blood disorders

1. COAGULATION DISORDERS
PRESENTERS;
• SAID A. SAID
• CHARLES MADARAKA
• REUBEN MLYAKADO
• SARAH MAREGES
• CHRISTINA KISONGELA
• JUSTINE KWIMENYA
SS

2. Outline
Introduction
Congenital coagulation disorder
Acquired coagulation disorders

4. Hemostasis cont.
• Normal hemostasis.
A, After vascular injury, local neurohumoral factors induce a transient
vasoconstriction.
B, Platelets bind via glycoprotein 1b (GpIb) receptors to von
Willebrand factor (vWF) on exposed extracellular matrix (ECM) and
are activated, undergoing a shape change and granule release.
Released adenosine diphosphate (ADP) and thromboxane A2 (TxA2)
induce additional platelet aggregation through binding of platelet
GpIIb-IIIa receptors to fibrinogen. This platelet aggregate fills the
vascular defect, forming the primary hemostatic plug.

5. Hemostasis cont.
C, Local activation of the coagulation cascade (involving tissue factor
and platelet phospholipids) results in fibrin polymerization,
“cementing” the platelets into a definitive secondary hemostatic plug
that is larger and more stable than the primary plug and contains
entrapped red cells and leukocytes.
D, Counterregulatory mechanisms, such as release of t-PA (tissue
plasminogen activator, a fibrinolytic product) and thrombomodulin
(interfering with the coagulation cascade), limit the hemostatic
process to the site of injury.

10. HEREDITARY COAGULATION DISODERS
• Hereditary coagulation disorders occurs due to the absence or
deficiency of specific clotting protein
• Either quantitavive or qualitative defects in single coagulation factor

11. Haemophilia A
Is the most common of the hereditary clotting factor
deficiencies.
The prevalence is 1 in 10,000 males
 The inheritance is sex‐linked recessive
One‐third of patients have no family history and these
cases result from recent mutation.

12. Factor 8 and 9 Genes on X-Chromosome

13. Molecular genetics
The defect is an absence or low level of plasma factor
VIII.
Approximately half of the patients have missense or
frameshift mutations or deletions in the factor VIII gene.
In others a characteristic ‘flip‐tip’ inversion is seen in
which the factor VIII gene is broken by an inversion at
the end of the X chromosome.
 This mutation leads to a severe clinical form of
haemophilia A.

14. Inheritance pattern in haemophilia

16. Clinical features
Soft tissue bleeding and excessive bruising when they start to
be active.
Recurrent painful haemarthroses and muscle haematoma.
Prolonged bleeding occurs post trauma, after dental
extractions, surgical procedures.
Spontaneous haematuria and gastrointestinal haemorrhage,
sometimes with obstruction resulting from intramucosal
bleeding, can also occur.
Spontaneous intracerebral haemorrhage(rare)

18. Laboratory findings
The following tests are abnormal:
 Activated partial thromboplastin time (APTT).
Factor VIII clotting assay.
Mixing study-Normalize in deficiency and low in
inhibitors.
The platelet function analysis‐100 (PFA‐100) and
prothrombin time (PT) are normal.

19. Factor IX deficiency (haemophilia B,
Christmas disease)
The inheritance and clinical features of factor IX
deficiency (Christmas disease, haemophilia B) are
identical to those of haemophilia A.
Indeed, the two disorders can only be distinguished by
specific coagulation factor assays.
The incidence is 1 in 25,000 males.

20. Cont…..
Factor IX is coded by a gene close to the gene for
factor VIII near the tip of the long arm of the X
chromosome
Its synthesis is vitamin K‐dependent.

21. Laboratory test
 Abnormal
APTT
Factor IX clotting assay.
 Mixing study
As in haemophilia A, the PFA‐100 and PT tests are
normal

22. Treatment
PRBC
FFP
Cryoprecipitate
Antifibrinolytics
Antipain

23. Treatment
Bleeding episodes are treated with factor VIII replacement
therapy, and spontaneous bleeding is usually controlled if the
patient’s factor VIII level is raised to 30–50% of normal.
For major surgery, serious post‐traumatic bleeding or when
haemorrhage is occurring at a dangerous site, the factor VIII
level should be elevated to 100%
Maintaine above 50% when acute bleeding has stopped, until
healing has occurred.
On average, factor VIII infusion produces a plasma increment
of 20 U/L for each unit infused/kg body weight.

