nocturnal
hemoglobinuria; Antiphospholipid syndrome
(especially SLE);
Post-transfusion purpura; Hypersplenism;
Zika virus
Rx induced Mylosuppression- Valproic acid;
Methotrexate; Carboplatin; Interferon;
Isotretinoin;
• H2 blockers and proton-pump inhibitor

44. Excessive bleeding disorders due to
platelets - Immune thrombocytopenic
purpura (ITP) (formerly idiopathic TP)
• Most common thrombocytopenia after
destruction
• IgG antibody targets platelet glycoproteins
• Antibody-coated platelets are sequestered
and removed from the circulation
• Acute form develops after viral infections
One of the most common childhood bleeding
disorders

45. ITP- bleeding disorder
S and Sx
Minor bleeding problems petechia and purpura
Major bleeds: epistaxis, hematuria, bleeding gums
Weight loss, fever headache
Dx CBC
Tx Acute form generally resolves w/o complications
Chronic form (Adults)
Prednisone -= to suppress anti-platelet antibodies
IV- immunoglobulin
Splenectomy

46. DIC- bleeding disorder
Disseminated Intravascular Coagulation (DIC)
a. Acquired disorder characterized by widespread
activation of coagulation and hemorrhage-
simultaneously occur; can be sudden, as in
endotoxic shock or amniotic fluid embolism, or it
may be insidious and chronic, as in cases of
malignancy.
b. continued activation of clotting, results in the
consumption of platelets and clotting factors leads
to severe bleeding- consumption coagulopathy
Results in multiple organ failure (MODS) and a high
mortality rate

47. DIC- bleeding disorder
• Unregulated release of thrombin with
subsequent fibrin formation and accelerated
fibrinolysis
• d. activating the fibrinolytic system (plasmin),
person’s fibrin degradation product and D-dimer
levels increase
• e. etiology- endothelial damage is primary initiator,
may be caused by sepsis, cancer, trauma, blood
transfusion, aortic aneurysm, eclampsia
• Gram negative endotoxins, viruses, fungi, protozoa
all have been implicated
• High incidence with brain trauma, pregnancy

48. DIC- bleeding disorder
• f. Clinical signs and symptoms demonstrate a
hemorrhagic disorder-wide variability
• Bleeding, Purpura, petechiae, and hematomas
• Symmetric cyanosis of the fingers and toes
• Microthrombosis to end organs
• g. Dx- rapidly declining platelet counts < 100,000;
PTT, PT, D-dimer; fibrinogen levels
• h. Tx- Replacement therapy: platelets, FPP,
cryoprecipitate ("Cryoprecipitated Antihemophilic
Factor or CAF"; "cryo" is prepared by collecting the
precipitate from FFP contains: I, VIII, vWF, XIII)

49. DIC
Picture: Micrograph showing an acute thrombotic microangiopathy, the
histologic correlate of DIC, in a kidney biopsy PAS stain.

50. Platelet Disorders
A. Excessive bleeding disorders due to platelets
vWD
Thrombocytopenia
Immune thrombocytopenic purpura (ITP)
Disseminated Intravascular Coagulation (DIC)
Glanzmann’s thromboasthenia-defect in the platelet
activation; defect in GPIIB/IIIA receptor
B. Thrombosis and ischemia due to platelets
Essential (primary) thrombocythemia
(thrombocytosis)
Thrombotic thrombocytopenic purpura (TTP)
Heparin Induced thrombocytopenia (HIT)

51. Thrombosis and ischemia due to
platelets-Thrombocytosis
4. Essential (primary) thrombocythemia
(thrombocytosis)
Thrombocythemia is characterized by platelet
counts >600,000/mm3
Myeloproliferative disorder of platelet precursor
cells
Megakaryocytes in the bone marrow are
produced in excess
Microvasculature thrombosis occurs

52. TTP- a thrombotic thrombocytopenia
with HA and purpura
Acute, potentially fatal
Rare 1:100,00
Thrombocytopenia
purpura
end organ ischemia
skin, kidney, lungs,
heart GI tract, fever
HA

53. Thrombotic thrombocytopenic
purpura (TTP)-Thrombotic disorder
due to a deficiency of ADAMTS13 aka von
Willebrand factor-cleaving protease (VWFCP);
vWF multimers accumulate on endothelial cells
where they cause increased platelet adhesion to
areas of endothelial injury, particularly at
arteriole-capillary junctions;
about half of cases a trigger is identified, include
bacterial infections, certain medications,
autoimmune diseases such as lupus, and
pregnancy.

