Transcript Disoders of secondary hemostasis - Cal State LA

DISODERS OF SECONDARY
HEMOSTASIS
Disorders of plasma clotting factors
DISORDERS OF SECONDARY HEMOSTASIS
Disorders of the proteins of fibrin formation
 Disorders of proteins associated with fibrinolysis
 Symptoms of secondary hemostatic disorders
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Delayed bleeding
Deep muscular bleeding
Spontaneous joint bleeding
Symptoms common to primary and secondary
hemostatic disorders
Ecchymoses
 GI bleeding
 Hematuria
 Hypermenorrhea
 Gingival bleeding
 Increased bleeding after tooth extraction
 Intracranial bleeding
 Epistaxis
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DISORDERS OF PROTEINS
OF FIBRIN FORMATION
Hereditary vs acquired
 Quantitative vs qualitative deficiencies
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Laboratory screening tests (PT, APTT)
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Does not differentiate quantitative vs qualitative disorders
Qualitative abnormal proteins will
Prolong clotting test
 Be recognized by immunologically-based procedures
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Activity assays
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Essential when screening for deficiencies
COAGULATION SCREENING TESTS IN
CONGENITAL DEFICIENCIES
Platlet PT
count
APTT
PFA
TT
Congenital Deficiency
N
N
N
N
N
XIII, mild deficiency of any factor,
plasminogen activator inhibitor-1, α2 antiplasmin
N
A
N
N
N
VII
N
N
A
N
N
XII, XI, IX, VIII, prekallikrein, high
molecular weight kininogen
N
A
A
N
N
X, V, II
N
A
A
N
A
Fibrinogen
N
N
A or N
A or N
N
Von Willibrands
VON
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Inherited hemorrhagic disorder
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WILLEBRAND DISEASE
Genetically and clinically heterogeneous
Caused by a deficiency/dysfunction of VWF
Most common hereditary bleeding disorder
VWF
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Multimeric blood protein
Performs two major roles in hemostasis
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Mediates adhesion of platelets to sites of vascular injury
Is a carrier protein for F-VIII
Inherited defects in VWF may
Interfere with biosynthetic processing or disrupt specific ligand
binding sites
 Cause bleeding by impairing either platelet adhesion or blood
clotting
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VWD
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Three major categories of VWD
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Type 1 VWD – partial quantitative deficiency of VWF
Type 2 VWD – qualitative deficiency of VWF
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Divided into 4 variants
Type 2A – ↓ platelet-dependent function
 Absence of high-molecular weight VWF multimers
Type 2B – ↑ affinity for platlet GPIb
Type 2M – ↓ platelet-dependent function
 Not caused by the absence of HMW multimers
Type 2N – Markedly ↓ affinity for F-VIII
Type 3 VWD – total deficiency of VWF
Types 1 and 2 – autosomal dominant inheritance
Type 3 – autosomal recessive inheritance
Diagnosis
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Specific tests
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Quantify VWF and F-VIII activity
VWD – CLINICAL MANIFESTATIONS
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Hemorrhagic tendency is highly variable
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Depends on the type and severity of disease
Patients with Type 1 and 2 disease
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May have mild bleeding symptoms
Characterized by hemorrhage from delicate mucocutaneous tissues
Epistaxis, easy bruising, GI bleeding, menorrhagia
Hematoma and hemarthroses, characteristic of hemophilia A, are not
prominent
Patients with severe type 3 VWD
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Severe hemorrhagic tendency
Spontaneous hemorrhage
 Mucous membranes, GI tract
 Can be frequent and may be life threatening
Low F-VIII level
 Deep hematomas
 Joint hemorrhages – similar to hemophilia
VWD – THERAPY
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Goal
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Correct both bleeding time and coagulation abnormalities
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Raise both F-VIII and VWF to normal levels
 Desmopressin acetate (DDAVP) stimulates release of vWF from
endothelial cells – won’t work for type 3
 Intermediate purity factor VIII which contains intact vWF
HEMOPHILIAS
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Hemophilia A
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Factor VIII Deficiency
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Hemophilia B
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Factor IX Deficiency
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Antihemophilic Factor
X-linked recessive disorder
Most common type of hemophilia
Christmas Factor (from family of first patients diagnosed with the
disorder)
X-linked recessive disorder
Hemophilia C
Factor XI Deficiency
Autosomal recessive disorder seen primarily in the Ashkenazi
Jewish population
 Symptoms range from mild to severe
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COAGULATION SCREENING TESTS IN
CONGENITAL DEFICIENCIES
Platlet PT
count
APTT
PFA
TT
Congenital Deficiency
N
N
N
N
N
XIII, mild deficiency of any factor,
plasminogen activator inhibitor-1, α2 antiplasmin
N
A
N
N
N
VII
N
N
A
N
N
XII, XI, IX, VIII, prekallikrein, high
molecular weight kininogen
N
A
A
N
N
X, V, II
N
A
A
N
A
Fibrinogen
N
N
A or N
A or N
N
Von Willibrands
HEMOPHILIA
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Insufficient generation of thrombin by
F-IXa/VIIIa complex through the intrinsic pathway of
coagulation cascade
 Bleeding severity complicated by excessive fibrinolysis
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Clinical severity corresponds with level of factor
activity
 Severe hemophilia
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Factor coagulant activity <1% of normal
