A schematic approach to diagnose a case of bleeding disorders

1. COAGULATION DISORDERS
AJAY KUMAR YADAV
PGY3,INTERNAL MEDICINE
IOM-TUTH, Kathmandu
2075/05/10

2. LAYOUT
• Normal coagulation
•
• Interaction of VWF , FVIII and platelet
• Function of WWF
• VWD
• Diagnosis
• Management
• Hemophilia
• Diagnosis
• Management
• Complications

3. COAGULATION PROCESS

4. INTERACTION PLATELET AND VWF

5. ROLE OF VWF

6. Von Willebrand Factor(VWF)
• VWF is synthesized in platelets and megakaryocytes.
• Undergoes further processing,including dimerization and polymerization, to form very LMW
“multimers”.
• Majority present in plasma with concentration of 10 mcg/ml.
• About 15% of circulating VWF is present intracellularly within platelets.
• T1/2 : 8-12 hrs.

7. INHERITED DISORDERS OF COAGULATION

8. VON WILLEBRAND DISEASE

9. INTRODUCTION
Angiohemophilia
Vascular
hemophilia
Pseudohemophilia
Constitutional
thrombopathy
Idiopathic
prolonged
bleeding time

10. INTRODUCTION
• Most common inherited bleeding disorder.
• Prevalence of approximately 1%.
• VWF serves two major roles:
 As the major adhesion glue that tethers the platelet to the exposed sub-endothelium;
 As the molecular chaperone for factor VIII  significant prolongation of the FVIII half-life in
circulation(5 fold)

11. INTRODUCTION cont..
• Platelet-adhesive function of VWF is critically dependent on the presence of large VWF
multimers, whereas FVIII binding is not.
• Most of the symptoms of VWD are “platelet-like” except in more severe VWD when the FVIII is
low enough to produce symptoms similar to those found in FVIII deficiency (hemophilia A).
• 3 Types
 Quantitative defect : Type 1 ( mild defect ) , Type 3 ( severe defect )
 Qualitative defect :Type 2 , 4 subtypes = 2A , 2B , 2C , 2D .

12. DIAGNOSIS
• Diagnosis of VWD — In order to make the diagnosis of VWD, one must take into account:
• The patient's personal and family history of bleeding
• The laboratory assessment.

13. Tests for diagnosis of VWD

14. Classification of VWD
Type Pathophysiology Clinical features Laboratory diagmosis
Type 1  Partial quantitative
deficiency
 Most common type :
¾th
 AD inheritance
 Usually manifest later
in childhood with
excessive bruising and
epistaxis.
 Menorrhagia-
common
 Dental extractions,
particularly wisdom
tooth extraction, or
tonsillectomy.
 VWF activity and RIPA
decreased
• RIPA may be normal in
mild disease
• Multimer
electrophoresis: All
multimers present and
uniformly decreased

15. Classification cont..
Type Pathophysiology Clinical features Lab diagnosis
Type 2 (qualitative variant) : 4 types ,2A-2N
Type 2A  Increased susceptibility to
cleavage of VWF
multimers by ADAMTS13
or decreased secretion of
multimers decreased
VWD multimers
 Accounts for approx.
1/10th -1/5th of pts.
 Moderate to severe
bleeding
 AD or AR inheritance
 VWF activity and RIPA
decreased
 Factor VIII levels may be
normal or reduced
 Multimer electrophoresis:
Decreased large
multimers
Type 2B  Gain-of-function
mutation increased
spontaneous binding of
VWF to platelets in
circulation subsequent
clearance of this complex
by the RES.
 Approx. 5% of pts with
VWD
 Moderate to severe
bleeding
 AD inheritance
 VWF activity decreased
 RIPA increased
 Factor VIII levels may be
normal or reduced
 Thrombocytopenia/giant
platelets
 Multimer electrophoresis:
Decreased large
multimers

