COAGULATION CASCADE

DISORDERS

Chairperson: Dr.Vandana Balgi

Presenting PG:Dr.Kripa
• Factor l - Fibrinogen
• Factor ll - prothrombin
• Factor lll - Tissue factor
• Factor lV - Calcium
• Factor V - Proaccelerin
• Factor Vl - Activated form of factor V
• Factor Vll - Proconvertin, SPCA
• Factor Vlll – Antihaemophilic factor A
• Factor lX – Antihaemophilic factor B, Christmas factor
• Factor X – Stuart factor
• Factor Xl – Antihaemophilic factor C
• Factor Xll – Hageman factor
• Factor Xlll – Fabrin stabilising factor
• Petechiae are characteristic of an abnormality of the vessels or the
platelets, such as thrombocytopenia
• telangiectasias or angiomas blanch with pressure, whereas petechiae
do not.
Coagulation disorder Thrombocytopenia

Onset of bleeding after trauma(dental extraction) Immediate in onset

Is delayed
Bleeding persists even after use of Responds to local measures
vasoconstrictors,packing

Why there is delayed bleeding in coagulation disorder?

For example, bleeding after a tooth extraction may stop completely, only to recur in a matter of hours,is
because primary hemostasis is achieved by plateletplug.
Disorders in Which Results of Primary
Screening Tests Are Normal
• hereditary hemorrhagic telangiectasia,
• allergic purpura,
• scurvy, and
• senile purpura.
• factor XIII (fibrin-stabilizing factor) deficiency,
• mild forms of vWD, and
• dysfibrinogenemia or abnormal fibrinolysis.
Evaluation of a patient with bleeding and an isolated,
prolonged partial thromboplastin time (PTT)
COAGULATION DISORDERS
• INHERITED COAGULATION DISORDER
• ACQUIRED COAGULATION DISORDER
Inherited Deficiencies of Coagulation
Factors II, V, VII, X, XI, and XIII
Prothrombin deficiency
• Pathogenesis
• Hypoprothrombinemia or dysprothrombinemia may be involved.
• Both are inherited as autosomal recessive disorders.
• Both interfere with hemostasis by impairing thrombin generation.

• Clinical Features
• The disorders are characterized by mucocutaneous and soft-tissue bleeding
• Hemarthroses may occur.
• Laboratory Features
• The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged. The thrombin time
(TT) is normal.
Treatment
• Bruises and mild superficial bleeding do not require treatment.
• Prothrombin deficiency may be corrected with intravenous prothrombin complex concentrates
but with risk of transmission of viruses
• Fresh-frozen plasma is also effective but carries a risk of transmitting infectious agents. Solvent
detergent
treatment of pooled plasma reduces this risk, but viruses that are not inactivated in the pooled
plasma source may still be transmitted (eg, parvovirus, hepatitis A virus).
• The biologic half-life of prothrombin is 3 days, and a single treatment for a bleeding episode may
suffice.
• Prothrombin levels of 10% to 25% are usually sufficient for hemostasis.
 FACTOR V DEFICIENCY
Pathogenesis
• Inherited factor V deficiency is transmitted as an autosomal recessive disorder.
• Homozygotes have a moderate bleeding tendency that is usually due to a true deficiency, but the disorder
may also be caused by dysfunctional factor V.
• Heterozygotes are usually asymptomatic.

Clinical Features
• Patients with 1% to 10% factor V activity have lifelong bleeding, usually expressed as ecchymoses, epistaxis, gingival
bleeding, excessive bleeding from minor lacerations, and menorrhagia.
• Hemarthroses or intracranial hemorrhage has been reported.
• Severe bleeding may occur after trauma, dental extraction, or surgery.

