1. Dr M A Maleque Molla, FRCP, FRCPCH
Bleeding disorder
Dr M A Maleque Molla, FRCP, FRCPCH
September

2. OBJECTIVES Overview of hemostasis
Clinical approach in making a diagnosis
Review the most common bleeding conditions
Discuss the current treatment strategies

3. Hemostasis
Hemostasis is the active process that clots blood in areas of blood vessel injury & simultaneously limits the clot size only to the areas of injury.
Over time, the clot is lysed by the fibrinolytic system
Normal hemostasis needed to;
Arrests bleeding
Keeps blood in fluid state
Repair and reestablish the blood flow through the injured vessels
Remove hemostatic plug and normal blood flow is restored

4. Hemostasis(cont.) Normal hemostasis requires integrity of 3 elements:
Blood vessels
Platelets
Soluble clotting factors

5. Hemostasis(cont.) Role of Blood vessels
Injury to the blood vessels elicit 3 response to control the bleeding;
Vasoconstriction
Activation of platelets and coagulation factors
Release tissue factor which activates extrinsic coagulation path way

6. Hemostasis(cont.) Role of Platelets
Platelets involves in hemostasis by;
Platelet adhesion
Platelet aggregation
Platelet secretion:
Serotonin, Thromboxane A2 -Augment vasoconstriction
ADP- Platelet aggregation

7. Hemostasis(cont.) Role Clotting factors
Clotting factors involves in hemostasis by;
Initiating process of coagulation via series of reaction
Extrinsic path way
Intrinsic path way
Common path way

8. Coagulation factors
Plasma coagulation factors are protein synthesize in liver & endothelium of blood vessels.
II, VII, IX, X are called vitamin K dependent clotting factors.
Factors have specific name but are known by Roman numeral from I-XIII.
There are 12 factors.
Factors remains inactive form & indicated by simple numerals, except factors III & IV.
A lower case “a” indicates the active factor e.g. factor IXa

9. Coagulation Factors
Factor I (Fibrinogen): Precursor of fibrin, which forms clot
Factor II (Prothrombin).
Factor IIa (Thrombin): most important protease of the coagulation pathway
Factor III (Tissue thromboplastin): lipoprotein complex from tissues.
Factor IV: Ionized calcium .
Factor V (Proaccelerin); Essential to the thromboplastin formation
Factor VII (proconvertin); Activates tissue thromboplastin and the acceleration of the production of thrombin from prothrombin
Factor VIII (Antihemophilic Factor): Consists von Willebrand factor (vWF)
Factor IX (Plasma Thromboplastin component); It is an essential component of the intrinsic thromboplastin generating system
Factor X (Stuart Factor)
Factor XI (Plasma Thromboplastin Antecedent); Essential to the intrinsic thromboplastin-generating mechanism
Factor XII (Hageman factor)
Factor XIII (Fibrin-Stabilizing Factor).

10. Fig. Coagulation cascade
Intrinsic pathway
Extrinsic Pathway X Xa
IXa IX XI
XIa
XII
XIIa
II (Prothrombin)
IIa (Thrombin)
Fibrinogen
Fibrin (Soft clot)
VII
VIIa
Tissue factor (TF)
XIII
XIIIa
Fibrin Polymer (Hard clot)
HMK, PK
Pl,Va,Ca++
Ca ++ PL
Common Pathway
PL=Platelet, phospholipid
Fig. Coagulation cascade

11. Intrinsic pathway Intrinsic pathway
Intrinsic pathway begins with formation of the primary complex on collagen by
High-molecular-weigh kininogen (HMWK),
Prekallikrein(PK),
FXII (Hageman factor).
Prekallikrein is converted to kallikrein and activate FXII to FXIIa.
FXIIa converts FXI into FXIa.
Factor XIa activates FIX to IXa,
FIXa + with co-factor FVIIIa form the tenase complex, which activates FX to FXa.
HMK, PK X Xa
IXa IX XI
XIa
XII
XIIa
Ca ++
Ca ++
VII PL
Ca ++

12. Extrinsic pathway Extrinsic PathwayXa
VII
VIIa + TF
Tissue factor (TF) X
Following damage to the blood vessel, FVII leaves the circulation
FVII comes into contact with tissue factor (TF) & forms an activated complex (TF-FVIIa).
TF-FVIIa activates F X to Xa.

13. Common pathway Final common Pathway
FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
Thrombin then activates fibrinogen to fibrin
Finally leads to formation of fibrin network.
Xa +Va
II (Prothrombin)
IIa (Thrombin)
Fibrinogen
Fibrin

14. Mechanism of Hemostasis
Injury to a blood vessel
Phase I. Primary hemostasis
3 to 5 min
Immediate response blood vessel constrict
Platelets adhere and aggregate at the site of the injury and form a plug
Activated platelets secretes & initiate the coagulation factors forming a fibrin network or clot completely.
Phase II
Coagulation
5 to 10 min
WBC, RBC & platelets are trapped and form a solid plug of blood(coagulation) seals off the injury vessel completely.
Phase III. Fibrinolysis48-72 hour
Finally slow lysis of the clot, fibrinolysis, begins and the site of the injury is repaired.

