DISORDERS OF SECONDARY

HEMOSTASIS
 Hemorrhage

• is a severe form of bleeding that requires

immediate intervention and transfusion.
Inherited Disorders of Coagulation
Inherited Disorders of Coagulation:
Intrinsic Pathway Disorders
Prekallikrein (Fletcher Factor) Deficiency
• believed to be transmitted as an autosomal
recessive trait.
LABORATORY FINDINGS:
▪ laboratory findings are similar to Factor XII
deficiency except that APTT’s result is shortened
if the plasma is incubated with a surface
activating substance such as kaolin.
Inherited Disorders of Coagulation: Intrinsic
Pathway Disorders
High Molecular Weight Kininogen (Fitzgerald
Factor) Deficiency
• absence of HMWK results in poor contact –phase
reactions, a deficiency of kinin formation (active
forms derived from kininogen), and defective
fibrinolysis reaction.
LABORATORY FINDINGS:
▪ APTT results typically are prolonged
▪ Other tests are within normal limits.
Inherited Disorders of Coagulation: Intrinsic Pathway Disorders

Factor XI Deficiency (Hemophilia C; Rosenthal Syndrome)

• Originally described in 1953
• An autosomal dominant hemophilia.
• Presents mild to moderate bleeding.
• Treatment with frequent infusions of fresh plasma.
• Represents the first inherited disorder of the intrinsic
cascade to which a clinical bleeding syndrome is attributed.
• Prevalent in Jewish population.
Intrinsic Pathway Disorder:
Factor XI Deficiency (Hemophilia C;
Rosenthal Syndrome)
CLINICAL FINDINGS:
✓ patients present mild bleeding tendencies which usually respond to therapy.
✓ Most patients are symptomatically “silent” until stressed by trauma or surgery.
✓ Clinical syndromes may include episodes of epistaxis, hematuria and menorrhagia.
LABORATORY FINDINGS:
▪ Prolonged APTT which is corrected by aged serum and adsorbed plasma.
▪ One-stage PT and bleeding time are not affected.
THERAPY:
➢ NO SPECIFIC BLOOD COMPONENT exist to treat factor XI deficiency.
Inherited Disorders of Coagulation: Intrinsic
Pathway Disorders
Factor VIII:C Deficiency (Hemophilia A;
Classic Hemophilia)
• First scientifically described in 1803 .
• Referred to as “royal disease”.
• It is a sex-linked disorder transmitted on an
X chromosome by carrier women to their
sons.
 Intrinsic Pathway Disorder:
Hemophilia A
Nomenclature of Factor VIII of the International Committee on Thrombosis and Hemostasis

VIII/ vWF The entire molecule as it circulates in the plasma. Composed of VIII:C and
VIII:vWF portions noncovalently bound.

VIII:vWF Portions of molecule responsible for binding to endothelium and supporting