Laboratory Features
• Factor V deficiency is characterized by prolongation of both the aPTT and the PT.
• Diagnosis requires specific demonstration of a factor V deficiency
Treatment
• Severe or continuing mild bleeding is treated with replacement therapy
using fresh-frozen plasma. A factor V level of 25% is usually sufficient for
hemostasis. The plasma factor V half-life is 12 to 14 hours.
• Infusion of a loading dose of 20 mL/kg of fresh-frozen plasma followed
by 5 to 10 mL/kg every 12 hours for 7 to 10 days is usually adequate to
ensure hemostasis.
• Minor lacerations may be treated with local measures.
• Antifibrinolytic therapy may be effective in epistaxis or gingival bleeding.
COMBINED DEFICIENCY OF FACTORS V AND VIII

• A rare, autosomal recessive trait with reduced levels of both factor V and factor
VIII expressed as a moderately severe lifelong bleeding disorder.
• The molecular basis of this condition relies on mutations in the endoplasmic
reticulum–Golgi intermediate compartment (ERGIC)-53 gene, now called the
LMAN1 gene.
• Diagnosis requires specific assays of both factor V and factor VIII.
• Minor bleeding may respond to antifibrinolytic therapy.
• For severe bleeding or prophylaxis before surgery or dental extraction,
replacement of both factor V, using
fresh-frozen plasma, and factor VIII, using a factor VIII concentrate, is required.
FACTOR VII DEFICIENCY
• Factor VII deficiency is inherited as an autosomal recessive trait.
• The disease may be caused by decreased production of factor VII, production of a factor VII with decreased
functional activity, or both.
• Patients with factor VII levels below 1% may have a severe bleeding disorder indistinguishable from severe hemophilia A or B.
• Most patients with levels of factor VII of 5% or more have disease characterized by easy bruising, gingival bleeding, epistaxis,
and menorrhagia.
• The diagnosis is suggested by a prolonged PT with a normal aPTT.
• Diagnosis requires demonstration of isolated factor VII deficiency by specific assay.
• Skin lacerations require only local hemostasis. Antifibrinolytic therapy is usually effective in patients with menorrhagia,
epistaxis, and/or gingival bleeding.
• Replacement therapy is necessary in patients with severe bleeding, such as hemarthroses or intracerebral hemorrhage, and may
be required with surgery, depending on the severity of the deficiency, bleeding his- tory, and the operative site.
• The half-life of factor VII is approximately 5 hours. Hemostasis is achieved with levels between 10% and 25%.
• If plasma is used for major surgery, the recommended initial dose is 15 mL/kg, followed by 4 mL/kg every 6 hours for 7 to 10
days.
FACTOR X DEFICIENCY
• Factory X deficiency is inherited as an autosomal recessive trait.
• Patients with factor X levels of less than 1% have severe bleeding, primarily in the joints, in soft tissues, and from mucous
membranes. Menorrhagia may be a major problem.
• In patients with mild to moderate factor X deficiency, bleeding usually occurs after trauma or surgery.
• The PT and aPTT are both prolonged, as is the Russell viper venom time. The TT is normal.
• Factor X deficiency may be treated with prothrombin complex concentrates that contain factor X. Because of the
(theoretical) risk of thrombosis with these concentrates, it is recommended that divided doses be used if more than 2000
units are required.
• For soft-tissue, mucosal, or joint hemorrhages, replacement of factor X to 30% of normal is recommended. More serious
bleeding requires replacement to 50% to 100%.
• The biologic half-life of factor X is 24 to 40 hours. Continuing therapy should be given every 24 hours.
• Fresh-frozen plasma may also be used to replace factor X deficiency but carries the risks of viral infection
and fluid overload.
FACTOR XI DEFICIENCY
• autosomal recessive disorder
• Factor XI is essential for the activation by thrombin of thrombin-activatable fibrinolysis inhibitor (TAFI) or
carboxypeptidase B, an enzyme that inhibits fibrinolysis. This may result in increased fibrinolytic activity,
with consequent increase in bleeding.
• Bleeding is usually related to trauma or surgery.
• The aPTT is prolonged; the PT is normal.
• Patients with severe factor XI deficiency may be given replacement therapy with fresh-frozen plasma,
recognizing the attendant risk of transmission of infectious agents or allergic reactions.
• The mean half-life of factor XI is about 48 hours.
• Trough levels of factor XI of 45% maintained for 10 to 14 days provide adequate hemostasis after major
surgery or surgery at sites with high fibrinolytic activity.
• Antifibrinolytic therapy may be effective in achieving hemostasis after dental extraction and is a similarly
useful adjunct for treating patients after operation on sites with high local fibrinolytic activity.
