Download Clinical analysis of patients with different variants of hemorrhagic

Hemorrhagic diathesis
is a disease, characterized by excessive
bleeding. According to pathogenesis, it is
classified into coagulopathy, platelet
disorder (thrombocytopenia and
thrombocytopathy) and vasopathy. Each
type is subdivided into congenital and
acquired.
NORMAL
BLEEDING DISORDER
vascular injury
vascular injury
vasoconstriction
vasoconstriction
platelet plug
fibrin clot
incomplete
platelet plug
incomplete
or delayed
fibrin clot
The main bleeding types
Petechial-ecchymosis
Hematoma
Mixed (Petechia & Hematoma)
Vasculatic
Angiomatosic
The main bleeding sickness types


Hematomic (massive, deep, painful; bleeding may occur
anywhere. The most common sites of bleeding are into joints
(knees, ankles, elbows), into muscles, from the gastrointestinal
tract, cause of the bleeding can be intramuscular injection;
characterized by early postoperative & posttraumatic bleeding)
 hematoma
 petechia-spotted
(macula)
macula-hematoma
vasculitic purpura
angioma
The main coagulogram indexes
Index
Hypo
coagulation
Normo
coagulation
Hyper
coagulation
>5
5-3
<3
<180
180-320
>320
<23
23-44
>45
>120
120-60
<60
Heparin tolerance test,
min
>11
11-8
<8
Prothrombin index, %
<80
80-100
>100
U-factor
<80
80-100
>100
Procorventin (VII
factor), %
<80
80-100
>100
<2
2-4
>4
Bleeding time (by LeeWhite methods), min
Platelets number
Platelet adhesiveness
Time of plasma
recalcification, sec
Fibrinogen, g/l
Screening tests for bleeding disorders
Test
Abnormality detected
Blood count and film
Anaemia, leukaemia, disseminated
intravascular coagulation
Thrombocytopenia
Platelet count
Activated partial
thromboplastin time
Deficiency of all coagulation factors
except VII, especially follows VIII and IX;
heparin
Prothrombin time
Deficiency of factors I, II, V, VII, and X;
warfarin
Thrombin time or fibrinogen
Hypofibrinogenaemia or
dysfibrinogenaemia; heparin; fibrin
degradation products
Test of platelet-vessel wall interaction
Bleeding time
Coagulopathy
I. Congenital
• Deficiency of coagulation factor VIII (hemophilia A)
• Deficiency of coagulation factor IX (hemophilia B)
• Deficiency of coagulation factor XI (hemophilia C)
• 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)
Coagulopathy
II. Acquired
1) Hypoprothrombinemia
• Deficiency of vitamin K due to acholia of GIT (in
cholestatic jaundice)
• In overdose of indirect anticoagulant (antagonist of
vitamin K)
• In liver cirrhosis (due to reduced protein production)
 2) Consumption of coagulation factors (II stage of DIC)
 3) Heparin overdose
 4) Activation of fibrinolytic system
 • In administration of streptokinase etc.
• In trauma, obstetrical or surgical operations
• In malignant neoplasms
• In shock, sepsis, hematological malignancies, III stage
of DIC



