Dr Nannika Pradhan:Presentation on Bleeding Disorders North Bengal Medical College,Siliguri

1. APPROCH TO
BLEEDING
DISORDERS

2. Presenter
Dr. Nannika Pradhan
Chairman
Prof .Dr Spandhan Bhadury
Dt.of Presentation-28.02.24
BLEEDING DISORDERS

3. AGENDA
Haemostasis
Platelet activation and Coagulation cascade
Fibrinolytic System
Approach to a patient with bleeding disorder
Classification of bleeding disorder
 Blood Vessel Wall Disorders
 Platelet Disorders
 Coagulation Disorders
Investigation
Treatment

4. Primary and Secondary Hemostasis

5. Coagulation Cascade

6. Classification of Bleeding Disorders

7. EVALUATION
OF PATIENT
WITH
BELEEDING
DISORDERS

8. Vascular Disorder: Idiopathic Thrombocytopenic
Purpura
ITP is a disease of increased
peripheral platelet destruction.
Most patients produce auto-
antibodies to specific platelet
membrane glycoproteins.
 Most patients have either normal or
increased platelet production in BM
Primary :Acute and Chronic
Secondary ITP-HIV Infection, CLL,
Hepatitis C Virus infection,SLE
Hemorrhage represents the most serious
complication
 Mortality rate from hemorrhage is
approximately 1% in children and 5% in
adult
Increase risk of severe bleeding in adult
ITP
Spontaneous remission : occur in more
than 80 % in children : uncommon in adult

9. Idiopathic Thrombocytopenic Purpura
Clinical Manifestation
 Purpura /Petechiae /Ecchymoses
 Menorrhagia
 Epistaxis
 Gingival bleeding
 Recent virus immunization (acute ITP)
 Recent viral illness (acute ITP)
 Bruising tendency
 Retinal hemorrhage
 Evidence of intracranial hemorrhage
 Nonpalpable spleen
Clinical Appearance
 1.Acute ITP (children)
 2.Chronic ITP (adults

10. ITP: Laboratory Examination
Complete Blood Cell Count (CBC)
-Isolated thrombocytopenia
Increased Bleeding time
Bone Marrow Examination -
Megakaryocyte, Megakaryoblast
& Promegakaryocyte -->
increase/normal -Other cellular
component--> normal
Platelet Auto-antibody -PAIgG
(non-specific) -GP specific
antibody

11. Treatment & Prognosis
Acute ITP
• Self remission 80 %
• Platelet transfusion in severe bleeding
• Corticosteroid therapy within 3-4 weeks
• No response to corticosteroid > 6 months (15 %) consider Splenectomy
Chronic ITP
• Complete remission (10-20 %)
• Corticosteroid therapy to reduce phagocytic activity of RE system & suppress
antibody production
• Consider Splenectomy : -No response to high dose steroid -Cerebral haemorrhage

12. Vascular Disorder: Thrombotic Thrombocytopenic Purpura
Fulminant and lethal disorder
 Characterized by the formation of hyaline microthrombi within the
microvasculature throughout the body
 The thrombi is composed of platelets and fibrin
Initiated by endothelial injury with subsequent release of vWF and other
procoagulant materials
Severely reduced activity of ADAMTS13
The terrible PENTAD
Incidence ≈4/million/year; Often strikes young adults, mainly female
 Untreated, mortality >90%

13. Vascular Disorder: TTP
Labs:
Features of Hemolytic Anemia with a negative DCT
Thrombocytopenia,Proteinuria,ANA (+) ,elevation of BUN,Creatinine
Treatment:
o Treated with plasmapheresis, mortality <20%
o Plasmapheresis-60-80ml/kg of plasma should be removed and replaced with FFP
o Glucocorticoids
o Caplacizumab-11mg IV at least 15minutes prior to exchange ,followed by 11 mg S/C
after completion of plasma exchange on Day 1-30
o Rituximab-375mg/m2 once weekly for 4 doses
o Vincristine

14. Ehlers Danlos Syndrome
Compromises a group of autosomal
dominant disorders
Mutation in one or more of the several
genes (COL1A1,COL3A1,TNXB)
Skin hyper-elasticity and fragility, joint
hypermotility, diaphragmatic
hernias,dehiscenceof surgical incision
Ocular fragility
Genetic test can confirm the diagnosis
No cure
Physiotherapy Analgesics
Surgery to the damaged joints