54. TTP- decreased platelets and HA
• Inherited- rare (aka “Familial TTP” ;
Upshaw-Schulman Syndrome)
• Acquired- (aka “Microangiopathic hemolytic
anemia”) – involves an autoantibody against
ADAMTS13 (VWFCP)
• Platelet-VWF thrombi cause microangiopathy →
Organ ischemia: brain, kidney, myocardium, GI
tract and skin.
• Symptoms- anemia, purpura and bleeding,
weakness, confusion, abdominal pain, nausea and
vomiting,

55. Thrombotic Thrombocytopenia
Purpura (TTP)
• Diagnosis- clinical symptoms
• Thrombocytopenia < 20,000 platelets,
anemia; elevated LDH
• Tx- plasma exchange; corticosteroids;
rituximab;
caplacizumab (an anti-vWF antibody)

56. Heparin-induced thrombocytopenia (HIT)-
the development of thrombocytopenia, due to the
administration of various forms of heparin,
predisposes to thrombosis, typically the platelet
count will fall 5–14 days after heparin is first given;
b. etiology: antibodies (IgG) form against heparin
when it is bound to platelet factor 4 (PF4);
antibody then binds to the FcγIIa platelet receptor,
resulting in platelet activation and the formation of
platelet microparticles, which initiate the formation
of blood clots; usually takes about five days.

57. HIT
• complications:
• appears similar to “warfarin necrosis,” the
development of skin gangrene in those
receiving warfarin or a similar vitamin K
inhibitor.

58. Heparin-Induced Thrombocytopenia
(HIT)-Thrombotic disorder

59. Heparin Induced thrombocytopenia
(HIT)-Thrombotic disorder
Dx: 1. CBC, every other day while on heparin
2. routine Doppler sonography of the leg
veins to identify deep vein thromboses, or
expansion of the previous thrombus.
3. detecting antibodies against heparin-PF4
complexes(ELISA)
4. serotonin release assay (SRA) shows high
serotonin release, confirms diagnosis of
HIT

60. HIT-Treatment
Argatroban- a intravenous direct thrombin inhibitor
prophylaxis or treatment of thrombosis in
patients with heparin-induced thrombocytopenia
(HIT)
Lepirudin-an anticoagulant that functions as a direct
thrombin inhibitor.
Fondaparinux, Factor Xa inhibitor

61. Coagulation and Thrombosis
Part 2- Plasma Protein caused:
Thrombophilia-Hypercoagulability-
Prothromobotic state
Hemophilia- bleeding tendencies

62. Disorders of Coagulation- Thrombophilia
Hypercoagulability or a
“Prothrombotic state” is an
abnormality of blood coagulation that
increases the risk of thrombosis (blood
clots in blood vessels).
50% of people who have VTE, not
provoked by other causes
The most common conditions
associated with thrombophilia are DVT
& PE;

63. Thrombophilia-Hypercoagulability
• DVT usually occurs in the legs,
and is characterized by pain,
edema, erythemaof the limb.
• It may lead to Post-phlebitic
syndrome: chronic edema, leg
fatigue, myalgia, and heaviness
due to damage to valves in the
veins

64. Hypercoagulable- causes:
A. Over-activity of coagulation factors:
factor V Leiden -
5% most common
cause mutation
prothrombin G20210A, a mutation
hyperfibrinogenemia

65. Hypercoagulability- deficiency of.....
antithrombin III
protein C
protein S
plasminogen.

66. Hypercoagulability- more causes:
Pregnancy
Estrogen- when used in the combined BCP or HRT- ↑
thrombotic tendency by 3-4 x;
increased the plasma concentration of clotting
factors: I, II, VII, VIII, X, XII
Obesity- - Increased levels of PAI-1 an inhibitor of
fibrinolysis
Platelet aggregation is increased, and
Increased levels of I , VII, VIII
Surgery

67. Thrombophilia- more causes:
• Anti-phospholipid antibody
• HIT
• TTP

68. Thrombophilia- more causes:
Paroxysmal nocturnal hemoglobinuria (PNH thrombosis
associated with hemolytic anemia.
Sickle-cell disease ia mild prothrombotic state induced
by impaired flow;
Myeloproliferative disorders, in which the bone marrow
produces too many blood cells, particularly in
polycythemia vera
Essential thrombocytosis
Cancer
Nephrotic syndrome
Inflammatory bowel disease (ulcerative colitis and
Crohn's disease)

69. #1 Thrombophilia-Hypercoagulability
• Factor V Leiden- the most common
hypercoagulability due to an overexpression
of a mutant form of V.
With this mutation, protein C, cannot bind to FV
and inhibit its action causing an overactive FV
and a hypercoagulable state.

