This document discusses coagulation disorders and provides information on hemophilia A, hemophilia B, and disseminated intravascular coagulation (DIC). It notes that hemophilia A is an X-linked bleeding disorder caused by a deficiency in coagulation factor VIII, while hemophilia B is caused by a deficiency in factor IX. Von Willebrand disease is described as the most common inherited bleeding disorder involving a quantitative or qualitative abnormality of von Willebrand factor. DIC is defined as an acquired syndrome characterized by systemic intravascular coagulation that can lead to thrombosis and bleeding complications.

1. Coagulation disorders
Dr Vijay Shankar S

2. Learning objectives
 Introduction to coagulation disorders
 Hemophilia A
 Hemophilia B
 Disseminated Intravascular Coagulation

3. Hemostatic Process
3 main steps
 Primary hemostasis: local vasoconstriction & platelet
plug formation
 Coagulation cascade
 Fibrinolysis

4. Hemostatic Process
Platelet Plug Formation
• vascular injury
• release and binding of vWF to exposed blood
vessel collagen
• glycoprotein IB on platelet surface membrane
binds to vWF
• TxA2 → vasoconstriction & platelet adhesion
• platelet factor 3 (PF3) phospholipid layer
(procoagulant)

5. Platelet Activation & Aggregation
exposed endothelial surface
platelets exposed to collagen
“activated”
release contents of cytoplasmic granules
adenosine diphosphate (ADP) thromboxane (Tx A2)
accelerates platelet vasoconstriction
aggregation/activation ↑ ADP release from platelets

6. Hemostatic Process
Coagulation Cascade
 to stabilize and reinforce the weak platelet plug
 fibrinogen → fibrin
 3 main steps:
1. formation of prothrombin activator
2. conversion of prothrombin into thrombin
3. conversion of fibrinogen to fibrin

7. Figuring It Out
 Different factors in two pathways …I-XIII (which
number is missing?)
 Separate but interacting pathways (which is faster,
which is quantitatively more important?)
 anything that interferes blocks final outcome
 Calcium (Factor IV) required for most steps (note
which)
 Several factors are made in liver (II, VII, IX, X)

8. Coagulation Factors
 I – Fibrinogen
 II – Prothrombin
 III- Thromboplastin
 IV- Ca++
 V Proaccelerin/ labile factor
 VII – Proconvertin/ Stable factor.
 VIII - AHF
 IX – AHF B/Christmas factor
 X – Stuart- Prower factor
 XI – Plasma thromboplastin antecedant
 XII – hageman factor/Glass factor
 XIII- Fibrin stabilizing factor/ laki lorand factor.
 HMWK – Fitzgerald factor.

9. Clot Formation (Coagulation)
Intrinsic Pathway Extrinsic Pathway
Final Common Pathway
Prothrombin Activator Substance (PAS)
Prothrombin Thrombin
Fibrinogen Fibrin monoomers
Polymers, threads

10. Final Common Pathway
Prothrombin Activator Substance (PAS)
Prothrombin
Thrombin
Fibrinogen
Fibrin monoomers
Polymers, threads
Fibrin
Stabilizing
Factor

11. Coagulation Cascade
TF =tissue factor
PK = prekallikrein
HK=high molecular
kininogen
a = activated

12. Coagulation Mechanism
 activation of clotting factors
 requires a phospholipid surface
 tissue factor (TF) extrinsic to the blood
 activated platelet (platelet factor 3 phospholipid)
intrinsic to blood
 vitamin-K dependent factors (II, VII, IX, X)
 formation of reaction complex
 labile factors : factors V and VIII

13. Factor VIII
 extrahepatic origin
 2 components (separate genetic control)
1. VIII R : Ag VIII antigen + vWF
2. VIII : C coagulant activity
*absence → hemophilia A
 von Willebrand factor (vWF)
• mediates adhesion of platelets to surface collagen
• carrier of VIII:C
• vWD: appears to have defect in primary hemostasis &
hemophilia A

14. Coagulation Disorders

15. Common presentation
 Commonly manifests in the form of large
ecchymosis and hematomas – delayed bleeding
 Bleeding from the nose, gums, GIT, GUT
 Joint bleeds, muscle bleeds
 Excessive bleeding
 post vaccination
Post dental extraction
Post surgical
trauma

16. Investigations of Coagulation
disorders.
Screening tests
1. APTT
2. PT
3. TT
Special tests
Coagulation factor assays

17. Laboratory Monitoring
Activated Partial Prothrombin Time (aPTT)
 test for intrinsic and common pathways
 dependent on activity of all coagulation factors, except VII
and XIII
 normal values: 30 -40 seconds
 monitors heparin tx & screen for hemophilia