15. Platelet Disorder(Qualitative/Quantitative ):Bernard –Soulier Syndrome

16. Platelet Disorder(Qualitative)Glanzmann’s Thrombasthenia

17. Glanzmann’s
Thrombasthenia

18. Drug Induced Bleeding
 Heparin-UFH,LMWHs and fondaparinux are anticoagulants that potentiate the action of antithrombin by
increasing its inhibitory action
 Warfarin and Vit K Antagonist-Warfarin is a 4 hydroxycoumarin derivative that exerts its action by blocking
the regeneration of Vitamin K form its epoxide
 Thrombolytic agents-act by stimulating endogenous fibrinolysis,convert plasminogen to plasmin
 Anti-platelets drugs-Platelet release defect-Aspirin,Clopidogrel,NSAIDS,Penicillin ,Uremia

19. Hemophilia :Introduction
Haemophilia is an X linked
disorder
History goes back to second
century when an inherited
bleeding disorder in males was
recognized in Talmudic records
First review of haemophilia
published by Nasse in 1820
FVIII was identified in 1937 by
Patek and Taylor which they
called antihemophilic factor (AHF)
In 1952, hemophilia B was
described and was named
Christmas disease

20. Types of Hemophilia
 Hemophilia A -classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting
protein.
 Hemophilia B - Christmas disease, is a genetic disorder caused by missing or defective factor IX, a clotting
protein. Only can be distinguished by specific coagulation factor assays
The incidence is only about 1 in 30 000 males
Hemophilia B is treated with factor IX concentrate
 Acquired hemophilia
• Persons without FVIII deficiency develops antibodies to FVIII
• Causes: Idiopathic usually in people >50 yrs
connective tissue disease
peripartum acquired hemophilia
malignancies, lymphoproliferative malignancies.
postpartum acquired hemophilia seen 2 to 5 months after delivery
 About 30 percent of people with hemophilia have no family history of the disorder. In these people
hemophilia is caused by a genetic change (spontaneous mutation)

21. Classification of Hemophilia

22. Clinical presentation
 Neonatal bleeding : ICH, severe hematoma and
prolonged bleeding from the cord or umbilical area
 Young children: oral bleeding during teeth
eruption, hemarthroses and hematomas occur
 The hallmark of hemophilia is haemorrhage into
joints
 A joint that has had repeated bleeds, at least 4
bleeds within a 6-month period is termed a target
joint. Commonly affected joints are the knees,
ankles and elbows
 Pseudotumors: buttock, pelvis, and thighs are
common locations for a pseudotumor

23. Prophylaxis dose
Prophylaxis intensity Hemophilia A Hemophilia B
High dose 25-40 IU FVIII/kg every 2 days 40-60 IU FIX/kg twice per week
Intermediate dose 15-25 IU FVIII/kg 3 days per week 20-40 IU FIX/kg twice per week
Low dose 10-15 IU FVIII/kg 2-3 days per week 10-15 IU FIX/kg 2 days per week

24. Treatment
Desmopressin
 Effective in the treatment of mild to moderate
disease
 Dose is 0.3 mcg/kg of body weight
 Intranasal spray (1.5 mg/mL)
Emicizumab
 First-in-class bispecific monoclonal antibody that
performs the function of activated FVIII
 In 2018, the FDA extended approval for use of
Emicizumab to patients without FVIII inhibitors,
based on the HAVEN 3 trial results
N Engl J Med. 2017 Aug 31. 377 (9):809-818.
N Engl J Med. 2018 Aug 30. 379 (9):811-822
FEIBA
 is a "bypassing agent," a factor product containing
several other clotting proteins, enabling it to
"bypass" the need for the deficient clotting factors
VIII or IX
 FDA has approved FEIBA for routine prophylaxis in
patients with inhibitors
ITI
 Rituximab has been used with success in the factor
VIIIITI.
 The choice of FVIII dosing regimen for ITI has
ranged from 50 IU/kg 3 times weekly to 300
IU/kg/d.