normal platelet adhesion and function. Tested by bleeding time.
VIII:C Portions of molecule acting in intrinsic system as cofactor to factor Ixa (with
Ca++) in the conversion of Factor X to Xa. Tested by PTT.
VIIIC:Ag Antigenic property of procoagulant portion as measured by immunologic
monoclonal antibody techniques
VIIIR:Ag Factor VIII-related antigen, which is a property of the large vWF portion of
the molecule and measured by immunologic techniques of Laurell rocket or
immunoradiometric assay.
VIIIR:RCo Ristocetin cofactor activity, which is factor VIII related activity required for
aggregation of human platelets with ristocetin in in vivo aggregation studies.
Intrinsic Pathway Disorder:
Hemophilia A
CLINICAL FINDINGS:
✓Bleeding diathesis arises from decreased or defective factor VIII:C.
✓Bleeding into soft tissues or joints, epistaxis, hematuria, GIT or
intracranial hemorrhages and post-operative bleeding constitute the
majority of hemorrhagic events in the hemophiliac.
✓Joints of the knee, elbow, ankle and shoulder are the most vulnerable
parts of the patient.
✓Repeated hemarthroses can cripple and deform the patient.
✓Tragically,70% of hemophiliacs treated before 1984 are HIV positive and
have died from AIDS.
Intrinsic Pathway Disorder:
Hemophilia A
LABORATORY FINDINGS:
▪ Prolonged APTT which is corrected by adsorbed
plasma but not with aged serum.
▪ Levels of factor VIII:C differ in the daughters of
carrier females (maternal carrier) and the daughters
of hemophiliacs (paternal carriers).
 Intrinsic Pathway Disorder:
Hemophilia A
THERAPY:
➢Cryoprecipitate product infusion to replace factor VIII:C .
➢For milder cases, administration of pharmacologic agent such
as 1-desamino-8-D-arginine-vasopressin (DDAVP) may be
substituted for donor component.
➢Intravenous administration of DDAVP rise plasma levels of
plasma factor VIII:C threefolds to sixfolds.
➢Factor assays- used to monitor therapeutic progress of
patients.
➢Patients who have developed antibodies against factor VIII:C
may be given with plasma pheresed component to purge the
antibody from plasma. But this was believed to be ineffective.
➢Porcine factor VIII:C and prothrombin factor components are
used or reserved especially for life threatening situations.
Inherited Disorders of Coagulation: Intrinsic
Pathway Disorders
Factor IX Deficiency (Hemophilia B; Christmas Disease)
• Caused by the deficiency in factor IX (vitamin K dependent
factor).
• Represents approximately 14% of hemophilia cases in the
United States.
• Milder form of hemophilia than factor VIII:C deficiency.
• Deficiency reduces thrombin production and may lead to
soft tissue bleeding that is indistinguishable from
hemophilia A.
• Three variants of the disease based on antigenic reactivity
of factor IX: Cross-reactive material positive (CRM+),
cross-reactive material negative (CRM-), cross-reactive
material reduced (CRMR).
Intrinsic Pathway Disorder:
Hemophilia B
LABORATORY FINDINGS:
▪ Prolonged APTT which is corrected with aged serum
but not with adsorbed plasma.
▪ Specific Factor IX assay- used for diagnosis and to
assess activity levels during therapy.
THERAPY:
➢Administration of commercial concentrate products.
➢Plasma exchange with normal donor plasma have
been performed to achieve 50% to 100% activity
levels and to prevent cardiac overload.
Inherited Disorders of Coagulation: Intrinsic
Pathway Disorders
Factor XI Deficiency (Hemophilia C; Rosenthal
Syndrome)
• An autosomal dominant hemophilia.
• Presents mild to moderate bleeding.
• Treatment with frequent infusions of fresh plasma.
Inherited Disorders of Coagulation: Intrinsic
Pathway Disorders
von Willebrand’s Disease
• In 1926, Eric von Willebrand described this disorder as
autosomal dominant disorder that produces a prolonged
bleeding time and evidence of vascular fragility.
• Caused by defects in both in factor VIII:C and VIIIR:Ag of
factor VIII complex.
• In 1971, Zimmerman demonstrated that the vWF portion
of the VIII complex is reduced or absent in this disease.
• Platelets in von Willebrand’s plasma, in contrast to platelets
in normal plasma, do not aggregate in the presence of
ristocetin.
• Patients demonstrate easy bruisability, epistaxis,
menorrhagia and hemorrhage from tooth extraction.
• It is the most frequently inherited disorder.
Intrinsic Pathway Disorder:
von Willebrand’s Disease
Classification of Type of von Willebrand’s Disease
TYPE MODE OF EFFECT RESULTS
INHERITANCE
Homozygous Autosomal Severe VIII:vWF and VIIIR:Ag absent to
(“doubly recessive trace; VIIIR:RCo markedly
heterozygous”) decreased; VIII:C and VIIIC:Ag
present but decreased.

Heterozygous I Autosomal Variably; VIIIR:RCo, VIIIR:Ag & VIII:C

dominant mild to variably decreased; VIIIR:Ag
moderate present in platelets and in
endothelial cells; all normal
mutlimers are decrease but
present.
Intrinsic Pathway Disorder:
von Willebrand’s Disease
Classification of Type of von Willebrand’s Disease
TYPE MODE OF EFFECT RESULTS
INHERITANCE
Heterozygous II Autosomal Variable VIIIR:Ag large multimers absent
dominant
VIIIR:Rco absent or deficient;
Subtype IIa Autosomal Variable VIII:C, VIIIR:Ag & VIIIR:Rco levels
dominant are discrepant.