Platelet disorders
Thrombocytopathy
I. Congenital (deficiency
of platelet membrane glycoprotein) –
Glanzmann's Thrombasthenia
II. Acquired
(normal platelet count in blood and bone marrow
but its functions are decreased)
• Drugs (after intake of antiplatelet agents: aspirin, Ticlide®);
• Immune, toxic, septic processes;
• Hematological malignancies and anemias
Thrombocytopenia (decrease in the number of platelets)
I. Werlhof’s disease - autoimmune thrombocytopenic purpura
II. Symptomatic
• Immune (heteroimmune, isoimmune,)
• Toxic (in phosphorus poisoning etc.)
• Methaplastic (in hematological malignancies or
myelocarcinosis)
• Drug-induced (cytostatics)
Thrombocytopenia
Thrombocytopenia (decrease in the number of
platelets)
o - Idiopathic thrombocytopenic purpura (ITP)
o - Thombotic thrombocytopenic purpura (TTP)
o - Heparin-induced thrombocytopenia (HIT)
o - Hemolytic-Uremic Syndrome
o - Chronic liver disease
o
Vasopathy
I. Congenital
• Telangiectasiae
(Rendu-Osler-Weber disease)
• Aneurysm of fine vessels
• Ehlers-Danlos syndrome, Marfan’s syndrome, retinocerebral
angiomatosis (von Hippel-Lindau syndrome), encephalotrigeminal
angiomatosis (Sturge-Kalisher-Weber syndrome)
II. Acquired
• Hemorrhagic vasculitis – Henoch-Schönlein purpura
• Immune vasculitis
• Systemic vasculitis
• Avitaminosis of vitamin C
THE CLOTTING MECHANISM
EXTRINSIC
INTRINSIC
Collagen
XII
XI
Tissue
Thromboplastin
VII
IX
VIII
X
FIBRINOGEN
(I)
V
PROTHROMBIN
(II)
THROMBIN
(III)
FIBRIN
Coagulation pathway
◦ Two pathways for fibrin clot formation:
 Intrinsic
◦ Initiated by negatively charged surface
 Extrinsic
◦ Initiated on tissue injury
◦ Both pathways converge on a final
common pathway
 Prothrombin  Thrombin (Most critical
step )
 Fibrinogen
Fibrin  Clot
◦ The pathways are complex and involve
many different proteins (called blood
clotting factors)
Coagulation Cascade - continued
Control of coagulation
 Antithrombins (e.g., antithrombin III)
◦ Proteins C and S
◦ Fibrinolytic cascade
 Plasminogen  plasmin  fibrin break down
products (*FDP or FSP) – d-dimer is most
important of the FDPs
*FDP /
FSP – Fibrin degradation products / Fibrin split products
Bleeding
disorders
Vascular
abnormalities
Platelet disorders
Clotting factor
abnormalities
DIC
A “Royal Disease”
Queen Victoria (1837 to 1901) passed hemophilia on to German, Russian and
Spanish royal families. Her son, Leopold, had frequent hemorrhages (British
Medical Journal,1868) and died of a brain hemorrhage at 31. His grandson
also died of a brain hemorrhage in 1928.
www.themegallery.com
Haemophilia
А
factor VIII
deficiency
В
factor IX
deficiency
С
factor XI
deficiency
Company Logo
X-Linked Recessive Inheritance
New mutation
in germ cell
• Affected males (XY):
–sons unaffected (no male to male
transmission)
–daughters obligate carriers
• Carrier female (XX):
–½ sons affected; ½ daughters carriers
• Affected females: very rare.
New mutation
in maternal or
paternal germ
cell
Carrier female
Affected male
Normal male
46, XX
46, XY
ovary
Germline
/Gonadal
Mosaicism
testes
Factor VIII allele - normal
Mutant VIII allele - normal
Forms
Haemophilia A -
factor VIII deficiency, "classic
haemophilia" (X-linked)
Haemophilia B - factor IX deficiency, "Christmas
disease" (X-linked)
Haemophilia C - factor XI deficiency (Ashkenazi
Jews, autosomal recessive)
The unrelated type 1
and type 2
von Willebrand
disease (vWD)
Classification (F VIII C
level)
2
1
F
VIII C
level 5-25
%
Mild form
F
VIII C
level 1-5
%
Moderate
form
3
F
VIII C
level less
than 1 %
Severe form
Company Logo
Clinical severity of haemophilia A and B
Factor value*
Bleeding tendency
Less than 0.02
Severe - frequent spontaneous bleeding
into joints, muscles, and internal organs
0.02-0.05
Moderate—some “spontaneous” bleeds,
bleeding after minor trauma
Mild—bleeding only after significant
trauma or
surgery
More than 0.05
* Normal value of factors VIII and IX is 0.5-1.5
Hemophilia
Diagnostic
criteria
Hematomic
bleeding sickness
types
Arhtropathy
Family_history_of
_coagulation_disor
ders: positive
APTT:abnormal
 Mixing_APTT:cor
rected
Factor_VIII:C_act
ivity: abnormal

Diagnostic
Criteria
Condition
Vitamin K
deficiency or
warfarin
Disseminated
intravascular
coagulation
von Willebrand
disease
Hemophilia
Aspirin
Thrombocytopeni
a
Uremia
Glanzmann's
thrombasthenia
Bernard-Soulier
syndrome
Prothrombin
time
Partial
thromboplastin
time
prolonged
normal or mildly
unaffected
prolonged
unaffected
prolonged
prolonged
prolonged
decreased
unaffected
prolonged
prolonged
unaffected
unaffected
unaffected
prolonged
unaffected
unaffected
prolonged
unaffected
unaffected
unaffected
unaffected
prolonged
decreased
unaffected
unaffected
prolonged
unaffected
unaffected
unaffected
prolonged
unaffected
unaffected
unaffected
prolonged
decreased or
unaffected
Bleeding time
Platelet count
Treatment
In mild bleeding: 1-desamino-8-D-arginine
vasopressin (DDAVP). The level of factor
VIII must be maintained at least 30%.
 In non-life-threatening bleeding or pre-op:
factor VIII concentrates. The minimal
hemostatic level of factor VIII:C in this case
is 50%.
 Central nervous system hemorrhage and
severe bleeding: factor VIII concentrates.
The level of factor VIII:C must be
maintained at 80% - 100%.