16. Classification cont..
Type  Pathophysiology  Clinical features Lab diagnosis
Type 2M  Mutation leading to
dysfunction of VWF
but do not affect
multimeric structure.
 Uncommon
 Moderate to severe
bleeding
 AD or AR inheritance
 VWF activity and RIPA
decreased
 Factor VIII levels may
be normal or
decreased
 Multimer
electrophoresis: All
multimers present and
uniformly decreased
Type 2N  Mutation in VWF
leading to impaired
binding of VWD TO
FVIII
 Uncommon
 Clinically similar to
hemophilia A with
joint, soft tissue,
urinary bleeding
 AR inheritance
 VWF activity and RIPA
normal
 Factor VIII levels low
(5 to 15%)
 Multimer
electrophoresis:
Normal

17. Classification cont..
Type Pathophysiology Clinical features Laboratory diagnosis
Type 3  Severe quantitative
defect in VWF
 Rare
 Clinically similar to
hemophilia A with
joint and soft tissue
bleeding
 Severe mucosal
bleeding
 AR inheritance
 VWF activity and RIPA
absent or markedly
decreased
 Factor VIII levels low
(1 to 10%)
 Multimer
electrophoresis:
Undetectable or too
faint to visualize.

18. ACQUIRED VWD : when do we suspect ?
S/b suspected
• Onset of bleeding later in life; history of prior uneventful surgery prior to bleeding episode(s)
• Negative family history for VWD
• Presence of an inhibitor to VWF or VWF-binding antibodies
• Remission of bleeding after treatment of an underlying aVWS-associated disorder
• Response to treatment with IVIG, suggesting IgG MGUS-associated aVWD
• Short-lived response to VWF-containing concentrates or desmopressin

19. Causes of Acquired VWD

20. Cont..

21. • HEYDE’S SYNDROME ( AS with GI bleed )
 Attributed to the presence of angiodysplasia of the GIT in patients with AS.
 The shear stress on blood passing through the stenotic aortic valve change in VWF susceptible
to serum proteasesacquired type 2 VWD.
 Reversible when the stenotic valve is replaced

22. Just for fun!!!

23. TREATMENT
• The mainstay of treatment for type 1 VWD is DDAVP (desmopressin)
• DESMPRESSIN
 MOA : Release of VWF and FVIII from endothelial stores.
 Route : IV or by a high-concentration intranasal spray (1.5 mg/mL).
 The peak activity when given IV is approximately 30 mins, whereas it is 2 hr when given
intranasally.

24.  Dose : The usual dose is 0.3 μg/kg IV or two squirts (one in each nostril) for patients >50 kg (one
squirt for those <50 kg).
 If pt. respond  increase in VWF level 2-4 fold  use every 12-24 hrs for procedure with mild to
moderate risk .
 A/E : Hyponatemia d/t decreased free water clearance.

25. • Type 2A and 2M may also respond to desmopressin.
• Type 3 : VWF replacement
• Antifibrinolytic drugs
 EACA
 Tranexamic acid

26. Specific circumstances
• Menorrhagia
 Do not desire pregnancy : OCP > LNG-IUD , DDAVP
 If pregnancy desired : Antifibrinilytic therapy and/or VWF replacement
• Pregnancy
 T/t is not needed: levels may rise 2-3 fold during 2nd to 3rd trimester may reach normal value
during labour.
 DDAVP : increase uterine contraction ?  use VWF replacement or antifibrinolyic therapy to
treat bleed or for invasive procedure.

27. • Delivery
 Hospitalize pt. where VWF and FVIII can be monitored.
 It is recommended that levels of VWF and FVIII be maintained at least 50 IU/dl during delivery
and for at least 3-5 days after delivery.
• Postpartum
 S/b treated with VWF or DDAVP as appropriate to bleeding episode.
• CVD
 DDAVP

28. • SURGERY
• Minor bleeding and surgery
 DDAVP every 12-24 hrs for 2-4 doses
 Maintain VWF level at least 30 IU/dl : optimal  50 IU/dl.
• Major bleeding and surgery
 VWF concentrate > DDAVP
 Target VWF ristocetin cofactor activity of approx. 100 IU/dl to be maintained for 7-14 days.