15. Bleeding disorder
Bleeding disorders are coagulopathies with reduced clotting of the blood
Can be congenital or aquired.

16. Bleeding disorders
Bleeding for longer than normal is due to defect in hemostasis
Can be due to the abnormality of
Blood vessels
Platelet
Clotting factors leading to coagulation abnormality

17. Disorders of blood vessels
Excessive capillary fragility -Ehlers-Danlos syndrome
Vasculitis e.g. Henoch-Schonlein purpura
Hereditary hemorrhagic telangiectasia
Vitamin C deficiency

18. 2. Disorders of Platelets
Normal platelet 150, ,000 x 103/µl
Thrombocytopenia(<150,000 x 103/µl) is the most common cause of bleeding.
Platelet disorder may be
Quantitative disorder- Decrease number of platelet;
Decrease production
Bonemarrow failure e.g pancytopenia
Congnital Amegakaryocytic thrombocytopenia
Thrombocytopenia absent radius syndrome(TAR) AR
Wiskott-Aldrich syndrome, XR
Increase destruction
Immune mediated thrombocytopenia(ITP)
Hypersplenism
Dessiminated intravascular coagulation(DIC)
Qualilative disorder-Abnormal platelet function;
Congenital e.g Glanzmann’s disease. Bernard-Soulier synd
Aquired e.g Drug induced like Aspirin

19. 3. Disorders of Coagulation factors
Congenital deficiency- usually single factor defect;
Hemophilia A, B, C
von Willebrand’s disease
Acquired-usually multiple factor deficiency;
Disseminated Intravascular coagulation(DIC): Consumption of platelet, FII, V, VIII
Vit K Deficicency; Deficiency of Vit k dependent factors II, V, VII, IX & X
Liver disease.

20. Disorders of Coagulation factors(cont..)
Deficiencies of most procoagulant proteins lead to bleeding
Deficiencies of contact factors e.g. prekallikrein, high molecular weight kininogen, and Hageman factor [XII] are not associated with a predisposition to bleeding

21. Bleeding disorder Presentation
Bruising may be spontaneous or recurrent:
Large bruises on the trunk are more indicative of a bleeding disorder.
Prolonged bleeding:
After minor cuts or abrasions.
After circumcision in young infant.
Nosebleeds lasting >10 minutes despite compression (especially in children).
Bleeding from gums without gingival disease.
Following dental extraction.
Severe menorrhagia causing anemia, with normal uterus.
Postpartum hemorrhage in adult.
After injections or surgical procedures.

22. Bleeding disorder (cont..) History
Family history of bleeding tendency.
Current medication:
Aspirin, non-steroidal anti-inflammatory drugs, warfarin.
Alcohol intake in adolescelent & adult.
Other constitutional symptoms - eg, malaise, weight loss.
Past history or thrombosis (can be suggestive of thrombophilia).
Previous blood transfusions.
Renal or hepatic impairment.

23. Bleeding disorder (cont..) Physical
Skin, palate and gums for:
Petechia (non-blanching haemorrhagic spot <2 mm diameter)
Purpura (2-10 mm diameter)
Bruising >10 mm diameter
Ecchymosis (>10 mm diameter)
Joints for hemarthrosis.
Fundi for retinal hemorrhages.
Reticulo- endotheilial system

24. Karnath B; Easy Bruising and Bleeding in the Adult Patient, 2005
Comparing coagulation factor and platelet defects 
Coagulation factor defects
Platelet disorders and von Willebrand's disease
Bruising on trunk and limbs
Large bruises
Small bruises
Bleeding from cuts
Relatively slight
Profuse
Nosebleeds
Uncommon
Common, frequently profuse and of long duration
Gastrointestinal bleeding
Common
Haematuria
Rare
Haemarthrosis
In severe haemophilia
Very rare
Bleeding after surgery or dental extraction
Up to a day's delay before bleeding occurs
Immediate bleeding
Karnath B; Easy Bruising and Bleeding in the Adult Patient, 2005

25. Investigations
FBC, blood film and platelet count: may detect ITP, leukaemia, lymphoma or abnormal platelets.
U&Es: to exclude uremia causing a platelet disorder.
LFTs: to detect hepatic disorder.
Bone marrow biopsy.