Each unit of factor VIII concentrates will raise the level of
factor VIII by 2%/kg of body weight.
Adjunctive therapy in dental surgery for mild and moderate
hemophelia A: epsilon-aminocaproic acid (EACA).
Avoidance of aspirin-containing compounds.
For monitoring therapy, factor VIII assay is the test of choice.
Dosage: the (activity ) units of factor
 VIII required can be calculated from: 40*BW*
(desired factor level-actual
factor level)/100
 where BW is body weight in kg

Treatment

The dose of factor VIII concentrate is calculated assuming
that one unit of factor VIII is the amount present in 1 mL of
plasma. Plasma volume is 40 mL/kg, and the volume of
distribution of factor VIII:C is 1.5 times the plasma volume.
Thus, to raise the level 100%, the dose should be 40 x 1.5 =
60 units/kg, or approximately 4000 units for a 70-kg
individual. To raise the levels to 25% would require 1000
units. The half-life of factor VIII:C is approximately 12 hours.
Thus, during major surgery, to achieve an initial level of
100% and maintain it continuously at greater than 50%, a
dose of 60 units/kg (approximately 4000 units) initially
followed by 30 units/kg (approximately 2000 units) every 12
hours should be adequate. During surgery, initially verify that
these doses give the anticipated factor VIII levels. If factor
VIII levels fail to rise as expected, an inhibitor should be
suspected.
Hemophilia B
 DEFICIENCY
OF FACTOR IX
Factor IX deficiency
 X-linked recessive
 Much less common
 Clinically= indistinguishable from Hemophilia A
with Similar lab findings
 Diagnosis by factor IX levels
 Treat with recombinant IX

Family_history_of_coagulation_disorders:positive
 Mixing_APTT:corrected
 Factor_IX_assay:abnormal
 APTT:abnormal

Diagnostic Criteria
Treatment
For
patients with mild form of factor IX deficiency with non-lifethreatening bleeding, the treatment of choice is FFP. For the severe
form of hemophelia B or in life- threatening situation, prothrombin
complex concentrates are the treatment of choice.
Target levels of factor IX for therapy: Severe hemorrhage: 20% 50% for 3-5 days, then 10% - 20% for the next 10 days.
Minor hemorrhage: 20% for 7 days.
Surgery: 50% - 70% for 2 days, then 30% - 40% for 3 days, then
20% for 7 days.
Dosage: the (activity) units of factor IX required can be calculated
from: 80*BW*(desired factor level-actual factor level)/100
where BW is body weight in kg
Note that in-vivo recovery of factor IX is about 50%.
Hemophilia
A Treatment (cryoprecipitate)
1
Mild
15-20 UN/kg
2
3
Moderate
Severe
.
35-40 UN/kg
70 UN/kg
Company Logo
von Willebrand's Disease
Essentials of Diagnosis
Family history with autosomal dominant pattern of inheritance.
Prolonged bleeding time, either at baseline or after challenge with aspirin.
Reduced levels of factor VIII antigen or ristocetin cofactor.
Reduced levels of factor VIII coagulant activity in some patients.
Symptoms and Signs
von Willebrand's disease is a common
disorder affecting both men and women.
Most cases are mild. Most bleeding is
mucosal (epistaxis, gingival bleeding,
menorrhagia), but gastrointestinal
bleeding may occur. In most cases,
incisional bleeding occurs after surgery
or dental extractions. von Willebrand's
disease is rarely as severe as hemophilia,
and spontaneous hemarthroses do not
occur (except in the rare type III). The
bleeding tendency is exacerbated by
aspirin. Characteristically, bleeding
decreases during pregnancy or estrogen
use.
The main bleeding sickness types