Subtype IIb Autosomal Variable Increased sensitivity of vWF to

dominant ristocetin; VIIIR:Ag binds to
platelets at lower concentration
of ristocetin than required for
normal subjects; VIIIR:Rco is
normal, borderline or reduced.
Intrinsic Pathway Disorder:
von Willebrand’s Disease
LABORATORY FINDINGS:
▪ Prolonged bleeding time.
▪ Inc APTT results
▪ Decreased activity of VIII:C
▪ Abnormal ristocetin platelet factor VIII related activity
(VIIIR:RCo)
▪ Decreased levels of large vWF multimers.
THERAPY:
✓Infusion of cryoprecipitate
✓Infusion of commercial factor VIII:C
✓Intravenous DDAVP administration.
 Hereditary Coagulation Disorders
Laboratory Test vWD Hemophilia A Hemophilia B

Platelet Count N N N

Bleeding Time N/Increased N N

Platelet Aggregation Decreased/ N N

(Ristocetin) Absent

Prothrombin Time N N N

aPTT N/ Increased Increased Increased

Thrombin Time N N N

Factor VIII assay N/ Decreased Decreased N

Facotr IX assay N N Decreased

vWF:Ag assay Decreased N N

Fibrinolysis tests N N N
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder
Factor VII (Proconvertin; Stable Factor) Deficiency
• A predominant plasma protein of the extrinsic
coagulation pathway.
• Autosomal recessive genetic abnormality with
intermediate expression.
• A very rare disorder that occurs in 1 for every 500,000
individuals.
• Has CRM+ and CRMR variants of antigenic activity
• Correlation between clinical tendency and activity
levels are poor.
• Patients are vulnerable to thrombotic events.
Extrinsic & Common Pathway Disorder:
Factor VII Deficiency
LABORATORY FINDINGS:
▪ Diagnosis is based on family history.
▪ Prolonged PT
▪ Normal thrombin clotting time and APTT
▪ Chromogenic substrate procedures measure the
ability of factor VII to cleave factor X.
▪ Increased levels of factor X in pregnant women.
THERAPY:
✓Infusion of donor plasma, serum components or
commercial concentrates containing prothrombin
complex (Autoplex T preparations).
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder
Factor X (Stuart- Prower Factor) Deficiency
• It is inherited as autosomal trait that is incomplete
recessive but shows high penetrance.
• Immune variants also exist.
• The disorder is uncommon in the general
population.
• Symptoms of patients having the disorder are
variable.
Extrinsic & Common Pathway Disorder:
Factor X (Stuart-Prower Factor)Deficiency
LABORATORY FINDINGS:
▪ Prolonged APTT, PT and Stypven Time
▪ Prothrombin utilization is abnormal
▪ PT is corrected by aged serum but not with adsorbed
plasma.
THERAPY:
✓FFP or Prothrombin complex concentrates are used
for therapy.
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder
Factor V Deficiency (Owren’s Disease; Labile Factor
Dificiency)
• Discovered in 1944 by Professor Owren.
• An autosomal recessive trait which is most
commonly demonstrated by homozygotes and is
mild to silent in heterozygotes.
• Also described as deficient in conjunction with
factor VIII deficiency due to genetic defect traced
to chromosome 18.
Extrinsic & Common Pathway Disorder:
Factor V Deficiency (Owren’s Disease; Labile Factor
Deficiency)
FACTOR V LAIDEN MUTATION (R506Q)
• In 1993, a new and very common inherited
thrombophilic syndrome was described: activated
protein C resistance (APCR)
• Molecular defect (single point mutation) was identified
involving the transition of a guanine (G) to adenine (A)
at nucleotide 1691 of factor V gene.
• Mutation results in the substitution of arginine (R) with
glutamine (Glu) at number 506.
• Screening for the presence of APCR is easily performed
by clottable assays utilizing modified APTT & Russell’s
viper venom time methods.
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder

Factor II (Prothrombin) Defeciency

• May be inherited as a deficiency or a
dysfunction.
• Hemarthroses in patients are rare.
• Medications of aspirin may cause serious
bleeding.
Extrinsic & Common Pathway Disorder:
Factor II (Prothrombin) Defeciency