24. Treatment cont.
This advance has reduced the occurrence of crippling
haemarthroses and the need for inpatient care. Severely affected
patients are now reaching adult life with little or no arthritis.
 After the first spontaneous joint bleed, most boys with severe
haemophilia are started on prophylactic factor VIII three times a
week, aiming to keep their factor VIII trough levels above 1%.
Haemophiliacs are advised to have regular conservative dental care.
Haemophiliac children and their parents often require extensive help
with social and psychological matters.
Lifestyle of a haemophilic child can be almost normal but certain
activities such as extreme contact sports are to be avoided, or
undertaken with extra prophylaxis

25. Cont….
Monoclonal antibody(Emicizumab)
By passing agents(Feiba(An activated prothrombin
complex concetrate) and Nove Seven(Activated
recombinant factor VII))-In pts with inhibitors
Gene therapy

26. Cont.
Gene-therapy-To maintain factor levels above 1% to prevent
most of the mortality and morbidity of factor VIII or IX deficiency
Various viral vectors (retroviral, adeno‐associated) as well as
non‐viral vectors are being explored.
 Durable (>2 years after a single injection) increased levels of
factor IX have been obtained with an adenoviral vector carrying
the gene to the liver, sufficient to obviate the need for
replacement therapy except for trauma or surgery.
Trials of factor VIII gene therapy are also planned

27. Von Willebrand disease
In this disorder there is either a reduced level or abnormal
function of von Willebrand factor (VWF) resulting from a wide
variety of mainly missense mutations in different parts of the
gene.
VWF is produced in endothelial cells and megakaryocytes.
It has two roles
It promotes platelet adhesion to sub endothelium and each
other at high shear rates
It is the carrier molecule for factor VIII, protecting it from
premature destruction.

28. Cont….
Chronic elevation of VWF is part of the acute phase
response to injury, inflammation, neoplasia or
pregnancy.
VWF is synthesized as a large 600‐kDa protein which
then forms high molecular weight multimers which are
the largest molecules in blood.
Affects up to 1% of the population

29. Cont…..
VWD is the most common inherited bleeding disorder. Usually,
the inheritance is autosomal dominant.
 The severity of the bleeding is highly variable, depending on
mutation type
 Women are more badly affected than men at a given VWF
level.
Typically, there is mucous membrane bleeding (e.g. epistaxes,
menorrhagia), excessive blood loss from superficial cuts and
abrasions, and operative and post‐traumatic haemorrhage.

30. Laboratory findings
The PFA‐100 test is abnormal. Factor VIII levels are
often low. If low, a factor VIII/VWF binding assay is
performed.
The APTT may be prolonged.
VWF levels are usually low.
There is defective platelet aggregation by patient
plasma in the presence of ristocetin (VWF: Rco)

31. Treatment
 Local measures and antifibrinolytic agent (e.g. tranexamic
acid for mild bleeding).
 DDAVP infusion for those with type 1 VWD. This releases
VWF from endothelial cells 30 minutes after intravenous
infusion.
 High‐purity VWF concentrates for patients with very low
VWF levels.
 Plasma‐derived factor VIII/VWF concentrates are used.
Recombinant VWF is now in clinical trials.

32. Treatment cont.
•Desmopressin is indicated for patients with
haemophilia A with factor 8 activity>5% It
increases factor 8 levels-Maintains hemostasis in
haemophilia A during surgery and post op and
admistered 30 mins before procedure.Not for
haem B and activity < 5% and pts with factor 8
antibodies.

34. Hereditary deficiency of other coagulation
factors
All these disorders (deficiency of fibrinogen,
prothrombin, factors V, VII, combined V and VIII, factors
X, XI, XIII or mutation of thrombomodulin) are rare.
 In all the inheritance is autosomal recessive except for
factor XI deficiency where there is variable penetrance.
Recombinant factor VII is available for therapy.
 Factor XI deficiency is seen mainly in Ashkenazi Jews
and occurs in either sex.

35. Cont……
The bleeding risk shows incomplete correlation to severity
of the deficiency.
Bleeding only occurs after trauma such as surgery.
Treatment is with fibrinolytic inhibitor, factor XI concentrate
or fresh frozen plasma.
 Factor XIII deficiency produces a severe bleeding
tendency, characteristically with umbilical stump bleeding.
Plasma concentrates and recombinant preparation of factor
XIII are available.

