1. BLEEDING & CLOTTING DISORDERS
Dr. M. A Sofi
MD; FRCP (London); FRCPEdin; FRCCSEdin

2. BLEEDING DISORDERS

3. HEMOSTASIS 1. VASCULAR PHASE PLATELET PHASE COAGULATION PHASE
FIBRINOLYTIC PHASE

4. Stable Hemostatic Plug
Lab Tests
CBC-Plt
BT,(CT) PT
PTT
Hemostasis
BV Injury
Platelet
Aggregation
Activation
Blood Vessel
Constriction
Coagulation
Cascade
Stable Hemostatic Plug
Fibrin formation
Reduced
Blood flow
Tissue Factor
Primary hemostatic plug
Neural
Plt Study
Morphology
Function
Antibody

5. NORMAL CLOTTING Response to vessel injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor binds damaged vessel and platelets)
3. Activation of clotting cascade with generation of fibrin clot formation
4. Fibrinolysis (clot breakdown)

6. WHEN A BLOOD VESSEL IS DAMAGED, VASOCONSTRICTION RESULTS.
VASCULAR PHASE
WHEN A BLOOD VESSEL IS DAMAGED, VASOCONSTRICTION RESULTS.

7. PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG.
PLATELET PHASE
PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG.

8. COAGULATION PHASE
THROUGH TWO SEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE.

9. THE CLOTTING MECHANISM
INTRINSIC
EXTRINSIC
Collagen
Tissue Thromboplastin
XII XI
VII IX
VIII X V
FIBRINOGEN
(I)
PROTHROMBIN THROMBIN
(II)
(III)
FIBRIN

10. FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE ACTIVATED TO ALLOW CLOT DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL.

11. HEMOSTASIS DEPENDENT UPON: Adequate Numbers of Platelets
Vessel Wall Integrity
Adequate Numbers of Platelets
Proper Functioning Platelets
Adequate Levels of Clotting Factors
Proper Function of Fibrinolytic Pathway

12. LABORATORY EVALUATION
PLATELET COUNT
BLEEDING TIME (BT)
PROTHROMBIN TIME (PT)
PARTIAL THROMBOPLASTIN TIME (PTT)
THROMBIN TIME (TT)

13. PLATELET COUNT NORMAL 100,000 - 400,000 CELLS/MM3
< 100, Thrombocytopenia
50, ,000 Mild Thrombocytopenia
< 50, Severe Thrombocytopenia

14. PROVIDES ASSESSMENT OF PLATELET COUNT AND FUNCTION
BLEEDING TIME
PROVIDES ASSESSMENT OF PLATELET COUNT AND FUNCTION
NORMAL VALUE
2-8 MINUTES

15. PROTHROMBIN TIME Measures Effectiveness of the Extrinsic Pathway
NORMAL VALUE
10-15 SECS

16. PARTIAL THROMBOPLASTIN TIME
Measures Effectiveness of the Intrinsic
Pathway
Mnemonic - PITT
NORMAL VALUE
25-40 SECS

17. THROMBIN TIME Fibrinogen Fibrin A Measure of Fibrinolytic Pathway
Time for Thrombin To Convert
Fibrinogen Fibrin
A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS

18. What Causes Bleeding Disorders?
VESSEL DEFECTS
PLATELET DISORDERS
FACTOR DEFICIENCIES
OTHER DISORDERS ?

19. VESSEL DEFECTS BACTERIAL & VIRAL INFECTIONS
VITAMIN C DEFICIENCY
BACTERIAL & VIRAL INFECTIONS
ACQUIRED & HEREDITARY CONDITIONS

20. Vascular defect - cont.
Infectious and hypersensitivity vasculitides
Rickettsial and meningococcal infections
Henoch-Schonlein purpura (immune)

21. THROMBOCYTOPENIA THROMBOCYTOPATHY
PLATELET DISORDERS
THROMBOCYTOPENIA
THROMBOCYTOPATHY

22. THROMBOCYTOPENIA
INADEQUATE NUMBER
OF PLATELETS

23. THROMBOCYTOPENIA DRUG INDUCED BONE MARROW FAILURE HYPERSPLENISM
OTHER CAUSES

24. OTHER CAUSES
Lymphoma
HIV Virus
Idiopathic Thrombocytopenia Purpura (ITP)

25. THROMBOCYTOPATHY UREMIA INHERITED DISORDERS
MYELOPROLIFERATIVE DISORDERS
DRUG INDUCED

26. FACTOR DEFICIENCY (CONGENITAL)
HEMOPHILIA A
HEMOPHILIA B
von WILLEBRAND’S DISEASE

27. FACTOR DEFICIENCIES HEMOPHILIA A (Classic Hemophilia)
80-85% of all Hemophiliacs
Deficiency of Factor VIII
Lab Results - Prolonged PTT
HEMOPHILIA B (Christmas Disease)
10-15% of all Hemophiliacs
Deficiency of Factor IX
Lab Test - Prolonged PTT

