1. Bleeding Disorders
By:
Dr.Fawaz A.F Al-Kasim MD Head of Hematology/Oncology Department- Children Hospital- King Saud Medical City
Head of blood disorders committee-Ministry of health-Saudi Arabia Chairman of Pediatric board, Hematology/Oncology Fellowship committee, Hematology/Oncology Fellowship exam committee and member of pediatric exam committee-Saudi Commission For Health Specialties

2. Objective The normal hemostasis Classification of bleeding disorders
Difference between platelet and coagulation disorders
Evaluation of patient with thrombocytopenia
Discuss the management of different coagulation disorders including hemophilia, VWD, and DIC

3. Normal hemostasis
Hemostasis is the active process that clots blood in areas of blood vessel injury, and limits the clot to the areas of injury
The main components of the hemostatic process are:
-Vasoconstriction (vascular phase)
- Platelet plug formation (primary hemostatic – platelet phase)
Fibrin thrombus formation (secondary hemostatic
coagulation phase).
- Fibrinolysis (clot breakdown)

4. Contact/ Tissue Factor Stable Hemostatic Plug
Hemostasis overview
Blood vessel injury
Contact/ Tissue Factor
Neural
Coagulation
Cascade
Blood Vessel
Constriction
Platelet
Aggregation
Primary hemostatic plug
Reduced
Blood flow
Platelet
Activation
Fibrin formation
Stable Hemostatic Plug

5. Note the central location of red blood cells and the peripheral margination of platelets. This radial distribution of cells results from a fluid dynamic effect called rheophoresis. The location of plasma and platelets at the vessel surface is important for efficient repair of the vessel injury.

6. With an injury to the endothelial lining of the vessel at least two parameters are changed. First collagen is exposed to the platelets that are spatially approximated to the vessel surface. Secondly, rheologic factors further enhance platelet activation.

7. Once thrombin is present fibrin can be formed
Once thrombin is present fibrin can be formed. Thrombin leads to numerous other important events, including activation and recruitment of other platelets to the injury site.

8. Bleeding child diagnostic approach
The bleeding child my present as:
1- increase in severity or frequency of bleeding from one site e.g.; nose.
2- bleeding from unusual sites such as joints or internal organs.
3- excessive bleeding for the degree of the trauma experienced.

9. Bleeding child diagnostic approach
Abnormal bleeding can be the result of an acquired or congenital disorders of vessel wall, platelets, or the coagulation factors
It is necessary to decide whether the bleeding is
Significant or not?
Generalized or localized?.
Acquired or hereditary?

10. Bleeding child diagnostic approach
Nature of bleeding; is the bleeding due to vascular, platelet, coagulation or a combination of this?
It is not always possible to categorize Vascular and platelet dysfunction usually present with:
- subcutaneous or mucus membrane bleeding eg; purpura, petechiae, epistaxis.

11. Bleeding child diagnostic approach
Coagulation factors deficiency:
Usually occur deep into joins, muscles,
retroperotineal space.

12. Bleeding child diagnostic approach
History:
Symptoms: epistaxis, gingival bleeding, easy bruising, menorrhagia, hematuria, neonatal bleeding, gastrointestinal bleeding, hemarthrosis, prolonged bleeding after lacerations
Response to hemostatic challenge: circumcision, surgery, phlebotomy, immunization/intramuscular injection, suture placement/removal, dental
procedures
Underlying medical conditions: known associations with hemostatic defects (liver disease, renal failure)

13. Bleeding child diagnostic approach
Medications:
antiplatelet drugs (Aspirin), anti-coagulants (warfarin, heparin, LMW, prolonged use of antibiotics causing vitamin K deficiency
Family history: siblings, parents, aunts, uncles, grandparents
1- sex linked recessive (hemophilia A&B,WAS)
2-autosomal recessives disease( clotting factors defeciency 2,5,7,10,11,13.
3- autosomal dominant( VWF, qualitative platelet disorders)

14. PRACTICAL APPROACH TO A CHILD WITH BLEEDING HISTORY
PHYSICAL EXAMINATION-
> PETICHEAE
>ECHYMOSES
>JOINT BLEED
> HEPATOSPLENOMEGALY
>SIGNIFICANT LYMPHADENOPATHY
> ACTIVE AND PLAYFUL VS. ILL LOOKING
> DYSMORPHIC FEATURES
> CAFÉ-AU-LAIT SPOTS
>HEMANGIOMAS

15. Tests to evaluate bleeding disorders
Platelet counts: x103/mm3
Prothrombin time (PT): Measures the extrinsic and common coagulation pathways second
activated Partial thromboplastin time (aPTT): Measures the intrinsic and common coagulation pathways the normal range is 30 – 50 second
Thrombin time: Time for thrombin to convert fibrinogen to fibrin 9-13 second
Bleeding time: 2-9 minutes. Prolonged in platelet disorder.
Other specific tests

16. Some bleeding disorders might not be associated with any abnormalities in the screening tests like:
Mild factors deficiency
Factors 13 deficiency.
HSP.
Ehler danlos syndrome .
Scurvy.