LABORATORY FINDINGS:
▪ APTT & one-stage PT will be prolonged.
▪ TCT (Thrombin clotting time) is normal.
▪ Two-stage prothrombin method and immune based
factor assay using antiprothrombin antisera are the
diagnostic test procedures.
THERAPY:
➢Infusion of FFP is the usual choice of treatment.
➢Vitamin K concentrates may also be given to patients
but there is a risk of thrombosis after administration.
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder
FibrInogen (Factor I) Deficiency
• Defect may result to the following conditions:
a. Afibrinogenemia –inherited lack of fibrinogen.
b. Hypofibrinogenemia –inherited deficiency of fibrinogen.
c. Dysfibrinogenemia –inherited production of dysfunctional
fibrinogen molecule.
• History and clinical features aid in the differentiation
between inherited and acquired forms.
Extrinsic & Common Pathway Disorder:
Factor I (Fibrinogen) Deficiency
AFIBRINOGENEMIA
• A recessive and severe condition.
• Patients having this condition have nearly undetectable
amounts of fibrinogen.
• Molecular structure of fibrinogen is normal.
• Patients’ platelets appear affected in that prolonged
bleeding time may be measured. (Platelets have a
surface receptor for fibrInogen, and fibrinogen
apparently is necessary for platelets to function in vivo)
LABORATORY FINDINGS:
▪ Prolonged bleeding time, PT, APTT & TT
▪ Abnormal platelet adhesion and aggregation
Extrinsic & Common Pathway Disorder:
Factor I (Fibrinogen) Deficiency

AFIBRINOGENEMIA
THERAPY:
➢Treatment requires administration of
cryoprecipitate
➢FFP may be used; however, volume overload is a
major concern.
➢Whole blood transfusions may be required if
significant bleeding has occurred.
Extrinsic & Common Pathway Disorder:
Factor I (Fibrinogen) Deficiency