28. FACTOR DEFICIENCIES VON WILLEBRAND’S DISEASE
Deficiency of VWF & amount of Factor VIII
Lab Results - Prolonged BT, PTT

29. OTHER DISORDERS (ACQUIRED)
ORAL ANTICOAGULANTS
COUMARIN
HEPARIN
LIVER DISEASE
MALABSORPTION
BROAD-SPECTRUM ANTIBIOTICS

30. INHIBITORS
30% of people with haemophilia develop an antibody to the clotting factor they are receiving for treatment. These antibodies are known as inhibitors. These patients are treated with high does of FVIIa for bleeds or surgery. This overrides defect in FVIII or FIX deficiency.
Longterm management involves attempting to eradicate inhibitors by administering high dose FVIII (or FIX) in a process called immune tolerance

31. Clinical Features of Bleeding Disorders
Platelet factor Coagulation disorders disorders
Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum, vaginal,
GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
usually mild often severe

32. Coagulation factor disorders
Inherited bleeding disorders
Hemophilia A and B
vonWillebrands disease
Other factor deficiencies
Acquired bleeding disorders
Liver disease
Vitamin K deficiency/warfarin overdose
DIC

33. Coagulation factor deficiency Factor VIII Factor IX Inheritance
Hemophilia A and B
Hemophilia A
Hemophilia B
Coagulation factor deficiency
Factor VIII
Factor IX
Inheritance
X-linked recessive
Incidence
1/10,000 males
1/50,000 males
Severity
Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma
Complications
Soft tissue bleeding

34. HEMOPHELIA Disorder caused by deficiency of clotting factor VIII.
Inherited but acquired forms do exist, largely in older patients, due to auto-antibodies directed against factor VIII or hematological malignancy.
Severity of disease depends upon levels of remaining factor activity, with normal range expressed as %
Severity of factor VIII deficiency
Severity
Factor VIII activity level
Age of presentation
Percentage of sufferers
Severe disease
<1%
Infancy
43-70%
Moderate disease
1-5%
Before 2 years
15-26%
Mild disease
>5%
Older than 2 years
15-31%

35. Hemophilia
Clinical manifestations (hemophilia A & B are indistinguishable)
Hemarthrosis (most common)
Fixed joints
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions

36. Hemarthrosis (acute)

37. PRESENTATION Signs and symptoms
Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage.
Signs of hemorrhage include:
General: Weakness, orthostasis, tachycardia, tachypnea
Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain
Genitourinary: Hematuria, renal colic, and post circumcision bleeding

38. Laboratory findings:
Laboratory studies for suspected hemophilia include:
Complete blood cell count
Coagulation studies
FVIII assay
Expected laboratory values are:
Hemoglobin/hematocrit: Normal or low
Platelet count: Normal
Bleeding time: Norrmal
Prothrombin time: Normal
Activated partial thromboplastin time (aPTT):
Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia
Screening tests include: PT
aPTT (Normal aPTT does not exclude the possibility of mild hemophilia)
Platelet count

39. Treatment of hemophilia A
Intermediate purity plasma products
Virucidally treated
May contain von Willebrand factor
High purity (monoclonal) plasma products
No functional von Willebrand factor
Recombinant factor VIII
Virus free/No apparent risk

40. Dosing guidelines for hemophilia A
Mild bleeding
Target: 30% dosing q8-12h; 1-2 days (15U/kg)
Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
Major bleeding
Target: % q8-12h; 7-14 days (50U/kg)
CNS trauma, hemorrhage, lumbar puncture
Surgery
Retroperitoneal hemorrhage
GI bleeding
Adjunctive therapy
-aminocaproic acid (Amicar) or DDAVP (for mild disease only)

41. Complications of therapy
Formation of inhibitors (antibodies)
10-15% of severe hemophilia A patients
1-2% of severe hemophilia B patients
Viral infections
Hepatitis B Human parvovirus
Hepatitis C Hepatitis A
HIV Other

42. Treatment of hemophilia B
Agent
High purity factor IX
Recombinant human factor IX
Dose
Initial dose: 100U/kg
Subsequent: 50U/kg every 24 hours

43. Von Willebrand's Disease
This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. 
Pathophysiology
Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF).
vWF is a multimeric glycoprotein encoded for by gene map locus 12p13. 
It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:
It assists in platelet plug formation by attracting circulating platelets to the site of damage.
It binds to coagulation factor VIII preventing its clearance from the plasma.