Mixed (Petechial & Hematomic)
(combined features of both types, but
there are some difference: in contrast
to hematomic - bleeding are into
joints very rare, mostly it is located in
subcutaneous, retroperitoneal,
mesenteric, subserous intestinal layer
or into internal organ);in contrast to
petechial-ecchymosic bleeding hemorrhagic syndrome characterized
by large bruise)
Treatment
The bleeding disorder is characteristically mild, and no treatment is
routinely given other than avoidance of aspirin. However, patients
often need to be prepared for surgical or dental procedures. The
bleeding time is probably the best indicator of the likelihood of
bleeding, and prophylactic therapy may be reasonably withheld if the
procedure is minor and the bleeding time is normal.
 Desmopressin acetate (DDAVP) is useful for mild type I von
Willebrand's disease and should be considered first. The dose is 0.3
mcg/kg, after which vWF levels usually rise two- to threefold in 30–
90 minutes. It can also be given as a nasal spray; levels peak 2 hours
after use.
 The antifibrinolytic agent
aminocaproic acid (EACA)
is useful as adjunctive therapy
during dental procedures.

1. Pl stimulate vasoconstriction of injured vessels
 2. Pl form hemostatic plug (platelet adhesion) + platelet
aggregation to seal small vessel wall
 3. Pl play role in fibrin clot formation

Platelet hemostatic activity
Bleeding
disorders
Vascular
abnormalities
***
Platelet disorders
Clotting factor
abnormalities
DIC
Bleeding disorders
Platelet disorders
↓production
↑destruction
Primary/Idiopathic
ITP
Acute/Chronic
Sequestration
Hypersplenism
Secondary
Drugs, HIV
INCREASED DESTRUCTION

Immune destruction
◦ Platelets are destroyed by
antibodies
 Platelets with bound
antibody are removed by
mononuclear phagocytes in
the spleen
 Anti-platlet antibody tests
to identify antibodies on
platelets are available
Fibrin
XIIIa
Cross-linked
fibrin





Thrombocytopenia (or -paenia, or
thrombopenia in short) is the presence
of relatively few platelets in blood.
Generally speaking a normal platelet
count ranges from 180,000 and 320,000
per mm3.
Signs and symptoms
Often, low platelet levels do not lead to
clinical problems; rather, they are
picked up on a routine full blood count.
Occasionally, there may be bruising,
nosebleeds and/or bleeding gums.
It is vital that a full medical history is
elicited, to ensure the low platelet count
is not due to a secondary process. It is
also important to ensure that the other
blood cell types red blood cells, and
white blood cells, are not also
suppressed.
Thrombocytopenia
Diagnostic
criteria
Petechialecchymosic
1. Decreased
platelets
Immune Thrombocytopenic Purpura
Cause
◦ Antiplatelet antibodies
◦ Antigen - platelet membrane glycoprotein
complexes IIb-IIIa and Ib-IX
 Morphology
◦ Peripheral Blood
 thrombocytopenia, abnormally large platelets
(megathrombocytes or Giant platelets),
◦ Marrow
 Normal or Increased magakaryocyte #
 Diagnosis - by exclusion
◦ Bleeding time - prolonged, but PT & PTT - normal

↓ Marrow magakaryocyte # - your Diagnosis of ITP is ?????
Necessary Evaluation
• History: Isolated bleeding symptoms consistent with
thrombocytopenia without constitutional symptoms
(e.g. significant weight loss, bone pain, night sweats).
• Physical examination: Bleeding symptoms in the absence of
hepatosplenomegaly, lymphadenopathy, or stigmata of congenital
conditions.
• Complete blood count: Isolated thrombocytopenia (platelet count <100
x 109/L). Anemia only if due to significant bleeding - otherwise normal red
cell indices, white blood cell count and differential.
• Peripheral blood smear:
Identified platelets should
be normal to large in size.
Red and white blood cell
morphology should be normal.
• History: Isolated bleeding symptoms consistent with
thrombocytopenia without constitutional symptoms
(e.g. significant weight loss, bone pain, night sweats).
• Physical examination: Bleeding symptoms in the absence of
hepatosplenomegaly, lymphadenopathy, or stigmata of congenital
conditions.
• The presence of abnormalities in the history, physical examination, or
the complete blood count and peripheral blood smear should be further
investigated, e.g. with a bone marrow examination or other appropriate
investigations, before the diagnosis of ITP is made.
Bone Marrow
Evaluation
The main bleeding sickness types