26. Investigations(cont..)
A coagulation screen
APTT: Measures intrinsic pathway (F I, II, V, VIII, IX, X, XI and XII deficiency) and the common pathway
PT: Measures extrinsic and final common pathway of the coagulation cascade, thus can detect factor I, II, V, VII or X deficiency
Thrombin time: Measures the final step in the clotting cascade.
Bleeding time : sometimes used in the investigation of vWD although it has poor specificity
Fibrinogen: detect afibrinogenaemia or hypofibrinogenaemia
D- Dimer: Fibrin degradation product. Measure to detect DIC, Deep vein thromosis.
INR- The INR is a standardized prothrombin time designed to account for differences in thromboplastin. Normal range

27. Investigations(cont..)
Specific factor assays:
F VIII or FIX to determine severity of hemophilia;
Factor VIII and vWF in vWD
Other factor deficiency
Gene analysis looking for specific gene defects.

28. Investigations(cont..)
Tests in bleeding disorders
Platelet count PT
APTT BT TT
Additional tests
Haemophilia A N
Factor VIII low
Haemophilia B
Factor IX low
Von Willebrand's disease
or N
VWF and factor VIII activity low and impaired ristocetin-induced platelet aggregation
Liver disease
Low
(rarely )
DIC
N- Normal, =Prolonged
Hayward CP; Diagnosis and management of mild bleeding disorders. Hematology Am Soc Hematol Educ Program. 2005:423-

29. Coagulopathies Congenital Aquired:
Hemophilia A: Deficiency of FVIII, Inheritance XR
Hemophilia B: Deficiency of FIX , Inheritance XR
Hemophilia C: Deficiency of FXI, Inheritance AR
Deficiency of other coagulation factors : I, II, V, VII, IX, X and XIII  
Deficiency of XII factor, prekallikrein or kininogen, protein C and S (without excessive bleeding)
von Willebrand’s disease (angiohemophilia) AD
Aquired:
Vit K deficiency; Hemorrhagic disease of the new born, Liver disease
DIC

30. von Willebrand Disease
The most common inherited bleeding disorder
Inheritance is usually AD, rarely AR.
Occurs in 1% of the population
Less than 10% of patients have bleeding events due to vWD.
Caused by deficiency of von Willebrand Factor(vWF).
vWF may be either
Quantitatively deficient -Type 1 or Type 3
Qualitatively abnormal- type 2.
80% of patients have classic type 1 disease - a mild to moderate deficiency of vWF.

31. Clinical features Easy bruise Epistaxis or gingival bleeding
Post-surgical bleeding
Bleeding post-dental extraction
Post-partum hemorrhage
Menorrhagia
In severe disease may have manifestations similar to hemophilia A (hemarthrosis)

32. Investigation Measurement of: vWF -the vWF antigen (vWF:Ag).
vWF activity (vWF:Act)- is measured functionally in the ristocetin cofactor assay (vWFR:Co), which uses the antibiotic ristocetin to induce vWF to bind to platelets.

33. Classification of von Willebrand disease
Type
Inheritance
VWF activity
RIPA
Type 1 (partial quantitative deficiency) AD
Decreased
Decrease
Type 2 (qualitative variant)
Type 2A
AD or AR
Type 2B
Increase
Type 2M
Type 2N AR
Normal
Type 3 (severe)
Markedly decreased or absent
Markedly Decrease
RIPA: ristocetin-induced platelet aggregation

34. Treatment The treatment depends on the severity of the bleeding.
The five categories of medications for the treatment of von Willebrand disease (VWD) include
Desmopressin (DDAVP);
Replacement therapy with vWF containing concentrates(Humate P)
Antifibrinolytic drugs; Epsilon aminocaproic acid(EACA) and Tranexamic acid
Topical therapy with thrombin or fibrin
Estrogen therapy in some settings in women

35. Treatment Guidelines in VWD
TYPE
TREATMENT 1
DDAVP 2A
DDAVP/FVIII-vWF 2B
FVIII-vWF 2M 2N 3
DDAPV=1-desamino-8-D-arginine vasopressin

36. Hemophilia
Caused by an absence or decreased amount of a procoagulant.
VIII -Hemophilia A
XI -Hemophilia B
XI –Hemophilia C
Incidence
Hemophilia A - 1:5,000
Hempohilia B – 1: 30, 000

37. Types of Hemophilia A & B
Severe: <1% factor activity level - Spontaneous bleeds
Moderate: 1 to 5% activity -Trauma/surgery bleeds Occasional joint bleeds
Mild: 5 to 30% activity - Major trauma/surgery Rare joint bleeds
Hemophilia A & B are clinically indistinguishable.
The hemostatic level for factor VIII is >30-40%, and for factor IX, it is >25-30%
The lower limit of levels for factors VIII and IX in normal individuals is approximately 50%.

