Coagulation Disorders:

Primary Hemostasis
 CLINICAL MANIFESTATIONS OF BLEEDING
DISORDERS
Type of bleeding indicates which component of the
hemostatic system is
Defects in primary hemostasis
Easy bruising, petechiae (small dots), purpura (bleeding into the skin),
ecchymoses (large superficial hemorrhaging), and spontaneous bleeding,
especially from mucosal surfaces
Defects in secondary hemostasis
Prolonged deep bleeding into joints/muscles or hematomas: With these
disorders can see spontaneous bleeding (severe factor deficiency) or post-
injury (mild factor deficiency)
Combination
Multiple site bleeding occurs in severe combined defects (DIC). Platelet
activity and coag proteins are related so disorders of one can affect the
other since platelets provide phospholipid binding sites for clotting factor
interaction.
 EVALUATION OF POTENTIAL BLEEDING
DISORDER
Obtain Medical history Order and interpret lab
Age of onset screening tests
Symptoms Platelet count
Family history PT
Drug history PTT
Exposure to toxins BT or PFA
Physical exam
Type and sites of
bleeding
Spontaneous/ result of
trauma
 VASCULAR SYSTEM DISORDERS
Defects may be due to abnormalities in
the endothelial cell lining of the blood
vessel(acquired) or the connective tissue
supporting the vessels(hereditary)
Symptoms
Superficial bleeding
Hemostatic testing is normal
 VASCULAR DISORDERS

Inherited
Rare
Bleeding is a common symptom
Conditions
Marfan syndrome
Ehlers-Danlos syndrome
 VASCULAR DISORDERS
Acquired
Classification
Purpura due to decreased connective tissue
Collagen and elastin fibers, which form the support for blood
vessels, are lost, causing fragility
Senile purpura( elderly people)
Scurvy ( deficiency of vitamin C)
Purpura associated with paraprotein disorders
Purpura due to vasculitis
Inflammation of small blood vessels due to complement activation on
subendothelium
drugs and infectious agents
Purpura: miscellaneous
 PLATELET DISORDERS
Platelet disorders are the most common cause of
abnormal bleeding.
Qualitative: abnormalities of platelet function
Quantitative: platelet count is below or above
reference range
Blood smears may show platelets larger than normal
(megathrombocytes), decreased or absent granules or a
combination of both
MEGATHROMBOCYTES: GIANT PLATELETS