FACTOR XIII DEFICIENCY
• transmitted as an autosomal recessive trait.
• Factor XIII deficiency leads to clots that are less stable mechanically and more susceptible to fibrinolysis,
resulting in the bleeding disorder.
• Ecchymoses, hematomas, and prolonged posttraumatic bleeding are common.
• Bleeding from the umbilical cord of newborns occurs frequently.
• Intracranial hemorrhage occurs more often with factor XIII deficiency
• Habitual abortion and poor wound healing also occur.
• Screening tests for coagulation abnormalities are all usually normal in factor XIII deficiency, although in some cases,
the thrombin time may be minimally prolonged.
• Acquired factor XIII deficiency may occur in DIC, primary fibrinolysis, or if an inhibitor develops to factor XIII.
Factor XIII levels may also be decreased after major surgery, during chronic inflammatory conditions (eg,
inflammatory bowel disease), and after major trauma.
• Replacement therapy may be achieved with plasma or cryoprecipitate
• Factor XIII levels of less than 5% will achieve hemostasis.
• The half-life of factor XIII is 19 days.
DIC
• Disseminated intravascular coagulation also called consumption
coagulopathy and defibrination syndrome.
• Its systemic process causing thrombosis and hemorrhage
• It can present as acute (life threatening) or chronic DIC.
ETIOLOGY OF DIC
PATHOPHYSIOLOGY
• Anormal activation of coagulation and fibrinolysis .
• Sequence of events include:
• 1) procoagulant exposure
• 2)coagulation
• 3)fibrinolysis
• 4)compensatory changes-acute decompensated DIC,chronic
(compensated)
• 5)End organ damage
 1.Procoagulant exposure
• Blood is exposed to tissue factors(tf) can activate coagulation
• Sources of tissue factors
1. Bacterial products-lipopolysaccharides
2. Meningococcal sepsis
3. Cancer procoagulant
4. Trauma-damage to vascular endothelium and tissue release
phospholipids or procoagulant enzymes.
5. Acute hemolytic transfusion reaction-ABO Mismatch -TF released by
monocytes and cytokines generation TNF,IL 1.
6. Neutrophil- neutrophil extracellular traps
2.Coagulation cascade
• Activation of coagulation cascade leads to production of thrombi
consisting of fibrin and platelets
• Can occur in microvasculature / larger vessels
• Extensive formation of thrombi in turn leads to consumption of
endogenous coagulation factors producing “consumption
coagulopathy”
3. Fibrinolysis
• Fibrinolysis is activated at sites of thrombus formation with
generation of fibrin degradation products(FDP)
• Excess FDP interfere with clot formation and platelet aggregation by
disrupting normal fibrin polymerisation and fibrinogen binding to
platelets surface GPIIbIIIa.
Compensatory changes
• ACUTE DIC -develop when blood is exposed to large amounts of tissue
factors over brief period of time.
• Seen in sepsis,trauma,acute promyelocytic leukemia.
• CHRONIC DIC- chronic dic can develop when blood is continuously or
intermittently exposed to smaller amounts of tissue factors.
• Coagulation factors and platelets are consumed but production is able to
compensate and the liver is able to clear the FDPs.
• Clotting time may be normal,thrombocytopenia may be mild or
absent,thrombosis predominates over bleeding.
• Seen in advanced malignancy like pancreatic,ovarian,gastric,brain tumors.
ACUTE VS CHRONIC
End organ damage
• Tissue or organ damage results from reduced perfusion,thrombosis and /or
bleeding.
1. Kidney failure- Aki in 25-40% of patients with acute DIC
2. Liver dysfunction
3. Acute lung injury- pulmonary hemorrhage with hemoptysis and dyspnea
result from damage to pulmonary vascular endothelium,pulmonary
microthrombi leads to lung injury in ARDS patients
4. Neurologic dysfunction-coma ,delirium,transient neurological symptoms.
5. Adrenal failure-water house friderichsen syndrome.
6. Purpura fulminans –rare life threatening condition in DIC with
extensive tissue thrombosis and hemorrhagic skin necrosis.
Clinical Features
• bleeding-often of serious magnitude and abrupt onset
• a variable element of shock that is often out of proportion to apparent blood loss
• Acute renal failure
• Evidence of major organ dysfunction is a common finding in patients with DIC, most often
including signs, symptoms, and laboratory evidence of abnormal pulmonary, renal, hepatic,
and central nervous system function.
• Patients with DIC due to obstetric disorders all had bleeding, but only 20% had organ
dysfunction. In contrast, of patients with DIC due to sepsis, only 15% had bleeding, but
76% had organ failure
Laboratory testing
• CBC- thrombocytopenia is more common in acute Dic

• PT,Appt-often prolonged more typical for acute than chronic

• Fibrinogen- low in acute DIC

• D-dimer- Increased in both acute and chronic DIC.