70. #2 Cause of Hypercoagulability:
Prothrombin Mutation (G20210A)- specific gene
mutation in which a guanine (G) substitutes for
adenine (A) at position 20210 of the DNA of the
prothrombin gene F2 (chromosome 11);
Increases the risk of DVT/PE; One copy of the mutation
increases the risk of a blood clot from 1 in 1,000 per
year to 2.5 in 1,000.
Two copies increases the risk to up to 20 in 1,000 per
year;
Does not need routine anticoagulation;
BCP not recommended

71. Antiphospholipid syndrome (APS), affects all vessels,
especially smaller arterioles; affects females> males;
greater in Blacks, Asians, Amer Indians Hispanics;
• an autoimmune, hypercoagulable state caused by
antiphospholipid antibodies : lupus anticoagulant
(SLE), anti-cardiolipin antibodies, and anti-β2-
glycoprotein 1 antibodies
• Anti-cardiolipin antibodies bind to ApoH, which in turn
inhibits Protein C, and thus decreases inactivation of
FV.
• Lupus anticoagulant (LAC) antibodies bind to
prothrombin, thus increasing its cleavage to thrombin,
its active form.
• Also antibodies binding to Protein S, which is a co-
factor of protein C. Thus, anti-protein S antibodies
decrease protein C efficiency.

72. Diagnosis of the hypercoagulable
CBC, PT, PTT, thrombin time,
retiplase time, lupus anticoagulant,
anti-cardiolipin antibody,
anti-β2 glycoprotein 1 antibody,
activated protein C resistance,
fibrinogen tests, factor V Leiden and
prothrombin mutation, and basal
homocysteine levels.

73. Coagulopathy or hypocoagulability
Hemophilia – a group of hereditary genetic disorders
characterized by impaired coagulation:
Hemophilia A a recessive X-linked genetic- lack of
functional clotting Factor VIII and represents 80% of
haemophilia cases- 1 in 5,000–10,000 male births
Hemophilia B is a recessive X-linked genetic lack of
functional clotting Factor IX. It comprises approximately
20% of haemophilia cases- 1 in about 20,000–34,000 male
births,
Hemophilia C is an autosomal genetic disorder (i.e. not X-
linked) involving a lack of functional clotting Factor XI.

74. Bleeding tendency:
Coagulation Factor deficiency: (usually congenital)
afibrinogenemia , Factor V, VII, Factor XII, Factor X
Glanzmann's thrombasthenia
Bernard-Soulier syndrome - a deficiency of
glycoprotein Ib (GPIb), the receptor for von
Willebrand factor

75. Bleeding Tendency: possible causes:
Vitamin K deficiency or warfarin
ITP; DIC;
Von Willebrand disease- Aspirin
Thrombocytopenia
Liver failure
Uremia

76. Coagulation Studies:
1. Platelet Count: 130,000-400,000/microliter
2. Bleeding time- finger stick ("duke") 1-4 min. (for defective
platelet function)
3. PFA-100 is a platelet function analyser that aspirates blood in
vitro from a blood specimen into disposable test cartridges
through a microscopic aperture cut into a biologically active
coated with collagen and adenosine diphosphate (ADP) or
collagen and epinephrine inducing a platelet plug to form which
closes the aperture.
Col/Epi closure time (normal is <180 seconds)
Col/ADP result is normal (<120 seconds)
IF elevated, platelet dysfunction is most likely.