18. Laboratory Monitoring
Prothrombin Time (PT)
 test of extrinsic pathway activity and common
pathway.
 measures vitamin K - dependent factors activity
(factors II, VII, IX, X)
 thromboplastin + Ca+2 to plasma = clotting time
 normal values: 10-14 seconds

19. LABORATORY
TEST
COMPONENTS
MEASURED
NORMAL
VALUES
Bleeding time platelet function
vascular integrity
3 - 10 mins
PT
I, II, V, VII, IX, X
10 - 14 secs
PTT
I, II, V, VIII, IX, X, XI, XII
30 - 40 secs
Thrombin time I, II
12 - 20 secs

20. Disorders of Coagulation
Hereditary
Either quantitative or
qualitative defect in
single coagulation factor
Acquired
Deficiencies of
Multiple coagulation factors
1. Haemophilia A
2. Haemophilia B
3. VWD
1. Vit K Def
2. Liver Disorders
3. Fibrinolytic defects
4. DIC

21. Hereditary Factor Deficiencies
Hemophilia A
 x-linked recessive disorder that is due to
defective and / or deficient factor VIII
molecules
 Incidence – 1 in 10,000 live births.
The gene for hemophilia is carried on the X
chromosome and the gene is recessive -- X
linked recessive disorder.

22. History's most famous carrier of the gene for hemophilia
was Victoria (1819-1901), Queen of England
and grandmother to most of the royalty in Europe
Also known as
“The Royal Disease”

23. Czar Nicholas II of Russia and his family, photographed c. 1916, showing
his wife Alexandra (who was a carrier of hemophilia),
his four daughters, and (in the foreground) his son Alexis,
perhaps the most famous European royal with hemophilia.

24. Inheritance pattern in hemophilia

26. Hemophilia A
 Severity linked to level of VIII:C activity
 1% Severe
 1%-5% Moderate
 6-30% mild ( little risk of spontaneous bleeding)

27. Hemophilia A
 Bleeding can occur anywhere
 Deep muscles
 Joints
 Urinary Tract
 Intracranial
 Recurrent Hemarthrosis and progressive join
destruction are major cause of morbidity
 Intracranial bleed is major cause of death in all
hemophiliacs

32. Hemophilia Progression

33. Hemophilia A
 Mucosal bleeding is rare unless associated with
von Willebrands or Platelet inhibition
 Unlike platelet defects Trauma initiates bleeding
 Bleeding can occur usually by 8 hours but as late
as 1 to 3 days after trauma

34. Hemophilia A
 Management:
 General measures – avoidance of aspirin
 Home therapy is increasingly common and most report to
ER only with complicated problems or Trauma
 Hospitals should have files of known hemophiliacs in the
area
 Accepted therapy is with Factor VIII replacement or VIII:C
 Newer preparation carry lower risk for Hep B and Hep C
transmission

35. Hemophilia B (Christmas Disease)
 Clinically indistinguishable from hemophilia A
 Deficiency of factor IX
 Incidence – 1 in 25,000 to 30,000 live births
 Specific assays are the only way to distinguish
hemophilia A & B
 Factor IX preparation used in treatment
 Gene manipulation in animals shows promising
results for the future

36. Hereditary Platelet Disorder
von Willebrand Disease (vWD)
 most common congenital bleeding disorder
 quantitative or qualitative abn. of vWF
 VWF plays role in both formation of platelet plug
as well as fibrin clot
By mediating adhesion
of platelets to the
injured endothelium
By functioning as a
Protective carrier of
Factor VIII

37. Clinical features
 Bleeding symptoms resemble those of platelet
function defect, since platelet adhesion is
impaired.
 MC symptoms are easy bruising, epistaxis ,
menorrhagia etc…
 Hemarthrosis occurs only in severely affected
patients, unlike hemophilia who often have joint
bleeds.

38.  Type 1: most common form
 partial quantitative deficiency of vWF
 autosomal dominant
 mucocutaneous bleeding
 hematology consult prior to surgery
 prolonged bleeding time, normal platelet
TYPES

39. Type 2: qualitative alterations in the vWF structure
& function
Type 3: least common and most severe
 Complete absence of vWF in plasma or storage organelle
 Autosomal recessive
 acquired vWD
 Lymphoproliferative disease ▪ cardiac/valvular disease
 Tumors ▪ medications (valproic acid)
 Autoimmune disease ▪ hypothyroidism

40. Lab Findings
 Increased bleeding time with normal platelet
count
 Decreased VWF concentration in plasma
 Decreased factor VIII activity.