44. Von Willebrand factor
Von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome

45. Von Willebrand's Disease
Epidemiology
Prevalence is as high as 1-2% in the general population on unselected screening.
Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected.
Most patients have mild disease.
It is more common in females.
It is more severe with blood type O.

46. Von Willebrand's Disease
Etiology
Hereditary - three types
vWD Type I, vWD Type II, and vWD Type III
Within the three inherited types of vWD there are various subtypes.
Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in:
Lymphoproliferative
Myeloproliferative disorders
Solid tumors
Immunological disorders
Cardiovascular disorders e.g., aortic stenosis, 
Wilms'tumor, 
Hypothyroidism.

47. Laboratory evaluation of von Willebrand disease
Classification
Type 1 Partial quantitative deficiency
Type 2 Qualitative deficiency
Type 3 Total quantitative deficiency
Diagnostic tests:
vonWillebrand type
Assay
vWF antigen ß Normal ßß
vWF activity ß ß ßß
Multimer analysis Normal Normal Absent

48. Von Willebrand's Disease
Types of hereditary von Willebrand's disease (vWD)
Type 1
60-80%
Quantitative defect (19-45% of enzyme level present)
Heterozygous for defective gene
Inherited as AD
Normal lifespan
Occasionally easy bruising and/or menorrhagia
Bleeding after dental work, major surgery
Type 2
20-30%
Qualitative defect - multimers abnormal or subgroups absent
Usually AD inheritance (rarely AR)
Bleeding tendency varies
Four  subtypes: 2A, 2B, 2M, 2N
Type 3
Rare - the most severe form; 1-5% of cases
Quantitative - levels very low or undetectable
Homozygous for defective gene
AR inheritance
No vWF antigen
Low factor V
Severe mucosal bleeding
May have haemarthrosis (as in haemophilia
Platelet type
Rare - fewer than 70 cases described
Functional mutations of vWF receptor on platelet
Autosomal dominant

49. Treatment of von Willebrand Disease
Cryoprecipitate
Source of fibrinogen, factor VIII and VWF
Only plasma fraction that consistently contains VWF multimers
DDAVP (deamino-8-arginine vasopressin)
 plasma VWF levels by stimulating secretion from endothelium
Duration of response is variable
Not generally used in type 2 disease
Dosage 0.3 µg/kg q 12 hr IV
Factor VIII concentrate (Intermediate purity)
Virally inactivated product

50. Vitamin K deficiency
Source of vitamin K Green vegetables Synthesized by intestinal flora
Required for synthesis Factors II, VII, IX ,X Protein C and S
Causes of deficiency Malnutrition Biliary obstruction Malabsorption Antibiotic therapy
Treatment Vitamin K Fresh frozen plasma

51. Common clinical conditions associated with Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis
Triggered by
Sepsis
Trauma
Head injury
Fat embolism
Malignancy
Obstetrical complications
Amniotic fluid embolism
Abruptio placentae
Vascular disorders
Reaction to toxin (e.g. snake venom, drugs)
Immunologic disorders
Severe allergic reaction
Transplant rejection

52. Disseminated Intravascular Coagulation (DIC) Mechanism
Systemic activation
of coagulation
Depletion of platelets
and coagulation factors
Intravascular
deposition of fibrin
Thrombosis of small
and midsize vessels
with organ failure
Bleeding

53. Release of thromboplastic material into
Pathogenesis of DIC
Release of thromboplastic material into
circulation
Consumption of
coagulation factors;
presence of FDPs
 aPTT
 PT
 TT
 Fibrinogen
Presence of plasmin
 FDP
Intravascular clot
 Platelets
Schistocytes
Coagulation
Fibrinolysis
Fibrinogen
Thrombin
Plasmin
Fibrin
Monomers
Fibrin(ogen)
Degradation
Products
Fibrin
Clot
(intravascular)
Plasmin

54. Disseminated Intravascular Coagulation Treatment approaches
Treatment of underlying disorder
Anticoagulation with heparin
Platelet transfusion
Fresh frozen plasma
Coagulation inhibitor concentrate (ATIII)