• Peripheral smear –MAHA,with schistocytes and helmet cells seen.

Differential Diagnosis
• Primary fibrinogenolysis:
1.hypofibrinogenemia
2. increased levels of FDP
3.abnormalities of the PTT, PT, and thrombin time
4.deficiencies of factors V and VIIIc.
5.platelet count is usually normal
6.the D-dimer level should be normal or only minimally elevated
7.and protamine sulfate tests should be negative
8.hypoprothrombinemia and deficiencies of stable coagulation factors VII, IX, X, and XI are
rare.
9.thus, routine coagulation tests should be able to distinguish DIC from primary
fibrinogenolysis.
• Liver disease:
1. coagulation abnormalities and thrombocytopenia
2. chronic or intermittent fibrinogenolysis with high levels of FDP is common,
particularly in patients with cirrhosis.
3. Factor VIIIc levels are usually elevated
4. the levels of factors VII and IX typically are low.
5. helpful test in discriminating between the coagulopathy of liver disease and
DIC is the D-dimer test, the results of which should be abnormal in DIC but
normal in liver disease
 TREATMENT
1)Treat the underlying cause
2)Supportive measures-
• Hemodynamic/ventilatory support
• Aggressive hydration for acute hemolytic transfusion reaction
• Rbc transfusion for severe bleeding.
• Platelet transfusion
• Ffp and cryoprecipitate
• Avoid antifibrinolytic agents like tranexamic acid due to increase of
thrombotic events.
• Heparin in case of thrombosis causing digital gangrene of fingers.
Replacement therapy with platelets and coagulation
factors
• The major aim of replacement therapy with blood products in DIC is to replenish
fibrinogen
• This goal is best accomplished by the administration of cryoprecipitate, each unit
of which contains approximately 250 mg of fibrinogen.
• As a general guide, 3 g of fibrinogen can be expected to raise the plasma level of
an adult patient approximately 100 mg/dL
• Fibrinogen administration probably should be restricted to the occasional patient
with hypofibrinogenemia and significant bleeding, in whom DIC is self-limited
• Patients with DIC, bleeding, and platelet counts <50 000/μL should be considered
for platelet transfusion
Anticoagulants:
• Heparin is a specific activator of the physiologic antithrombin system and thereby inhibits a
number of proteolytic enzymes, including factors IXa and Xa and thrombin
• In patients with chronic DIC, the results of heparin therapy are usually favorable and may be
dramatic.
• This drug typically does reduce the severity of bleeding and thromboembolic manifestations
and produces parallel improvement in the abnormalities of laboratory test values.
• Elevated levels of D-dimer and FDPs drop rapidly
• Accelerated fibrinolysis, if present, disappears after the administration of heparin, often
before the coagulation defect has been alleviated.
• The response of the platelet count to heparin therapy for DIC is slow and often erratic.
Obstetrics disorders
Abruptio Placentae :
• DIC complicates abruptio placentae in approximately 10% of case
• Shock develops rapidly
• Brisk external hemorrhage may originate from episiotomies and lacerations, and large amounts of blood
may be concealed behind the placenta and within the wall of the uterus.
• Hemorrhage is the major factor leading to shock and renal complications in abruptio placentae, and the
most essential therapeutic measures are the vigorous treatment of blood loss and the prompt evacuation of
the uterus. Often, fibrinogen replacement is given if immediate surgical treatment is necessary.
• If the coagulation defect and thrombocytopenia are severe or persist for an unusually long time, the
administration of platelets, fibrinogen in the form of cryoprecipitate, and fresh-frozen plasma may reduce
hemorrhage.
Intrauterine Fetal Death :
Definite laboratory abnormalities are not seen until the dead fetus has been
retained for ≥5 weeks
plasma levels of FDPs then begin to rise, and the platelet count and fibrinogen
level gradually decline.
In most women in whom delivery of the dead fetus is induced promptly
according to usual obstetric practice, bleeding is not serious, even in the presence
of low-grade DIC.
Operative intervention is dangerous when hypofibrinogenemia is severe, and
such patients should receive heparin until safe fibrinogen levels are restored.
If immediate surgery is imperative, heparin administration should be followed
by platelet replacement and enough fibrinogen, in the form of cryoprecipitate, to
produce plasma fibrinogen levels of 150 mg/dL or greater.
Amniotic Fluid Embolism
In women who survive amniotic fluid embolism (mortality rate of up to
80% in early studies), DIC with severe hemorrhage may develop within
1 to 2 hours.
More recent surveys indicate a mortality rate of 20% to 30%.
Hypoxia and other sequelae of pulmonary vascular obstruction dominate
the clinical picture and usually determine the outcome.
The release of serotonin and other vasoactive substances from platelets
may contribute to the profound pulmonary vasoconstriction.
DIC in Neonates and Infants:
Purpura Fulminans
• Develop several days after an acute infection; these are most commonly scarlet fever or various viral
respiratory diseases.
• Purpura fulminans is most common in children but is also well documented in adults.
• symmetric ecchymoses of the lower extremities and buttocks, sharply circumscribed infarcts of the
skin and genitalia, and gangrene of the extremities that often involves the digits symmetrically.
• These ecchymotic lesions often become necrotic, ultimately forming blood-filled bullae
• Petechiae are rare. Fever and prostration are seen, but visceral lesions, including renal involvement,
are relatively uncommon.
• The mortality rate associated with purpura fulminans ranges from 18% to 40% to 70%.
• Heparin in therapeutic doses has often proved therapeutically effective,
Neoplastic Disorders
Carcinoma
• often consists of a combination of bleeding and thromboembolic phenomena, including arterial embolism.

