Bleeding disorder hematology medical .pdf

bleeding disorders

1. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Hematology:
Bleeding Disorders
Dr. Nabil Abdelrazik, M.D, FEB pedOncol
Consultant Pediatrics
Pediatric Hematology/Oncology
Dr.Erfan& Bagedo General Hospital

2. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Hemostasis
BV Injury
Platelet
Aggregation
Platelet
Activation
Blood Vessel
Constriction
Coagulation
Cascade
Stable Hemostatic Plug
Fibrin
formation
Reduced
Blood flow
Damage/contact.
Primary hemostatic plug
Neural
•CBC-Plt
•BT,(CT)
•PT
•PTT
Platelet study
Antibody tests
Factor Assay
Contact

3. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
HEMOSTASIS
Primary Hemostasis
–Blood vessel contraction
–Platelet Plug Formation
Secondary Hemostasis
–Activation of Clotting Cascade
–Deposition & Stabilization of Fibrin
Tertiary Hemostasis
–Dissolution of Fibrin Clot
–Dependent on Plasminogen Activation

4. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Classification:
•Disorders of Blood vessels
•Scurvy, senile purpura, Henoch-Schonlein syndrome.
•Disorders of Platelets
•Thrombocytopenia ITP, TTP, HUS, DIC.
•Aspirin therapy, Thrombasthenia,
•Disorders of Coagulation
•Extrinsic, intrinsic, combined.
•Other disorders
•Post transfusion purpura, MPS, MDS.

5. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
XIIa
Coagulation cascade
IIa
Intrinsic system (surface contact)
XII
XI XIa
Tissue factor
IX IXa VIIa VII
VIII VIIIa
Extrinsic system (tissue damage)
X
V Va
II
Fibrinogen Fibrin
(Thrombin)IIa
Vitamin K dependant factors
Xa

6. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Fibrinolytic Pathway

7. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Tests of Hemostasis:
Screeningtests:
–Bleeding.T -10m. Platelet & BV function
–Prothrombin.T –Extrinsic,
–aPTT –Instrinsic
–Thrombin.T –common path. (DIC)
Specifictests:
–Factor assays –hemophilia.
–Tests of thrombosis –TT, FDP, DDA,
–Platelet function studies:
»Adhesion, Aggregation, Release tests.
–Bone Marrow study

8. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Bleeding: Clinical Features
Local -Vs -General, spontaneous . .
Hematoma / Joint Bleeds-Coag
Skin / Mucosal Bleeds –PLT
wound / surgical bleeding –
Immediate -PLT
Delayed -Coagulation

9. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Platelet Coagulation
Petechiae, PurpuraHematoma, Joint bl.

10. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Vascular disorders:
Petechiae, purpura, ecchymoses
senile purpura
vitamin C deficiency (scurvy)
Connective tissue disorders
Infections –Meningococcus
Henoch-Schonlein Purpura-Immu

11. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Senile Purpura

12. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Petechiae in
Vasculitis
(Rocky Mountain Spotted Fever)

13. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Henoch-Schonleinpurpura
Immune disorder
Children
Follows infection
Petechiae with edema
and itching.

14. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Henoch-Schonlein purpura
20y Male, fever, painful symmetric polyarthritis for a day. During the next two days, edema
and palpable purpura developed.

15. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Objectives
I.Clinical aspects of bleeding
I.Hematologic disorders causing bleeding
•Coagulation factor disorders
•Platelet disorders
II.Approach to acquired bleeding disorders
•Hemostasis in liver disease
•Surgical patients
•Warfarin toxicity
III.Approach to laboratory abnormalities
•Diagnosis and management of thrombocytopenia
I.Drugs and blood products used for bleeding

16. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Objectives -I
Clinical aspects of bleeding

17. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Clinical Features of Bleeding Disorders
Platelet Coagulation
disorders factor disorders
Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficialLarge, deep
Hemarthrosis / muscle bleedingExtremely rare Common
Bleeding after cuts & scratchesYes No
Bleeding after surgery or traumaImmediate, Delayed (1-2 days),
usually mild often severe

18. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Petechiae
Do not blanch with pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
(typical of platelet disorders)

19. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Ecchymoses
(typical of coagulation
factor disorders)

20. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Objectives -II
Hematologic disorders causing bleeding
–Coagulation factor disorders
–Platelet disorders

21. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
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

22. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Hemophilia A and B
Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linked
recessive 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

23. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
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

24. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Hemarthrosis (acute)

25. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment of hemophilia A
Intermediate purity plasma products
–Virucidally treated
–May contain von Willebrand factor
High purity (monoclonal) plasma products
–Virucidally treated
–No functional von Willebrand factor
Recombinant factor VIII
–Virus free/No apparent risk
–No functional von Willebrand factor

26. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
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: 80-100% 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)

27. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
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

28. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Formation of inhibitors(antibodies)
Infusion of the deficient clotting factor may
initiate an immune response in patients with
either factor VIII or factor IX deficiency.
Inhibitors are antibodies directed against factor
VIII or factor IX that block the clotting
activity.

29. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
C/P of inhibitors (antibodies)
Failure of a bleeding episode to respond to
appropriate replacement therapy is usually the
first sign of an inhibitor.
Inhibitors develop in approximately 25–35%of
patients with hemophilia A; the percentage is
somewhat lower in patients with hemophilia B.

30. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment of inhibitors(antibodies)
Many patients who have an inhibitor lose this
inhibitor with continued regular infusions.
Others have a higher titer of antibody with
subsequent infusions and may need to go
through desensitization programs, in which
high doses of factor VIII or factor IX are
infused in an attempt to saturate the antibody
and permit the body to develop tolerance.

31. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment of inhibitors(antibodies)
Factor IX immune tolerance programs have
resulted in nephrotic syndrome in some
patients.
Rituximabhas been used, off label, as an
alternate therapy for patients with high titer
inhibitors who have failed immune tolerance
programs.

32. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment of inhibitors(antibodies)
If desensitization fails, bleeding episodes are
treated with either recombinant factor VIIa or
activated prothrombin complex concentrates.
The use of these products bypasses the inhibitor
in many instances, but may increase the risk of
thrombosis.

33. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Viral infections in hemophiliacs
HIV -positive HIV-negative
(n=382) (n=345)
53% 47%
Hepatitis serology % positive % negative
Negative 1 20
Hepatitis B virus only 1 1
Hepatitis C virus only 24 45
Hepatitis B and C 74 34
Blood 1993:81;412-418

34. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment of hemophilia B
Agent
–High purity factor IX
–Recombinant human factor IX
Dose
–Initial dose: 100U/kg
–Subsequent: 50U/kg every 24 hours

35. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Deficiencies of the Contact Factors
(Nonbleeding Disorders)
Deficiency of the “contact factors” (factor XII,
prekallikrein, and high molecular weight
kininogen) causes prolonged PTT, but no
bleeding symptoms.
They do not need treatment, even for major
surgery.

36. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Factor VII Deficiency
May have spontaneous intracranial hemorrhage
Frequent mucocutaneous bleeding.
Prolonged PT
Normal PTT.
Factor VII assays show a marked reduction of factor VII.

37. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Therapy
Therapy with FFP is difficult and is often
complicated by fluid overload.
A commercial concentrate of recombinant factor
VIIa.
Not approved by the FDA.

38. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
DEFICIENCIES IN THE FACTORS OF THE
COMMON PATHWAY
(FACTORS I, II, V, AND X)
CAUSING
PROLONGATION OF BOTH PTAND PTT

39. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Factor X Deficiency
Is a rare autosomal disorder that results in
mucocutaneous and post-traumatic bleeding.
In patients with hereditary factor X deficiency,
factor X levels can be increased using either FFP
or prothrombin complex concentrate, 1 U/kg will
increase the plasma level of factor X by 1%.

40. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Prothrombin (Factor II) Deficiency
Caused either by a markedly reduced prothrombin level
(hypoprothrombinemia) or by functionally abnormal
prothrombin (dysprothrombinemia).
Prothrombin assays show a markedly reduced
prothrombin level.
Patients are treated with either prothrombin complex
concentrates 1 IU/kg or FFP.

41. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Factor V Deficiency
An autosomal recessive
Termed parahemophilia.
Hemarthroses occur rarely;
mucocutaneous bleeding and hematomas are the most common
symptoms.
Severe menorrhagia is a frequent symptom in women.
FFP is the only currently available therapeutic product that
contains factor V.

42. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Fibrinogen Deficiency (Factor I)
Congenital afibrinogenemiais a rare AR disorder in which there is an absence of
fibrinogen.
Dysfibrinogenemia
Do not bleed as frequently as patients with hemophilia.
Rarely have hemarthroses.
Neonatal period: GI hemorrhage or hematomas after vaginal delivery.
Prolonged PT, PTT, and TT.
In the absence of consumptive coagulopathy, an unmeasurable fibrinogen level is
diagnostic.

43. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Treatment
Currently, no fibrinogen concentrates are commercially
available.
Treatment: FFP or cryoprecipitate.
The hemostatic level of fibrinogen is >60 mg/dL.
Each bag of cryoprecipitate contains 100–150 mg of
fibrinogen.

44. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Factor XIII Deficiency (Fibrin-
Stabilizing Factor Deficiency)
Typically, patients have trauma 1 day and then have a
bruise or hematoma the next day.
Clinical symptoms include →mild bruising,
→delayed separation of the
umbilical stump >4 wk,
→poor wound healing,
→recurrent spontaneous
abortions in women.

45. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Results of the usual screening tests for hemostasis are normal.
More specific assays for factor XIII are immunologic.
Infusion of FFP or cryoprecipitate will correct the deficiency in
these patients.
In patients with significant bleeding symptoms, prophylaxis can be
achieved with infusion of cryoprecipitate every 3–4 wk.

46. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Summary
Factors II, V, VII, X, XI, fibrinogen deficiencies cause
bleeding
Prolonged PTand/or PTT
Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubilityabnormal
Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding

47. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
von Willebrand Disease
Is the most common hereditary bleeding
disorders.
Some reports suggest that it is present in 1-2% of
the general population.

48. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
von Willebrand Disease: Pathophysiology
von Willebrand factor
–Is a large multimeric glycoprotein that is
synthesized in endothelium and
megakaryocytes

49. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
von Willebrand Disease: Pathophysiology
–During normal hemostasis, V WF adhers to the
subendothelial matrix after vascular damage →
the conformation of VWF is changed so that it
causes platelets to adhere to VWF through their
glycoprotein IB (GPIb) receptor.

50. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
von Willebrand Disease: Pathophysiology
–These platelets are then activated, causing the
recruitment of additional platelets, and exposing
phosphatidylserine, which is an important
regulatory step for factor V and factor VIII-
dependent steps in the clotting cascade.

51. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
von Willebrand Disease: Pathophysiology
VWF also serves as the carrier protein for
plasma factor VIII. A severe deficiency of
VWF may cause a secondary deficiency in
factor VIII, even though the gene for factor
VIII is normal. This is the cause of autosomal
deficiency of factor VIII, now known to be a
molecular abnormality of VWF and termed
type 2N VWD.

52. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Von-Willebrand Disease
vWF: F-VIII & PLT function.
Defective Platelet Adhesion
Skin Bleeding
Prolonged Bleeding time.
Low Factor VIII levels.

53. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Clinical features
Inheritance -autosomal dominant
Incidence -1/10,000
Clinical features -mucocutaneous bleedingincluding
excessive bruising, epistaxis, menorrhagia, and postoperative
hemorrhage, particularly after mucosal surgery such as
tonsillectomy or wisdom tooth extraction. .
The American College of Obstetrics and Gynecology recommends
VWD testing on all teenage females with menorrhagia before
initiating hormonal therapy or oral contraceptives.

54. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Clinical features
Rarely, patients with VWD may have gastrointestinal
telangiectasia. This combination results in major bleeding and
accounts for numerous hospital admissions for patients with
severe disease.
In patients with type 3 or homozygous VWD, bleeding symptoms
are much more profound. These patients are usually diagnosed
early in life and may have severe epistaxis or menorrhagia that
results in major blood loss and possibly shock.
Rarely, patients with severe type 3 VWD have joint hemorrhages
or spontaneous central nervous system hemorrhages.

55. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Differences between von Willebrand
Disease and Hemophilia A

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Variants of von Willebrand Disease

57. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Laboratory evaluation of
von Willebrand disease
Classification
–Type 1 Partial quantitative deficiency
–Type 2 Qualitative deficiency
–Type 3 Total quantitative deficiency
–While the platelet count is usually normal in most patients, those with type 2B
disease or platelet type (pseudo-VWD) may have lifelong thrombocytopenia.
Diagnostic tests:
vonWillebrand type
Assay 1 2 3
vWF antigen  Normal 
vWF activity   
Multimer analysis Normal Normal Absent

58. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
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

59. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Replacement therapy
Current replacement therapy uses plasma-derived VWF containing concentrates that also
contain factor VIII.
The plasma half-life of both factor VIII and VWF is 12hr, but the alteration of VWF
during fractionation results in half-lives of 8–10 hours when infusing concentrates.
Purified VWF concentrates or recombinant VWF concentrates (containing no factor
VIII) may become available in the near future. These will be useful in presurgical
management or in prophylaxis. When used for acute bleeding, however, these VWF
concentrates may need to be supplemented by an infusion of recombinant factor VIII for
the first infusion. Both VWF and factor VIII are required for normal hemostasis. If only
VWF is replaced, the endogenous correction of the factor VIII level takes 12–24 hr.
Dental extractions and sometimes nosebleeds can be managed with both desmopressin
and an antifibrinolytic agent such as e-aminocaproic acid (Amicar).

60. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Recommended Treatment in von
Willebrand Disease

61. Copyright © 1982 -2009 Dr. Erfan & Bagedo Hospital
Thank you