Petechia-ecchymosis (is usually localized to superficial sites such
as the skin and mucous membranes, wich often combined with
menorrhagia, nose bleeding, gumms bleeding; rare – with
gastrointestinal bleeding or brain hemorrhage; it is small, painless,
provoked by simple action like skin cleaning, measure of blood
pressure etc; pinch test is positive)
Diagnostic Criteria:
Plt_count: abnormal (low)
Peripheral blood smear:no increase
in schistocytes
Bone_marrow:megakaryocytosis
Immune Thrombocytopenic Purpura
Feature
Age / Sex
Onset
Predisposing
Factors
Duration
Pathogenesis
Peripheral
smear
Bone marrow
Acute
Children
Abrupt
Viral infection/
vaccine
<2 months
-
Chronic
Adult/Female
Gradual
-
>6 mnoths
Ig G against
Platelet GP
Thrombocytopenia & Same
Giant PLTS
Normal or
Same
↑Megakaryocytes
ITP
Feature
Acute
Tests
Prolonged BT & Same
Normal PT & PTT
Intracranial
Same
bleed
Complication
(most
dangerous)
Clinical course
Treatment
 PLT. Transfusion
 Splenectomy
Chronic
Spontaneous
remission
No
If <20,000
No
If <50,000
Yes (refractory
cases)
Condition
Partial
Prothrombin
thromboplast Bleeding time Platelet count
time
in time
prolonged
normal or
mildly
prolonged
unaffected
unaffected
Disseminated intravascular
prolonged
coagulation
prolonged
prolonged
decreased
von Willebrand disease
unaffected
prolonged
prolonged
unaffected
Hemophilia
unaffected
prolonged
unaffected
unaffected
Aspirin
unaffected
unaffected
prolonged
unaffected
Vitamin K deficiency or
warfarin
Thrombocytopenia unaffected unaffected prolonged decreased
Uremia
Glanzmann's
thrombasthenia
Bernard-Soulier
syndrome
unaffected
unaffected
prolonged
unaffected
unaffected
unaffected
prolonged
unaffected
unaffected
unaffected
prolonged
decreased or
unaffected
Initial Management of ITP
Assessment of Disease Status:
 • What bleeding is the patient experiencing?
 • Determine the timing, location, and severity of
 bleeding symptoms.
 • Does this patient have any additional risk factors
for bleeding such as use of antithrombotic agents or
high-risk occupation?
 • Is a surgical procedure anticipated?
 • Is this patient likely to comply with recommended
treatments?
 • Is the bleeding experienced by this patient
interfering with his or her daily activities or causing
significant anxiety?

• The majority of patients with no bleeding or mild
bleeding (defined here as skin manifestations only,
such as petechia and bruising) can be treated with
observation alone regardless of platelet count.
• First-line treatment includes observation,
corticosteroids, IV Ig, or anti-D immunoglobulin
(anti-D).
• Anti-D should be used with caution given recent
FDA warnings of severe hemolysis. It is therefore
not advised in patients with bleeding causing a
decline in hemoglobin, or those with evidence of
autoimmune hemolysis.
General Considerations for Initial
Management
Drug induced thrombocytopenia
Heparin induced thrombocytopenia (HIT)
Seen in 3-5% of patients treated with unfractionated heparin
thrombocytopenic after 1-2 weeks of Rx
 Caused by IgG antibodies against platelet factor 4/heparin
complexes on platelet surfaces
 Exacerbates thrombosis, both arterial and venous (in setting
of severe thrombocytopenia)
◦ Antibody binding results in platelet activation and
aggregation.
 Rx - cessation of heparin

Other drugs???
Platelet functional disorders
Bleeding
disorders
Vascular
abnormalities
Platelet disorders
Clotting factor
abnormalities
DIC
Causes
Infections
Meningococcemia,
Rickettsioses,
Infective endocarditis
Drug reactions
Hereditary hemorrhagic
telangiectasia
 Autosomal dominant
Cushing syndrome
Henoch - Schönlein Purpura
systemic hypersensitivity disease of
unknown cause
polyarthralgia, and acute
Glomerulonephritis
Palpable purpuric rash, colicky
abdominal pain
◦Scurvy and the Ehlers-Danlos
syndrome
◦Amyloid infiltration of blood vessels
Vascular
abnormalities
The main bleeding sickness types
Vasculatic (hemorrhage due to inflammatory
changes of small vessels, the main cause are
immune disorders
or infectious agent)

The main bleeding sickness
types

Angiomatosic (hemorrhage due to vascular
dysplasia, teleangiectasia; the main clinical
criteria is relapsing bleeding without
hemorrhage in skin, subcutaneous and other
tissue; nose bleeding are most often,
dangerous and massive)