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

19. VESSEL DEFECTS Vascular causes –
-Vasculitis – Henoch-Schonlein Purpura
-Hemangiomas- Kassalback-Merritt syndrome

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

22. Hematopoietic stem cell
PLETELET PHYSIOLOGY
Platelets Production:
Hematopoietic stem cell 
Megakaryoblast
Megakaryocyte
 Fragmentation
of cytoplasm
Platelets

24. PLATELET CIRCULATION Normal count is 150,000- 450,000
Normal life span 7-10 days.
About 1/3 are trapped in the spleen.

25. Bleeding disorders
Platelet disorders
↓production
↑destruction
Sequestration
Hypersplenism
Primary/Idiopathic
ITP
Acute/Chronic
Secondary
Drugs, HIV

26. Causes of thrombocytopenia
Bone marrow disorders
Hypoplasia
Idiopathic
Drug-induced (cytotoxic, alcohol)
Infilteration
Tumors (leukemia, lymphoma, neuroblastoma)
Increased consumption of platelets
Immune thrombocytopenic purpura
Disseminated intravascular coagulation (DIC)
Viral infections (HIV, Epstein-Barr virus)
Bacterial infections (gram-negative septicemia)
Hypersplenism
Primary
Thalassemia
Liver disease
Malaria

28. Clinical presentation of thrombocytopenia
Petechiae
Purpura
Gum bleding
Epistaxis
Excessive bleeding after surgery
Gastrointestinal bleeding (Fresh blood or melena)
Hematuria

30. Acquired Disorders of Platelet Function
Drugs:
Best example is ASPIRIN which is the MOST COMMON cause of acquired platelet function disorder.
Aspirin irreversibly affect the cyclo-oxygenase enzyme The effect last 4-7 days
Presents as elevated bleeding time but purpura is unusual.

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

32. Coagulation Factors Symbol Synonym Half-life I Fibrinogen 92-136
II Prothrombin
V Proaccelerin
VII Proconvertin
VIII Antihaemophilic Factor A
IX Antihaemophilic Factor B
X Stuart Prower Factor
XI Plasma thrombin antecedent 60
XII Hageman factor
XIII Fibrin stabilising factor 100
N.B: Vit.K dependent: II, VII, IX and X

33. FACTOR DEFICIENCIES (CONGENITAL)
HEMOPHILIAS
Caused by lack of coagulation factors
VON WILLEBRAND’S DISEASE
Caused by lack of von willebrand´s factor

34. Types of Hemophilia Hemophilia A Absence or deficiency of Factor VIII
Hemophilia B (Christmas Disease)
Absence or deficiency of Factor IX
Hemophilia C
Absence or deficiency of Factor XI
Very rare and mild
von Willebrand Disease deficiency or abnormality of VWF

35. Haemophilia Inheritance
Hemophilia is an X-linked gene disease.
A father with the X-linked gene will pass it to all his daughters resulting in heterozygous carriers.
A mother who is a carrier of the mutant gene will pass the gene on to half her sons and half her daughters. All her sons will have hemophilia and all her daughters will be heterozygous carriers.
Females are carriers
Males have the disease

36. Haemophilia XY Xx xY XY xX XX 50% haemophiliac sons
Unaffected male + carrier female XY Xx
xY XY xX XX
50% haemophiliac sons
50% carrier daughters

37. Haemophilia xY Xx xY XY xX xx 50% haemophiliac sons
Carrier female + haemophiliac male xY Xx
xY XY xX xx
50% haemophiliac sons
50% carrier daughters
50% haemophiliac daughters

38. Haemophilia XY XX xY XY XX XX Spontaneous mutation.
Unaffected Male & Female XY XX
xY XY XX XX
Spontaneous mutation
(responsible for approx. 30% of all haemophilia)

39. Hemophilia A & B Occurrence: 85% Haemophilia A; 15% Haemophilia-B
Clinical manifestations :
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

40. Severity of hemophilia depends upon the level at which factor VIII is deficient.
Factor VIII levels
>1%
1% - 5%
5% - 25%
Type
Severe hemophilia
Moderate hemophilia
Mild hemophilia
Symptoms
Severe hemorrhage, deep tissue bleeding.
Present within first year of life.
Bleeding after mild trauma.
Present during childhood.
Bleeding after severe trauma and surgery.
Present during adulthood.