HYPOFIBRINOGENEMIA
• Patients possess 20-100 mg/dL level of fibrinogen
(normal range: 200-400 mg/dL).
• Inherited as heterozygous, autosomal recessive
disorder.
• Molecular structure of fibrinogen is said to be normal.
• Bleeding episodes are usually mild and not spontaneous
which may occur after severe trauma or surgery.
• Cryoprecipitate & FFP are the treatment of choice for
this condition.
 Extrinsic & Common Pathway Disorder:
Factor I (Fibrinogen) Deficiency
DYSFIBRINOGENEMIA
• Inherited as an autosomal dominant trait.
• Patients demonstrate abnormal fibrinogen function but usually
have normal levels in antigenic assay.
• Substitution of amino acids in fibrinogen’s polypeptide chains is
the striking feature of this disorder, which may result in:
1. Inability to submit proteolysis by thrombin, because the
cleavage sites are inappropriate.
2. Peculiar behaviour during polymerization stages secondary to
aberrant charge distribution across the molecule.
3. Addition of inappropriate side groups that affect reactivity.
4. Persistence of fetal fibrinogen into adulthood.
 Extrinsic & Common Pathway Disorder:
Factor I (Fibrinogen) Deficiency
DYSFIBRINOGENEMIA
LABORATORY FINDINGS:
▪ Normal PT, APTT
▪ Normal bleeding time and platelet function tests
▪ Normal quantitative level of fibrinogen
▪ Mild to markedly prolonged thrombin time
▪ Prolonged ReptilaseR (venom) clotting time.
Inherited Disorders of Coagulation:
Extrinsic and Common Pathway Disorder
Factor XIII (Fibrin-Stabilizing Factor) Deficiency
• A rare disorder
• An autosomal recessive trait in which only homozygotes
express the syndrome.
• Patients exhibit spontaneous bleeding and poor wound
healing processes with unusual scar formation.
• All patients should avoid aspirin intake.
Extrinsic & Common Pathway Disorder:
Factor XIII (Fibrin Stabilizing Factor)Deficiency
LABORATORY FINDINGS:
▪ Patients have inadequate cross-linking of fibrin which
results in an unstable and friable clot with excessive
red cell “fall out”.
▪ Condition cannot be evaluated in the presence of
heparin
▪ Specific Factor XIII assays are available but are not
suitable for routine clinical use.
▪ Immunologic Factor XIII procedures are available to
measure quantities of the said factor.
THERAPY:
➢Infusion of donor plasma or commercial purified,
lyophilized placental factor XIII.
Acquired Disorders of Coagulation
Acquired Disorders of Coagulation: Hepatic
Disease
Liver disorders present two challenges:
• Decreased synthesis of coagulation, lyses and
inhibitory proteins.
• Impaired clearance of activated hemostatic
component.
Hepatic diseased may also be subdivided into two
categories:
Neonatal hepatic disease- there is a decreased level of
plasma contact factors secondary to hepatic immaturity;
insufficient levels of antithrombin III and plasminogen;
expression of a unique fetal fibrinogen which behaves
differently as to matured ones.
Acquired Disorders of Coagulation: Vitamin
K Deficiency
• Vitamin K is produce by normal flora of the GIT and
absorbed.
• Deficiency is due to (1) absence of normal flora in
GIT due to intake of broad spectrum antibiotics, (2)
absorption is decreased as seen in obstructive
jaundice, (3) if antagonistic drug like coumarin is
taken by the patient.
• One-stage PT is used to asses levels of vitamin K-
dependent factors in the new born.
Acquired Disorders of Coagulation:
Therapeutic Anticoagulation
Heparin
• Intravenous anticoagulant most commonly used in
clinical medicine.
• It is used extensively in preventing fibrin deposition
on intravenous tubing devices residing in vessels.
• It is a mucopolysaccharide that acts in conjunction
with antithrombin III to inhibit most of serine
proteases in the coagulation pathways.
• It is metabolized by the liver and has a half-life of
approximately 3 hours.
Acquired Disorders of Coagulation:
Therapeutic Anticoagulation
Coumarin Drugs (Oral anticoagulants)
• Discovered in Wisconsin.
• Warfarin is most frequently used coumarin which is
water soluble and administered orally. It interferes
with the carboxylation of vitamin K dependent
procoagulants in the liver by interrupting the
enzymatic phase of this reaction.
• Nonfunctional proteins that circulates in the plasma
as a result of warfarin activity is referred to as
proteins induced by vitamin K antagonist (PIVKA).
Acquired Disorders of Coagulation:
Circulating Anticoagulant (Inhibitory)
Substance
Circulating anticoagulant- substance produced by the
body that inhibit coagulation.
• Stimuli include infusion of blood or blood products,
release of tumor substances into the circulation and
autoimmune disorders.
• Patients having this kind of acquired disorder have
increased levels of fibronogen (as seen in DIC,
coagulation and lytic disorders)
• Laboratory testing includes FSP agglutination test,
measurement of fibrin monomers, platelet counts,
fibrnogen levels, APTT & PT.
Acquired Disorders of Coagulation: Massive
Transfusion Effects
Massive transfusion can jeopardize hemostatic comptency
because:
a. Excessive quantities of infused citrates
b. Donor product is incompatible to recipient’s system.
c. Deficient labile clotting factors or platelets in stored
blood.
• Bleeding time is considered as sensitive indicator of
depressed platelet function in extensively transfused
patients.
• APTT & PT are less sensitive but useful in deciding
whether to supplement therapy with cryoprecipitate
or FFP
Acquired Disorders of Coagulation:
Disseminated Intravascular Coagulation
• A complication of other primary disorders.
• It results in consumption of coagulation proteins and
platelets into thrombi which are deposited locally or
widely in the circulation.
• No age group or gender preference for this disorder.
• Acute DIC has a mortality rate of 60-80%.
• Progress of DIC may be controlled by plasmin or
thrombin.
• Laboratory result reveals prolonged APTT, TCT & PT,
decreased platelet count, fibrinogen level and
antithrombin III, elevated FSP and fibrin monomers,
positive D-dimer.
Acquired Disorders of Coagulation:
Disseminated Intravascular Coagulation
THERAPY
➢Replacement therapy with blood components are
necessary following acute DIC
➢Infusion of FFP, PC and cryoprecipitate may be used.
➢Complete profile of coagulation and lysis should be
performed at clinically determined intervals to
assess this syndrome during management.