25. Gene Therapy Other modalities
 Ex vivo gene therapy : cells are genetically
modified to secrete factor VIII and then are
replanted into the recipient
 In vivo gene therapy: a vector ,typically a virus
altered to include FVIII DNA, is directly injected
into the patient
 Non-autologous gene therapy: cells modified to
secrete FVIII are packaged in immunoprotected
devices and implanted into recipients
 Recombinant activated factor VII
• Recombinant FVIIa is a vitamin K–dependent
glycoprotein
• structurally similar to human plasma–derived
FVIIa
 Activated prothrombin complex concentrate
(APCC)
• The recommended dose is 50−100 U/kg every
8−12 h, up to a maximum of 200 U/kg/day

26. FDA Approved gene therapy
First gene therapy approved for Hemophilia A- Valoctocogene Roxaparvovec, in June
2023.
In November 2022, the FDA approved Etranacogene ,Dezaparvovec, an AAV5-based gene
therapy, for the treatment of adults with Hemophilia B
N Engl J Med. 2022 Jul 21. 387 (3):237-247

27. Von Willbrands Disease
 (vWF) -glycoprotein crucial to primary hemostasis through platelet and subendothelial collagen
adhesion, and the intrinsic coagulation cascade, through factor VIII stabilization
 Hereditary coagulation abnormality caused by either:
Reduced level of vWF
Abnormality in vWF
 Due to Point mutation or Major deletion
 Diagnoses of importance related to vWF include von Willebrand disease, Thrombotic Thrombocytopenic
purpura, and Bernard-Soulier syndrome

28. Classification of VWD
TYPE I
Partial quantitative vWF deficiency
Usually inherited as an autosomal dominant.
TYPE II
Qualitative vWF deficiency
Usually inherited as an autosomal dominant
TYPEIII
Total VWF deficiency
Usually inherited as autosomal recessive.

29. Clinical Manifestations
Signs of external bleeding
 Slow, persistent, prolonged bleeding from minor trauma and small cuts
 Uncontrollable haemorrhage after dental extraction
Epistaxis
 GI bleeding from ulcers and gastritis
Neurologic signs such as pain and paralysis
 Hemarthrosis
Excessive bleeding following surgery
Bleeding from cuts that resumes after stopping for a short time
Haematuria

30. A vWF Multimer Analysis

31. vWD: Type 2N

32. Treatment :vWD
Transfusion with Factor VIII during bleeding
Treatment for Type 1 vWD is 1diamino 8 arginine vasopressin(DDAV or
desmopressin )which results in release of vWF and FVIII from endothelial stores.
vWF replacement Therapy-For Type 3,severe Type 1,Type 2A,2B and 2M disease
for major procedure requiring longer periods of hemostasis.
Recombinant vWF Concentrates -50-80units/kg
EACA or Tranexamic acid

33. Disseminated Intravascular Coagulation(DIC)
deposition of fibrin within blood vessels with consumption of coagulation factors
and platelets
consequence of many disorders which release procoagulant material into the
circulation or diffuse endothelial damage or generalized platelet aggregation

34. Causes of DIC
Infections – Gram negative septicaemia – Septic abortion
Malignancy – Widespread mucin secreting adeno-carcinoma – Acute
promyelocytic leukaemia
 Hypersensitivity reactions – Anaphylaxis – Incompatible blood transfusion
Obstetric complications – Amniotic fluid embolism – Eclampsia, retained
placenta
 Widespread tissue damage – Following surgery/trauma – After severe
burns
Miscellaneous – Liver failure – Severe burns – Hypothermia – Snake
venoms – Acute hypoxia

35. Clinical Features
 Bleeding, particularly from venipuncture
 Purpura
 Generalized bleeding in GIT, oropharynx,
lungs, urogenital tract, vaginal bleeding
 Less frequently, microthrombi may cause
skin lesions, renal failure, gangrene of fingers
Laboratory finding
 The platelet count is low
 Fibrinogen low
 Thrombin time is prolonged
 High level of fibrin degradation products (FDP)
 PT and APTT are prolonged in acute syndromes
 Blood film
 Fragmentation of red cells

36. International Society of Thrombosis& Hemostasis(ISTH) DIC
Score

37. Treatment
Treat underlying cause
 Supportive therapy with fresh frozen plasma (FFP-10-20 ml/kg)and
platelets concentrates (1-2 U/kg)
 Cryoprecipitate may also required (1-2 bags /10kgs)
Antifibrinolytics –EACA and TXA is contraindicated

38. Summary of DIC

39. Coagulation Disorders

40. Take Home Message
If there is active bleeding, consultation with the specialist may be considered to
assist with definitive diagnosis
 For patients who are ultimately diagnosed with a bleeding disorder,
individualized long-term haemostatic management is to be considered
Treatment planning is essential for good outcome and should involve liaison
between the physician and the hemophilia center
Written post-procedural instructions should be provided and must include
emergency contact numbers