• The association of chronic DIC, thromboembolism, and cancer is often called Trousseau syndrome.
• Risk factors associated with the occurrence of DIC included older age, male gender, advanced disease, breast
cancer, and necrosis of the tumor specimen.163
• Those cancers with a high risk of thrombosis included uterine, brain, leukemia, ovary, and pancreas (2-fold or
greater risk), whereas prostate, liver, head or neck, bladder, and breast cancer had less than a 1-fold risk
(compared to noncancer patients).
• DIC in association with carcinoma resolves with effective treatment of the underlying tumor. Heparin or low–
molecular-weight heparin (LMWH) in therapeutic doses has proved effective in controlling the hemorrhagic
and thromboembolic symptoms.
Acute Promyelocytic Leukemia
• DIC has been reported in association with all forms of acute leukemia, but it is most
common in the “hypergranular” promyelocytic variety (APL), in which it may occur in
60% to 100% of cases.
• The cause of the coagulopathy is multifactorial: tissue factor is present in the granules
of the abnormal promyelocytes as well as leukocyte proteases, including elastase.
• Enhanced fibrinolysis also results from increased promyelocyte expression of annexin
II, a receptor for plasminogen and tissue plasminogen activator.Additionally, the
malignant promyelocytes contain plasminogen activators.
• Heparin has produced clear-cut remissions
• An earlier approach, recommended fibrinogen replacement therapy for fibrinogen levels
<100 mg/dL and platelet transfusion for platelet counts <20 000/μL. Fresh-frozen
plasma was given to patients with prolonged PT and PTT values who were bleeding.
Kasabach–Merritt Syndrome (Giant Hemangiomas)
• incidence of DIC tends to parallel the size of the vascular tumors in the
Kasabach–Merritt syndrome.
• Platelet consumption, activation of coagulation, and microangiopathic red cell
destruction take place mainly within the hemangioma (“sequestered” or
localized intravascular coagulation)
• Recurrent bleeding from the surface of the tumor is the major hemorrhagic
manifestation; in the presence of DIC, this bleeding may be intractable.
• Irradiation and corticosteroids have produced favorable results in a few cases,
but surgical removal of the tumors has ultimately been required in most patients.
• Interferon-α has been successful in some patients
• Antifibrinolytic therapy has been reported to be useful in controlling the
coagulopathy.
Snakebite
• Hemorrhage may be relatively inconspicuous, even in the presence of incoagulable blood.
• When present, it is mainly the result of a vascular toxin.
• Platelets are often spared, although the venom of the timber rattlesnake (Crotalus
horridus horridus) contains a unique serine protease that acts as a potent platelet
activator.
• The specific coagulopathy seen in individual patients in large part depends on venom
constituents present in the particular snake species.
• The treatment of snakebite involves the administration of specific antivenom and intensive
supportive care. Heparin therapy has proved marginally effective at best.
• In general, it is not indicated when specific antivenom is available.
• Cryoprecipitate should be given to maintain the fibrinogen level over 100 mg/dL.
VON WILLEBRAND DISEASE