36. AQUIRED COAGULATION DISORDERS
• More common than the inherited disorders.
• Unlike the inherited disorders, multiple clotting factor
deficiencies are usual

37. AQUIRED COAGULATION DISORDERS
• Disseminated Intravascular Coagulation
• Vitamin k deficiency
• Liver disease
• Antibodies against factor VIII or other factors
• Massive transfusion

38. Disseminated Intravascular coagulation
Widespread inappropriate intravascular deposition of fibrin with
consumption of coagulation factors and platelets
Occurs as a consequence of many disorders that release
procoagulant material into the circulation or cause widespread
endothelial damage or platelet aggregation .
It may be associated with a fulminant haemorrhagic or
thrombotic syndrome with organ dysfunction
The main clinical presentation is with bleeding but 5–10% of
patients manifest thrombotic lesions

39. Types of DIC
Acute DIC
Develops when sudden exposure of blood to procoagulants (
tissue factor [TF], ) generates intravascular coagulation.
 Compensatory hemostatic mechanisms are quickly
overwhelmed as result consumptive coagulopathy leading to
hemorrhage develops.
Chronic DIC
Reflects a compensated state that develops when blood is
continuously or intermittently exposed to small amounts of TF.
There is minimal laboratory and clinical changes

41. Pathogenesis
 The key event underlying DIC is increased activity of thrombin
in the circulation that overwhelms its normal rate of removal by
natural anticoagulants .
This can come from tissue factor (TF) release into the
circulation from damaged tissues present on tumour cells
 Widespread endothelial damage and collagen exposure (e.g.
endotoxaemia, Gram‐negative and meningococcal septicaemia,
septic abortion), certain virus infections and severe burns or
hypothermia.

42. Cont……
Proinflammatory cytokines and activation of monocytes by
bacteria up‐regulate tissue factor
In addition to its role in the deposition of fibrin in the
microcirculation, intravascular thrombin formation produces
large amounts of circulating fibrin monomers
Intense fibrinolysis is stimulated by thrombi on vascular walls
and the release of split products interferes with fibrin
polymerization, thus contributing to the coagulation defect.
The combined action of thrombin and plasmin causes depletion
of fibrinogen and all coagulation factors.

43. Clinical features
Bleeding, particularly from venepuncture sites or
wounds .
There may be generalized bleeding in the GI tract, the
oropharynx, into the lungs, urogenital tract and in
obstetric cases, vaginal bleeding may be particularly
severe.
 Less frequently, microthrombi may cause skin lesions,
renal failure, gangrene of the fingers or toes or cerebral
ischaemia.

45. Laboratory investigations
 The platelet count is low.
Fibrinogen concentration is low
 The thrombin time is prolonged
High levels of fibrin degradation products such as
D‐dimers are found in serum and urine
The PT and APTT are prolonged in the acute
syndromes
Blood film examination- Haemolytic anaemia
(‘microangiopathic’)

46. Treatment
Treatment Treatment of the underlying cause is most important.
The management of patients who are bleeding differs from that
of patients with thrombotic problems.
Bleeding
 Supportive therapy with fresh frozen plasma and platelet
concentrates is indicated in patients with dangerous or
extensive bleeding.
Cryoprecipitate or fibrinogen concentrates provide more
concentrated fibrinogen; red cell transfusions may be required.

47. Cont…
Thrombosis
Heparin or antiplatelet drugs to inhibit the coagulation
process is considered in those with thrombotic problems
such as skin ischaemia.
Fibrinolytic inhibitors should not be used because of
consequent failure to lyse thrombi in organs such as the
kidney

48. Vitamin K deficiency
Fat‐soluble vitamin K is obtained from green
vegetables and bacterial synthesis in the gut.
 Deficiency may present in the newborn (haemorrhagic
disease of the newborn) or in later life.
Deficiency of vitamin K is caused by an inadequate
diet, malabsorption or inhibition of vitamin K by vitamin
K antagonist drugs such as warfarin.

49. Vitamin K deficiency
It is acofactor for vitamin K dependent carboxylation
which includes many enzymes
The process of vitamin K carboxylation allows the
coagulation factors to bind to Calcium ions which further
facilitates cascade pathway.
Warfarin is associated with a decrease in the functional
activity of factors II, VII, IX and X and proteins C and S

50. Management
• It depends on severity and underlying cause
• Vit K 10mg IM
• FFP 15-20mg/kg

51. Liver diseases
Liver synthesize fibrinogen, factors II,VII,IX,X, XI and
XIII.
Also it produce natural anticoagulants protein C,S,
antithrombin
Chronic liver disease is characterized by reduced
synthesis of procoagulant proteins (FII, FV, FVII, FIX,
FX, and FXI).