41. Clinical Severity

42. Joint Hemorrhages (Hemarthrosis)
Most common problem in haemophilia
Symptoms include, pain and disabled joints
Repeated joint bleeding leads to synovial inflammation and increased vascularity and thickening of the synovium.

43. Thigh muscle bleedings

44. Aims of therapy Laboratory Investigations and Diagnosis:
APTT prolonged
PT is normal
Factor VIII (or IX) is low (<40%)
Aims of therapy
Prevention of bleeding episodes
Treatment of bleeds
Preservation of joint function
Complete social integration & Quality of Life

45. Precautions in Haemophilia
Aspirin is strictly contraindicated .
NSAID’s (used for the treatment of arthritic pain) should be prescribed with caution
Intramuscular injections are contraindicated because they may provoke severe intramuscular bleeding
Childhood immunisations can be given after FVIII prophylaxis
Activities and sports are encouraged to maintain a healthy musculoskeletal system which reduces risk of bleeding
Only sports with high risk of head& neck injury i.e. boxing should be avoided

46. Haemophilia A Treatment
Evolution of Therapy
Whole Blood
FFP
Cryo-Precipitate
DDAVP
FVIII- concentrate (human source)
rFVIII
If inhibitor:
Porcine FVIII
PCC (prothrombin complex concentrate)
rFVIIa

47. Treatment
Treating the patient after a bleed is known as “on demand” or “crisis” therapy
It is crucial to treat as soon as possible after bleeding
The dose of factor required depends on the site and severity of bleeding and is calculated according to the following formula:
1 IU FVIII/ kg raises FVIII levels by 2%
therefore:
required units= body weight(kg) x desired FVIII: rise x 0.5

48. FVIII Dosage

49. Haemophilia B Factor IX deficiency Factor IX half-life = 18- 36h
Incidence: 1 : males
20% severe
50% moderate
30% mild
World-wide 70,000 people with severe Haemophilia B
Clinically indistinguishable from haemophilia A

50. Haemophilia B Treatment
Evolution of Therapy
Whole Blood
FFP
N.B: FIX not in Cryoprecipitate
FIX concentrate
rFIX

51. FIX Dosage therefore: 1 IU FIX:C /kg increases FIX levels by 1%
Required dose= body weight (kg) x desired FIX increase(%)

52. FIX Dosage - on demand

53. Prevention Preventative treatment is known as “prophylaxis”
Only for severe Haemophilia
FVIII is administered by the patient or suitably trained relative x 3 / week, starting soon after diagnosis
Dosage: IU / kg / x 3/week
Aim: to maintain trough levels of FVIII > 1 % i.e. converting patient from severe to moderate disease and preventing spontaneous bleeds

54. FIX Dosage - Prophylaxis
20-30 IU / kg body weight x 2/ week

55. VON WILLEBRAND’S DISEASE
FACTOR DEFICIENCIES
VON WILLEBRAND’S DISEASE

56. von Willebrand Disease
Autosomal inheritance disease
Males and females are equally affected
Most frequent inherited bleeding disorder
Incidence - 1/10,000
Very wide range of clinical manifestations

57. Clinical Manifestations
Epistaxis
Easy bruising / hematomas
Menorrhagia
Gingival bleeding
GI bleeding
Dental extraction bleeding
Trauma/wound bleeding
Post-partum bleeding
Post-operative bleeding

58. Von Willebrand Disease
Types:
Type 1 (60-80%)
5-30% quantitative reduction in vWF
Type 2 (10-30%)
Qualitative defect in vWF
Sub-types 2a, 2b,2m, 2n
Type 3 (1-5%)
Absent vWF
This type may also present with a clinical picture of hemophilia A

59. Treatment Guidelines in VWD
TYPE 1 2A 2B 2M 2N 3
TREATMENT
DDAVP
DDAVP/VWF
VWF

60. Acquired bleeding disorders
Liver disease
Vitamin K deficiency
Disseminated intravascular coagulation (DIC)
Infection

61. Vitamin K deficiency
Source of vitamin K Green vegetables Synthesized by intestinal flora
Required for synthesis Factors II, VII, IX ,X
Causes of deficiency Inadequate intake Biliary obstruction Malabsorption Antibiotic therapy

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

63. Disseminated intravascular coagulation (DIC)

64. What is DIC? Is an acquired bleeding disorder
Is not a disease entity but an event that can accompany various disease processes
In DIC, a systemic activation of the coagulation system simultaneously leads to :
Inadequate fibrin removal (inhibition of fibrinolysis ) and increase fibrin deposition (results in thrombus formation).
Exhaustion of platelets and coagulation factors (results in bleeding).
Is a Paradoxical Clinical Presentation “clotting and hemorrhage”