77. Coagulation studies
Lee-White Clotting Time (whole blood coagulation time)
crude test; variable results 6-10 minutes aspirin-induced
Prothrombin Time (PT/INR) "; (control +/- 1 sec.) normal 12-17 secs.; test to test extrinsic
pathway and Coumadin therapy (International Normalized Ratio, INR)
INR in absence of anticoagulation therapy is 0.8-1.2.
INR for 'low intensity' is between 2.5 and 3.5 and for 'high intensity'
between 3.0 and 4.0.
Partial Thromboplastin time (aPTT) "PITT"; normal = 25-35 seconds; test for Intrinsic
pathway and for heparin therapy (should be 1.5-2.5 of normal)
Tourniquet Test: for capillary fragility (e.g.Vit.C deficiency or Ehlers-Danlos Synd) draw
circle/antecubital area/venous tourniquet 70-90 mm hg./time and number of
petechii;40 mm. for (2-3 mins.)
Fibrinogen: 200-400 mg/dl.
Factor assays (II, V, VII, IX, X, XI, XII) 60-100%

78. Anticoagulants
1. Indications- venous thrombosis, DVT, PE, atrial
fibrillation with embolism, MI, surgical prophylaxis
2. Contraindications for use of Anticoagulants-
allergy to the agents; active bleeding disorders;
blood dyscrasias; CNS surgery; eye surgery; GI
ulceration; severe hypertension; pregnancy, L & D;
previous cerebral hemorrhage;
coumarin type - are secreted in breast milk; use
with caution in pts. with liver/pancreatic disease

79. Heparin
mast cells; basophils, endothelium; a naturally occurring (neg.
charged) mucopolysaacharide espec.
High conc. in liver and lungs.
1. method of action: interferes with the formation of fibrin by:
a. slows conversion of prothrombin to thrombin
b. complexes w/potentiates with ATIII to prevent Xa
c. decreases platelet adhesiveness
d. prevents activation of PTC(IX) and AHG (VIII)-
2. complications: heparin induced thrombocytopenia
3. heparin antagonist: protamine sulfate does 1 mg./100 units
of heparin (dose at 50 mg. max.)
4. half-life only 1.5 hrs., therefore, anticoagulant effect
disappears in 2-3 hours; Rx q 4 h

80. heparin
Dosage: do not give IM (causes hematoma); must use IV
or subq. (only parenteral)
a. initial heparin bolus 80 U/kg. (2500-5000 U.)
b. then, continuous IV drip: 25,000 units diluted l liter of
N. saline. and order 100 U.
per hour. The dose should range from 25,000-40,000
U./24 hrs. ideal PTT is 55-85 secs.
c. Or may give repeated sq injections of 5000 units/4-6 h.
d. order PT and CBC q d; no ASA or anti-platelet Rx;
e. no IM injections; get baseline PT/PTT

81. LMWH
LMWH preparations- obtained by the depolymerization of
unfractionated porcine heparin
enoxaparin sodium (Lovenox)
dalteparin (Fragmin) 5000 U. sq q d
tinzaparin (Innohep) no longer available in US
indications- prophylaxis for prevention of DVT and PE after
hip, knee, abdominal surgery; unstable in angina, NQWMI;
acute STEMI, restricted mobility and Tx of DVT/PE
contra- same as regular heparin; pregnancy cat B
action- binds to and accelerates AT III, inhibits thrombin and
factor Xa and Iia
SQ injections only; slow onset; begin 12 hrs post-op and
continue 7-10 d

82. LMWH
Monitoring- Anti-factor Xa levels can be measured,
and are generally used to monitor enoxaparin activity
in certain subgroups of patients.
Anti-factor Xa levels may be recommended in
underweight, obese, , pregnant, or renal impaired
Anti-Xa levels should be checked at their peak at 4
hours after dosing (both q12 and q24 variations).
Reversal- is less effective at reversing enoxaparin
compared to heparin, with a maximum neutralization
of approximately 60% of the anti-factor Xa effect.

83. Fractionated Heparin
enoxaparin (Lovenox)
DVT prophy: 30 mg SQ q 12 h x 7-10 d;
start 12-24 h post-op
DVT prophy-restricted mobility: 40 mg SQ x 6-11 d
Tx DVT/PE: 1 mg/kg SC q 12 h x 5 d and overlap
with warfarin until INR 2-3
dalteparin (Fragmin) 5000 U. sq q d
tinzaparin (Innohep) 175 anti-Xa IU/kg SQ qd for at least
6 days and until anticoagulated with warfarin (INR ≥2 for
2 consecutive days). Begin warfarin within 1-3 days of
therapy.

