SECONDARY HEMOSTASIS

COAGULATION DISORDERS
DISORDERS OF THE PROTEINS OF FIBRIN FORMATION

 In these disorders, fibrin formation ineffective and slowed so

patient presents with abnormal bleeding
 Two categories
 Inheritance of a defective gene
 Failure of synthesis of a hemostatic protein
 Malfunction or impaired molecule
 Acquired: Acquisition of a deficiency secondary to another condition
TERMS

 Quantitative: amount of a coagulation protein

 Qualitative: Present in plasma but functionally defective
GENERAL LAB FEATURES LAB

- PT prolonged

- aPTT prolonged

- Platelet count normal

- BT variable
 CLINICAL FINDINGS

Coagulation Factor Platelet Disorders

Disorders
Bleed from ruptured arterioles Bleed from capillaries
Deep muscular & joint bleeding Superficial bleeding
Delayed bleeding Acute bleeding
Ecchymoses Ecchymoses
Hematuria Hematuria
No petechiae Petechiae
HEREDITARY DISORDERS OF
SECONDARY HEMOSTASIS

Involve a single factor

Bleeding originates from one site

 • Von Willebrand's Disease –
lack of or defective VIII:vWF
• Autosomal dominant – seen in
both males and females
• Most common inherited blood
disorder
• Platelet abnormalities –
FACTOR VIII adhesiveness and aggregation,
DEFICIENCY bleeding times
 VON WILLEBRAND’S
DISEASE

Clinical Features Lab Findings

Mild bleeding in mucosal & cutaneous PTT normal or increased
tissues PT normal
Easy bruising Platelet count normal
Hallmark is variability of symptoms BT abnormal
FACTOR VIII
DEFICIENCY
Hemophilia A – classical
hemophilia
• Sex-linked recessive (carried by
female, manifested in the male)
causing a marked decrease in VIII:C
(VIII:vWf is normal)
• Deficiency of factor VIII portion of
VIII/vWf complex
• Patient has normal circulating vWf
• Accounts for 80% of all
hemophiliacs
HEMOPHILIA A
 Etiology
Abnormal bleeding
 Caused by delayed and inadequate
fibrin formation
 Caused by a secondary increase in
fibrinolysis
Lack of thrombin and fibrin
 TAFI fails
FACTOR VIII THERAPY
Replace clotting factors to
achieve hemostasis
DDAVP (desamino-D-
vasopressin)
Stimulates storage cells to release VIII
and vWF into plasma.
Disadvantage is not all patients can
take it
FACTOR IX DEFICIENCY – HEMOPHILIA B,
CHRISTMAS DISEASE

 <20% of all hemophiliacs

 Sex-linked recessive
 No Factor IX function
 Clinically indistinguishable from hemophilia A, so we see the
same disease course
 Bleeding occurs with NO trauma or trivial injury

Spontaneous bleeding into joints, causes

extreme pain and destroys cartilage of knees,
CLINICAL elbows, ankles
FINDINGS OF
HEMOPHILIA A Deep tissue hemorrhage – internally

AND B
Hematuria

CNS bleeding
 <5% of all hemophiliacs

FACTOR XI Autosomal recessive

DEFICIENCY –
ROSENTHAL'S
Highest incidence in Jewish persons of
DISEASE OR Russian decent
HEMOPHILIA
C Mucosal bleeding

Requires therapy only following

childbirth or surgery
 LAB FEATURES: COMPARISON
vWD Factor VIII Factor IX
Deficiency Deficiency

Platelet count Normal Normal Normal

Bleeding Time Normal-increased Normal Normal

Platelet Function Normal-increased Normal Normal

Assay

PT Normal Normal Normal

PTT Normal-increased Increased Increased

Factor VIII Assay Normal- Decreased Normal

decreased
Factor IX Assay Normal Normal Decreased

vWF: Ag Assay Decreased Normal Normal

CONGENITAL DISORDERS OF THE OTHER FACTORS

1 2
The following factors are
rarely deficient or defective
to the extent that
coagulation is slowed – I, II,
V, VII, X, XII, XIII
3 4
Very rarely seen Severity of bleeding PK and HMWK disorders do
dependent upon exist but patients do not
concentration of factor have bleeding tendencies.
present • Defective activation of the
fibrinolytic system are
seen;therefore an increased
chance of thrombosis
• PTT results are often
markedly prolonged in these
asymptomatic patients.
ACQUIRED COAGULATION DISORDERS

01 02 03 04
Two or more Bleeding from More common Classification
factors generally multiple sites than hereditary • DIC
affected, more disorders • Primary
complicated Fibrinogenolysis
• Liver Disease
• Vitamin K Deficiency
• Acquired Pathologic
Inhibitors
  Consumption Coagulopathy
 As fibrin is formed, clotting proteins and
naturally occurring inhibitors and platelets
are consumed faster than they are made
1. DIC:  Thrombo-hemorrhagic disorder
DISSEMINATED  Clotting and lysing occurring in blood
INTRAVASCULAR vessel, at the same time
 Life threatening
COAGULATION
 Bleeding is the most apparent characteristic
 Initiating events are thrombotic, where
material enters circulation
 Occurs due to lack of the negative feedback
mechanism
 Affects young and elderly
COURSE OF
DIC
• Step 1: Out of control
clotting
• Causes widespread fibrin
deposits in vessels of tissues
and organs
DIC: HOW
• Subsequent event: Hemorrhage
• Clotting proteins consumed at a
DOES IT
high rate
• Causes multiple factor deficiencies,
OCCUR?
especially fibrinogen group
• Platelets caught in thrombi and
removed
DIC: HOW
 Step 2: Triggers Fibrinolytic system to
remove fibrin
 Results in:

DOES IT  Circulating degradation products that

interfere with platelet function &

OCCUR? normal clot formation

 Degradation of Factor V & VIII
 Step 3: Uncontrolled plasmin
and thrombin enter
DIC: HOW
circulation
 Why?
DOES IT
OCCUR?
 Inhibitors such as AT have been
depleted
 Step 4: Appearance of
Symptoms
 Bleeding from multiple sites DIC: HOW
 Petechiae
 Purpura
 Occlusions in organs
DOES IT
 Oozing from arterial lines, vein
puncture sites
OCCUR?
 Shock
 DIC: TRIGGERS
Obstetric – usually Acute leukemias –
due to major tissue Promyelocytic – Massive trauma
Intravascular
damage such as increase number of (especially crushing
hemolysis – ex: Heat stroke
retained dead fetus, granules released injuries), burns,
transfusion reaction
abruptio placentae, into circulation as surgical procedures
or placenta previa cells break down

Septicemias and
infections – viral,
Prosthetic devices –
bacterial, rickettsial, Vascular disease –
Tumors – foreign heart valves, aortic
Snake venoms fungal, protozoan damaged endothelial
tissues and cells balloon, peritoneal
(especially gram lining
shunting
negative that release
endotoxins)
 platelet count:
decreased (40-75 x
109/L)
PT: increased

LAB
PTT : increased

Fibrinogen:
FEATURES decreased
FDP /D-dimer: • **Most helpful in
positive diagnosis
RBC fragments:
present

AT : decreased
DIC

 Treatment
 Goal is to treat the underlying condition
 Remove the triggering process – treat with
antibiotics, antineoplasms, remove dead tissue,
treat the diseases or conditions
 Heparin – to prevent or limit further coagulation
 Replace factors, platelets = give FFP
 Similar to DIC

Plasminogen is inappropriately activated to

plasmin
2. PRIMARY
FIBRINOGENOLYSI Plasmin circulates overwhelming the antiplasmin
inhibitors and degrading fibrinogen and factors
S V,VIII, XIII

No thrombin is generated

Liver disease is a common trigger

3. LIVER  Affects all proteins made in the liver that
function in fibrin formation, fibrinolysis and
DISEASE inhibition.
4. VITAMIN K DEFICIENCY

 Causes
 Malabsorptive syndromes
 Sprue
 Obstruction in biliary tract
 Antibiotic therapy
 Kills off normal flora in gut which made vitamin K
 Develop in patients with
certain disease states and
others with no underlying
conditions

5. ACQUIRED Circulating anticoagulants

which may develop against

PATHOLOGIC any clotting factor

Either IgG or IgM

INHIBITORS
Classed as immunoglobulins
Not normally synthesized by
the body, bind with the
Can be alloantibodies or
factors making them
autoantibodies
unavailable for use in the
cascade
 1. Directed against a single coagulation
factor
 Seen in patients with inherited factor
deficiencies that have had replacement
therapy for bleeding complications
TYPES OF  Less commonly seen in healthy people and
those taking certain drugs
INHIBITORS
 Rare, except Factor VIII & IX
 How do we find them?
 Interfere with clotting factor activity
 PTT prolonged, other tests normal
 Mixing study: test will still be prolonged
 2. Lupus Inhibitor/Anticoagulant
TYPES OF  Seen in patients with autoimmune
diseases, drug reactions, but also in

INHIBITORS 
normal patients
Autoantibodies interfere with
phospholipid-dependent
reagents used in PTT tests
 Patients have no in vivo bleeding
problems (though some have an
increase risk of thrombosis)
 In vitro, any coag test using a
phospholipid reagent will be falsely
prolonged (PT, PTT)
 Coag studies must be performed
using reagents that do not contain
phospholipids
 COMPARISON OF ACQUIRED DISORDERS
Test DIC Primary Severe Vitamin K Factor Lupus
Fibrinogenoly Liver Deficienc Inhibitor Anticoagulan
sis Disease y t
Platelet Dec Normal Dec Normal Normal Normal
Count
PT Inc Inc Inc Inc Normal, Normal
except
VII
inhibitor
APTT Inc Inc Inc Inc Inc Inc

Fibrinoge Dec Dec Dec Normal Normal Normal

n

D-dimer Inc Normal Normal Normal Normal Normal

Plasmino Dec Dec Normal- Normal Normal Normal

gen dec
Antithro Dec Normal Dec Normal Normal Normal
mbin
Blood Fragme Normal Macrocyte Normal Normal Normal
Smear