@2007 Rector and Visitors of the University of Virginia

Charles E. Hess, M.D and Lindsey Krstic, B.A
 QUANTITATIVE DISORDERS
Thrombocytopenia
Decrease in the number of circulating
platelets- below 100,000/L
Bleeding time is prolonged
 QUANTITATIVE DISORDERS:
THROMBOCYTOPENIA
Increased destruction : bone marrow function is normal
Immune Mediated Destruction
Immune Thrombocytopenic Purpura (ITP): caused by antibodies
that cover the platelets
Alloimmune Thrombocytopenia
Drugs (HIT: Heparin Induced Thrombocytopenia)
Collagen disorders
 QUANTITATIVE DISORDERS:
THROMBOCYTOPENIA
Increased destruction : bone marrow function is normal
Nonimmune: excessive consumption
Platelets are activated without the cascade activating
TTP: Thrombotic Thrombocytopenic Purpura
DIC: Disseminated intravascular coagulation
HUS: Hemolytic uremic syndrom
Mechanical destruction by artificial heart valves
 QUANTITATIVE DISORDERS:
THROMBOCYTOPENIA
Decreased production : bone marrow is abnormal
Bone marrow impairment, radiation, malignancy, drugs,
congenital conditions
Abnormal distribution (sequestering by the spleen or liver)
Conditions with multiple mechanisms of thrombocytopenia
Example: Alcoholism: Patients that have cirrhosis present,
can have problems with the coagulation proteins as well as their
platelets. Alcohol reduces platelet numbers and causes defects
of aggregation, release and procoagulant activity. Platelet
production is suppressed by the toxic effect of alcohol on the
bone marrow.
 QUANTITATIVE DISORDERS:
Thrombocytosis
Thrombocytosis
Temporary rise in the number of circulating platelets,
secondary to stimulus. Platelets have normal function.
Counts > 1000 x 109/L
Primary thrombocytosis: uncontrolled production of
megakaryocytes
CML
Polycythemia vera
Essential thrombocythemia
 QUANTITATIVE DISORDERS:
Thrombocytosis
Thrombocytosis
Counts > 1000 x 109/L
Secondary or reactive thrombocytosis: due to another
disease or condition
Surgery, particularly splenectomy ( since spleen
normally contains 20-30% of the platelets
Inflammation
Acute blood loss
Transient thrombocytosis
Childbirth
Exercise
 QUALITATIVE DISORDERS: FUNCTIONAL
Manifestations include:
Petechiae
Easy and spontaneous bleeding from mucous
membranes
Prolonged bleeding from trauma
Lab Diagnosis
Platelet count is normal to slightly decreased
Prolonged bleeding time
PT, PTT, Fibrinolysis tests are normal
Platelet aggregation studies variable
 QUALITATIVE (FUNCTIONAL) DISORDERS:
INHERITED
Disorders of Platelet Adhesion: platelet to vessel wall interaction
Bernard-Soulier syndrome
Deficiency of a membrane glycoprotein (GPIb/IX)
Giant platelets with coarse granulation and vacuoles may be
seen.
Platelet adhesion, aggregation and bleeding time are
abnormal
No treatment available, only supportive measures
Von Willebrands disease
Deficiency of the von Willebrand factor (vWF) OR production
of a dysfunctional protein
Abnormal platelet adhesion and bleeding time as well as
abnormal PTT ( due to VIII defect)
 QUALITATIVE (FUNCTIONAL) DISORDERS:
INHERITED
Disorders of Platelet Aggregation: platelet to platelet interaction
Glanzmanns thrombasthenia
Deficiency of thrombasthenin
Lack the GPIIb/IIIa complex, which is where fibrinogen
attaches to platelet surface
Abnormal platelet aggregation, clot retraction and bleeding
time
 QUALITATIVE (FUNCTIONAL) DISORDERS:
INHERITED
Disorders of Platelet Secretion & abnormalities of granules
Deficiencies of Dense Granules
Storage pool disease
Platelets appear normal on peripheral smear, but there is a
decrease or absence of dense granules
Platelet aggregation abnormal
Defective Thromboxane A2 Synthesis
Gray Platelet Syndrome
Deficiency in - granules
Agranular platelets
 QUALITATIVE (FUNCTIONAL) DISORDERS:
INHERITED
Disorders of Platelet Procoagulant Activity
Scott syndrome
Activated platelets secrete and aggregate normally but
fail to bind coagulation factors
 Disorder
INHERITED
Defective
PLATELET
Platelet
DISORDERS
BT Other
Platelet Count
Component
Bernard- Glycoprotein Normal or Increased Giant platelets
Soulier Ib/IX decreased
Syndrome
Glanzman Glycoprotein Normal Increased
thrombasthenia IIb/IIIa
Storage pool Dense granule Normal Increased
disease deficiency
Gray Platelet Alpha granule Decreased Variable Agranular
syndrome deficiency platelets
Defective Deficiency of Normal Increased
thromboxane A2 cyclooxygenase
synthesis , or TXA2
synthase
 QUALITATIVE DISORDERS:
ACQUIRED
Uremia
Due to toxin or waste products affect on the platelets
Drugs
Aspirin: prevents the release of thromboxane A2, thus decreasing
platelet secretion. Those platelets affected by aspirin still circulate
but are nonfunctional
Antibiotics: penicillins & cephalosporins. Drug coats the platelet
membrane blocking ADP and epinephrine receptors, so platelet can
not respond to agonist.
Alcohol: mechanism unclear
Hematologic Disorders
Myeloproliferative Disorders, Acute leukemias, myelodysplasia,
multiple myeloma and macroglobulinemia
 SCREENING TESTS OF PRIMARY HEMOSTASIS
Platelet PT aPTT Template
Count BT

Vascular Disorders Normal Normal Normal Normal or

abnormal

Thrombocytopenia Decreased Normal Normal Abnormal

Platelet Usually Normal Normal Normal of
Dysfunction normal abnormal
Coagulation Disorders:
Secondary Hemostasis
 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
Disorders Platelet Disorders

Bleed from ruptured Bleed from capillaries

arterioles Superficial bleeding
Deep muscular & joint Acute bleeding
bleeding Ecchymoses
Delayed bleeding Hematuria
Ecchymoses Petechiae
Hematuria
No petechiae
 Hereditary Disorders of
Secondary Hemostasis
Involve a single factor
Bleeding originates from one site
 Factor VIII Deficiency

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 adhesiveness and
aggregation, bleeding times
 Von Willebrand's Disease

Clinical Features Lab Findings

Mild bleeding in PTT normal or
mucosal & cutaneous increased
tissues PT normal
Platelet count normal
Easy bruising
BT abnormal
Hallmark is variability
of symptoms
 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
 Clinical Findings of Hemophilia A and B
Bleeding occurs with NO trauma or trivial injury
Spontaneous bleeding into joints, causes extreme
pain and destroys cartilage of knees, elbows, ankles