84. Oral Anticoagulants
1. Vitamin K antagonists-
coumarin (Warfarin), Indandione
2. Factor Xa Inhibitors
rivaroxaban (Xarelto) –
apixaban (Eliquis)
3. Direct Thorombin Inhibitors
dabigatran etexilate (Pradaxa)

85. Coumadin (warfarin)
or Panwarfin (bishydroxycoumarin) Dicumarol
1. method of action: inhibits the production of the Vitamin
K dependent factors: II (prothrombin), VII, IX, X; prot C and S
2. requires 3 days for the anticoagulant effect to begin
3. half-life is 36 hours; it can take 1-8 days for the P.T. to
return to `normal
4. O/D: epistaxis; hematuria; purpura
5. antidote: minor bleed: Vitamin K 2.5-10 mg. IM/subq;
major bleed: 25-50 mg Vit K
IV(Aquamephyton)
or fresh frozen plasma
6. dosage: 35-50 mg. initially then 2.5-10 mg./day p.o.
(single daily dose)

86. Coumadin (warfarin)
4. Pharmacokinetics- rapidly and completely absorbed- 97% bound to albumen eg. NSAIDS
slow onset: 36-72 hours (max anticoag effect in 3-5 days)
long duration: 4-5 days (plasma half-life 36 hrs.)
O/D: bleeding: ecchymosis, hematuria, epistasis, hematochezia, hematoma
5. Rx interactions: e.g. and plasma binding with concomitant use of NSAIDS
Rx which increase coumadin effect: erythromycin; oral conazoles; dilantin;
antibiotics
Rx which decrease coumadin effect: griseofulvin; barbiturates; BCP/estrogens;
thiazides
6. Dx tests- PT and INR (international normalized ratio)
PT= 10-12 secs should be in the range of 20-24 secs
INR= 0.9-1.4 should be in the range of 2-3
(note: PT will be increase due to the following: alcoholism, gingival bleed, hemoptysis,
hematomesis, hepatic insufficiency eg. jaundice/hepatitis; Vit K deficiency; poor
nutrition; steatorrhea; diarrhea; CHF; hyperthyroid; NSAIDS; alcohol; allopurinol;
antibiotics; diuretics; methyldopa; metronidazole; pentoxifyllline, sulfinpyrazone.

87. Oral Factor Xa Inhibitors
Oral factor Xa Inhibitors
rivaroxaban (Xarelto)
apixaban (Eliquis)
1. action: an oral direct factor Xa inhibitor,
2. indications: prevention of deep vein thrombosis (DVT/PE prophylaxis)
in patients undergoing knee/ hip replacement surgery; CVA prophylaxis;
Tx of DVT/PE
3. BB warning: ↑ risk of thrombosis upon discontinuing if before
completion of Tx course;
↑ risk of bleeding- epidural, spinal, hematoma risk- , which tended to
be more common with rivaroxaban than with enoxaparin. Unlike
warfarin, which can be reversed by vitamin K, and enoxaparin, which is
partly reversible by protamine, there is no specific antidote for
rivaroxaban-induced bleeding, and due to the high percentage of drug
bound to protein in plasma;
category C (risk cannot be ruled out) for use during pregnancy.

88. Rivaroxaban- Dose:
Renal dosing: CrCl <30: avoid use;
is a CYP3A4 and P-gp substrate
Pre-op: D/C use 24 hours before surgery.
DVT/PE prophylaxis: 10 mg po q d x 12-35 days
DVT/PE Tx: 20 mg q d x 21 d

89. Oral Direct Thrombin Inhibitors:
dabigatran Etexilate (Pradaxa)
a. action: a reversible direct thrombin inhibitor;
inhibits both clot-bound and circulating thrombin; decreases
thrombin-stimulated platelet aggregation; The anticoagulant
effect is much less variable than that of warfarin and monitoring
is not required. Unlike warfarin, dabigatran has no effective
antidote that could be used in case of bleeding or emergency
surgery, but it is dialyzable.
b. indications: prevention of deep vein thrombosis
(DVT/PE prophylaxis) in patients with non-valvular atrial
fibrillation or recurrent DVT/PE prophylaxis; ; CVA prophylaxis;
Tx of DVT/PE
c. BB warning: ↑ risk of thrombosis upon discontinuing
if before completion of Tx course; ↑ risk of bleeding- epidural,
spinal, hematoma risk-; Pregnancy Cat C