 Frequent spontaneous bleeding into joints and soft tissues
 Prolonged bleeding with trauma or surgery
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HEMOPHILIA
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Moderate hemophilia
Factor coagulant activity 1-5% of normal
 Occasional spontaneous bleeding
 Excessive bleeding with surgery or trauma
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Mild hemophilia
Factor coagulant activity >5% of normal
 Usually no spontaneous bleeding
 Excessive bleeding with surgery or trauma
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HEMOPHILIA –
CLINICAL PRESENTATION
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Readily diagnosed
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In severe disease and patients with prior family history
Diagnosis based on
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Unusual bleeding symptoms early in life
Age of first bleeding varies with severity of disease
Family history
Physical exam
Laboratory evaluation
HEMOPHILIA – TREATMENT
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Replacement of clotting factor to achieve hemostasis
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Annual cost for patient with severe hemophilia
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$20,000-100,000
Various products available
Plasma-derived low, intermediate and high purity products
 Plasma-derived ultrapure products
 Ultrapure recombinant products
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Replacement products – benefits vs risks
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Blood-born pathogens
Hepatitis A, B, C, G; HIV, Parvovirus B-19
 Thrombotic complications with some F-IX concentrations
 Development of alloantibody inhibitors
 Neutralize coagulant effects of replacement therapy
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ACQUIRED DISORDERS
More
common than hereditary
disorders
Usually involve defects of multiple hemostatic factors
 Bleeding often simultaneously from >1 site
 May occur in response to another disease process
 Can be produced by a variety of mechanisms
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DISSEMINATED INTRAVASCULAR COAGULATION
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Normal balance of hemostasis is altered
Results in the uncontrolled inappropriate formation and
lysis of fibrin within the blood vessels
Activation of coagulation occurs systemically
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Rather than locally at site of injury
Fibrin is deposited diffusely within capillaries, arterioles
and venules
Clotting proteins, inhibitors and platelets are consumed
faster than they are synthesized
Acquired deficiency of multiple hemostatic components
 Fibrinolysis follows fibrin formation
 Patient generally bleeds spontaneously at the same time that
disseminated clotting is occurring
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CLINICAL CONDITIONS ASSOCIATED WITH DIC
DIC - PATHOPHYSIOLOGY
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Fibrin strands within small vessels result in
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Traumatic destruction of RBC
Microangiopathic hemolytic anemia
 Formation of schistocytes
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Fibrin deposition in and obstruction of
microvasculature
Tissue anoxia/microinfarcts
 Renal failure, liver failure, respiratory failure, shock and
death
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DIC
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HELLP syndrome
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High blood pressure
Elevated liver enzymes
Low platlets
Occurs in pregnancy and is life-threatening
If the CBC of a woman in labor shows schistocytes
and low platlets alert the physician immediately –
the baby must be delivered immediately to save the
mom!
DIC – LABORATORY DIAGNOSIS
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Laboratory diagnosis is difficult
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Available tests are nonspecific
No single test can establish the definitive diagnosis of DIC
PT, APTT, TT prolonged
Fibrin degradation products are (+)
Platelet count ↓; platelet function tests abnormal
Schistocytes, thrombocytopenia on peripheral blood smear
DIC – THERAPY
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Eliminate underlying cause, if possible
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Acute DIC is often self-limited
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Will disappear when fibrin is lysed
Replacement therapy
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Platelets, RBC, Cryoprecipitate or fresh frozen plasma
VITAMIN K DEFICIENCY
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Precursor proteins synthesized by hepatocytes
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Not γ-carboxylated
Ca++-binding sites are nonfunctional
Induced functional deficiencies of all vitamin-K dependent
proteins
Causes of vitamin K deficiency in adults
Malabsorptive syndromes
 Biliary tract obstruction
 Prolonged broad-spectrum antibiotics
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Most often seen in newborns
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Hemorrhagic disease of the newborn
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Due to newborn hepatic immaturity
ACQUIRED PATHOLOGIC INHIBITORS
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Circulating anticoagulants
Usually IgG or IgM immunoglobulins
 Inhibitors of single factors
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Patients with inherited factor deficiencies
 After treatment with replacement concentrates
 Associated with other conditions
 Diseases, drugs
 Occasionally seen in otherwise healthy individuals
 Interfere with or neutralize clotting factor activity
 Prolonged screening test not corrected by 1:1 mixture with normal
plasma
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