Deep tissue hemorrhage internally

Hematuria
CNS bleeding
Factor XI Deficiency Rosenthal's Disease
or Hemophilia C
<5% of all hemophiliacs
Autosomal recessive
Highest incidence in Jewish persons of
Russian decent
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- Normal Normal
increased
Platelet Function Normal- Normal Normal
Assay increased

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
The following factors are rarely deficient or defective to the extent
that coagulation is slowed I, II, V, VII, X, XII, XIII
Very rarely seen
Severity of bleeding dependent upon concentration of factor
present

PK and HMWK disorders do exist but patients do not have bleeding

tendencies.
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
Two or more factors generally affected, more complicated
Bleeding from multiple sites
More common than hereditary disorders
Classification
1. DIC
2. Primary Fibrinogenolysis
3. Liver Disease
4. Vitamin K Deficiency
5. Acquired Pathologic Inhibitors
1. DIC: Disseminated Intravascular
Coagulation
Consumption Coagulopathy
As fibrin is formed, clotting proteins and naturally occurring
inhibitors and platelets are consumed faster than they are made
Thrombo-hemorrhagic disorder
Clotting and lysing occurring in blood vessel, at the same time
Life threatening
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
 DIC: How Does It Occur?

Step 1: Out of control clotting

Causes widespread fibrin deposits in vessels of
tissues and organs
Subsequent event: Hemorrhage
Clotting proteins consumed at a high rate
Causes multiple factor deficiencies, especially fibrinogen
group
Platelets caught in thrombi and removed
 DIC: How Does It Occur?

Step 2: Triggers Fibrinolytic system to

remove fibrin
Results in:
Circulating degradation products that interfere with
platelet function & normal clot formation
Degradation of Factor V & VIII
 DIC: How Does It Occur?

Step 3: Uncontrolled plasmin and thrombin

enter circulation
Why?
Inhibitors such as AT have been depleted
 DIC: How Does It Occur?

Step 4: Appearance of Symptoms

Bleeding from multiple sites
Petechiae
Purpura
Occlusions in organs
Oozing from arterial lines, vein puncture sites
Shock
 DIC: Triggers
Obstetric usually due to major tissue damage such as retained dead
fetus, abruptio placentae, or placenta previa
Acute leukemias Promyelocytic increase number of granules
released into circulation as cells break down
Intravascular hemolysis ex: transfusion reaction
Massive trauma (especially crushing injuries), burns, surgical
procedures
Heat stroke
Snake venoms
Septicemias and infections viral, bacterial, rickettsial, fungal,
protozoan (especially gram negative that release endotoxins)
Tumors foreign tissues and cells
Prosthetic devices heart valves, aortic balloon, peritoneal shunting
Vascular disease damaged endothelial lining
 Lab Features
platelet count: decreased (40-75 x 109/L)
PT: increased
PTT : increased
Fibrinogen: decreased
FDP /D-dimer: positive
**Most helpful in 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
2. Primary Fibrinogenolysis
Similar to DIC
Plasminogen is inappropriately activated to plasmin
Plasmin circulates overwhelming the antiplasmin
inhibitors and degrading fibrinogen and factors V,VIII,
XIII
No thrombin is generated
Liver disease is a common trigger
3. Liver Disease
Affects all proteins made in the liver that
function in fibrin formation, fibrinolysis and
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
5. Acquired Pathologic Inhibitors

Develop in patients with certain disease states and others

with no underlying conditions
Circulating anticoagulants which may develop against any
clotting factor

Classed as immunoglobulins
Either IgG or IgM
Can be alloantibodies or autoantibodies
Not normally synthesized by the body, bind with the
factors making them unavailable for use in the cascade
 Types of Inhibitors

1. Directed against a single coagulation factor

Seen in patients with inherited factor deficiencies that
have had replacement therapy for bleeding complications
Less commonly seen in healthy people and those taking
certain drugs
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
 Types of Inhibitors

2. Lupus Inhibitor/Anticoagulant
Seen in patients with autoimmune diseases, drug
reactions, but also in 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
Fibrinogenolys Liver Deficiency Inhibitor Anticoagulant
is Disease
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

Plasminog Dec Dec Normal-dec Normal Normal Normal

en
Antithrom Dec Normal Dec Normal Normal Normal
bin

Blood Fragme Normal Macrocytes Normal Normal Normal

Smear nts Targets