38. Haemophilia A Due to the deficiency of factor VIII
Inharitence XR. Males are affected.
There is usually a clear family history but sporadic cases do occur due to novel mutations or effects of mosaicism
Females born to affected fathers can (rarely) have the disease due to homozygosity for the gene, where there is marriage to close relatives
Severity of disease depends upon levels of remaining factor activity

39. Severity of factor VIII deficiency
Haemophilia A
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%

40. Haemophilia A Severe disease
Neonatal bleeding in around a third to a half of cases.
This may follow circumcision or other operative procedures.
Neonatal intracranial hemorrhage can be a presenting feature of in about 3-4%,
Hematoma and prolonged bleeding from the cord or umbilical area.
Intracranial hemorrhage occurs in about 5% of all untreated cases.
History of spontaneous bleeding into joints, especially the knees, ankles and elbows, without a history of significant trauma.
Spontaneous hemarthroses are virtually pathognomonic.
Intramuscular haemorrhage may also occur.
Gastrointestinal and mucosal haemorrhage do occur but are more often associated with hemophilia B/von Willebrand's disease.
Haematuria may be a feature, which can vary from self-limiting minor episodes to gross haematuria.

41. Haemophilia A Mild & Moderate disease
Often presents with bleeding following venepuncture.
Bleeds after minor trauma or surgery
Mild disease
Only bleed after major trauma or surgery.

42. Investigations
APTT- usually prolonged in Hemophilia A & B, but can be normal in mild disease.
Specific factor assay:
Factor VIII C - is reduced in Hemophilia A
F IX is reduced in Hemophilia B
Percentage of factor activity represents severity of disease
Prothrombin time, bleeding time, fibrinogen levels and von Willebrand factor - are normal.

43. Management
Early, appropriate factor replacement therapy is the aim of optimal hemophilia care
For treatment of acute bleeds, target levels by hemorrhage severity are as follows:
Mild hemorrhages (eg, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
Major hemorrhages: (eg, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of at least 50%
Life-threatening bleeding episodes: (ie, major trauma or surgery, advanced or recurrent hemarthrosis, CNS bleeding): Maintain an FVIII level of %

44. Prophylaxis
Prophylaxis to be considered for children with severe hemophilia
Usually initiated with the first joint hemorrhage
For routine prophylaxis, rVFIIIFC is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days.

45. Disseminated Intravascular Coagulation(DIC)
Called Consumptive coagulopathy
Usually there is a balance between the clotting and lysis systems. This balance is altered.
In DIC, the coagulation mechanism is activated inappropriately and in a diffuse way by tissue damage from a variety of underlying diseases .
Coagulation factors, especially platelets, fibrinogen, and factors II, V, and VIII, are consumed.
This may lead to thrombosis in the sub acute or chronic form but more often hemorrhage occurs as the clotting factors are exhausted.

46. Risk factors Infection e.g septicaemia Major trauma including burn
Malignency
Some collagen disease
Incompatible blood transfusion.
Heat stroke.
Dissecting aortic aneurysm.
Some snake bites

47. Clinical feature
Obvious features are usually those of the underlying condition
There may be large bruises or spontaneous bleeding at venepuncture sites, on the soft palate, legs and the site of trauma.
There may be gastrointestinal or pulmonary hemorrhage or evidence of peripheral gangrene or thrombosis suggests the diagnosis of DIC.

48. Investigation PT & aPTT are elevated.
Platelet counts is typically low, especially in acute sepsis-associated DIC, but may be increased in malignancy-associated chronic DIC.
Fibrinogen level low.
The D-dimer elevated.
Elevated fibrin degradation products (FDPs ).
Microangiopathic hemolytic anemia .

49. Scoring system for overt DIC
Platelet count:
>100 x 109/L = 0, <100 x 109/L = 1, <50 x 109/L = 2
Elevated fibrin marker - eg, D-dimer, fibrin degradation products –
no increase = 0, moderate increase = 2, strong increase = 3)
Prolonged PT :
<3 secs = 0, >3 but <6 secs = 1, >6 secs = 2)
Fibrinogen level:
>1 g/L = 0, <1 g/L = 1
Calculate score:
≥5 - compatible with overt DIC: repeat score daily
<5 - suggestive for non-overt DIC: repeat next 1-2 days

50. Management Treat the underlying cause.
Support the patient by correcting hypoxia, acidosis, and poor perfusion.
Platelet transfusion if <50 x 109/L
Fresh frozen plasma
Prothrombin concentrate
Severe hypo fibrinogenemia may need replacement of fibrinogen or cryoprecipitate
In cases of DIC where thrombosis predominates, e.g.arte rial or venous thromboembolism, severe purpura fulminans, therapeutic doses of heparin should be considered
Severe sepsis and DIC may be treated with recombinant human activated protein C

51. Thanks for attention