29. HEMOPHILIA

30. INTRODUCTION
• X-linked recessive hemorrhagic disease due to mutations in the
 F8 gene (hemophilia A or classic hemophilia): 80% of all cases or
 F9 gene (hemophilia B).
• Hemophilia C – Inherited deficiency of factor XI : aka Rosenthal syndrome; an AR disorder.
• The disease affects 1 in 10,000 males worldwide, in all ethnic groups.
• Males are clinically affected and females who carry single mutated gene are generally
asymptomatic/carriers.
• Family history absent in 30% of cases, and in these cases,80% of mothers are carriers of the de novo
mutated allele.

33. SEVERITY OF HEMOPHILIA
• Severe hemophilia : <1 pc factor activity, corresponds to <0.01 IU/mL.
• Moderate hemophilia : 1-5 pc of normal, corresponding to ≥0.01 and ≤0.05 IU/mL.
• Mild hemophilia : >5 pc of normal and <40 percent of normal (≥0.05 and <0.40 IU/mL)

35. CLINICAL FEATURES
• Infants – Intracranial bleed, extracranial sites such as cephalohematoma, and sites of medical
interventions including circumcision, heel sticks, and venipunctures.
• Children – Bruising, joint bleeds, and other sites of musculoskeletal bleeding become more
common once children begin walking . Frenulum and oral injuries are also common sites in young
toddlers.
• Older children and adults – Joint and muscle bleed.
• Hemarthroses : most common presentation ; spontaneous or with trivial trauma ; wt. bearing
joints most commonly affected eg. Knee joints.
• Visceral bleed : GI bleed , urogenitary bleed.

36. Stages of hemarthrosis
• Acute hemarthrosis : rupture of synovial blood vessels complete or incomplete absorption
• Target joint : joint may remain swollen, painful and tender for months and may suffer re-bleed.
• Chronic proliferative synovitis
• Reccurent bleed  Proliferating synovium often fills and distends the joint, which remain swollen
and enlarged in the absence of bleeding or pain.
• Chronic hemophilic arthropathy
• Terminal stage : fibrous or bony ankylosis

39. TREATMENT: TRANSFUSION THERAPY
• Factor replacement therapy for acute bleeding episode or as a prophylactic treatment.
• Primary prophylaxis is defined as a strategy for maintaining the missing clotting factor at levels
~1% or higher on a regular basis in order to prevent bleeds, especially the onset of hemarthroses.
• Regular infusions of FVIII (3 days/week) or FIX (2 days/week) .
• General considerations
 T/t should begin as soon as possible.
 Drugs that hamper platelet function such as Aspirin or NSAIDs s/b avoided.

40. • 1 unit is defined as amount of FVIII (100 ng/mL) or FIX (5 μg/mL) in 1 mL of normal plasma.
• 1 unit of FVIII per kg of BW increases the plasma FVIII level by 2%.
• One can calculate the dose needed to increase FVIII levels to 100% in a 70-kg severe hemophilia
patient (<1%) using the simple formula below.
 Thus, 3500 units of FVIII will raise the circulating level to 100%.
 FVIII dose (IU) = Target FVIII levels – FVIII baseline levels× body weight (kg) × 0.5 unit/kg
 FIX dose (IU) = Target FIX levels – FIX baseline levels× body weight (kg) × 1 unit/kg

41. • The FVIII half-life of 8–12 h requires injections twice a day to maintain therapeutic levels,
whereas the FIX half-life is longer, ~24 h, so that once-a-day injection is sufficient.
• Cryoprecipitate
 Enriched with FVIII ( each bag contains 80 IU of FVIII)
 Risk of blood-borne disease.
 Not longer used

42. NON-TRANSFUSION THERAPY IN HEMOPHILIA
• DDAVP (1-Amino-8-d-Arginine Vasopressin)
 Synthetic vasopressin analog
 Transient rise in FVIII and VWF, but not FIX, through a mechanism involving release from endothelial cells.
 DDAVP at doses of 0.3 μg/kg body weight, over a 20-min period, is expected to raise FVIII levels by 2-3 fold over
baseline, peaking between 30 and 60 min after infusion.
 No role in severe hemophilia ???
 Repeated dosing results in tachyphylaxis .
 More than three consecutive doses become ineffective, and if further therapy is indicated, FVIII replacement is
required to achieve hemostasis.