• Most common bleeding disorder

• Occured on chromosome 12
• Genetic disorder caused by defective or missing VWF
• Incidence equal in men and women
Function
• VWF binding to platelet cause platelet adhesion and aggregation.
• Binding to factor VIII increase the life span of Factor VIII.
VWF DISEASE
Three types
• Type I It is due to quantitative deficiency of VWF
Levels of VWF in blood ranges from 20 – 50% of normal
i.e, less than 30 IU/dL
Type I is found in 60-80 percent of patients.
TYPE 2 – It is due to qualitative defect in VWF.
Four subtypes present.
Type 2A
• most common in type 2, autosomal dominant inheritance
• Selective loss of large and intermediate VWF multimers from
plasma
• There will be marked elevation in 176 – kDa multimers.
• Type 2B
Autosomal dominant inheritance
Characterized by thrombocytopenia and loss of large vWF multimers

• Type 2M
Decreased affinity for platelet GP1b

• Type 2N
Markedly decreased binding affinity for FVIII
Type 3

• Autosomal dominant type of inheretance

• Most severe form of disease
• Undetectable level of vWF
• Since the level of vWF is low FVIII will also be low resulting in severe
bleeding manifestation
Clinical features
• Mucocutaneous bleeding (mc)
• Epistaxis (60%)
• Easy bruising
• Hematomas
• Gingival bleeding
• Menorrhagia
• GI bleed occur(10%)
• Hemarthrosis
Diagnosis
• Tests routinely performed are
1. Bleeding time
2. APTT
3. Assay of FVIII activity
4. vWF antigen
5. Platelet dependent vWF activity
6. Ristocetin cofactor activity
7. Ristocetin induced platelet aggregation
Treatment
1.DESMOPRESSIN
• Act on type 2 vasopressin receptors in endothelial cells resulting in
release of FVIII and vWF.

2. FACTOR REPLACEMENT THERAPY

3.FIBRINOLYTIC INHIBITORS
E- aminocaproic acid and tranexamic acid
Hemostatic Dysfunction Related to Liver Diseases
• Loss of hepatic parenchymal cells leads to decreased plasma levels of all plasma
coagulation factors except factor VIII and von Willebrand factor, which are produced
primarily by endothelial cells.
• Thrombocytopenia occurs frequently and is usually a result of splenic sequestration
Enhanced fibrinolysis is common and appears to be caused by complex pathogenetic
mechanisms, including release and impaired clearance of plasminogen activators.
• Dysfibrinogenemia is relatively frequently found in patients with chronic liver
disease.
• Patients with chronic liver disease may develop a consumption coagulopathy
• Patients with liver disease may present with purpura, epistaxis, gingival bleeding,
and/or menorrhagia. They are also predisposed to gastrointestinal bleeding from
cirrhosis-driven esophageal or gastric varices.
• The coagulopathy of liver disease may also predispose the patient to
thromboembolic complications.
• Correction of coagulation is only required in case of bleeding or when an
invasive procedure has to be performed.
• Replacement of all the deficient coagulation factors may be attempted with
fresh-frozen plasma
• Prothrombin complex concentrates may be used to correct deficiency of the
vitamin K–dependent factors but do not contain factor V and fibrinogen.
• Vitamin K administration is effective in patients with vitamin K deficiency.
Due to a relative resistance to vitamin K, high doses (10 mg orally or 2–5
mg intravenously) are advised.
• Platelet transfusion may be useful in correcting thrombocytopenia