90. Injectable Direct Thrombin Inhibitors
lepirudin
bivalrudin (Angiomax)
desirudin (Ipravask) given SC
argatroban
action: IV reversible direct thrombin inhibitors (free and clot bound thrombin
derived from the saliva of medicinal leeches, Hirudo medicinalis)
no risk for Heparin Induced Thrombocytopenia/Heparin Induced Thrombosis-
Thrombocytopenia Syndrome (HIT/HITTS).
indic: Adjunct to aspirin for anticoagulation in patients with unstable angina
undergoing percutaneous transluminal coronary angioplasty (PTCA) or
percutaneous coronary intervention (PCI).
Patients with, or at risk of, HIT/HITTS undergoing PCI;

91. Antiplatelet Therapy
TXA2 inhibitors
ASA
Phosphodiesterase inhibitors
dipyridamole, cilostazol
P2Y12 ADP receptor antgonists
clopidogrel, ticlopidine, ticagrelor (Brilinta),
prasugrel (Effient)
Protease (thrombin) active receptor blockers (PAR-1)
vorapaxar (Zontivity)
GP IIb/IIa receptor blockers
Abciximab, eptifibatide, tirofiban

92. Anti-platelet
• A. indications: acute coronary syndrome
(ACS); thrombotic event prevention especially
in pts with recent MI, CVA, PAD;
• B. contraindications: active bleeding, caution
if trauma, elective surgery within 5 days; GI
disorder

93. ASA
Aspirin (ASA) ie. low dose ie. less than 100 mg/day-
selectively inhibits platelet cyclooxygenase,
thereby decreasing the relative amounts of TXA-2
(thromboxane)
net effect: decreased platelet aggregation and
increased vasodilation;
increases BT; takes 7-10 days for the platelet effect
to return to normal; ($1.50 one month)

94. Phosphodiesterase inhibitors
dipyridamole, cilostazol
dipyridamole (Persantine) - ↓ the breakdown of cAMP within platelets →
increased cyclic AMP within the platelets which inhibits aggregation;
coronary vasodilator
inhibit thromboxane A2 synthesis; believed to prolong the life of platelets-
normally shorted and thrombosis occurs when exposed to artificial heart
valves
indications- adjunctive to coumarin anticoagulants in the prevention of
thromboembolic events; usual dose- 75 mg po qid
Aggrenox ASA 25 mg; with dipyridamole ER 200 mg po bid ($88.50)
cilostazol (Pletal)- an inhibitor of PDE III therefore suppresses cAMP
degradation and increases levels of cAMP in platelets, smooth muscle →
vasodialation and
↓ platelet aggregation;
indications: intermittent claudication 100 mg bid
contra: CHF; causes and increased HR;
Adv. React: freq headaches

95. P2Y12 ADP receptor antgonists
clopidogrel, ticlopidine (Ticlid), ticagrelor
(Brilinta), prasugrel (Effient)
clopidogrel (Plavix) 75 mg. po q d
action: irreversibly binds and inhibits platelet glycoprotein IIb/IIIa ADP
activated fibrinogenreceptor and is important in platelet aggregation and the
cross-linking of platelets by fibrin;
Platelet inhibition in two hours after a single dose of oral dose
onset of action is slow, so that a loading-dose of 300–600 mg
slightly more effective than ASA
BB Warning: decreased efficacy in poor metabolizers- clopidogrel is a
prodrug → Must be metabol via CYP 2C19 in order to work; some pts
fail to activate
ASA and clopidogrel resistance- the reported incidence of resistance to these
Rx varies from 5%-75%; this is very controversial

96. Protease (thrombin) active receptor blockers (PAR-1)
vorapaxar (Zontivity)
a. action- antagonizes protease-activated
receptor-1 (PAR-1) → ↓ platelet aggregation
induced by thrombin and thrombin receptor
agonist peptide (TRAP)
b. indic: thrombotic event (VTE/DVT/ PE/ CVA/
MI) prophylaxis
c. 2.08 mg po qd for pts with MI Hx or PAD
given with ASA or clopidogrel.

97. Glycoprotein IIb/IIIa platelet receptor inhibitors
Abciximab
Eptifibatide
Tirofiban
a. action: bind to platelet glycoprotein IIb/IIIa
receptors → in ↓ platelet aggregation
b. indications: IV Rx for acute MI;
as a PCI adjunct; ACS-unstable angina; NSTEMI
or undergoing angioplasty with stent placement
and/or atherectomy.

98. Coagulation and Thrombosis
• This is the end of this lecture