41. Treatment
 VWF replacement therapy
“ To summarise, patients with VWD have a
compound defect involving platelet function
and the coagulation pathway.”

42. Disseminated
Intravascular
Coagulation

43. Hemostatic Balance
ATIIIClotting Factors
Tissue factor*
PAI-1
Antiplasmi
n TFPI
Prot. C
Prot. S
Procoagulant Anticoagulant
Fibrinolytic
System

44. DISSEMINATED INTRAVASCULAR
COAGULATION
 Defibrination syndrome/consumptive
coagulopathy
“ an acute, subacute/chronic
THROMBOHEMORRHAGIC disorder
occuring as a secondary complication of some
diseases or conditions.”
“NOT A PRIMARY DISEASE” !!

45. DIC
 An acquired syndrome
characterized by
systemic intravascular
coagulation
 Coagulation is always the
initial event
SYSTEMIC
ACTIVATION OF
COAGULATION
Intravascula
r deposition
of fibrin
Depletion of
platelets and
coagulation
factors
Thrombosis of
small and
midsize vessels
Bleeding
Organ failure DEATH

46. Pathophysiology of DIC
 Activation of Blood Coagulation
 Suppression of Physiologic Anticoagulant
Pathways
 Impaired Fibrinolysis
 Cytokines

47. Diagnosis of DIC
 Presence of disease associated with DIC
 Appropriate clinical setting
 Clinical evidence of thrombosis, hemorrhage or
both.
 Laboratory studies
 no single test is accurate
 serial test are more helpful than single test

48. Conditions Associated With DIC
 Infectious/Septicemia
 Bacterial
 Gm - / Gm +
 Viral
 CMV
 Varicella
 Hepatitis
 Fungal
 Intravascular hemolysis
 Acute Liver Disease
 Tissue Injury
 trauma
 extensive surgery
 tissue necrosis
 head trauma
 Obstetric
 Amniotic fluid emboli
 Placental abruption
 Eclampsia
 Missed abortion

49. Conditions Associated With DIC
 Malignancy
 Leukemia
 Metastatic disease
 Cardiovascular
 Post cardiac arrest
 Acute MI
 Prosthetic devices
 Hypothermia/Hypertherm
ia
 Pulmonary
 ARDS/RDS
 Pulmonary embolism
 Severe acidosis
 Severe anoxia
 Collagen vascular
disease
 Anaphylaxis

50. Clinical Manifestations of DIC
ORGAN ISCHEMIC HEMOR.
Skin Pur. Fulminans
Gangrene
Acral cyanosis
Petechiae
Echymosis
Oozing
CNS Delirium/Coma
Infarcts
Intracranial
bleeding
Renal Oliguria/Azotemia
Cortical Necrosis
Hematuria
Cardiovascular Myocardial Dysfxn
Pulmonary Dyspnea/Hypoxia
Infarct
Hemorrhagic
lung
GI
Endocrine
Ulcers, Infarcts
Adrenal infarcts
Massive
hemorrhage.
Ischemic Findings
are earliest!
Bleeding is the most
obvious
clinical finding

51. Clinical Manifestations of DIC

52. Microscopic findings in DIC
 Fragments
 Schistocytes
 Paucity of platelets

53. Laboratory Tests Used in DIC
 D-dimer*
 Antithrombin III*
 F. 1+2*
 Fibrinopeptide A*
 Platelet factor 4*
 Fibrin Degradation
Prod
 Platelet count
 Protamine test
 Thrombin time
 Fibrinogen
 Prothrombin time
 Activated PTT
 Protamine test
 Reptilase time
 Coagulation factor levels
*Most reliable test

54. Laboratory diagnosis
 Thrombocytopenia
 plat count <100,000 or rapidly declining
 Prolonged clotting times (PT, APTT)
 Presence of Fibrin degradation products or
positive D-dimer
 Low levels of coagulation inhibitors
 AT III, protein C
 Low levels of coagulation factors
 Factors V,VIII,X,XIII
 Fibrinogen levels not useful diagnostically

55. Treatment of DIC
 Stop the triggering process .
 The only proven treatment!
 Supportive therapy
 No specific treatments
 Plasma and platelet substitution therapy
 Anticoagulants
 Physiologic coagulation inhibitors

56. Summary
 DIC is a syndrome characterized systemic intravascular
coagulation.
 Coagulation is the initial event and the extent of intravascular
thrombosis has the greatest impact on morbidity and mortality.
 Important link between inflammation and coagulation.
 Morbidity and mortality remain high.
 The only proven treatment is reversal or control of the
underlying cause.