43.  Anti-fibrinolytic Drugs
 ε-amino caproic acid (EACA) or tranexamic acid.
 Duration of the treatment : 1 week or longer( depends on clinical indication )
 Tranexamic acid is given at doses of 25 mg/kg three to four times a day.
 EACA treatment requires a loading dose of 200 mg/kg (maximum of 10 g) f/b 100 mg/kg per
dose (maximum 30 g/d) every 6 h.
 Not indicated to control hematuria because of the risk of formation of an occlusive clot in the
lumen of genitourinary tract structures.

44. Just for fun !!!

45. COMPLICATIONS
1) Inhibitor formation
 Major complication.
 The prevalence of inhibitors to FVIII is estimated to be between 5 and 10% of all cases and ~20%
of severe hemophilia A patients.
 Inhibitors to FIX are detected in only 3–5% of all hemophilia B patients.

46. • High-risk group
 Severe deficiency (>80% of all cases of inhibitors),
 Familial history of inhibitor,
 African descent,
 Mutations in the FVIII or FIX gene resulting in deletion of large coding regions, or gross gene
rearrangements.
• Inhibitors usually appear early in life, at a median of 2 years of age, and after 10 cumulative days of
exposure.

47. When to suspect Factor inhibitors ?
• The clinical diagnosis of an inhibitor is suspected when pts do not respond to factor replacement
at therapeutic doses.
• Is there any test to confirm it ? : Yes Mixing test
• The results are expressed in Bethesda units (BU), in which 1 BU is the amount of antibody that
neutralizes 50% of the FVIII or FIX present in normal plasma after 2 h of incubation at 37°C.
• Clinically, inhibitor patients are classified as low responders or high responders.

48. THERAPY
• Two goals: the control of acute bleeding episodes and the eradication of the inhibitor.
• For the control of bleeding episodes
 Low responders, those with titer <5 BU, respond well to high doses of human or porcine FVIII
(50–100 U/kg), with minimal or no increase in the inhibitor titers.
 High-responder pts, those with initial inhibitor titer >10 BU do not respond to FVIII or FIX
concentrates. They respond to concentrates enriched for prothrombin, FVII, FIX, FX (prothrombin
complex concentrates [PCCs] or activated PCCs [aPCCs]), and more recently recombinant
activated factor VII (FVIIa) known as “bypass agents”.
 Therapeutic success : FVII > aPCC

49. Cont..
• Eradication of inhibitory antibody
• The most effective strategy is the immune tolerance induction (ITI) based on daily infusion of
missing protein until the inhibitor disappears.
• Typically requires periods longer than 1 year, with success rates of approx. 60%.
• Severe hemophilia and inhibitors resistant to ITI : Rituximab combined with ITI.

50. Complications cont..
2 ) Infectious diseases
 HCV infection : major cause of morbidity and 2nd leading cause of death.
 Co-infection of HCV and HIV : 50% of hemophilic pts.
 Response to HCV antiviral therapy :< 30% and even poor with HIV-HCV co-infection
3 ) Severe arthropathy
4 ) Chronic pain

51. Management of hemophilic carriers
• Usually not at risk of bleeding.
• Lyonisation(?)- may increase the risk.
• During pregnancy, both FVIII and FIX levels increase gradually until delivery : approx. 2-3 fold compared
to nonpregnant .
• After delivery, there is a rapid fall  represents an imminent risk of bleeding.
• Can be prevented by infusion of factor concentrate to levels of 50–70% for 3 days in the setting of
vaginal delivery and up to 5 days for cesarean section.
• In mild cases, the use of DDAVP and/or antifibrinolytic drugs is recommended.

52. Reference
• Wintrobe’s clinical hematology 13th edition
• Harrison 19th edition
• UptoDate 2018

53. THANK YOU