65. 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

66. Common clinical conditions associated with DIC
In DIC, Activation of both coagulation and fibrinolysis triggered by:
Sepsis
Trauma
Head injury
Fat embolism
Malignancy
leukemias
Obstetrical complications
Amniotic fluid embolism
Abruptio placentae
fetal death syndrome
Vascular disorders
Reaction to toxin (e.g. snake venom, drugs)
Liver disease, pancreatitis
Immunologic disorders
Severe allergic reaction
Transplant rejection

67. Signs and Symptoms
Most common signs of DIC are bleeding and thrombosis
Manifested by ecchymosis, petechiae and purpura
Bleeding from multiple sites either oozing or frank bleeding
Cool and or mottled extremities may be noted
Thrombosis leads to tissue ischemia and infarction
Dyspnea and chest pain if pleura and pericardium involvement
Hematuria

68. Diagnosis/Lab Findings
Test
Platelet count
Bleeding time PT
Activated PTT
Thrombin time
Fibrinogen
Fibrin degradation product (FDP)
Abnormality
Decreased
Increased
Prolonged

69. MCQs 1-Which of the following medication cause platelet dysfunction?
Aspirin
Nonsteroidal anti-inflammatory drugs
Heparin
Warfarin
2- Which of the following is the most common cause of
thrombocytopenia in children?
A. Drugs
B. Immune thrombocytopenic purpura
C. Bone marrow infiltration
D. Hypersplenism

70. MCQs
3- Which of the following is the mode of inheritance of Hemophilia A ?
Autosomal recessive
Autosomal dominant
X-linked recessive
Multifactorial
4- Hemophilia B cause by deficiency of which of the following factor ?
A. VIII
B. IX
C. X
D. XI

71. MCQs 5- Which of the following is the most common site of bleeding in
Hemophilia ?
Subcutaneous tissue
joints
Internal organs
CNS

72. 1. A 10-year old male has an erythematous rash shown below
1. A 10-year old male has an erythematous rash shown below. Laboratory: CBC, differential, Platelet count, PT, PTT are normal.   Which of the following is the most likely diagnosis?   a. Immune thrombocytopenia purpura b. Thrombotic Thrombocytopenic Purpura c. Non-accidental trauma d. Henoch-Schönlein purpura

73. 2-Newborn male with Physical anomalies shown below CBC: WBC 50,000; Hb: normal. Platelet: Which of the following is the most likely diagnosis? A. TAR syndrome (thrombocytopenia absent radius syndrome) B. Immune thrombocytopenia purpura C. Thrombotic Thrombocytopenic Purpura D. Fanconi anemia

74. 3. A 3- year old boy is admitted with a day history of a painful, swollen right knee slide shown below. His mother gives a history of easy bruising since he started crawling. He is the only child, but according to his mother one of his nephews also has a bleeding tendency. White cell count1: 12.5 x 109/l [ ]. Hemoglobin: 11.8g/dl [ ]
Platelet count: 300 x 109/l [ ] INR : 0.96 [ ] PTT: 72 sec [ ]
Thrombin Time: 15 sec [13 -15] Fibrinogen: 325 mg/dl [ ]
Which of the following is the most likely diagnosis ?
A. Hemophilia
B. Von Willebrand disease
C. Immune thrombocytopenia purpura
D. Leukemia

75. 4. A 6-year old male has severe hemophilia A (FVIII deficiency) present to the ER after head trauma his weight is 20 kg. Head CT scan shown below
Which of the following is the most appropriate dose of recombinant factor VIII?
a. 500 units
b units
c units
d units

76. 5. A 13-year old female is referred for easy bruising and mennorrhagia
5. A 13-year old female is referred for easy bruising and mennorrhagia. Her father has a life long history of easy bruising and bleeding after dental extraction.   Which of the following is the most likely diagnosis in this family?   a. Mild hemophilia A (FVIII deficiency) b. Factor XII deficiency c. Von Willebrand disease. d. Congenital thrombocytopenia

77. Case scenario
A woman takes her three year old child to the general practitioner with a history of a skin rash of 3 days duration. Ten days before the onset of the rash the child had mild upper respiratory symptoms with cough and fever. The mother managed this symptomatically without consulting a doctor. 
On examination the child appears well with no temperature and no signs of an upper respiratory infection. There is a fine peticheal rash on the skin and mucous membranes. No lymphadenopathy or hepatosplenomegaly is found

78. Laboratory Results:
WBC: 10.1 x 109/l [ ] Haemoglobin:11.5g/dl [ ] Platelet count: 4.0 x 109/l [ ] MCV:75.1 fl [ ] MCH: 28.9 pg/l [ ] Normal differential white cell count

79. What do you think is the possible diagnosis?

80. Immune thrombocytopenic purpura [ITP]
Answer:
Immune thrombocytopenic purpura [ITP]