52. Liver disease
 Clotting factor levels usually fall in parallel with the
progression of liver disease, although levels vary
considerably.
 Fibrinogen levels are normal or increased in most
patients with stable cirrhosis.
 An acquired dysfibrinogenemia develops in 50%-78%
of patients with chronic liver disease.

53. Liver disease
PT and PTT prolonged ,decreased in protein C,S, AT
and decreased fibrinogen in advanced stage.
Moderate thrombocytopenia.

54. Treatment
• FFP 10-15ml/kg if bleeding
• Platelet transfusion if bleeding is severe
• Keep fibrinogen >100mg/dl

55. Acquired hemophilia A
Acquired hemophilia A (AHA) is a rare disorder with an
incidence of approximately 1 per million/year.
 The disease occurs due to autoantibodies against
coagulation factor VIII (FVIII) which neutralize its
procoagulant function and result in severe, often life-
threatening bleeding.
 The antibodies arise in individuals with no prior history
of hemophilia A.

56. Acquired hemophlia A cont..
• It is associated with pregnancy, autoimmune diseases,
malignancy, infections or medication and occurs most
commonly in the elderly.
• Approximately 50% of the patients remain idiopathic
with no known underlying pathological condition..

57. Pathophysiology
AHA is an autoimmune disease caused by the
spontaneous production of neutralizing immunoglobulin
G (IgG) autoantibodies (inhibitors) targeting
endogenous FVIII.
Recent research suggests that the breakdown of
immune tolerance is caused by a combination of genetic
and environmental factors.

58. Clinical features
Spontaneous hemorrhages into the skin, muscles or
soft tissues or excessive bleeding during surgery.
Hemarthrosis which is the hallmark of congenital
severe hemophilia,

59. Diagnosis
CBC, PT, and isolated PTT
Mixing test
FVIII inhibitor –confirmed and quantified by Bethesda assay

60. Treatment
Treatment of underlying causes
Elimination of inhibitor
Prednisolone 1mg/kg
Rituximab
Control of bleeding
Low titer inhibitor:FVIII concentrate
rFVIIa

61. Acqired VWD
Is a rare bleeding disorder that due to structural or
functional alteration in von Willebrand factor (VWF) that
is not inherited and causes bleeding.

62. Pathogenesis of acquired VWD

63. Pathogenesis
The defects in VWF structure or function associated
with AVWS depend primarily on the underlying cause of
the condition .
Development of VWF aoutoantibodies
Mechanical destruction of VWF under high shear stress
Reduced synthesis

64. Laboratory tests
The routine tests recommended are essentially the
same as those used to diagnose inherited VWD
Normal PT and PTT
VWF antigen assays (VWF:Ag)
Ristocetin cofactor assay (VWF:RCo) -decreased
Multimer analysis(qualitative visual assessment of the
size sprectrum and banding pattern of VWF multimer).

65. Treatment
Underlying cause
Desmopressin, tranexamic acid and recombinant factor
VIIa (rFVIIa) .
 VWF-containing concentrates are effective in most
patients with AVWS

66. Massive transfusion syndrome
Many factors may contribute to a bleeding disorder following
massive transfusion.
Blood loss results in reduced levels of platelets, coagulation
factors and inhibitors.
 Further dilution of these factors occurs during replacement with
red cells.

67. Treatment
Management Platelet concentrates are given to maintain a
platelet count above 75 × 109/L or 100 × 109/L in cerebral injury
or after trauma.
The PT and APTT should be kept to less than 1.5 times normal
with fresh frozen plasma given initially at 15 mL/kg. It is usually
necessary to give 4–6 units of FFP for every 6 units of red cells
transfused.
FFP is started early with red cell transfusion. Some protocols
include 1 : 1 : 1 for red cells, platelet packs and FFP.
Cryoprecipitate or fibrinogen concentrate is given to keep
fibrinogen above 1.5 g/L.

69. Refferences
• Essential hematology
• Robins pathology
• Haematology ABC
• Hematology clinical principles and applications

70. Thank you