55. Classification of platelet disorders
Quantitative disorders
Abnormal distribution
Dilution effect
Decreased production
Increased destruction
Qualitative disorders
Inherited disorders (rare)
Acquired disorders
Medications
Chronic renal failure
Cardiopulmonary bypass

56. Thrombocytopenia Immune-mediated Idioapthic Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia

57. Liver Disease and Hemostasis
Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
Dietary Vitamin K deficiency (Inadequate intake or malabsortion)
Dysfibrinogenemia
Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
DIC
Thrombocytoepnia due to hypersplenism

58. Management of Hemostatic Defects in Liver Disease
Treatment for prolonged PT/PTT
Vitamin K 10 mg SQ x 3 days - usually ineffective
Fresh-frozen plasma infusion
25-30% of plasma volume ( ml)
immediate but temporary effect
Treatment for low fibrinogen
Cryoprecipitate (1 unit/10kg body weight)
Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia
Replacement therapy

59. Treatment Approaches to the Bleeding Patient
Red blood cells
Platelet transfusions
Fresh frozen plasma
Cryoprecipitate
Aminocaproic acid
DDAVP
Recombinant Human factor VIIa

60. RBC transfusion therapy Indications
Improve oxygen carrying capacity of blood
Bleeding
Chronic anemia that is symptomatic
Peri-operative management

61. Red blood cell transfusions Adverse reactions
Non-immunologic reactions
Congestive heart failure Volume overload
Fever and shock Bacterial contamination
Hypocalcemia Massive transfusion

62. Transfusion-transmitted disease
Infectious agent Risk
HIV ~1/500,000
Hepatitis C 1/600,000
Hepatitis B 1/500,000
Hepatitis A <1/1,000,000
HTLV I/II 1/640,000
CMV % donors are sero-positive
Bacteria 1/250 in platelet transfusions
Creutzfeld-Jakob disease Unknown
Others Unknown

63. Platelet transfusions
Source
Platelet concentrate (Random donor)
Pheresis platelets (Single donor)
Target level
Bone marrow suppressed patient (>10-20,000/µl)
Bleeding/surgical patient (>50,000/µl)

64. Platelet transfusions - complications
Transfusion reactions
Higher incidence than in RBC transfusions
Related to length of storage/leukocytes/RBC mismatch
Bacterial contamination
Platelet transfusion refractoriness
Alloimmune destruction of platelets (HLA antigens)
Non-immune refractoriness
Microangiopathic hemolytic anemia
Coagulopathy
Splenic sequestration
Fever and infection
Medications (Amphotericin, vancomycin, ATG, Interferons)

65. Fresh frozen plasma Content - plasma (decreased factor V and VIII)
Indications
Multiple coagulation deficiencies (liver disease, trauma)
DIC
Warfarin reversal
Coagulation deficiency (factor XI or VII)
Dose (225 ml/unit)
10-15 ml/kg
Note
Viral screened product
ABO compatible

66. Cryoprecipitate Prepared from FFP Content
Factor VIII, von Willebrand factor, fibrinogen
Indications
Fibrinogen deficiency
Uremia
von Willebrand disease
Dose (1 unit = 1 bag)
1-2 units/10 kg body weight

67. Hemostatic drugs Aminocaproic acid (Amicar)
Mechanism
Prevent activation plaminogen -> plasmin
Dose
50mg/kg po or IV q 4 hr
Uses
Primary menorrhagia
Oral bleeding
Bleeding in patients with thrombocytopenia
Blood loss during cardiac surgery
Side effects
GI toxicity
Thrombi formation

68. Hemostatic drugs Desmopressin (DDAVP)
Mechanism
Increased release of VWF from endothelium
Dose
0.3µg/kg IV q12 hrs
150mg intranasal q12hrs
Uses
Most patients with von Willebrand disease
Mild hemophilia A
Side effects
Facial flushing and headache
Water retention and hyponatremia

69. Recombinant human factor VIIa (rhVIIa;
Mechanism
Direct activation of common pathway
Use
Factor VIII inhibitors
Bleeding with other clotting disorders
Warfarin overdose with bleeding
CNS bleeding with or without warfarin
Dose
90 µg/kg IV q 2 hr
“Adjust as clinically indicated”

70. Approach to bleeding disorders Summary
Identify and correct any specific defect of hemostasis
Laboratory testing is almost always needed to establish the cause of bleeding
Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categories
Specialized testing is usually necessary to establish a specific diagnosis
Use non-transfusional drugs whenever possible
RBC transfusions for surgical procedures or large blood loss

71. THANK YOU
FOR
ATTENTION